key: cord-304056-2bo0s0hz
authors: Lezotre, Pierre-Louis
title: Part I State of Play and Review of Major Cooperation Initiatives
date: 2014-12-31
journal: International Cooperation, Convergence and Harmonization of Pharmaceutical Regulations
DOI: 10.1016/b978-0-12-800053-3.00002-1
sha: 
doc_id: 304056
cord_uid: 2bo0s0hz

Abstract The basic principle of international cooperation is to establish bilateral and multilateral efforts to leverage the human, scientific and financial resources and the knowledge and experience of other key regulatory authorities to avoid duplication of efforts, to make activities more efficient and to allow the focussing of limited resources on higher-risk areas of concern. This increased cooperation between worldwide regulators has necessitated proactive deliberate efforts towards convergence/harmonisation of regulation, practices and requirements to eliminate or reduce differences. Cooperation and harmonisation of standards in the pharmaceutical domain are already a reality and have become increasingly important during recent decades, with a high level of commitment to these activities by all stakeholders. The worldwide Drug Regulatory Authorities (DRAs) have been working to end an isolationist attitude that cannot resolve current worldwide issues and challenges caused by an ever increasing globalisation. As a result, many cooperation and harmonisation initiatives have been established at the bilateral, regional and global levels as a response to the changing geo-economic-political situation. The spectrum of collaboration varies from simple informal technical cooperation to full integration of systems and regulations. Indeed, all these initiatives can be very different in scope (some are part of a broader harmonisation initiative), level of harmonisation (depending on the political support/commitment), organisation (well-structured versus simple discussion) or advancement (established process vs. pilot projects), but they all work towards convergence of requirements and/or practices. All these multiple worldwide cooperation and harmonisation programmes have evolved rapidly over the past decades. This book section provides the current status of this complex and broad phenomenon of cooperation, convergence and harmonisation in the pharmaceutical sector. It reviews all major global, regional and bilateral cooperation initiatives.

Many aspects of increased globalization also have profound implications on pharmaceutical regulation worldwide. In general, globalization of the economy (with increased travel of people and exchange of goods, finance, and information), and also globalization of the pharmaceutical market (including development, manufacture, and distribution activities), requires increased cooperation and harmonization of pharmaceutical standards and regulation. Pharmaceutical industries have asked for better harmonization of requirements for the development and manufacture of pharmaceutical products to avoid duplication of work that ultimately creates delays in drug availability [23] .

In this context, harmonization of pharmaceutical regulations has naturally become an important topic of discussion among worldwide Drug Regulatory Authorities (DRAs). Over the past several decades, they have been working to end an isolationist attitude that cannot resolve current worldwide issues and challenges. As a result, many cooperative initiatives (bilateral, regional, and global) were established, and harmonization efforts have been enhanced. All these initiatives can be very different in scope (some are part of a broader harmonization initiative), level of harmonization (depending on the political support/commitment), organization (well structured versus simple discussion), or advancement (established process versus pilot projects), but they all work towards harmonization of requirements and/or practices. Increased exchange of information on a regular basis (e.g., more than 26 countries and international organizations from Australia to Vietnam now have agreements to share information with the United States Food and Drug Administration [US FDA]) [24] also contributes to the natural convergence of requirements and practices.

Harmonization models can be distinguished by their scope and objectives. Indeed, the spectrum of collaborations varies from simple technical cooperation to full integration of systems and regulations: ▸ Integration model: In this type of agreement, most of the time driven by political decision, deeper harmonization of regulation is achieved with the creation of supranational central authorities in order to support integration and/or creation of a single market (e.g., EU, the Association of Southeast Asian Nations [ASEAN] ). In this case, harmonization of standards and regulations is critical in reducing trade barriers. In this model, countries give up some of their autonomy on certain matters by transferring the power to make decisions to the common supranational authority or by automatically recognizing decisions from the other party (via mutual agreement mechanisms).

The African Medicines Registration Harmonization (AMRH) initiative has defined five identifiable levels of harmonization ( Figure 1 ).

To facilitate cooperation, a Mutual Recognition Agreement (or Arrangement) (MRA) can be signed by one or more parties to mutually recognize or accept some or all aspects of one another's requirements. They can be concluded at the technical level (e.g., the Status and Future Plans," November 2009. confidentiality arrangements between the US FDA and European Medicines Agency [EMA] , or the MRA between EU and Australia) or at the government level (e.g., European Treaty).

These multilateral initiatives are major projects as they involve multiple organizations and countries and represent the highest degree of harmonization. The objective of this technical and scientific intergovernmental cooperation is to globally discuss scientific issues that support the decisions made by individual governments and international regulatory bodies in order to achieve global scientific consensus. The goal is to facilitate the development of new medicines and to make them available to the maximum number of people worldwide. There is no intent of full integration of systems and regulations. The main difficulty faced by these initiatives is the complexity and management of the structure due to the important number of participants (e.g., the World Health Organization [WHO] has 194 Member States) and the diversity of needs, challenges, and level of development of its members.

The World Health Organization (WHO) was established in 1948 as a specialized agency of the United Nations (UN) [25] . It is accountable to its Member States and works closely with other entities of the UN system. This agency has a very broad scope of responsibilities as it is the directing and coordinating authority for international health matters and public health within the UN system. WHO is well known for some of its work (e.g., the coordination of influenza surveillance and monitoring activities, emergency assistance to people affected by disasters, mass immunization campaigns or actions against Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome [HIV/AIDS], tuberculosis, and malaria). However, WHO undertakes many more activities because it is responsible for providing leadership on global health matters, shaping the health research agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries, and monitoring and assessing health trends. Most of these core functions, as further defined in its "11th General Programme of Work," [26] rely on cooperation and harmonization of standards.

This focus on regional and global collaboration, and especially aid from developed countries to developing countries, is aligned with the UN Millennium Development Goals (MDGs). a a The United Nations Millennium Development Goals (MDGs) are eight international goals that UN Member States (and international organizations) have agreed to achieve by the year 2015. They are derived from the United Nations Millennium Declaration, signed in September 2000, which endorsed a framework for development and commits world leaders to combat poverty, hunger, disease, illiteracy, environmental degradation, and discrimination against women. These MDGs are interdependent and several relate either directly or indirectly to health. WHO is therefore very involved in this process and works with countries to achieve the health-related MDGs.

Indeed, the objective of these MDGs is that countries and development partners work together to improve the global situation and resolve major issues. A number of specific targets and indicators have been identified to monitor progress towards the goals. Goal 8 ("Develop a global partnership for development") specifically recognizes the role of developed nations and addresses global cooperation and partnerships.

WHO has worked in the area of pharmaceuticals since its creation approximately 60 years ago. During this time, many products and services have been created that are widely recognized as core functions of WHO.

The role of WHO in pharmaceutical regulations is based on its constitutional mandate and various World Health Assembly (WHA) resolutions. This support is twofold. One aspect relates to the development of internationally recognized norms, standards, and guidelines. The second relates to providing guidance, technical assistance, and training in order to enable countries to implement global guidelines to meet their specific medicines regulatory environment and needs [27] .

All countries that are members of the UN may become members of WHO by accepting its constitution. Other countries may be admitted as members when their application has been approved by a simple majority vote of the World Health Assembly (WHA). Territories that are not responsible for the conduct of their international relations may be admitted as associate members upon application made on their behalf by the member or other authority responsible for their international relations. Members of WHO are grouped according to regional distribution.

WHO's strength lies in its neutral status and nearly universal membership. Today, it represents 194 countries and two associate members (Puerto Rico and Tokelau). One country is an observer (Vatican) [28, 29] .

The organization is headed by the Director-General, b but the WHA is the supreme decisionmaking body for WHO. It generally meets in Geneva, Switzerland in May of each year, and is attended by delegations from all Member States. Its main function is to determine the policies of the organization. The Health Assembly also appoints the Director-General (on the nomination of the Executive Board), supervises the financial policies of the organization, and reviews and approves the proposed budget.

The work of the Assembly is supported by the Executive Board, which it elects. This executive arm of the Assembly is composed of 34 members technically qualified in the health field. Members are elected for three-year terms. The main board meeting, at which the agenda for the forthcoming Health Assembly is agreed upon and resolutions for forwarding to the Health Assembly are adopted, is held in January. A second shorter meeting in May, immediately after the Health Assembly, is held to address more administrative matters. The primary functions of the Board are to give effect to the decisions and policies of the Health Assembly, to advise it, and generally to facilitate its work.

Under the leadership of the Director-General, c more than 8,000 people from more than 150 countries work for WHO. This WHO staff includes health professionals (including medical doctors, public health specialists, epidemiologists, and scientists) as well as managers, economists, administrators, and other professionals. They are located in country offices, six regional offices, and at the headquarters in Geneva, Switzerland [30] .

One of the unique aspects of WHO is its decentralized structure. WHO's work is a great combination of actions at the country, regional, and global levels. These efforts to decentralize its structure are aimed at getting closer to the ground (field) where decisions made can be more responsive to actual needs. Indeed, this decentralized and regionalized structure provides WHO with multiple opportunities for engaging with countries.

WHO's global headquarters is located in Geneva, Switzerland.

The team based at the global headquarters supports and builds on all of the regional and local efforts. It sets global policies and standards, facilitates technical support to regions and countries, monitors and publicizes progress, and helps mobilize political and financial support.

At the WHO headquarters, medicine activities are conducted within the cluster of Health Systems and Services (HSS) and are coordinated by the Department of Essential Medicines and Health Products (EMP). This department (which employs about 100 staff members [31] ) is involved in the harmonization of pharmaceutical regulations because it coordinates various activities in the areas of quality assurance (e.g., the International Pharmacopoeia, International Nonproprietary Names [INN] , prequalification of medicines, counterfeit medicines), regulation and legislation (e.g., International Conference of Drug Regulatory Authorities [ICDRAs]), and safety and efficacy (e.g., drug alerts). These activities comprise guideline development, workshops, and training courses, coordination and promotion of pharmacovigilance for global medicine safety, regulatory and other information exchange, and review of narcotic and psychotropic substances.

WHO Member States are grouped into six regions, each of them having a regional office: ▸ WHO Regional Office for Africa in Brazzaville, Republic of Congo. ▸ WHO Regional Office for Europe in Copenhagen, Denmark. ▸ WHO Regional Office for Southeast Asia in New Delhi, India. ▸ WHO Regional Office for the Americas/Pan American Health Organization (PAHO) in Washington DC, United States. ▸ WHO Regional Office for the Eastern Mediterranean in Cairo, Egypt. ▸ WHO Regional Office for the Western Pacific in Manila, The Philippines.

Each of WHO's regional offices are the first point of contact for country offices that need extra technical or financial help. These regional offices also give special attention to adapting global policies to fit specific needs in their regions. Indeed, the regional level is important in the WHO organization as it links the global strategy and plan with the country's reality and needs.

They play a key role in the implementation of WHO norms and standards by ensuring that:

▸ Country and regional needs are taken into consideration when WHO norms and standards are developed ▸ Global guidelines and internationally recognized norms and standards are appropriately implemented in their regions (in the context of their own specific regulatory environment and challenges) by providing guidance, technical assistance, and training

In addition to global activities coordinated from WHO headquarters, WHO regional and country offices can also carry out a variety of medicine-related activities specific to their regions.

In addition to the regional and headquarters offices, WHO has 145 country offices that cover 159 Member States. d There are also two field offices (the WHO Humanitarian Assistance Office in Pristina, Kosovo and the West Bank and Gaza Office) and offices covering two different areas, the US-Mexican border field office in El Paso, Texas (US), and the Office of Caribbean Program Coordination in Barbados. WHO has also established "WHO liaison offices" in key locations (e.g., at the European Union in Brussels, Belgium, at the African Union and the Economic Commission for Africa in Addis Ababa, Ethiopia, in Washington DC, US, and at the UN in New York City) and more than 10 "technical offices" (e.g., the European Observatory on Health Systems and Policies in Berlin, Germany) [32] .

d Some countries that do not have a physical WHO country office are served by the WHO Representative of another country (for instance, the WHO Representative to Malaysia covers not just Malaysia, but also Brunei, Darussalam, and Singapore) .

Approximately 40% of WHO country offices are either owned or supported by the government and ministries of health. Some of these WHO country offices are located in independent premises either rented or owned by WHO, while others are located within ministries of health or UN common premises.

These country offices are led by the Head of WHO Office (HWO), who are designated by the Director-General and by the respective regional Directors. The HWO manages WHO core functions at the country level and provides leadership in the following key functional areas: ▸ Advocacy, partnership, and representation ▸ Support for policy development and technical cooperation ▸ Administration and management

It is important to note that WHO is focused on needs of countries and emphasizes in particular the decentralization process that is aimed at increasing WHO's impact on health and development at the country level. This country focus tailors WHO's technical collaboration to the needs and capacities of each Member State, with a special emphasis on the poorest countries and most fragile contexts.

The key principles guiding WHO cooperation in countries are [33] : ▸ Ownership of the development process and projects by the country ▸ Alignment with national priorities and strengthening national systems ▸ Harmonization with the work of sister UN Agencies and other partners in the country towards better aid effectiveness ▸ Collaboration as a two-way process that fosters Member States' contributions to the global health agenda WHO's country presence is the platform for effective cooperation with countries for advancing the global agenda, contributing to national health strategies and planning, and bringing country realities and perspectives into global policies and priorities. According to the above principles and its structure, WHO is indeed able to focus on countries' needs and better define its priorities to actively support the development, implementation, monitoring, and assessment of national health policies, strategies, and plans. But it also allows for better monitoring implementation of global agreements such as the Millennium Development Goals (MDGs) and the International Health Regulations (IHR [2005] ).

These activities in countries are governed by the Country Cooperation Strategy (CCS), which is WHO's key instrument to guide its work in countries. It is a medium-term vision (generally covering four to six years) for its technical cooperation with a given Member State, in support of the country's national health policy, strategy, or plan. It is an organization-wide reference that guides partnership, planning, budgeting, and resource allocation.

WHO also established the Department of Country Focus (CCO) to support and advocate for WHO country offices, develop the capacity of WHO country teams for effective engagement in partnership platforms, and facilitate and monitor WHO's engagement in the aid effectiveness agenda at the country level. For example, CCO provides support for the development, dissemination, and use of the Country Cooperation Strategy.

▸ Expert Committees: Expert committees have an important role in WHO activities. They are defined in the WHO constitution. e In addition to the constitution, regulations for expert advisory panels and committees are also included in the WHO document entitled "Regulations for Expert Advisory Panels and Committees." f An expert committee is the highest official advisory body to the Director-General of WHO as well as to all the organization's Member States. It is established by the WHA or by an Executive Board decision. There are various types of WHO expert committees. For example, the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) has been providing, for more than 60 years, recommendations and tools to assure the quality of medicines from their development phase to their final distribution to patients. There is also the Expert Committee on Biological Standardization (ECBS), which is as old as the ECSPP.

In addition to its structured organization, the WHO has been supported since its creation by its "collaborating centers." These are institutions such as research institutes and parts of universities or academies that are designated by the Director-General to carry out activities in support of WHO programs. Currently there are over 800 WHO collaborating centers in over 80 Member States working with WHO in several areas (one of them being "Pharmaceuticals"). Several collaborating centers may exist for the same topic (e.g., international classifications or traditional medicines) and form a specific network to help WHO regarding this specific topic.

of Causes of Death. WHO also started to publish its Bulletin, which is today an international peer-reviewed monthly journal of public health with a special focus on developing countries. j In its early years, WHO's priority was the prevention and control of specific diseases (e.g., malaria, tuberculosis, smallpox, yaws, onchocerciasis, and venereal disease), some of which are still a problem today. They also focused on women's and children's health and nutrition, and environmental sanitation. WHO's work has since grown to cover other (sometimes new) health problems (including polio, HIV/AIDS, and Severe Acute Respiratory Syndrome [SARS] ), but it also works to control tobacco and alcohol use and to promote diet and physical activity to prevent the four main noncommunicable diseases (cardiovascular disease, cancer, chronic lung diseases, and diabetes) [36] .

WHO has also been increasingly involved in the global regulation and control of medicines. In 1977, the first essential medicines list was released two years after the WHA introduced the concepts of "essential drugs" and "national drug policy." One hundred and fifty-six countries today have a national list of essential medicines. WHO has also funded many projects over the years to facilitate global cooperation and harmonization of standards. The purpose of all these activities in the pharmaceutical domain is aimed at increasing global and equitable access to safe, effective medicines of assured quality. This specific goal is derived from the overall objective of WHO to improve and maintain global public health. This objective has been regularly reiterated in several WHA resolutions and during other events such as the ICDRAs. In 1978, the International Conference on Primary Health Care (Alma-Ata, Kazakhstan) set the historic goal of "Health for All," to which WHO continues to aspire. More recently, the UN MDGs have further clarified the objectives and priorities of global cooperation derived from the UN Millennium Declaration signed in September 2000.

One of WHO's mandates is "to develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products" [37] . WHO Member States (especially developing countries) rely on WHO for expertise and guidance in regulation, safety, and quality assurance of medicines through development and promotion of international norms, standards, guidelines, and nomenclature.

To achieve this goal, WHO relies on cooperation and uses its decentralized organization to facilitate implementation of projects and agreed-upon standards.

The harmonization activities are initiated according to the WHO's Medicines Strategy. Trigger actions to initiate a new project or development of a standard are given at different levels and bodies (i.e., the WHA, Executive Board Resolutions, ICDRAs, or WHO programs and j Since it was first published in 1948, the Bulletin has become one of the world's leading public health journals. As the flagship periodical of WHO, the Bulletin draws on both WHO experts (as editorial advisors, reviewers, and authors) and external collaborators. clusters). These projects and standards are then developed through a vast global consultation process involving WHO Member States, national and regional authorities, international agencies, and with specialists from industry, national institutions, nongovernmental organizations, etc. Project updates and approved standards become publically available through the extensive list of WHO publications to support national, regional, and global health strategies. k Because the global dissemination and exchange of information is important, WHO secures the broad international distribution of its publications and encourages their translation. l This ensures the widest possible availability of authoritative information and guidance on health matters.

The Department of EMP, based at the WHO global headquarters in Geneva, works closely with expert committees, other regulators, and relevant WHO collaborating centers to develop and implement these harmonization activities. This department coordinates these activities globally with the support of WHO's regional advisors and country project staff in each of the regional offices and many country offices. Each of the regional offices has two to five professionals coordinating the Medicines Strategy, and 40 WHO country offices have full-time pharmaceutical policy experts [38] .

It is worth mentioning that in addition to its normative activities and harmonization projects, WHO also assists countries in capacity building by assessing regulatory systems. It does this by facilitating cooperation and information exchange between countries and by providing technical support. It is very important to involve all countries (whatever their development level), and to facilitate the implementation of norms and standards.

Finally, WHO has developed relationships with a lot of nongovernmental and civil society organizations on a global basis via the Civil Society Initiative (CSI) , and also at regional and national levels. The objectives of WHO's relations with nongovernmental organizations (NGOs) are to promote the policies, strategies, and activities of WHO to facilitate their implementation.

WHO has a large repertoire of global normative work relevant for all levels of development. In the area of medicines, a lot of standards, norms, and classifications have been developed, and forums/networks have been created to enhance global cooperation. Important initiatives are presented below. k WHO publishes practical manuals, handbooks, and training material; internationally applicable guidelines and standards; reviews and analyses of health policies, programs, and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision makers. Also, the WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. l In 1978, the World Health Assembly turned multilingualism into a WHO policy by establishing six official languages (Arabic, Chinese, English, French, Russian, and Spanish) . Since the adoption of a 1998 resolution, all governing bodies' documents and corporate materials have been made available online in all official languages.

The International Conference of Drug Regulatory Authorities (ICDRAs) provides drug regulatory authorities of WHO Member States with a forum to meet and discuss ways to strengthen collaboration and harmonization of pharmaceutical regulations. This is a key accomplishment of WHO that has been instrumental in guiding DRAs, WHO, and interested stakeholders to develop national, regional, and international medicines regulation, and it continues to be a cornerstone of international harmonization of medicines regulation.

These conferences have been held since 1980, and they have involved both developed and developing countries. The 14th ICDRAs, held in Singapore from November 30 to December 3, 2010, involved 345 participants from over 90 agencies. The 15th ICDRAs, which took place in Tallinn, Estonia from October 23 to 26, 2012, was attended by over 300 participants from 100 countries.

The aim of these conferences is to promote the exchange of information and collaborative approaches to issues of common concern. Topics discussed include quality issues, herbal medicines, homeopathy, regulatory reform, medicine safety, counterfeiting, regulation of clinical trials, harmonization, new technologies, and e-commerce. Recommendations are proposed for actions to take among agencies, WHO, and related institutions. It is worth mentioning that the idea to create ICH began to formulate after background discussions between the US, the European Union (EU), and Japan during the 5th ICDRAs conference in Paris, France in 1989 [39] .

As a platform was established to develop international consensus, the ICDRAs continues to be an important tool for WHO and DRAs in their efforts to harmonize regulation and improve the safety, efficacy, and quality of medicines on a worldwide basis.

The WHO constitution mandates the production of international classifications on health. These internationally endorsed classifications, developed through the WHO network m are very important as they facilitate the storage, retrieval, analysis, interpretation, and comparison of data. They support global cooperation and harmonization by providing a consensual framework that governments, healthcare providers, and consumers can use as a common language. They also permit the comparison of data not only within populations over time, but also between populations.

WHO reference classifications are the International Classification of Diseases (ICD), the International Classification of Functioning, Disability and Health (ICF), and the International Classification of Health Interventions (ICHI). In addition, related and derived classifications (based on the reference classifications) have also been developed (e.g., the Anatomical Therapeutic Chemical Classification with Defined Daily Doses (ATC/DDD) that classifies m WHO has designated a number of collaborating centers to work with it in the development, dissemination, maintenance, and use of the WHO International Classifications. therapeutic drugs according to the organ/system on which they act, and their chemical, pharmacological, and therapeutic properties).

The WHO International Clinical Trials Registry Platform (ICTRP) is a global initiative that aims to make information about all worldwide clinical trials involving humans publicly available. This activity was launched during the 58th WHA in 2005 n following discussions and recommendations from a Ministerial Summit on Health Research in Mexico City, Mexico in November 2004.

The ICTRP is not itself a clinical trials registry, but a central repository that can be searched using the WHO search portal (http://apps.who.int/trialsearch/). All items in the trials registration data set are copied from individual registries onto the WHO central repository, and data is updated regularly. Indeed, details on clinical trials come directly from one of the primary registries o in the WHO Registry Network (e.g., the European Clinical Trials Register that became a member of the Network in September 2011 p ).

By consolidating clinical trials information from several worldwide sources using standardized data set format/criteria, and by implementing unambiguous identification (i.e., a Universal Trial Number [UTN] ), the ICTRP not only facilitates the exchange of information, but also promotes harmonization of this information. Harmonization is also further achieved because WHO proactively supports countries/regions in establishing WHO-compliant clinical trials registries or policies on trial registration.

Quality assurance is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. This is a major public health challenge, particularly in light of growing cross-border health issues and the growing international dimensions of trade. The quality of pharmaceuticals has been a concern of WHO since its inception. The development of norms, standards, and guidelines to promote quality assurance is an integral part of WHO's constitution, and has been endorsed and supported through numerous WHA resolutions. More recently, the WHO Medium-Term Strategic Plan for 2008-2013 requested that the organization develop international standards, recommendations, and instruments to assure the quality of medicines, whether produced and traded nationally or internationally. n Resolution WHA 58.34 called on the global scientific community, international partners, the private sector, civil society, and other relevant stakeholders to "establish a voluntary platform to link clinical trials registers in order to ensure a single point of access and the unambiguous identification of trials with a view to enhancing access to information by patients, families, patient groups and others." o A Primary Registry in the WHO Registry Network is a clinical trial registry with at least a national remit that meets WHO Registry criteria for content, quality and validity, accessibility, unique identification, technical capacity, and governance and administration. p The European Clinical Trials Register provides public access to information extracted from the EU clinical trial database ("EudraCT").

The WHO Medicines Quality Assurance Program, which is part of the EMP Department, produces norms, standards, and guidelines on the quality assurance of pharmaceuticals. These regulatory tools are prepared through a vast global consultative process, and are ultimately approved by the WHO ECSPP, q which meets annually. The report of each meeting (Technical Report Series) includes newly adopted guidelines in its annexes. When adopted, the norms, standards, and guidelines become international harmonized standards intended for use by national DRAs, manufacturers, and other interested parties.

Many important international standards and projects have been developed in this area:

▸ Good manufacturing practice (GMP) ▸ Guidelines for regulatory approval (e.g., the guidelines on stability testing or on registration requirements to establish the interchangeability of multisource generic pharmaceutical products and the proposal to waive in vivo bioequivalence requirements) ▸ Prequalification of medicines, laboratories, and supply agencies ▸ Model certificates for quality assurance-related activities ▸ Quality control testing ▸ New specifications for inclusion in the Basic Tests Series and the International Pharmacopoeia ▸ International Chemical Reference Substances (ICRS) r ▸ The INN program Some of these international guidelines and projects are further developed below.

▸ Good Manufacturing Practice: Good Manufacturing Practice (GMP) is the part of quality assurance that ensures products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMP is aimed primarily at diminishing the risks involved in any pharmaceutical production that cannot be eliminated through testing of the final product. s GMP covers all aspects of production: from the starting materials, premises, and equipment, to the training and personal hygiene of staff. Detailed, written procedures are essential for each process that could affect the quality of the finished product.

Panel on the International Pharmacopoeia and Pharmaceutical Preparations. r ICRS are used by laboratories to test pharmaceuticals for the purpose of quality control. These substances are mainly used for validating the results from specific tests, and as primary standards for calibrating secondary standards. WHO's collection of ICRS is now maintained by the Council of Europe's European Directorate for Quality of Medicines and HealthCare (EDQM) , which also distributes the substances worldwide. EDQM is responsible for obtaining candidate material, testing it to ensure its purity and suitability, and reporting results with recommendations to WHO. s The main risks are the following: unexpected contamination of products causing damage to health or even death; incorrect labels on containers, which could mean that patients receive the wrong medicine; and insufficient or too much active ingredient resulting in ineffective treatment or adverse effects.

Recognizing the importance of GMP in international commerce of pharmaceutical products, WHO developed requirements early on. The first WHO draft text on GMP was prepared in 1967 by a group of consultants at the request of the 20th WHA [40] . It was subsequently submitted to the 21st WHA under the title "Draft Requirements for Good Manufacturing Practice in the Manufacture and Quality Control of Medicines and Pharmaceutical Specialties" and was accepted. In 1968, the revised text was discussed by the WHO ECSPP and published as an annex to its 22nd report. The text was then reproduced, with some revisions, in 1971 in the Supplement to the 2nd edition of the International Pharmacopoeia (Ph. Int.).

Since then, WHO has further defined its general principles and requirements regarding GMP [41] , and it has also established several detailed guidelines covering specific needs for GMP of active pharmaceutical ingredients [42] , pharmaceutical excipients [43] , sterile pharmaceutical products [44] , biological products [45] , blood establishments [46] , pharmaceutical products containing hazardous substances [47] , investigational pharmaceutical products for clinical trials in humans [48] , herbal medicinal products [49] , radiopharmaceutical products [50] , and water for pharmaceutical use [51] . Finally, it also developed guidelines of a more general scope such as validation [52] , risk analysis [53] , technology transfer [54] , and inspection [55] , and has created appropriate training materials for countries.

Many countries have formulated their own requirements for GMP based on the WHO GMP.

The International Pharmacopoeia (Ph. Int.) comprises a collection of quality specifications for pharmaceutical substances (i.e., active ingredients and excipients) and dosage forms together with supporting general methods of analysis. It is intended to serve as source material for reference or adaptation by any WHO Member State. Clearly defined steps are followed in the development of new monographs.

The Ph. Int. is published by WHO with the goal of achieving a wide global harmonization of quality specifications for selected pharmaceutical products, excipients, and dosage forms. The Ph. Int., or any part of it, has legal status whenever a national or regional authority expressly introduces it into appropriate legislation.

The history of the Ph. Int. dates back to 1874 when the need to standardize terminology and to specify dosages and composition of drugs led to attempts to produce an international pharmacopoeia compendium. The first conference, called by the Belgian Government and held in Brussels in 1902, resulted in an agreement for the unification of the formulae of potent drugs, which was ratified in 1906 by 19 countries. The outcome considerably influenced the subsequent publication of national pharmacopoeias.

In 1947, the Interim Commission of the WHO took over the work on pharmacopoeias previously undertaken by the Health Organization of the League of Nations. The 3rd WHA, held in May 1950, formally approved the publication of the "Pharmacopoea Internationalis" and recommended, in accordance with Article 23 of the WHO Constitution, "the eventual inclusion of its provisions by the authorities responsible for the pharmacopoeias." It was thus recommended that the "Pharmacopoea Internationalis" not be used as a legal pharmacopoeia in any country unless adopted by the pharmacopoeial authority of that country. This first edition, published with the aim of creating a worldwide, unified pharmacopoeia, relied on collaboration with national pharmacopoeia commissions for its preparation.

In 1975, the purpose of the Ph. Int. was reconsidered. It was decided that the publication should focus more on the needs of developing countries (because developed countries had established their own pharmacopoeias), and recommended only simple, classical chemical techniques that had been shown to be sound. Since 1979, the drugs appearing in the Ph. Int. have therefore been selected from the list of essential drugs based on the first report of the WHO Expert Committee on the Selection of Essential Drugs. Also, whenever possible, classical procedures are used in the analytical methods so that the use of expensive equipment is minimized in the application of the Ph. Int. to facilitate its implementation by developing countries.

The work on the Ph. Int. is carried out by the WHO ECSPP in collaboration with members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations and other specialists [56] . The process involves consultation with, and input from, WHO Member States and DRAs, WHO collaborating centers and national drug quality control laboratories in all six WHO regions, standard-setting organizations and parties including regional and national pharmacopoeias, and manufacturers around the world.

In 1950, The WHA adopted a resolution [57] to create the International Nonproprietary Names (INN) Program in order to identify pharmaceutical substances unambiguously on a worldwide basis, and to provide a universal, unique, nonproprietary name to be used in Pharmacopoeia monographs. It began operating in 1953 when the first list of INNs for pharmaceutical substances was published. Today, this program is coordinated by the WHO EMP department.

The selection of a new INN relies on a strict procedure [58, 59] . This process is supported by the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, which provides advice on proposed names following an application made by the manufacturer or inventor. The procedure also involves the WHO Secretariat, which examines the suggested names for conformity with the general rules, similarities with published INNs, and potential conflicts with existing names. After a time period for objections has lapsed, the name will obtain the status of a recommended INN and will be published as such in "WHO Drug Information" if no objection has been raised. To make INNs universally available, they are formally placed by WHO in the public domain, hence their designation as "nonproprietary" names (also known as "generic names").

The existence of this international nomenclature for pharmaceutical substances is important for the clear identification, safe prescription, and dispensing of medicines to patients, but also for communication and exchange of information among health professionals and scientists and regulators worldwide. It provides them with a unique and universally available designated name to identify each pharmaceutical substance.

Today, INN names are widely used and globally recognized. At present, more than 8,000 INNs have been published, and this number is growing every year. The majority of pharmaceutical substances used in medical practice are designated by an INN, and their use is already common in research and clinical documentation. Nonproprietary names are intended for use in pharmacopoeias, labeling, product information, advertising and other promotional material, drug regulation and scientific literature, and as a basis for product names (e.g., for generics).

Also INN collaborates closely with numerous national drug nomenclature bodies. The use of INN names is normally required by national authorities and also by the European Community. As a result of ongoing collaboration, national names such as British Approved Names (BAN), Dénominations Communes Françaises (DCF), Japanese Adopted Names (JAN), and United States Adopted Names (USAN) are nowadays, with rare exceptions, identical to the INN.

In addition to the quality standards, WHO also developed norms and standards for pharmacovigilance, and promotes information exchange on medicine safety. The aim is to assure the safety of medicines by ensuring reliable and timely exchange of information on drug safety issues, promoting pharmacovigilance activities on an international basis, and encouraging participation in the WHO Program for International Drug Monitoring [60].

In 1968, WHO established its Program for International Drug Monitoring in response to the thalidomide disaster in 1961. At the end of 2010, 134 countries were part of the WHO Pharmacovigilance Program.

An international system for monitoring adverse drug reactions (ADRs) using information derived from Member States was established in 1971. This allows WHO to issue a rapid Drug Alert whenever a serious problem in the safety of any medicinal product arises. WHO headquarters in Geneva is responsible for policy issues, while the operational responsibility for the program rests with the WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre in Sweden. A common reporting form was developed, agreedupon guidelines for entering information were formulated, common terminologies and classifications were prepared, and compatible systems for transmitting, storing and retrieving, and disseminating data were created. The ADRs database in Uppsala currently contains over three million reports of suspected ADRs.

In 2003, a WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) was established to guide WHO on general and specific issues related to pharmacovigilance. Additionally, a network of "information officers" was established in 1980 to allow a direct relationship between WHO and all national DRAs in Member States. Each national information officer is charged with providing information to WHO on the safety and efficacy of pharmaceutical preparations, and with securing prompt transmission to national health authorities regarding new information on serious adverse effects.

This certification scheme was initially adopted by the 22nd WHA in 1969 [61], but since then it has been amended. It is an administrative instrument that requires each participating Member State, upon application by a commercially interested party, to attest to the competent authority of another participating Member State whereby:

▸ A specific product is authorized for placement on the market within its jurisdiction, or if it is not authorized, the reason why that authorization has not been accorded. ▸ The manufacturing plant in which it is produced is subject to inspections at suitable intervals to establish that the manufacturer conforms to GMP as recommended by WHO. ▸ All submitted product information, including labeling, is currently authorized in the certifying country.

The primary document delivered under this scheme is the Certificate of Pharmaceutical Product (CPP), but two other documents can be requested within the scope of the scheme. The first is a statement of licensing status of pharmaceutical product(s), and the second is a batch certificate of a pharmaceutical product (this document is rarely applied other than to vaccines, sera, and biologicals). These documents are used by DRAs of importing countries in their decision to approve, renew, extend, or vary a license.

WHO created models for these confidential documents and listed the information that such certificates need to include. Obligations that certifying authorities need to fulfill in order to be able to deliver a certificate have also been defined [62]: ▸ Possess an effective national licensing system, not only for pharmaceutical products, but also for responsible manufacturers and distributors. ▸ Have GMP requirements, in agreement with those recommended by WHO, to which all manufacturers of finished pharmaceutical products are required to conform. ▸ Effective controls must be in place to monitor the quality of pharmaceutical products registered or manufactured within its country, including access to an independent quality control laboratory. ▸ Have a national pharmaceuticals inspectorate, operating as an arm of the national DRA, and having the technical competence, experience, and resources to assess whether GMP and other controls are being effectively implemented, and the legal power to conduct appropriate investigations to ensure that manufacturers conform to these requirements by, for example, examining premises and records and taking samples. ▸ Support administrative capacity to issue the required certificates, to institute inquiries in the case of complaint, and to notify expeditiously both WHO and the competent authority in any Member State known to have imported a specific product that is subsequently associated with a potentially serious quality defect or other hazard.

GMP standards provide the basis for the WHO Certification Scheme that relies on the capacity, experience, and expertise of the certifying authority of the exporting country. This scheme is a great example of cooperation between countries and is an important tool to support a regulatory system in developing countries that do not have enough capacity, resources, or expertise.

Biological medicinal products, such as vaccines, blood and blood products, diagnostics, gene therapy, biotechnology products, cytokines and growth factors, and cell and tissue products, rely heavily on international standardization to ensure their quality and their equivalence across manufacturers. This is especially true due to the increasing globalization in the production and distribution of these biological medicines.

Over the past 50 years, WHO has worked to standardize these biological materials by establishing international biological reference materials t as well as developing international guidelines and recommendations on the production and control of biological products and technologies. Guidelines provide more general information on a range of topics of interest to national DRAs and manufacturers (e.g., "Guidelines on Evaluation of Similar Biotherapeutic Products, SBPs"), whereas recommendations establish the technical specifications for manufacturing and quality control of specific products (e.g., "Recommendations to Assure the Quality, Safety and Efficacy of BCG Vaccines"). WHO has also released many other documents on general topics (such as "Regulation and Licensing of Biological Products in Countries with Newly Developing Regulatory Authorities" [63] and "Good Manufacturing Practices for Biological Products" [64]) or on a specific type of product (e.g., blood products and related biologicals, cells and tissues, cytokines, or vaccines) to facilitate control of these biological products on a worldwide basis.

These norms and standards have been developed to assist WHO Member States in ensuring the quality and safety of biological medicines and related in vitro biological diagnostic tests worldwide. By adopting these guidance documents in their pharmacopoeias or equivalent legislation, each country ensures that the products produced and used in their country conform to current international standards. By advising national DRAs and manufacturers on the control of biological products, regulatory guidance documents also establish a harmonized regulatory framework for products in international markets.

WHO accomplishes its biological program through the WHO collaborating centers and the WHO ECBS. Members of the ECBS are scientists from national control agencies, academia, research institutes, public health bodies, and the pharmaceutical industry acting as individual experts and not as representatives of their respective organizations or employers. Its work is based on scientific consensus achieved through this international consultation and collaboration. This committee, which directly reports to the Executive Board, has met on an annual Additionally, WHO has been particularly active in the specific field of blood products and related biologicals. It has provided technical guidance and quality assurance tools to DRAs, National Control Laboratories, and manufacturers to support implementation of quality and safety systems for the production and control of blood products and related in vitro diagnostic devices worldwide. Indeed, many countries have significant difficulties in fulfilling their responsibilities in this field because processing blood (with inherent variability due to the nature of the source materials) is a highly specialized process that requires a high degree of expertise. This development of WHO International Reference Materials and Guidelines supports the technical capacity of national DRAs and assures the compliance of manufacturers to quality and safety measures globally in order to prevent transmission of diseases via blood products. It also contributes to technology transfer, global cooperation, and harmonization of regulations via the Blood Regulators Network (BRN).

Finally, the WHO has been very involved in the development of standards and guidelines regarding vaccines due to the importance of these products in public health. v Moreover, WHO established the "prequalification of vaccines" (regarding the acceptability, in principle, of vaccines from different sources for supply) to help the United Nations Children's Fund (UNICEF) and other UN agencies that purchase vaccines. Finally, through its regulatory pathways initiative it also helps to address the challenges faced by developing countries that are targets for clinical trials or introduction of new vaccines not registered in the country of manufacture. The objective is to support the establishment of regulatory mechanisms for the licensing of products in those countries that have not yet fully developed the expertise for the review of technical applications. This is achieved via workshops and technical assistance in collaboration with the European Medicines Agency (EMA) through its Article 58 Scientific Opinion procedure, w the US FDA, and other national DRAs in developed countries. A Developing Countries' Vaccine Regulators Network (DCVRN) was created in September 2004, and regional initiatives were also established. In many countries (developed and undeveloped), there is recognition of the significant need for research and development of medicines specifically for pediatric use (or data from pediatric studies using medicines that have been developed for adults). This lack of pediatric data became an important problem despite many initiatives from different regions or countries. The lack of suitable pediatric medicines, paired with inconsistent regulatory frameworks, poses significant risks to a particularly vulnerable patient population.

The overall aim of the PmRN x is to promote availability of quality medicines (including biological medicines and vaccines) for children by facilitating communication, collaboration, and regulatory harmonization across manufacturing, licensing, and research [66] . More specifically, among several objectives, this network tries to: ▸ Provide a forum for discussion between worldwide DRAs to build awareness of pediatric medicines regulatory considerations ▸ Facilitate the collaboration, discussion, and work towards consensus on regulatory standards for pediatric medicines (i.e., the development of international recommendations and common standards for clinical trials and registration of medicines for children based on the existing ICH, EMA, and US FDA guidelines) ▸ Strengthen licensing (approval) systems for pediatric medicines by increasing regulatory cooperation, information sharing, and training

Traditional medicines y have been used in many countries throughout the world over many centuries. Today, these medicines still represent an important part of healthcare in some countries. z For example, more than 100 countries have regulations for herbal medicines, but practices of traditional medicine vary greatly from country to country and from region to region, as they are influenced by factors such as culture, history, personal attitudes, and philosophy. However, while it is often necessary to tailor legislation and delivery to reflect the needs and traditions of the individual countries, a number of themes and issues are common, such as the importance of practitioner training, the issues related to safety, the need to enhance research into both products and practices, and the importance of labeling.

Also, the use of traditional medicines has expanded globally and has gained popularity in the last few decades. Specifically, these practices have not only continued to be used for primary healthcare of the poor in developing countries, but have also been used in other countries where conventional medicines are predominant in the national healthcare system. aa With this tremendous expansion in the use of traditional medicines worldwide, safety and efficacy as well as quality control of herbal medicines and traditional procedure-based therapies have become important concerns for many of these countries. For this reason, WHO has been increasingly involved in developing international standards and technical guidelines for these types of medicines, and also in increasing communication and cooperation between countries [67] . The challenge now is to ensure that traditional medicines are used properly, and to determine how research and the evaluation of traditional medicines should be carried out.

Supported by several WHA and Executive Board resolutions, WHO has developed and issued a series of technical guidelines (e.g., guidelines for the assessment of herbal medicines, research guidelines for evaluating the safety and efficacy of herbal medicines, and guidelines for clinical acupuncture research). In 1997, WHO developed draft guidelines for "methodology on research and evaluation of traditional medicine" that was finally approved in April 2000 [68] . The purpose of this document is to promote the proper development, registration, and use of traditional medicines and to harmonize the use of certain terms in traditional medicine. Moreover, in 2006, WHO established a global network (called the International Regulatory Cooperation for Herbal Medicines [IRCH]) to allow communication and exchange between worldwide regulatory authorities responsible for the regulation of herbal medicines.

The mission of this program is "to make quality priority medicines available for the benefit of those in need." This is achieved through evaluation and inspection activities, and in cooperation with national DRAs and partner organizations. The list of prequalified medicinal products (updated regularly) is used principally by UN agencies (including UNICEF and the Joint United Nations Programme on HIV/AIDS [UNAIDS]) to guide their procurement decisions. But, the list has also become a vital tool for any agency or organization involved in bulk purchasing of medicines, as demonstrated by the Global Fund to Fight AIDS, Tuberculosis and Malaria.

The strategy is to apply unified standards of acceptable quality, safety, and efficacy and to build the capacity of staff from national DRAs, quality control laboratories, and from manufacturers or other private companies, to ensure quality medicines. Technical assistance, training, and capacity building are an important part of the program [70] .

When a product is included on the WHO list, the relevant product dossier has been evaluated and the manufacturing sites inspected by WHO-appointed assessors and inspectors and found to comply with WHO standards. WHO also recognizes the evaluation of products by some major DRAs that apply stringent standards for quality, including, but not limited to, the US FDA, EMA, and Health Canada. bb However, it is important to note that the inclusion of a product (or a laboratory) on this list does not imply any approval by WHO because it is the sole prerogative of national authorities.

WHO inspections are done by a team of inspectors, including: ▸ An inspector/expert from one of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) countries ▸ A WHO representative (inspector/expert) ▸ An inspector (or inspectors) as an observer from the national DRA of the country in which the laboratory is located At the end of 2011, the WHO list of prequalified medicines included 269 products (manufactured in 25 countries); a total of 23 quality control laboratories had been prequalified (covering all WHO 6 regions). The program had also prequalified its first active pharmaceutical ingredients (APIs) [71].

The above projects are specifically related to the harmonization of pharmaceutical regulations and regulatory standards related to medicinal products. However, it is important to note that several other WHO projects not directly related to the harmonization of pharmaceutical bb When a product is listed with a reference to US FDA or EMA, the alternative listing procedure was used, and the products have been added to the list relying on the assessment and inspections conducted by the US FDA or EMA. regulations cc have been or are also very important because they facilitate implementation of common systems, agreements on terminology, and the establishment of a forum for exchange of not only information, but also expertise and experience. These other WHO projects ultimately facilitate overall dialogue, cooperation, convergence, and harmonization between countries and regions.

Moreover, other more general projects can also promote regional and subregional collaboration and harmonization of the regulation. For example, one of the principles of the general EC-ACP-WHO Partnership established in 2004 dd was to "strengthen existing collaborative arrangements (e.g. pooled procurement in the Caribbean) and catalyse the creation of new ones, which can work together to achieve pooled procurement, common policies and harmonization of legislation."

In addition, WHO publishes many documents regarding pharmaceuticals and regulations (i.e., newsletters, periodicals, reports status, or special publications such as the WHO Blue Book [72] ) that allow the diffusion and exchange of information and data everywhere in the world. For example, "WHO Drug Information" is a quarterly journal, launched in 1987, which provides an overview of topics relating to medicine development and regulation that is targeted to a wide audience of health professionals and policymakers. It communicates the latest international news and trends.

Finally, some other specific WHO projects are also very important in facilitating the implementation of the international standards. These following projects need to be reviewed even though they are not directly related to the harmonization of pharmaceutical regulations because they demonstrate the key role of WHO in the global regulatory system, and therefore show how this organization has the legitimacy to further coordinate global harmonization.

▸ WHO Review of Drug Regulatory Systems: To ensure that public health is appropriately supported, national regulatory capacity needs to be regularly assessed, areas of weakness need to be identified, and necessary measures need to be taken. The objectives of this review are to strengthen national regulatory and control capacity through the identification of specific needs and the provision of appropriate technical support and training. This is done via the evaluation of existing legal framework, regulations, and control activities in order to assess the national regulatory capacity against a set of predefined parameters. WHO can then provide technical input if gaps are identified.

This activity is very important, especially in developing countries, to ensure that international standards can be appropriately implemented at the national level. It is also an important tool to have a clear status of national regulatory systems to evaluate appropriate needs from developing countries and therefore necessary support from regional and international organizations. The WHO multicountry study (involving only 10 countries) also showed that such assessments represent significant opportunities to learn more about the strengths and weaknesses of DRAs and the different strategies used to improve drug regulation performance [75] .

The International Health Regulations (IHR), first adopted by the Health Assembly in 1969 and then significantly revised in 2005 in consideration of the growth in international travel and trade and the emergence or reemergence of international disease threats and other public health risks [76] , were finally adopted by the 58th WHA on May 23, 2005 and entered into force on June 15, 2007. The IHR is an international legal instrument that is binding on all the WHO Member States. These global rules were developed and implemented to enhance national, regional, and global public health security. Its aim is to help the international community prevent and respond to acute public health risks that have the potential to cross borders and threaten people worldwide. The stated purpose and scope of the IHR are "to prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade." The IHR has been used for the H1N1 pandemic crisis [77] .

The revised IHR requires countries to strengthen their core surveillance and response capacities so that they can report certain disease outbreaks and public health events to WHO. Building on the unique experience of WHO in global disease surveillance, alert, and response, the IHR defines the rights and obligations of countries to report public health events, and establishes a number of procedures that WHO must follow in its work to uphold global public health security.

As mentioned above, this document was not specifically developed for pharmaceutical products, but is an important global tool that enhances cooperation between all countries in the world. Indeed, even if this agreement does not specifically relate to the harmonization of pharmaceutical regulations, it is very interesting for many reasons. First, this project helps strengthen worldwide capacities for public health and global cooperation in general, which is important for the implementation of harmonized global standards. More importantly, this is one of the first agreements that manages public health as a truly global issue and proposes further action using an integrated international approach and network. It shows that further integrated global cooperation in the area of health (with WHO being at the center of this cooperation to coordinate this effort) is possible and beneficial [78].

The mission of WHO's program on medicines and pharmaceutical policies is to support the achievement of the health-related MDGs by assisting governments and organizations to ensure global and equitable access to safe, effective medicines of assured quality. Goal 8 ee and Target 8E ff are particularly applicable to WHO harmonization activities in the pharmaceutical domain.

Many of WHO's activities in the pharmaceutical domain support the achievement of these MDGs because they globalize the resolution of major public health issues (that cannot be resolved at the national/local level), they promote collaboration between countries and regions, and they provide tools and standards to allow such international collaboration. Since its creation, WHO has indeed played a significant role in the global harmonization of pharmaceutical regulations. As per its mandate and the responsibilities defined in its constitution, it has developed and maintained numerous international standards, norms, guidelines, classifications, and nomenclatures through a rigorous, international, and independent scientific consultative process. In addition to this normative role, WHO has also established important networks to facilitate global cooperation. For example, ICDRAs has been an important player in global regulatory harmonization. It launched many projects that have facilitated and promoted harmonization and cooperation between countries [79].

Cooperation projects have also been pioneered over the years with a specific interest in essential medicines. gg The WHO Prequalification Program has been an important step since it demonstrated that cooperation in the domain of medicine evaluation is possible and beneficial. Indeed, this program has been very positive and its scope has continually been extended since its creation in 2001. It has clearly accelerated the access of essential medicines worldwide (especially in low and middle income countries) [80] . This model should be used to further develop regional and global collaboration for medicine evaluation. The example of the 2010/2011 pilot WHO/East African Community (EAC) collaborative procedure initiated to facilitate registration of prequalified medicines in the EAC [81] was positive. The overall aim was to identify a framework for WHO/EAC, for joint evaluation and approval of dossiers and inspections of medicine manufacturing sites, and to ensure that these assessments are integrated into national regulatory decision making. Two assessors each from three EAC countries (Kenya, Tanzania, and Uganda) and six WHO assessors jointly assessed two product dossiers submitted by a single manufacturer. The dossiers were submitted in parallel, and with identical content, to each participating EAC country and to WHO. The products were both prequalified. The principal benefit of this joint assessment was that once the products had been jointly assessed and approved by WHO/EAC, they were granted immediate access to the markets of each of the countries that had participated in the joint assessment. Also, such joint assessment contributes to harmonization of regulatory requirements at the regional level. This pilot WHO/EAC project also exemplifies the role of WHO in providing technical assistance to countries and supporting local capacity building. Indeed, by acknowledging the important role of adequate systems to implement sound and effective pharmaceutical regulation, WHO has supported developing countries in addressing their deficiencies or capacity problems through various types of training, assessment of regulatory capacity, and the recommendation of institutional development plans. These activities have been very beneficial in the past, but work needs to continue and grow in this domain, as problems still exist. Indeed, the extent of implementation of standards varies from one region to another. There are a number of factors that explain observed weaknesses of medicine regulation, and these differ from country to country and depend also on the individual health systems. Countries may vary regarding their registration system, and not all of them can implement a comprehensive medicine evaluation and registration system. Also, WHO encourages regional and international collaboration among national DRAs in order to promote the harmonization of requirements and practices, and to strengthen professional competence [82] . However, as recognized in its Medicine Strategy Plan, cooperation with regional harmonization initiatives and organizations should be further enhanced [83] . Closer cooperation and coordination should also be sought with other global initiatives such as ICH.

Further assistance to countries and cooperation with other regional and global initiatives are indeed possible and can be facilitated by WHO's regionalized structure. This specific threelevel organization provides multiple opportunities for engaging with countries. The headquarters focus on initiation, development, and global coordination of harmonization projects, while regional offices focus on technical support and building national capacities to support implementation. WHO's presence in countries also allows a close relationship with ministries of health and its partners inside and outside of government. This work at the regional and country levels is critical in ensuring that local and regional needs and challenges are taken into consideration when international standards and projects are developed.

To conclude, although some improvements may address current challenges, WHO has been very successful and beneficial for all Member States (developing and also developed countries). It has promoted evidence-based debate, analysis, and recommendations for health through its own work and that of the numerous formal and informal networks and collaborating centers around the world. These networks facilitate lively cooperation between scientists across nations and allow governments to jointly tackle global health problems. Development and promotion of global norms and standards in medicine is one of WHO's efforts that is widely perceived as being in an area in which WHO has a comparative advantage. This advantage is due to the recognition of WHO as the global leader and coordinating authority on global public health. The achievement of the MDGs and the renewal of primary healthcare are indeed unthinkable without WHO's norms and standards, policy guidelines, and technical cooperation. This is why the development and promotion of global norms and standards are an area of continued focus for WHO [84] . It is indeed critical that WHO continue its work towards better harmonization and cooperation in the pharmaceutical domain. Acknowledging the unique neutral and independent role of WHO, its numerous successes in the past, and its nearly universal membership, it would be appropriate to further extend the leadership of WHO in this domain. This increased responsibility in the coordination of medicines would also further fulfill its mandate "to act as the directing and co-ordinating authority on international health work." [85]

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a 20-year-old program. This unique initiative was established with the objective to bring together the DRAs of Europe, Japan, and the United States and experts from the pharmaceutical industry in these three regions to discuss scientific and technical aspects of pharmaceutical product registration.

The drug regulatory systems in all three regions share the same fundamental concerns for the safety, efficacy, and quality of medicines. However, many time-consuming and expensive experiments have been repeated in all three regions to meet specific regional requirements. The goal of ICH has been to increase harmonization of technical requirements to ensure that safe, effective, and high-quality medicines are developed and registered in the most efficient and cost-effective manner in order to be delivered to the maximum number of patients in the world without delay.

These activities have been undertaken to promote public health, prevent unnecessary duplication of clinical trials in humans, and minimize the use of animal testing without compromising safety and effectiveness. By making recommendations on ways to achieve greater harmonization of technical requirements for product registration, the objective is indeed to reduce or obviate the need to duplicate the testing carried out during the research and development of a new product.

Since its inception in 1990, ICH has evolved, through its Global Cooperation Group (GCG), to respond to the increasingly global face of drug development, so that the benefits of international harmonization for better global health can be realized worldwide.

This ICH mission is embodied in its current Terms of Reference:

▸ To maintain a forum for a constructive dialogue between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the EU, US, and Japan in order to ensure a more timely introduction of new medicinal products, and their availability to patients; ▸ To contribute to the protection of public health from an international perspective (added upon revision in 2000); ▸ To monitor and update harmonized technical requirements leading to a greater mutual acceptance of research and development data; ▸ To avoid divergent future requirements through harmonization of selected topics needed as a result of therapeutic advances and the development of new technologies for the production of medicinal products; ▸ To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices, where these permit a more economical use of human, animal, and material resources, without compromising safety; ▸ To facilitate the dissemination and communication of information on harmonized guidelines and their use such as to encourage the implementation and integration of common standards.

ICH is comprised of representatives from six parties (the founding members of ICH) that represent the regulatory bodies and research-based industry in the EU, Japan, and the US: 

Since 1990, when ICH was initiated, members have been added:

▸ The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), the global nonprofit, nongovernmental organization, founded in 1968 to represent the research-based pharmaceutical, biotech, and vaccine sectors. Its members are comprised of over 20 leading international companies and over 40 national and regional industry associations covering both developed and developing countries. IFPMA is very involved in all subjects related to the improvement of global health. It has been closely associated with ICH since its inception to ensure contact with the research-based industry (especially outside the ICH regions). IFPMA provides the ICH Secretariat. This important group of nonvoting members was established as a link between ICH and non-ICH countries and regions.

The ICH organization consists of the ICH Steering Committee, ICH Coordinators, ICH Secretariat, and ICH Working Groups. The ICH Global Cooperation Group (GCG) and the ICH Medical Dictionary for Regulatory Activities (MedDRA) Management Board are subcommittees of the ICH Steering Committee.

The Steering Committee is the body that governs the ICH, determines the policies and procedures, selects topics for harmonization, and monitors the progress of harmonization initiatives. This committee, established at the first ICH meeting in April 1990, has met at least twice a year since, with the location rotating between three regions (EU, Japan, and US). During these committee meetings, new topics are considered for adoption, reports are received on the progress of existing topics, and maintenance and implementation of the guidelines are discussed. Each of the six ICH parties has two seats on the ICH Steering Committee. Each of the observers nominates nonvoting participants to attend the ICH Steering Committee Meetings. IFPMA also participates as a nonvoting member. Meetings of the ICH MedDRA Management Board, ICH GCG, and the Regulators Forum also occur during the same week as the Steering Committee meeting.

ICH Working Groups are the key players of the ICH harmonization process. They are responsible for the development, implementation, or maintenance of ICH guidelines. Each of the six ICH parties is represented in every working group. The official membership of an Expert Working Group/Implementation Working Group (EWG/IWG) is usually limited to two officials per party (one Topic Leader and one Deputy Topic Leader). One of these topic leaders is nominated Rapporteur (and sometimes a second is nominated Co-Rapporteur) by the Steering Committee. ICH Observers and Interested Parties hh can also nominate one representative. The pharmacopoeial authorities and representatives from the self-medication industry and the generic industry were invited to participate in the various Working Groups. Finally, the three regulatory parties of the Steering Committee officially designate a Regulatory Chair when a new ICH topic is formally adopted. The Regulatory Chair, designated among the three regulatory parties, regularly presents reports to the Steering Committee and ensures, in close collaboration with the Rapporteur, timely execution of the ICH process and adherence to the concept paper and business plan, including scope and timelines.

Depending on the type of harmonization activity required, the Steering Committee will endorse the establishment of one of three types of Working Groups:

▸ Expert Working Group (EWG): These Working Groups are appointed by the Steering Committee when new topics are accepted for harmonization. The objective of each EWG is to review the differences in requirements between the three regions and develop scientific consensus required to reconcile those differences. It is charged with developing a harmonized guideline that meets the objectives defined in the concept paper and business plan. ▸ Implementation Working Group (IWG): An IWG's task is to develop questions and answers (Q&A) to facilitate implementation of existing guidelines. ▸ Informal EWG/IWG: These Working Groups are formed prior to any official ICH harmonization activity. Their objective is to develop a concept paper and business plan.

Working Groups meet in the same week as the Steering Committee and report on their progress to the Committee. These one-week meetings are key for the ICH organization as they allow for a regular review of efforts and achievements and adjust them if necessary. ICH Discussion Groups are established to discuss specific scientific considerations or views (e.g., Gene Therapy Discussion Group) to facilitate the exchange of information on a specific topic, and ultimately the harmonization of the requirements.

The Coordinators are fundamental to the smooth running of the ICH and are nominated by each of the six parties. An ICH coordinator acts as the main contact with the ICH Secretariat and ensures that ICH documents are distributed to the appropriate persons within the area of their responsibility.

Each party has also established a contact network of experts within their own organization or region in order to ensure that, in the discussions, they reflect the views and policies of the cosponsor they represent. The way this network operates differs according to the administrative structure of the party concerned. Due to structural differences within the EU and MHLW, ICH technical coordinators are also designated from the EMA and PMDA, respectively. They support the ICH coordinator and facilitate every action of the Steering Committee members in the region, mainly by applying their scientific knowledge. Their roles include acting as a contact point between the experts within the EMA and PMDA and the ICH coordinator at the main regulatory body, and as a contact point with the ICH Secretariat.

The ICH Secretariat operates from the IFPMA offices in Geneva (Switzerland), and provides support to the ICH Steering Committee. The Secretariat is primarily concerned with preparations for, and documentation of, meetings of the Steering Committee, as well as coordination of preparations for Working Group (EWG, IWG, and Informal WG) and Discussion Group meetings. The Secretariat also provides administrative support for the GCG and the MedDRA Management Board, and maintains the ICH website.

The MedDRA Management Board, appointed by the ICH Steering Committee, has overall responsibility for direction of MedDRA, an ICH standardized dictionary of medical terminology. The Board oversees the activities of the MedDRA Maintenance and Support Services Organization (MSSO), which serves as the repository, maintainer, developer, and distributor of Med-DRA. The Management Board is composed of the six ICH Parties, the Medicines and Healthcare Products Regulatory Agency (MHRA) of the UK, Health Canada, and WHO (as Observer). The IFPMA acts as a nonvoting observer on the Management Board and also chairs the Board. As stated in its mission statement adopted by all parties in May 2005, this group "promotes a mutual understanding of regional harmonization initiatives in order to facilitate the harmonization process related to ICH guidelines regionally and globally, and to facilitate the capacity of drug regulatory authorities and industry to utilize them." This group ensures that the benefits of ICH harmonization extend beyond the three ICH regions (Japan, EU, and US).

The role of the GCG has changed over time as the focus on collaboration with the non-ICH regions increased. From its creation to today, three phases can be differentiated:

▸ First Phase (1999 to 2003 : Information Sharing Outside ICH: During these first three years, the GCG mandate was to share information outside ICH (via preparation of brochures, presentations at international meetings, etc.). The objectives were to make available to any country or pharmaceutical company that requested it information on ICH, ICH activities, and ICH guidelines. To this end, the group created a series of brochures intended to guide its activities as it answers requests for information and responds to non-ICH regulators and industry:

• ▸ Second Phase (2003 Phase ( to 2007 : Integration and Collaboration with RHIs: On November 9, 2003, the ICH GCG released their terms of reference in which they extended their action to act as the primary representative of the ICH Steering Committee outside the ICH regions, and equally as such as a conduit for non-ICH parties to the ICH Steering Committee. To do so, the group developed a privileged relationship with other non-ICH harmonization initiatives. This key activity of the GCG had three advantages:

• To share ICH discussions and actions with the non-ICH regions (allowing, when possible, harmonization and implementation of ICH activities on a worldwide basis) • To promote and organize the involvement of the non-ICH regions experts in ICH discussions (via expert meetings, comments on Step 2 Guidelines, and training on Guidelines) • To facilitate interregional collaboration in order to promote transparency, better understanding of challenges and potential solutions to harmonization issues, leverage collective experience and knowledge (allowing easier standardization and development of Good Harmonization Practice)

When, in 2003, the GCG decided to include representatives from the non-ICH regions, the relationship with the non-ICH regions became more collaborative and proactive, and the focus shifted from information sharing to a two-way dialogue to set up training and work on implementation.

The results of these collaborations allowed the organization of workshops in the regions (e.g., APEC Workshops on Clinical Research Inspections in 2008 and 2009 in Thailand, the SADC Quality Guideline Workshop in 2008 in Zambia, and the APEC Quality Guideline Workshop in 2008 in China). As an example, the GCG also endorsed the APEC Life Sciences Innovation Forum (LSIF) sponsored workshop on ICH Quality Guidelines (Q8, Q9 and Q10), held in September 2007 in Seoul, South Korea. This workshop was a great success for the spread of ICH concepts and recommendations in this region as it was attended by more than 400 participants (i.e., regulators, policymakers, academia, and industry) from 17 countries. This type of workshop allows for practical explanation of ICH guidelines, but also opens up discussion and exchange on the anticipated challenges and opportunities associated with the implementation of ICH guidelines in order to better prepare implementation. The participation of these individual countries is distinct and complementary to the participation of official RHI representatives.

In June 2008, the inaugural meeting of the expanded GCG occurred. Today, the key focus of the GCG continues to be the implementation of ICH guidelines via the organization of training that began in 2007. This training is indeed an important means for the promotion of better understanding of ICH and ICH guidelines beyond the ICH regions. It developed a framework and mechanism for policy [91-2], a procedure for selection and prioritization, a template for training requests, definitions of roles and responsibilities for the organization and coordination of training activities, and a clearinghouse of training events for public access. These training activities (most of the time coordinated with the respective RHIs) involve ICH experts.

During the meeting in October 2007 in Yokohama, Japan, the ICH Steering Committee also decided to complement the GCG with the Regulators Forum.

The ICH Regulators Forum is the latest idea implemented by ICH to increase communications and sow relationships between worldwide DRAs in order to ensure adoption and implementation of ICH guidelines. Following a proposal from the US FDA in 2007, the first meeting occurred in Portland, Oregon, US in June 2008. This is a good complement to the GCG activities and includes authorities from the three ICH regions, the Observers, the RHIs, and individual DRAs such as Australia, Brazil, China, Chinese Taipei, India, Korea, Russia, and Singapore. This ICH Regulators Forum allows frank discussion and the sharing of expertise among DRAs regarding best practices and challenges related to the implementation of ICH guidelines and their impact on regulatory systems. This discussion assists in identifying training and capacity needs for action by the GCG. More importantly, it also builds mutual understanding, relationships, and trust.

In the 1980s, many varied efforts of harmonization of pharmaceutical regulatory requirements were conducted. First, the European Community, who was developing a single market for pharmaceuticals, had shown that harmonization among different countries (with different medical cultures/practices and regulatory systems) was possible. At the same time, bilateral discussions between Europe, Japan, and the US on the possibility for harmonization were ongoing.

The concretization of these ad hoc discussions happened during the World Health Organization (WHO) International Conference of Drug Regulatory Authorities (ICDRAs) in Paris in 1989, where specific plans were agreed to. Following this meeting, the three authorities approached IFPMA to discuss a joint regulatory-industry initiative on international harmonization. The spirit and concept of ICH was then agreed on between the different parties.

In April 1990, ICH was officially created at its inaugural Steering Committee meeting, hosted by the EFPIA in Brussels, Belgium. Representatives of the regulatory agencies and industry associations of Europe, Japan, and the US met primarily to plan an international conference, but at the meeting the wider implications and terms of reference of ICH were also discussed. During this first meeting, the structure (including a Steering Committee and Expert Working Groups) and the focus of ICH activities (harmonization of safety, efficacy, and quality guidelines for human drugs and biological products) were agreed on. Eleven topics were selected for discussion at the first conference. Finally, it was agreed to expand the membership of the Steering Committee to include representatives from WHO, EFTA, and Canada as observers because the harmonized guidelines could be useful to other non-ICH regions. Additionally, agreement was reached on the full name of ICH. This name was chosen because one of the objectives of this group was to organize international conferences on harmonization. Today, this name is associated with the overall initiative.

The ICH members officially confirmed their commitment to ICH in a statement following the 2nd Steering Committee Meeting:

The Parties cosponsoring this Conference, represented at the 2nd Steering Committee Meeting in Tokyo, 23-24 October 1990 re-affirmed their commitment to increased international harmonization, aimed at ensuring that good quality, safe, and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimise the use of animal testing without compromising the regulatory obligations of safety and effectiveness. This Conference will provide a unique opportunity for regulators and industry to reach consensus on the steps needed to achieve this objective through greater harmonization of technical requirements and to set out practical and realistic targets for harmonising requirements where significant obstacles to drug development and the regulatory process have been identified.

Recognising the substantial progress which has already been made in achieving harmonization within Europe and through bilateral contacts between Europe, Japan, US, and other regions, the Conference will seek to make further progress through a trilateral approach, with clearly defined priorities, methods of work and recommendations to both industry and regulatory authorities.

Whilst the Conference will be an important step forward, it is not seen as an end in itself, but as a stage in a developing process, at a high level, between regulators and industry.

The Conference, its preparations, and follow-up activities will be conducted in an open and transparent manner and the presence of observers from other regulatory authorities and WHO is welcomed as a means of ensuring that the benefits of progress towards harmonization can be utilized world-wide.

The Conference will not only look at existing issues but will, based on past experience, seek to minimise future divergence of new registration requirements, as a consequence of technical progress.

This initial ICH statement is important because it provides the spirit of ICH that has been followed and implemented in all subsequent ICH activities since.

From its creation in 1990 to 2000, the initial focus of ICH was to promote technical and scientific exchanges and discussions in order to find consensus on divergent technical requirements for registration of medicinal products in the ICH regions. The goal was indeed to remove redundancy and duplication in the development and review process, such that a single data set could be generated to demonstrate the quality, safety, and efficacy of new products. During this first phase of its activities, the ICH structure and process were defined, a lot of harmonization activities started, and several guidelines/standards developed. These first harmonization discussions were directed to both technical scientific content (related to quality, safety, or efficacy topics) and to format and communication tools (development of E3 and the start of MedDRA, Electronic Standards for Transmission of Regulatory Information (ESTRI) and Common Technical Document (CTD) projects).

During these first 10 years, there was a growing interest in ICH products beyond ICH countries, and ICH recognized early that harmonization within the ICH regions would not suffice. However, during these first years, discussions and activities focused mainly on harmonization among ICH parties (even though ICH agreed to include observers as a link to the non-ICH regions) because it was important to start the process with a limited number of committed parties.

In November 2000, the 5th International Conference on Harmonization (ICH5) in San Diego, California, US marked the end of the first 10 years of ICH activity. This conference provided an opportunity to evaluate results and to identify future needs in the area of international harmonization. At the conference, results were presented of a survey on utilization of ICH guidelines confirming the positive contribution of ICH in improving the international drug regulatory approval process, thus speeding the availability of new medicines to the public.

In its statement titled "The Future of ICH" released at ICH5, the Steering Committee emphasized its intentions to focus the second phase of ICH on implementing and maintaining existing guidelines, preventing disharmony, encouraging scientific dialogue and harmonization in new areas, and undertaking efforts towards global cooperation with non-ICH regions and countries.

During its second phase, ICH continues to develop and implement tripartite guidance on specific technical requirements, and also increase its effort on the implementation of harmonized regulatory communication tools (i.e. MedDRA, CTD, ESTRI, etc.) between authorities and industry.

Indeed, one of the areas of focus of this second phase is to ensure adequate implementation and maintenance of all the guidelines developed since 1990. Today, new guidelines continue to be developed, but less frequently. These new guidelines cover important technical subjects related to pharmacovigilance (i.e., guidelines E2D, E2E, and E2F) or improvement of quality systems (i.e., guidelines Q8, Q9, and Q10). New emerging topics (such as gene therapy) have also been discussed. However, the main challenge of ICH is now to maintain and update the collection of guidelines already developed (i.e., follow the evolution of science, the experience gained, etc.).

The second focus and priority of this ICH phase has been, and continues to be, the extension of relationships with non-ICH regions. It began with the creation of the GCG as a subcommittee of the ICH Steering Committee in 1999. Since this time, ICH has developed its relationship with non-ICH regions and tried to facilitate the implementation of its standards and guidelines on a broader territory via collaboration and training. Even if some relationships existed before, the GCG has been key for this geographical extension, and its role increased over time by moving from information sharing (via preparation of brochures, presentations at international meetings, etc.) to a collaborative and proactive dialogue (via the incorporation of non-ICH regions and countries in the group). Further evolution of the ICH structure and the GCG's Terms of Reference are expected to continue to promote greater involvement of global regulators [92-1,92-2].

The first activity of ICH was to organize the ICH1 Conference in 1991, one year after its creation, in order to exchange points of view and discuss divergences among different parties involved. Since ICH1, five additional conferences have been organized (Table 1) . These regular, well-attended conferences helped communicate the results of the harmonization activities to the largest possible audience. They were designed as an open forum (in breakout sessions) to gather additional public comments and provide updates on ICH's scientific activities.

These six conferences were well attended (e.g., 2,400 participants representing industry and authorities of over 40 countries for ICH3 and 1,300 participants representing industry and authorities of over 140 countries for ICH5).

The early ICH conferences were very important in increasing visibility on the process of harmonization and for ensuring that the process was carried out in a transparent manner. ICH5 focused primarily on the finalization and completion of the CTD guideline. The last ICH conference organized, ICH6, focused on areas such as new technologies and global cooperation with regulatory harmonization initiatives outside the ICH regions. The three satellite sessions (related to "Partnerships in Harmonization," "Gene Therapy," and "MedDRA Users' Group") also confirmed the priorities of the meeting. During this conference, opportunities and new challenges for regulatory harmonization were discussed. The practical implementation of the CTD was also reviewed.

After ICH6, no additional international conferences were scheduled. ICH7 was planned to have taken place in Europe in 2007, but it was then canceled. Instead, in May 2007, the ICH Steering Committee decided to replace these large international ICH conferences with smaller and more frequent regional public meetings at the time of the ICH Steering Committee meetings in the region (in order to benefit from the presence of Steering Committee Members and ICH Experts). Now that the ICH process is well recognized, these smaller regional meetings allow for a better focus on regional issues and challenges. It also provides everyone the opportunity to meet with regulators and industry experts involved in ICH activities, to be regularly informed on recent developments, and to exchange information on different hot topics.

Following this decision, regional meetings have been organized:

▸ In Europe, the first EU regional public meeting took place in Brussels, Belgium in November 2008. ▸ In North America, the first regional public meeting took place in Washington, DC, US in October 2008. ▸ In Asia, the first regional public meeting took place in Tokyo, Japan in November 2007.

The ICH Process was first drawn up at the Steering Committee meeting in Washington, DC in March 1992, and amended in Tokyo, Japan in September 1992. Since then, the ICH procedures have been revised several times . Moreover, the new principles of governance, agreed to at the ICH Steering Committee meeting in June 2012, have revised the role of regulator and 

Suggestions for new harmonization initiatives may arise in a number of forums (ICH Regional Guideline Workshops; regional and international conferences, workshops, and symposia dealing with research and development (R&D) and regulatory affairs; recognized associations; testing and registration of medicines, etc.). From the suggestion of a new harmonization action to the development of a new guideline (or modification of an existing guideline), there are three sequential steps:

• Submission of a Concept Paper to the ICH Steering Committee by an ICH party or an Observer • Endorsement by the Steering Committee • Establishment of a Working Group

The Concept Paper is the start of all ICH harmonization activities. This document provides a short summary of the proposal (maximum two pages) and provides the information indicated below:

• Type of Harmonization Action Proposed: For example, a new harmonized tripartite guideline and recommendation, or a revision of an existing guideline (indicating the category of procedure). • Statement of the Perceived Problem: Brief description with an indication of the magnitude of the problem currently caused by a lack of harmonization, or anticipated if harmonization action is not taken. • Issues to be Resolved: A summary of the main technical and scientific issues that require harmonization. • Background to the Proposal: Further relevant information (e.g., the origin of the proposal, references to publications, and discussions in other forums). • Type of Expert Working Group: Recommendation on whether the EWG should be a six-party group (for topics related to the R&D of a new drug substance and product) or an extended EWG (e.g., GMP).

If necessary, further documentation and reports may be added to the Concept Paper. Depending on the category of harmonization activity, a Business Plan may also be required. The Business Plan outlines the costs and benefits of harmonizing the topic proposed by the Concept Paper.

Only when the ICH Steering Committee endorses a Concept Paper, and where appropriate a Business Plan, can the harmonization activity be initiated.

A preliminary determination will be made on whether the topic is of sufficient interest to all parties and can be accommodated within the ICH work schedule.

The Steering Committee takes the following points into account when discussing a Concept Paper:

• Objectives and Expected Outcome of the harmonization action • Categories of the ICH process • Composition of the EWG or IWG appointed to discuss the technical issues • Setting a Timetable and Action Plan for the EWG/IWG

The Concept Paper may need to be revised and updated to reflect the Steering Committee discussions and conclusions.

If the Steering Committee agrees that a topic may warrant further consideration and a Business Plan needs to be developed, an informal EWG/IWG will be formed and the group will work through e-mail, teleconference, and rarely, face-to-face meetings. The first tasks of the informal EWG/IWG will be to finalize a Concept Paper and develop a Business Plan. The revised Concept Paper and Business Plan will be sent prior to, and presented at, the next Steering Committee meeting.

At its meeting in Yokohama, Japan (in June 2006), the ICH Steering Committee agreed to have the final versions of the Concept Papers and Business Plans available on the ICH website, for public information.

Depending on the type of harmonization activity proposed, the ICH Steering Committee will endorse the establishment of either an EWG or an IWG.

ICH harmonization activities fall into four categories. As presented in Table 2 , these four categories cover the creation and development (stepwise progression), implementation, revision, and maintenance of guidelines. No procedure is in place for the withdrawal of existing ICH guidelines because it happens very rarely. When Guideline Q1F (Stability Data Package for Registration Applications in Climatic Zones III and IV) was withdrawn, an explanatory note was released following the endorsement of the withdrawal by the ICH Steering Committee at its meeting in Yokohama, Japan in June 2006. Withdrawal notifications were also released by the EMA, MHLW, and US FDA.

▸ The Formal ICH Procedure:

The formal ICH procedure follows a stepwise approach consisting of five steps with "decision points" at Step 2 and Step 4 that enable the Steering Committee to monitor the progress of the harmonization topics. This procedure is followed for the harmonization of all new ICH topics. A streamlined procedure is also available when necessary.

The procedure is initiated with the endorsement, by the Steering Committee, of a Concept Paper and Business Plan. An EWG with membership as specified by the Concept Paper is subsequently established.

The EWG works to develop a draft guideline and bring it through the various steps of the procedure that culminate in Step 5 and the implementation in the ICH regions of a harmonized tripartite guideline.

• Step 1: Consensus Building When the Steering Committee adopts a Concept Paper as a new topic, then the process of consensus building begins. The EWG prepares an initial consensus technical document, based on the objectives set out in the Concept Paper and in consultation with experts designated to the EWG. The initial draft and successive revisions are circulated for comments within the EWG, providing fixed deadlines for receipt of those comments. Work is conducted via e-mail, teleconferences, and web conferences. If endorsed by the Steering Committee, the EWG will also meet face-to-face at the biannual Steering Committee meetings. Interim reports on the progress of the draft are made to the Committee on a regular basis. When consensus is reached among all EWG members, the EWG signs the Step 1 Experts Signoff sheet. The Experts Document with EWG signatures is submitted to the Steering Committee to request adoption under Step 2a of the ICH process.

Step 2a is reached when the Steering Committee agrees, based on the report of the EWG, that there is sufficient scientific consensus on the technical issues for the technical document or recommendation to proceed to the next stage of regulatory consultation.This technical document is made public on the ICH website.

On the basis of the technical document, the three ICH regulatory parties take the actions they deem necessary to develop the "Draft Guideline." The consensus text approved by the three regulatory ICH parties is signed off by the three regulatory ICH parties as the Step 2b Draft Guideline.

•

Step 3: Regulatory Consultation and Discussion Regional Regulatory Consultation: At this stage, the guideline embodying the scientific consensus leaves the ICH process and becomes the subject of normal wide-ranging regulatory consultation in the three regions. In the EU it is published as a draft CHMP Guideline, in Japan it is translated and issued by the MHLW for internal and external consultation, and in the US it is published as draft guidance in the Federal Register.

Step 2 guidelines released for consultation are also available on the ICH website. DRAs and industry associations in non-ICH regions may also comment on the draft consultation documents by providing their comments to the ICH Secretariat.

After obtaining all regulatory consultation results, the EWG that organized the discussion for consensus building will be resumed. The same procedure described in

Step 1 is used to address the consultation results into the Step 2 final document.

The draft document to be generated as a result of Step 3 is called the Step 4 Draft Guideline.

The

Step 4 document with regulatory EWG signatures is submitted to the Steering Committee to request adoption as

Step 4 of the ICH process.

Step 4 is reached when the Steering Committee agrees, on the basis of the report from the regulatory chair and the regulatory rapporteur of the EWG, that there is sufficient scientific consensus on the draft guideline. This endorsement is based on the signatures from the three regulatory parties to ICH affirming that the guideline is recommended for adoption by the regulatory bodies of the three regions.

In the event that one or more parties representing industry have strong objections to the adoption of the guideline on the grounds that the revised draft departs substantially from the original consensus, or introduces new issues, the regulatory parties may agree that a revised document should be submitted for further consultation. In this case, the EWG discussion may be resumed. The

Step 4 final document is signed off on by the Steering Committee signatories for the regulatory parties of ICH as an ICH harmonized tripartite guideline at Step 4 of the ICH process.

•

Step 5: Implementation Having reached

Step 4, the harmonized tripartite guideline moves immediately to regulatory implementation, the final step of the process. This step is carried out according to the same national or regional procedures that apply to other regional regulatory guidelines and requirements in the EU, Japan, and the US. Information on the regulatory action taken and implementation dates are reported back to the Steering Committee and published by the ICH Secretariat on the ICH website.

In the EU, ICH guidelines are submitted to the CHMP for endorsement and the timeframe for implementation is established (usually six months). ICH Guidelines are available on the EMA website. In Japan, ICH texts are translated into Japanese and subsequent Pharmaceutical and Medical Safety Bureau notification for the promulgation of guidelines written in Japanese is issued with an implementation date. The notifications on guidelines in Japanese and also English attachments (ICH Texts) are available on the PMDA website. In the US, the US FDA publishes a notice with the full text of the guidance in the Federal Register.

Step 4 guidance is available for use on the date it is published in the Federal Register. They are available on the US FDA website.

▸ The Q&A Procedure: The Q&A procedure is followed when additional guidance is considered necessary to aid in the interpretation of certain ICH harmonized tripartite guidelines and ensure a smooth and consistent implementation in the ICH regions and beyond.

The Q&A Procedure is initiated with the endorsement of the Steering Committee of a Concept Paper. In the case of major implementation activities, the Steering Committee may also consider the need for a Business Plan. An IWG with membership as specified by the Concept Paper is subsequently established.

The development and adoption of the Q&A follow an established process. Questions received from stakeholders are collected, analyzed, reformulated, and ultimately used as model questions for which standard answers are developed and posted on the ICH website. The incoming questions are not answered individually, rather they serve to highlight areas that need additional clarification and are then used to develop a model question that will be answered in the Q&A document.

Based on the level of guidance given by the answers, the IWG will assess whether the Q&A document should be a Step 2b document and published for comments or a Step 4 document and published as final. The document should be Step 2b if, based on the answers provided, it sets forth substantial new interpretations of the guideline(s). The document should be a Step 4 if, based on the answers provided, it sets forth existing practices or minor changes in the interpretation or policy of the guideline(s).

The document then follows the normal path of a Step 2b/Step 4 document as per the formal ICH procedure.

The revision procedure applies when an existing adopted guideline needs to be revised or modified. It is almost identical to the formal ICH procedure (i.e., five ICH steps). The only difference is that the final outcome is a revised version of an existing guideline rather than a new guideline.

The revision of a guideline is designated by the letter R1 after the usual denomination of the guideline. When a guideline is revised more than once, the document will be named R2, R3, R4, and so on with each new revision.

The maintenance procedure is used to add standards to exist ing guidelines and/or recommendations or to provide an update based on new information. This procedure has been used to amend the addendum of Guideline S5(R2), "Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility," and Guideline M3(R1), "Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals," on November 9, 2000. It is currently applicable for changes to the Q3C Guideline on Residual Solvents, the Q4B Annexes, and M2 Recommendations. In each case, the procedure is used when there is new information to be added or when the scientific/technical content is out-of-date or no longer valid.

For the Q3C guideline, this maintenance procedure is used to revise the permitted daily exposure (PDE) as new toxicological data for solvents become available.

Since its creation, and pursuant to its main goal, ICH has released a number of guidances, each harmonizing technical requirements for registration of medicinal products. For each technical topic, the relevant EWG discussed the important question of whether there is scientific justification for the different regional requirements, and whether it would be possible to develop a mutually acceptable guidance. The objective of this scientific discussion is to reach a scientific consensus whatever the time and effort it requires [93] (and not a "compromise" that would be an unacceptable decrease of certain regional requirements without scientific justification/ basis). ICH has also worked on broader projects (e.g., MedDRA and CTD), which have been critical for the international exchange of information.

The ultimate goal of ICH activities is to remove redundancy and duplication in the development and review process such that a single set of data could be generated to demonstrate the quality, safety, and efficacy of a new medicinal product. The Steering Committee has given priority to harmonizing the technical content of the sections of the reporting data. The first ICH Guideline to deal with harmonizing the format of reporting data was E3, "Content and Format of Clinical Study Reports." This Guideline describes a single format for reporting the core clinical studies that make up the clinical section of a registration dossier.

The goal of developing a harmonized format has led to the creation of the ICH Guideline M4, "The Common Technical Document" (CTD), further described below.

At the first ICH Steering Committee meeting it was decided that the topics selected for harmonization would be divided into Safety, Quality, and Efficacy in order to reflect the three criteria that are the basis for approving and authorizing new medicinal products. Since then, ICH has created a fourth category called Multidisciplinary, which covers crosscutting topics that do not fit uniquely into one category or another. Therefore, today ICH topics are divided into four categories (Quality, Safety, Efficacy, and Multidisciplinary) and ICH topic codes are assigned according to these categories. A summary of harmonized topics is provided below. An updated list of these guidances (including their status) can also be downloaded from the ICH website (and also from the US FDA, PMDA, and EMA websites).

The guidelines under this category provide harmonization of information related to the development, manufacturing, and testing of medicines. They specifically cover stability testing (Q1), validation of analytical procedures (Q2), impurities testing (Q3), pharmacopoeial text harmonization and interchangeability (Q4), quality information on biotechnological products (Q5), specifications (test procedures and acceptance criteria) (Q6), GMP (Q7), pharmaceutical development (Q8), quality risk management (Q9), and pharmaceutical quality systems (Q10).

In addition, the ICH Steering Committee endorsed on April 11, 2008 the development of a new Q11 guidance related to the development and manufacture of drug substances (chemical entities and biotechnological/biological entities).

The guidelines under this category provide harmonization of information related to in vitro and in vivo preclinical studies. They cover all preclinical studies performed during the development of new pharmaceutical products, such as carcinogenicity studies (S1), genotoxicity studies (S2), toxicokinetics and pharmacokinetics studies (S3), toxicity studies (S4), reproductive toxicology studies (S5), pharmacology studies (S7), and immunotoxicology studies (S8). Guideline S6 specifically addresses preclinical safety evaluation for the biotechnological products. The ICH Steering Committee also endorsed on May 10, 2007 the development of a new S9 guideline that provides preclinical guidelines on oncology therapeutic development. Finally, the photosafety evaluation of pharmaceuticals was endorsed as a new topic (S10) by the ICH Steering Committee in June 2010.

The guidelines under this category provide harmonization of information pertaining to the clinical evaluation of pharmaceutical products.

Most of these guidelines relate to the assessment and management of safety data (E1 and E2 Guidelines). These guidelines cover:

• All the above Efficacy guidelines can be applied to all therapeutic classes of drugs. Until now, ICH has focused the discussion on general (i.e., nontherapeutic class-specific) guidances. However, there are, in some therapeutic classes, individual drug evaluation guidelines among the three regions. Differences between guidelines can result in obstacles to the mutual use and acceptance of clinical data. At the Steering Committee meeting in September 1998, it was agreed that this should be adopted as a new area of work for ICH, with the first such guideline being undertaken as a "pilot study" to assess the feasibility of extending work in this area. It was agreed to develop the first therapeutic class-specific guideline for antihypertensive drugs. No other guideline for clinical evaluation of a specific therapeutic category has been developed since this guideline (E12).

This category was created to include guidelines covering topics that do not fit uniquely into one of the above three categories.

In addition to the technical guidelines described in previous sections, ICH set up EWGs to harmonize Medical Terminology (M1: MedDRA), Drug Dictionaries (M5), and the format and organization of data in regulatory applications (M4: CTD) in order to ease the exchange of information. The creation of electronic standards (M2: ESTRI) was also critical for the quick exchange of common, agreed-upon data. In November 2010, the ICH Steering Committee endorsed the establishment of an EWG for the Electronic Common Technical Document (eCTD) and assigned the topic code "M8" (even though work in relation to the eCTD had previously been undertaken by the M2 EWG).

All these harmonization initiatives are critical achievements that required a lot of effort from their respective working groups. They are important activities that greatly contributed to the international harmonization of pharmaceutical regulations because they harmonized and facilitated the exchange of information between regulators and pharmaceutical companies. Due to the importance of these initiatives, each of them is detailed in the specific subsections below.

Guideline M3 covers a specific topic relating to both safety and efficacy issues. For this reason, it has been classified as a "Multidisciplinary Topic." This joint safety and efficacy guideline provides principles for nonclinical strategies (i.e., scope, timing, and duration of nonclinical safety studies) in relation to the conduct of clinical trials. It helps to reduce the differences between the ICH regions and it also provides recommendations to reduce animal use during research and development (e.g., inclusion of any in vivo evaluations as additions to general toxicity studies instead of performing separate studies). This guideline is definitively aligned with the overall ICH objectives, as its purpose is to facilitate the timely conduct of clinical trials, reduce the use of animals in accordance with the 3Rs (reduce/refine/replace) principles, and reduce the use of other drug development resources. It clearly promotes the safe and ethical development and availability of a new pharmaceutical as quickly as possible.

Finally, the ICH Steering Committee endorsed (in June 2010) the "Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk" as a new topic (M7).

MedDRA was developed by an ICH EWG in the early 1990s. It was designed to support the classification, retrieval, presentation, and communication of medical information internationally and throughout the product regulatory cycle.

Prior to MedDRA, different medical dictionaries (and also different versions of these dictionaries) were used, such as the World Health Organization Adverse Reaction Terminology (WHO-ART), the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) from the US FDA, and the Japanese Adverse Reaction Terminology (J-ART) from the MHLW. At that time, several worldwide authorities were looking for a more cost-and time-efficient way of processing suspected adverse reaction reports (e.g., the United Kingdom Medicines Control Agency [UK MCA] were developing a new system of coding called ADROIT). It became obvious that this activity should fall under the auspices of ICH.

The goal of ICH in developing MedDRA was to have an internationally recognized standard, and medically rigorous and well-maintained terminology to facilitate communication. It is indeed one of the most important ICH projects for ensuring the global exchange of clinical information. This international medical terminology is particularly important in the electronic transmission of adverse event reporting (both in the pre-and post-marketing areas), as well as in the coding of clinical trials data.

The MedDRA dictionary is a multi-axial terminology that provides a set of terms that consistently categorizes medical information. It includes terminology for symptoms, signs, diseases and diagnoses, and therapeutic indications. It is organized by System Organ Class (SOC), divided into High-Level Group Terms (HLGT), High-Level Terms (HLT), Preferred Terms (PT), and finally into Lower-Level Terms (LLT). The MedDRA dictionary has been translated into many languages.

As the terminology itself does not contain specific guidelines for its use, an ICH working group has been charged to develop two guides:

▸ "MedDRA Term Selection: Points to Consider": This document was created to achieve consistency in the way users assign particular terms to particular symptoms, signs, diseases, etc. ▸ "MedDRA Data Retrieval and Presentation: Points to Consider": This document provides guidance on retrieval and on sorting and presenting data in the most understandable and reproducible way for the benefit of drug development, pharmacovigilance, and risk management.

These two documents provide a best practice approach for the use of MedDRA. They are revised for each new MedDRA version release.

In addition, the MedDRA dictionary includes Standardized MedDRA Queries (SMQs) that were developed (in collaboration with CIOMS) to facilitate the retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development. SMQs are groupings of terms from one or more MedDRA System Organ Classes (SOCs) that relate to a defined medical condition or area of interest. They are intended to aid in case identification.

Because the terminology requires constant updating and maintenance, it was agreed that a Maintenance and Support Services Organization (MSSO) would be needed to carry out this task and to distribute the terminology, on license, to users in industry and regulatory agencies. The MSSO, contracted by ICH with technical and financial oversight by the MedDRA Management Board, is tasked to maintain, develop, and distribute Med-DRA.

Since the release of version 1.0 in 1994, MedDRA has become the accepted international standard for all worldwide regulatory activities (MedDRA is not yet mandatory in the US). As a single global, standardized medical terminology, MedDRA speeds the exchange of clinical information, facilitating research and safety monitoring, and making the regulatory approval process more efficient and responsive. Different translations of MedDRA have been released. In March/April 2008, MedDRA was also implemented in the WHO VigiBase, providing a global repository of MedDRA-coded safety data that can be used as a substantial tool for pharmacovigilance.

During a meeting on October 27-28, 2007 in Yokohama, Japan, the MedDRA Management Board announced fee reductions for lower revenue subscribers. These reductions are in keeping with the MedDRA Management Board's goal of facilitating the use of Med-DRA for all users. Since January 2007, access to MedDRA has been free for academic organizations, hospitals, healthcare providers, and other users involved in noncommercial activities.

The objective of the Electronic Standards for Transmission of Regulatory Information (ESTRI) project was to facilitate international electronic communication. To this end, an ICH Multidisciplinary Expert Working Group (called M2 EWG) was established during the ICH meeting of 1994 in Brussels, Belgium. The M2 EWG was to evaluate and recommend ESTRI that meet the requirements of the pharmaceutical companies and DRAs from the three ICH regions. Since 1994, the M2 EWG has developed the technological framework and recommended solutions for international information exchange. This was obtained by gathering requirements, assigning specific tasks, evaluating international standards and products, and recommending a functional architecture. This project included the verification of procedures for consistent, accurate information transfer, and the evaluation of encryption technologies and key certification procedures for the transfer of regulatory information. The working group has undertaken test projects to define logical electronic communication standards in order to ensure the integrity of information and data exchange between pharmaceutical companies and authorities.

To allow flexible change, some of the activities of the EWG result in recommendations that do not follow the formal ICH step process. They are agreed upon in the EWG, signed by all parties of the EWG, and are endorsed by the ICH Steering Committee at its different meetings. These recommendations, which have been modified and improved over time, provide various open international standards that allow for the international transmission of information regardless of the technical infrastructure. To facilitate the use of these recommendations, the M2 EWG has also developed a glossary for the technical terms.

Today, six M2 Recommendations are available. They cover and standardize general aspects, but also the choice of file format and information transfer as described in Table 3 . Recommendations were also prepared for the choice of physical media (i.e., floppy disks, CD-R, and DVD-RAM). Because these physical media are not relevant anymore, these recommendations were retired in June 2008.

In addition to the Recommendations, the M2 EWG also developed several specifications with regard to the electronic exchange of information:

▸ The first specification developed by the M2 EWG was related to the electronic transfer of the Individual Case Safety Report (ICSR) presented in ICH Guideline E2B (Data Elements for Transmission of Individual Case Safety Reports). Following the development of the E2B guideline, it became necessary to work on an electronic specification to guide the pharmaceutical companies on how to provide the information required by the E2B guideline. Indeed, successful electronic transmission of ICSR relies on the definition of common data elements (provided in the E2B guideline), but also a standard electronic transmission procedure. The first version of this specification was approved by the Steering Committee under

Step 2 in 1997. Since then this specification has been modified because its implementation and use had to be aligned with the evolution of the ICH E2B and M1 (MedDRA) guidelines. As a result of this activity, adverse event (AE) data can be extracted, populated, and electronically transmitted in the manner specified by the ICH ICSR message from safety and surveillance databases. Even if it has required a lot of work, the implementation of electronic reporting of ICSRs based on the ICH E2B, M1, and M2 standards progressed very rapidly across the ICH regions. Thanks to these standards, pharmaceutical companies can now exchange case reports electronically via gateway with some DRAs (such as the US FDA or EMA).

▸ The second specification developed by the M2 EWG was the Electronic Common Technical Document (eCTD) created as the electronic message for the Common Technical Document (CTD) detailed in ICH Guideline M4. This specification has since been maintained by the eCTD IWG. The eCTD specification, based on XML (Extensible Markup Language) technology, allows for the electronic submission of the CTD from applicant to regulator, taking into consideration the facilitation of the creation, review, lifecycle management, and archiving of electronic submissions. While the table of contents is consistent with the harmonized CTD, the eCTD also provides a harmonized technical solution to implementing the CTD electronically. This eCTD specification is applicable to all modules of initial registration applications and for other submissions of information throughout the lifecycle of the product, such as variations and amendments. The backbone has been developed to handle both the regional and common parts of submissions. Implementation of eCTD has begun across the ICH partner and observer regions. For example, since January 1, 2008, all electronic submissions to the US FDA are required to be in eCTD format.

▸ In 2003, the M2 EWG published the first version of the Study Tagging File (STF) specification, which is supplemental to the eCTD. This specification has since been modified several times. For each study included in Modules 4 and 5 of an eCTD submission, the STF includes information allowing for the identification of all the files associated with this specific study. This is additional information to the eCTD backbone files that already include many items, but do not contain enough information on the subject matter of several documents (e.g., study report documents) to support efficient processing and review of applications. 

The Common Technical Document (CTD) is one of the major and most well-known achievements of ICH, and like all other big harmonization projects of ICH, required much effort. It provides a harmonized structure and format for regulatory applications. The objective is to reduce the time and resources needed to compile applications for registration of medicines in the different ICH regions. Additionally, this new common format allows DRAs to have more consistent reviews, helping them to perform analysis across applications and to exchange information among them.

Before the development of the CTD, each region had its own requirements for the organization of technical reports in the submission and for the preparation of the summaries and tables. In Japan, applicants had to prepare the GAIYO, which organized and presented a summary of the technical information. In Europe, expert reports and tabulated summaries were required, and written summaries were recommended. The US FDA had specific guidelines regarding the format and content of the New Drug Application (NDA).

In 1996, the ICH industry representatives proposed assembling the information generated during the development of a product in the same order. This proposal followed an industry survey in May 1996 that assessed the time and resources needed to convert an EU Marketing Authorization Application (MAA) into a US NDA (and the reverse). This survey showed that an average of three to four months and 20 to 30 people were required for the conversion from one format to the other. With the acceptance in all three regions, the CTD now avoids the need to generate and compile different regional versions of most of the registration dossier sections.

The CTD was adopted as an ICH topic at the Steering Committee Meeting that took place just before the ICH4 meeting (July 1997). The CTD specifications reached

Step 2 of the ICH process at the Steering Committee meeting in July 2000. After public consultation, Step 4 was achieved at the ICH5 Conference in San Diego, California in November 2000. On September 12, 2002 (at the Washington, DC meeting), numbering and section headers were then edited for consistency and use in the eCTD.

The CTD consists of five modules (Module 1 is region specific, and Modules 2, 3, 4, and 5 are intended to be common for all regions):

▸ Module 1 includes administrative information (i.e., application form) and proposed prescribing information. ▸ Module 2 summarizes data included in Modules 3, 4, and 5 and is organized in seven subsections:

• CTD The CTD is defined by a general ICH Guideline (M4) and three specific technical guidelines (M4Q, M4S, and M4E, which cover the quality, safety, and efficacy parts of the CTD, respectively). A Q&A document is associated with each of these four guidelines to facilitate implementation of the CTD.

The ICH parties agreed to implement this harmonized format in the three regions by July 2003. It is indeed used today in the three ICH regions: it is mandatory in the EU and Japan, and "highly recommended" in the US (the current legislation does not allow the US FDA to make it mandatory). Moreover, this format is also used in other countries (e.g., Australia, Canada, Turkey, etc.), and derivatives of the CTD have been developed in other regions (e.g., the ACTD developed by the ASEAN countries).

This harmonized format is indeed one of the great successes of the ICH process. While the realization of the CTD took many years, there is now a common format for the regulatory submissions across the three ICH regions (Europe, Japan, and the US) and beyond. This facilitates pharmaceutical companies in making simultaneous filings in the ICH regions as it eliminates the extensive work previously required to convert from one format to another.

However, the CTD is not a "Global Dossier." It remains only a harmonization of format instead of a harmonization of content. This initial misunderstanding, certainly created by the desire of many people to accelerate the harmonization of technical requirements, led to a lot of criticism against this new format. However, the CTD cannot be a truly global identical dossier (including the same information/data/level of detail) if all technical requirements are not fully harmonized. Moreover, the submission's content may also be different for several reasons, such as different individual regulations, legal status, or requirements, and different manufacturing situations for the three regions. Indeed, although the CTD provides a common format for regulatory applications, the actual content must still meet local regulations, laws, and statutes. As a result, despite being presented in the same order, the required content of Modules 2 to 5 may vary by region. For example, the Integrated Summary of Efficacy/Integrated Summary of Safety (ISE/ ISS) that were requested by the US FDA before the implementation of the CTD are still needed. Because these integrated summaries are unique to the US, the Table of Contents of the CTD does not specifically include them. A specific US FDA guidance was released in June 2007 to help pharmaceutical companies decide where to place these US-specific ISE/ISS documents within the structure of the CTD.

To conclude, even if the CTD is "only" an agreed-upon common format for the modular presentation of summaries, reports, and data, it provides obvious advantages. The CTD allows companies and DRAs to harmonize the terms and way of communication [94] . Having the same "language" will certainly help the harmonization of content, and ultimately the harmonization of technical requirements. Indeed, regulatory reviews and communication with the applicant will be facilitated by a standard document of common elements. In addition, exchange of regulatory information between DRAs will be simplified. This increase of communication between authorities and between authorities and pharmaceutical companies will obviously facilitate expertise and opinion sharing (related to the safety, efficacy, and quality of the development product) in a timely manner that will ultimately provide benefits to patients by providing quality medicines more quickly on the market.

Like MedDRA, the objective of this project was indeed to support all aspects of pre-and post-approval pharmacovigilance activities as well as communication of regulatory information. For example, MedDRA and the harmonization of drug dictionaries are critical in the transmission of the ICSR presented in ICH guideline E2B (Data Elements for Transmission of Individual Case Safety Reports). The transmission of structured data (especially electronically) does imply the use of controlled vocabularies.

Before the ICH initiative, there was no harmonized standard to document information and data on medicinal products. Regulators in the different regions had established their own standards, which differed in data format, content, language, and applied standard terminology (e.g., terminology used for substances, routes of administration, pharmaceutical forms, etc.). The WHO Drug Dictionary, or a modified version of this product, was sometimes used. This lack of internationally harmonized standards related to core sets of medicinal product information and medicinal product terminology made the scientific evaluation, comparison, and exchange of drug data (especially in the area of pharmacovigilance) very difficult.

The activity on the M5 Guideline only began in 2003. Following the example and success of MedDRA, the ICH Steering Committee at its meeting in November 2003 agreed to launch this new harmonization initiative and to develop a new tripartite guideline that defines the Data Elements and Standards for Drug Dictionaries. During the ICH meeting in Tokyo, Japan in February 2003, WHO presented a white paper regarding the concepts of a global drug-coding dictionary. During this meeting, the Steering Committee agreed to convene an informal discussion group in Brussels, Belgium during the ICH meeting in July 2003 to allow for a discussion of this proposal. An Informal Working Group was then established to develop a Concept Paper and prepare a Business Plan.

The M5 Guideline was released for consultation at Step 2 of the ICH process on May 10, 2005, along with controlled vocabulary lists for routes of administration and units of measurement. This Guideline was subsequently submitted to the ISO for development under this process.

Step 2 Guideline was updated based upon feedback received during consultation in 2005, as well as additional considerations following its submission to ISO for development as an international standard. Key parts of this updated guideline will be incorporated into the ICH "Implementation Guide for Identification of Medicinal Products Message Specification," which is currently undergoing development as an ISO standard.

▸ Achievements So Far: For two decades, the ICH process has achieved much success and benefited both DRAs [95-1] and pharmaceutical industries . More importantly, this harmonization has been pursued in the interest of patients and public health to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness. To achieve this objective, the goal of ICH has been to promote international harmonization by bringing together representatives from the EU, Japan, and US to discuss and establish common guidelines and standards.

Through the ICH process, considerable harmonization has been achieved in the technical requirements for the registration of pharmaceuticals for human use. This is now a mature harmonization initiative. Since its creation, over 50 harmonized guidelines have been developed in the areas of quality, safety, and efficacy in order to eliminate duplication in the development and registration process. Moreover, common harmonized tools for regulatory communication (MedDRA, CTD, ESTRI) have also been made available. This represents an extraordinary contribution to the global harmonization of pharmaceutical regulations. These guidelines already form a solid basis for harmonized application of technical requirements during the registration process.

While the technical output of the ICH process has been very positive, the importance of the unique way in which ICH operates should also be noted. Indeed, in addition to the practical harmonization of specific technical items, one of the major outcomes of ICH has been to create a forum that allows experts from different countries and with different backgrounds to communicate, exchange, discuss, and share their experience and information in a structured manner. This is of course an essential first step to any harmonization.

Finally, another important achievement of ICH is to be well recognized on a worldwide basis. ICH guidelines have been adopted and are now followed outside the ICH regions (e.g., Switzerland, Canada, and Australia, and also many RHIs). Although ICH's initial focus was the development of guidelines for use in the ICH regions, increased globalization drastically modified the international cooperation environment. In response to a growing interest from beyond the ICH regions in the use of ICH guidelines, the ICH Steering Committee took the first step in March 1999 of establishing the ICH GCG. In November 2003, new terms of reference and rules were endorsed for the GCG with the aim of establishing partnerships beyond the ICH regions to promote a better understanding of ICH guidelines globally. Since then, RHIs from across the globe, but also representatives from DRAs and Departments of Health (DoH) that are either a major source of API or clinical trials data have been invited to participate in the GCG meetings and listen to technical topics at the level of the Steering Committee (at the biannual ICH meetings). In addition, as per a decision of the ICH Steering Committee in November 2010, invited RHIs and DRAs/DoH may now also nominate technical experts as active members of ICH EWGs. The implementation of ICH recommendations and standards outside the three ICH regions is indeed very important as it allows industry to better develop medicinal products for the global market.

As a consequence of this expansion to non-ICH regions, training and capacity building have become a key focus of the ICH GCG. In 2006, the GCG implemented a strategy for addressing training and capacity needs to help ensure the most effective use of resources, opportunities, and the realization of desired outcomes. Over the past few years, the GCG has responded to numerous requests for training, providing ICH expertise both for the development of training programs and for the delivery of the training itself. Today, the GCG and the ICH Steering Committee continue to implement new tools to promote a better understanding and use of ICH guidelines and recommendations 96] .

One of the drivers of this success is in the fact that this harmonization process is based on scientific consensus developed between industry and DRA experts. Before ICH, the industry and regulators never sat at the same table in an international forum to discuss the science of drug development in order to develop best practices across different regions. This joint effort allows not only for the involvement of the best experts (from both the authorities and pharmaceutical industries) in specific technical discussions, but also for ensuring that discussions take into account both the regional legislations and the practical impact on the development of pharmaceutical products. This inclusion of both industry and regulators increases commitments to the common goal (i.e., implementation of the ICH tripartite, harmonized guidelines, and recommendations) that has obviously been a key factor in the success of ICH. The results of a survey on the impact of ICH, presented during the ICH6 Conference in Osaka, Japan, showed a high degree of satisfaction by both DRAs and industry with the completed ICH guidelines, and continuous support from both sides for ICH activities.

The second driver of ICH's success is linked to its well-defined structure and process. In the beginning years of ICH, the Steering Committee organized its structure around the working groups, which included world-recognized experts. This decision was critical because it allowed ICH to have very robust scientific and technical recommendations, most of the time accepted and implemented without fundamental criticism. The Steering Committee has of course also been key as the governing body that gives direction, selects the topics for harmonization, and ensures completion of projects in a timely manner (not always easy when one's goal is consensus). In addition to the structure, the Steering Committee has also been able to define a process that supported this incredible harmonization task in a structured and organized way, supported by different players such as the ICH Secretariat and coordinators. Indeed, the stepwise approach that has been put in place for the development of guidelines (the defined five-step process with decision points at Step 2 and Step 4) has been very important. This approach allowed for the creation of comprehensive drafts by a small number of experts (the best environment for facilitating focused discussion and development of consensus) and public review before implementation (which promotes transparency, and avoids surprises and post-approval issues). The creation of Concept Papers and Business Plans that the Steering Committee put in place at a later stage are also fundamental to (1) define clear goals, and (2) help to monitor progress towards the predefined goals. Finally, the review of progress during regular meetings also ensures commitment, follow-up, and therefore the seriousness of this initiative.

Finally, the extension of ICH beyond the ICH regions was possible because the Steering Committee understood early on that its activity could not be restricted to the ICH regions with the increasing globalization of drug development and manufacture. Indeed, research and manufacture of new products is not confined to the three ICH regions any longer. Clinical trials are carried out throughout the world and many non-ICH countries are involved in the development and manufacture of pharmaceutical products. To increase transparency and promote collaboration outside ICH regions, the Steering Committee accepted observers (e.g., Canada), worked with other international organizations (EFTA and WHO), and involved other regions/countries in this process via the ICH GCG, which evolved over time. All these actions allowed the ICH work to be expanded to most of the regions/countries in the world, and its harmonization benefits to be available worldwide. The collaboration with non-ICH regions is today one of the priorities of ICH in order to increase commitment of these regions and facilitate worldwide implementation of ICH recommendations.

▸ Limitations and Challenges for the Future: As mentioned above, ICH has been an incredible contributor to the international harmonization of pharmaceutical regulations. ICH has been successful in achieving harmonization (initially of technical guidelines and then on the format and content of registration applications), and has positively impacted the global development of new drugs. All parties agree that there is a need to maintain this harmonization in the interest of the patient and public health. Now that the process and networks are in place, it seems indeed obvious that ICH needs to continue its activities as one of the major players in the international harmonization of pharmaceutical regulations. Further harmonization activities should be continued in a focused manner. However, in an evolving international environment, some aspects of this initiative need to be reviewed as new approaches may be needed. Indeed, some aspects of this initiative may be optimized in order to better handle new and future challenges.

The first challenge of ICH, which the Steering Committee has already acknowledged, is the implementation and maintenance of already developed guidelines. The current magnitude of successful harmonization actions and the need for these to remain current in a rapidly changing environment calls for focusing more effort on the implementation and monitoring of ICH commitments. Development of IWGs or task forces to manage this challenge will be key to its success. This focus on implementation and maintenance should not, however, impact the work on new harmonization topics that still need to be discussed. These new topics for harmonization need to be rigorously assessed for need (i.e., scientific merit/emerging science) and feasibility (i.e., expected outcome, timeline, and resource requirements).

Another major challenge for ICH is to confirm its worldwide expansion and to continue to develop and strengthen its collaboration and partnership outside the ICH regions in order to better integrate these regions into the ICH process. At the time of ICH establishment, it was agreed that its scope would be confined to registration of new drugs and medicines in Western Europe, Japan, and the US because the vast majority of the new drugs were developed and manufactured in these three regions. However, since then, there has been strong involvement of other parts of the world. Canada and Australia are key markets for pharmaceuticals, and are often involved in global clinical studies. More recently, the emergence of other countries has been recognized in all areas, including the pharmaceutical industry. As already recognized by the ICH Steering Committee, the success of ICH in the ICH regions only will not be relevant any longer. The modification of the landscape obliges ICH to review and broaden its objectives. The current organization (with the GCG) that initially responded to this increased globalization may not be the most appropriate solution for future stages of development. The ICH organization and systems need to be reviewed and revised to better serve these broader objectives.

In 2000 (during ICH5), the ICH Steering Committee reviewed its structure and concluded that this structure continues to be appropriate. However, in order to increase transparency, they welcomed appropriate participation of other interested parties in a flexible and ad hoc manner on topics that also affected them. A decade later, the new evolving environment requires a bigger revision of its structure and process. The ICH Steering Committee understands this urgent need and has declared that a new ICH organizational structure will be adopted. The Steering Committee will set the framework for new rules on governance, decision making, and membership [92-1].

Finally, ICH has to become more proactive in new emerging topics to prevent future disharmony. The gene therapy topic is an interesting example that demonstrates the previous lack of commitment of ICH to "proactive harmonization." In September 2002, the ICH Steering Committee established a Gene Therapy Discussion Group (GTDG) in recognition of the rapidly evolving area of gene therapy medicines. The GTDG developed several ICH consideration documents in this area. Despite this first positive step/outcome, the development of these consideration papers and the activities towards the development of a new multidisciplinary guideline (Guideline M6) was discontinued in September 2011 because "currently the ICH regions do not have the resources to support the development of further ICH consideration documents" in this domain . Recently, the ICH Steering Committee started to define a new proactive approach to identify and creatively pursue advancements in science .

If ICH succeeds in these challenges, it will certainly become a real international organization/forum (vs. a multiregional initiative) where proactive discussion on all past and new technical requirements for registration of pharmaceuticals for human use will be discussed. However, some of these challenges are not new. ICH acknowledged these challenges years ago and has already tried to resolve them without succeeding (e.g., proactivity), confirming the difficulties of this task. To face these challenges, ICH needs to revise its structure and engage a new phase in order to address the evolution of regulations and the globalization of drug development and manufacturing, and to promote better proactivity in harmonization. The ongoing ICH reform is obviously an important milestone toward resolution of current limitations.

Europe was the first major regional bloc established after World War II. Following this, there have been many regional harmonization activities throughout the world, especially over the past 30 years. Countries in different regions of the globe have organized themselves into closer economic and political entities. These movements have transformed the world, both economically and politically, as they create new opportunities and also new challenges (e.g., the management of regulations and standards disharmony).

These regional harmonization initiatives include members with closer interests and needs, compared to global initiatives, allowing further harmonization and cooperation. This level of harmonization is also essential for developing countries that may not have access to all global harmonization discussions due to sparse resources or lack of expertise. Regional cooperation can represent their interests and challenges and allow them to be heard at the global level. ii This level of cooperation is also essential for establishing region-wide pooled procurement systems.

Very diverse initiatives (each with a different scope, objective, structure, and working model) were established due to different cultural, historical, and political contexts. They range from a simple technical and scientific intergovernmental cooperation model to an advanced integration model.

ii Although all countries are part of WHO, many countries are not represented at ICH where global standards are developed. However, most of the major regional harmonization initiatives are today represented via the ICH GCG group.

The political and economic development of each region, and sometimes subregions, has indeed shaped the level of harmonization in the pharmaceutical area:

▸ Scenario 1 -Pharmaceutical harmonization in the context of an economical and political integration: In certain regions, economic integration among countries implies integration of pharmaceutical regulations and the harmonization of technical standards. This degree of integration varies from one region to another (and sometimes from one subregion/country to another), but the harmonization of regulations and policies and standards are very important to create a consistent regional legislative framework and a common certification system for products across regions. Europe is the best example in terms of advanced harmonization and integration with the development of a centralized system, institutions, and procedures for the registration of medicines to be marketed in the single market. jj ▸ Scenario 2 -Pharmaceutical harmonization in the context of a general political agreement: Other initiatives follow a general political agreement, mostly signed to avoid conflicts or wars in certain areas in the world or to facilitate economic growth and trade within a region (e.g., Asia-Pacific Economic Cooperation [APEC]), without an integration goal. The output of this harmonization initiative is variable, but most of the time does not produce a deep harmonization of pharmaceutical regulations because it is not the primary objective of the agreement and therefore the resources and efforts from the countries for this pharmaceutical regulation harmonization are variable.

▸ Scenario 3 -Pharmaceutical harmonization based on a specific intergovernmental agreement: In other regions, a simple technical and scientific intergovernmental cooperation has been established, focusing solely on the harmonization of pharmaceutical regulations. This is the case of the PANDHR initiative in the Americas where regional integration has not been the objective because countries continue to present very different systems and degrees of development, and there are no political commitments to create a single market. Countries only cooperate to promote harmonization without creating common legislation and procedure. This is a scenario that produces good harmonization of pharmaceutical regulations because this is the focus of the initiative, compared to Scenario 2 above, which is a derivative of a broader political agreement. However, the risk and difficulty of this scenario is its implementation. Because there is not an ultimate economic and political goal (e.g., developing a single market as in Scenario 1), implementation of the agreed-upon recommendations in the national law is somewhat difficult. Its success clearly depends on the commitment of each country.

It is important to understand that the scenarios discussed above can also be considered as steps. Harmonization is a moving process and harmonization initiatives evolve over time.

For example: jj This central system is supported by the national DRAs that also continue to operate their own registration systems for products limited to national markets.

• The European model was initiated to stop war between its countries (Scenario 2), but has in the time since evolved to an integration model to create further economic and political bonds ( Scenario 1). • ASEAN is another evolving initiative that may follow the European model. Today, it is between Scenario 1 and 2.

This evolution to a more integrated model is obviously easier when the members are somewhat limited in number and share common geographical, historical, and cultural roots. It is indeed very difficult to imagine that APEC or PANDRH will evolve towards integration models such as Europe or ASEAN.

The European Community was created after World War II in order to develop a more peaceful Europe by promoting cooperative projects. Since then, it has rapidly evolved to become a unique partnership between 28 European countries. The main goal of the community is the progressive integration of Member States' economic and political systems, and the establishment of a single European market based on the free movement of goods, people, money, and services.

The European Union (EU) is not a federation like the United States of America (US), nor is it simply an organization for cooperation between governments like the United Nations. It is, in fact, unique in that the countries that make up the EU (its "Member States") remain independent sovereign nations, but pool their sovereignty in order to gain a strength and world influence that none could have on their own. kk With approximately 500 million people (representing 7% of the world's population), the EU is today the world's third largest population after China and India, representing a huge single market. The EU's Gross Domestic Product (GDP) is now bigger than that of the US, and it is the world's biggest exporter and importer [98] .

Diversity is an important characteristic of the EU as symbolized by its motto, "United in Diversity," with many differences existing among its Member States. This diversity is a positive attribute of the Union. However, considering the 24 official languages and the major historic, social, cultural, and economic differences between Member States, its development has not been easy. Its diversity has also influenced its organization and the way the harmonization process has been structured. It is therefore very important to understand the history and organization of the EU in order to understand how the European pharmaceutical regulation has been structured over time. effectively alone and where cooperative action at the community level is indispensable. These include major health threats and issues with a cross border or international impact, such as pandemics and bioterrorism, as well as issues relating to free movement of goods, services, and people. Acknowledging that all countries share common values (i.e., ensure high standards of public health and equity in access to quality healthcare), it is therefore logical that the EU has developed common standards for medicines. Moreover, the implementation of a single market requires harmonization of the pharmaceutical market. The ability to travel freely, or to live and work anywhere in the EU, only makes sense if EU citizens can be sure to obtain the same level of healthcare wherever they go. Therefore, a number of European Community rules have been adopted to ensure the highest possible degree of protection of public health while promoting the free movement of medicines in an internal market without barriers. The European Commission (EC)'s role is not to mirror or duplicate national activities, but to coordinate them. Work on healthcare at the community level adds value to Member States' actions, particularly in the area of illness prevention, including activity on the safety and efficacy of medicines [99] .

Today, the European pharmaceutical system is well developed and the vast majority of requirements have been harmonized. This successful European cooperation in pharmaceuticals is also recognized on a worldwide basis due to its major contribution to the global harmonization of pharmaceutical regulations (via its active involvement in international initiatives such as ICH and WHO).

Today the EU is composed of 28 Member States, but the size of the EU has changed over time as it has continually expanded since European integration first began in 1951 with only six countries ( Table 4 ). 

The final three enlargements (in 2004, 2007, and 2013 ) expanded the EU Member States from 15 to 28, and were rooted in the collapse of communism. It was a historic advancement that offered an unexpected and unprecedented opportunity to extend the Union into Central and Eastern Europe. Today, the landmass of the EU covers 4 million km 2ll and can rightly claim to represent a continent (Plate 1). Stretching from the Atlantic Ocean to the Black Sea, it reunites Western and Eastern Europe for the first time since they were separated by the Cold War.

In the future, the EU will continue to grow as an increasing number of countries express interest in membership. The Treaty on European Union sets out the conditions for such accession (Articles 6 and 49): Any European country which respects the principles of liberty, democracy, respect for human rights and fundamental freedoms, and the rule of law may apply to become a member of the Union. The applicant country must meet a core of criteria (e.g., having stable institutions and a functioning market economy) in order to ensure that EU principles will be respected and that EU rules and procedures will be effectively implemented. This is a long and rigorous process that starts when the country submits an application to the Council. Today, Iceland, the former Yugoslav Republic of Macedonia, Montenegro, Turkey, Albania, Bosnia and Herzegovina, Kosovo, and Serbia are candidates to join the EU, some of these countries being in more advanced stages of negotiation with the EU than others.

Membership is only granted when the necessary requirements are met and when candidate countries have demonstrated that they will be able to fulfill their part as members. in the EU regulatory network. For example, the IPA program supported the participation of nominated representatives of the concerned countries in selected meetings and training courses as observers. The program also supported the organization of conferences to prepare the countries for integration into the European regulatory network for medicines. These activities helped identify areas where additional action might be needed to ensure the smooth transposition of the EU "acquis communautaire" mm into the national legislation of these future EU Member States.

▸ The Specific Case of Iceland, Liechtenstein, and Norway:

In July 2009, Iceland submitted its application for EU membership and the accession negotiations have now been opened. Norway, despite two failed attempts by referendum to enter the European Community in 1972 and the EU in 1994, remains undecided whether or not it will apply once again for EU membership. Presently, however, neither Norway nor Liechtenstein are candidates for EU membership.

However, even if these three countries are currently not part of the EU, it is important to note that they have a specific strong relationship with the Union through the European Economic Area (EEA) Agreement that entered into force on January 1, 1994. This agreement allows these three EEA European Free Trade Association (EFTA) States nn to participate in the EU internal market on the basis of their application of internal market relevant acquis. oo All new relevant Community legislation is dynamically incorporated into the Agreement and thus applies throughout the EEA, ensuring the homogeneity of the EU internal market. Also, the EEA Agreement allows for EEA-EFTA States to participate in the internal market's relevant Community programs and agencies, albeit with no right to vote.

In the pharmaceutical sector, Norway, Iceland, and Liechtenstein have adopted the complete Community acquis on medicines, and are consequently parties to the European procedures. In the case of the Centralized Procedure, the representatives from these three countries do not vote, but their position is stated separately in the opinion, where relevant, in the minutes of the Committee and in the case of divergent opinions appended to the Committee's opinion. Their position is not counted in reaching the Committee's opinion [103] . According to Decision No. 74/1999 of the EEA Joint Committee (which entered into force on January 1, 2000), when decisions on approval of medicinal products are accepted by the Community, these three countries will accept corresponding decisions on the basis of the relevant acts. The Liechtenstein authorities have transposed into their national legislation a provision that makes Commission Decisions automatically applicable on their territory. However, legally mm "Acquis communautaire" is a French term referring to the cumulative body of EU laws, comprising the EC's objectives, substantive rules, policies, and in particular, the primary and secondary legislation and case law -all of which form part of the legal order of the EU. nn The European Free Trade Association (EFTA) is an intergovernmental organization set up for the promotion of free trade and economic integration to the benefit of its four Member States: Iceland, Liechtenstein, Norway, and Switzerland. Although Switzerland has many agreements with the EU, it is today not part of the EEA Agreement due to the rejection of accession by the Swiss people. oo The EEA Agreement is concerned principally with the four fundamental pillars of the internal market, "the four freedoms" (i.e., freedom of movement of goods, persons, services, and capital).

binding acts from the Community (e.g., Commission Decisions) do not directly confer rights and obligations in Norway and Iceland, but first have to be transposed into legally binding acts in these states [104] .

Since the end of World War II, the EU has steadily become more established and organized.

The unique European model (not a federation but a more integrated than simple cooperation between governments) requires a complex organization that not only protects the independent sovereignty of the Member States, but also allows for the delegation of some of decision-making powers to shared supranational institutions. Today, the structure in place was specifically designed to represent the interests of the Community, the Member States, and the European citizens. Within this overall European structure and context, many special domains have been harmonized and organized to support the functioning of the single market.

A number of institutions, committees, and technical bodies ( Table 5 ) play a significant role in the European pharmaceutical system.

The roles and characteristics of these are briefly described in the following sections.

▸ The European Parliament is the directly elected EU institution that represents the interests of the EU's citizens. Its 766 members are elected once every five years. Its origins go back to the 1950s and the founding treaties, but the Lisbon Treaty significantly increased its role in the decision-making process and budget approval. Its legislative powers were reinforced by the extension of the co-decision procedure. Today the European Parliament is firmly established as a co-legislator, has budgetary powers, and exercises democratic control over all the European institutions. Its work is organized through a system of specialized committees that review and prepare legislative proposals and reports to be presented at the plenary assembly. The Committee on the Environment, Public Health and Food Safety is responsible for the legislation covering pharmaceutical products and the EMA. The European Parliament has three working locations: Brussels (Belgium), Luxembourg, and Strasbourg (France). Luxembourg is home to the administrative offices of the General Secretariat. Meetings of the entire Parliament, known as "plenary sessions," take place in Strasbourg and sometimes in Brussels. Committee meetings are also held in Brussels.

▸ The Council of the European Union represents the individual Member States. It meets in different configurations and is attended by one minister from each of the EU's national governments (depending on the agenda). Health-related discussions are handled by the Employment, Social Policy, Health and Consumer Affairs Council (EPSCO). As with the European Parliament, the Council was set up by the founding treaties in the 1950s. It is a key decision-making body that, among other responsibilities (e.g., coordination of the EU's economic policies and foreign and security policy) shares lawmaking and budgetary powers with the European Parliament. Its work is facilitated by the Committee of Permanent Representatives (COREPER), which is responsible for preparing the work of the Council of the European Union (all issues must pass through COREPER before they can be included in the agenda for an EU Council meeting). This committee consists of the Member States' ambassadors to the EU. These permanent national representatives and their team are located in Brussels, Belgium, and protect national interests at the EU level.

▸ The European Commission (EC) is independent of national governments as it represents and upholds the interests of the EU as a whole. It acts as the "guardian of the Treaties" but remains politically accountable to the Parliament. Like the Parliament and Council, the EC was set up in the 1950s under the EU's founding treaties. A new Commission, which is formed by a President (designated by the Member States and approved by the Parliament) and the "commissioners" (each of them responsible for a specific policy area), is appointed every five years. Its role is to draft proposals for new European laws (which are presented to the European Parliament and the Council for adoption). It is also the EU's executive arm because it is responsible for implementing the decisions of the Parliament and the Council. This means managing the day-to-day business of the EU: implementing its policies, running its programs, allocating its funds, and representing the EU in international negotiations. The day-to-day running of the Commission is done by its administrative officials, technical experts (via its various committees and groups), translators, interpreters, and secretarial staff (which represent more than 20,000 people). This staff is organized in departments, known as Directorates-General (DG), and "services" (such as the Legal Service). The overall coordination is provided by the Secretariat-General. Each DG is responsible for a particular policy area and is headed by a Director-General who is answerable to one of the commissioners. The regulation of medicinal products was previously under the DG Enterprise and Industry, but this policy area has been transferred to the DG Health and Consumers (SANCO) as of March 1, 2010. The Commission is based in Brussels (Belgium), but it also has offices in Luxembourg, representation in all EU countries, and delegations in many capital cities around the world.

This "institutional triangle" produces the policies and laws (such as European pharmaceutical legislation) that apply throughout the EU. The Court of Justice upholds the rule of these European laws and makes sure that this EU legislation is interpreted and applied in the same way in all EU countries.

The other institutions of the EU (the European Council and the Court of Auditors) are critical for the functioning of the EU, but are not directly involved with the development and harmonization of pharmaceutical legislation.

The EU institutions are supported by a number of other bodies (e.g., the European Central Bank, the European Ombudsman, etc.). Specialized agencies (e.g., the EMA, the European Centre for Disease Prevention and Control, and the Executive Agency for Health and Consumers) have also been established to handle certain technical, scientific, or management tasks. This Agency is headed by an Executive Director (who is its legal representative responsible for all operational and staffing matters) and has a staff of about 900 full-time members [107] . The Management Board is the supervisory body responsible for setting the Agency's budget, approving the annual work program, and ensuring that the Agency works effectively and cooperates successfully with partner organizations across the EU and beyond.

In addition to its staff, the EMA is composed of seven committees that conduct the main scientific work of the Agency. These committees and their characteristics are reviewed below:

• human use. The CHMP plays a vital role in the EU marketing procedures as it is responsible for: -Conducting the initial scientific assessment and issuing opinions on an MAA for medicines registered via the Centralized Procedure (these opinions are used by the EC as a basis for its legally binding decisions) -Coordinating post-marketing activities for medicines registered via the Centralized Procedure -Arbitrating disagreements between Member States during Mutual Recognition and Decentralized Procedures (Arbitration Procedure) -Acting in referral cases, initiated when there are concerns relating to the protection of public health or where other community interests are at stake (Community Referral Procedure) This Committee (and its working parties) also provides assistance to companies during development, prepares scientific and regulatory guidelines, and cooperates with international partners on the harmonization of regulatory requirements for medicines.

• The Committee for Orphan Medicinal Products (COMP), established by Regulation (EC) No 141/2000, is charged with reviewing applications from companies seeking "orphan medicinal product designation" for products they intend to develop for the diagnosis, prevention, or treatment of rare diseases (so-called "orphan drugs"). This committee is also responsible for advising the European Commission on the establishment and development of a policy on orphan medicinal products in the EU, and assists the Commission in drawing up detailed guidelines and liaising internationally on matters relating to orphan medicinal products.

• submitted by pharmaceutical companies, and to adopt opinions on these plans. This includes assessing applications for full or partial waivers and assessing applications for deferrals of pediatric studies. This Committee also assesses data generated in accordance with the agreed-upon PIPs, provides opinions on the quality, safety, or efficacy of a medicine for use in the pediatric population (at the request of the CHMP or a Member State), and supports the development of the European Network of Pediatric Research at the European Medicines Agency (Enpr-EMA). ss

• The Committee for Advanced Therapies (CAT) is a multidisciplinary committee established in accordance with Regulation (EC) No 1394/2007. It is responsible for providing scientific opinions on advanced-therapy medicinal products (ATMPs) and any scientific questions related to this field. For example, it prepares a draft opinion on each ATMP application before the CHMP adopts a final opinion on the granting, variation, suspension, or revocation of a marketing authorization for the medicine concerned.

• The Committee for Medicinal Products for Veterinary Use (CVMP) is responsible for preparing the Agency's opinions on all questions concerning veterinary medicinal products.

• The Pharmacovigilance Risk Assessment Committee (PRAC) is the last committee established by the EMA to implement the new EU pharmacovigilance legislation. It is responsible for assessing and monitoring safety issues for human medicines. This includes the detection, assessment, minimization, and communication relating to the risk of adverse reactions, while taking the therapeutic effect of the medicine into account. It also has responsibility for the design and evaluation of post-authorization safety studies and pharmacovigilance audits. Its recommendations are considered by the CHMP when it adopts opinions for centrally authorized medicines and referral procedures, and by the CMDh when it provides a recommendation on the use of a medicine in Member States.

These EMA scientific committees are comprised of members of all EU and EEA-EFTA states (Iceland, Liechtenstein, and Norway); some committees include patients' and doctors' representatives. They are supported by a number of working parties and related groups that have expertise in a particular scientific field. The Committees consult with them on scientific issues relating to their particular field of expertise and delegate to them certain tasks associated with the scientific evaluation of an MAA or drafting and revision of scientific guidance documents. In particular, the CHMP is supported by an important number of groups (i.e., the Biologics Working Party, the Scientific Advice Working Party, or the numerous scientific advisory groups specialized by therapeutic area); some are standing parties and some temporary groups. All these groups are made up of members selected from the European expert list maintained by the EMA. Indeed it is worth noting that the EMA evaluation system works through a network of European experts made available to the Agency by the national DRAs of all EU Member States and of the three EEA-EFTA States (Iceland, Liechtenstein, and Norway). This system brings together the scientific resources and expertise of all these countries in a network of over 4,500 European experts who serve as members of the Agency's scientific committees, working parties, or scientific assessment teams. The EMA is today considered as the model of fruitful cooperation between national DRAs, working together within a Community body to serve Community purposes.

Also, to ensure that the European system is accessible to everyone, in 2005 the EMA launched a dedicated office to provide special assistance to small-and medium-sized enterprises ( -For the collection, preparation, storage, distribution, and appropriate use of blood components in blood transfusions -For the transplantation of organs, tissues, and cells

The role of the EDQM is essential in Europe in facilitating mutual recognition of quality control tests carried out on medicines and ensuring that patients receive the same quality of pharmaceutical products throughout Europe.

There is a substantial amount of interaction between the EMA and the EDQM. For example, the EDQM representatives participate as observers of the EMA's Quality Working Party (QWP) and Biologics Working Party (BWP) meetings, the GMP Inspection Services Group meetings, as well as HMPC meetings at the EMA.

It is important to note that the European Member State plays a significant role in the European pharmaceutical system.

The EMA works closely with the 28 EU Member States as well as the EEA-EFTA countries (Norway, Iceland, and Liechtenstein). Member State representatives are members of the Agency's management board while the Agency's scientific committees and its network of 4,500 scientific experts are nominated by the Member States. Without their support and expertise, the EMA would be unable to deliver on its responsibilities and mandate as laid down in European legislation.

It is also important to realize that many medicines available in Europe are not authorized by the EC on the recommendation of the EMA. Many products are still approved and supervised by the national DRAs via the Mutual Recognition Procedure, the Decentralized Procedure, or National Procedure.

To coordinate their efforts, the Member States established the Heads of Medicines Agencies (HMA) group, which is a network of the heads of the national DRAs. This HMA is comprised of more than 40 national agencies, some also having responsibility for veterinary products, medical devices, and cosmetics, and also pricing and reimbursement of products. The EMA is also a member of the HMA. The first meeting of the HMA took place in Amsterdam (The Netherlands) at Schiphol Airport, on February 20, 1996.

The HMA is focused on EU coordination and harmonization, decision making, and consensus on strategic issues of the European Medicines Regulatory Network. Its aim is to foster an effective and efficient European Medicines Regulatory system. More specifically, it works towards the following key objectives [111]:

▸ Addressing key strategic issues for the European Medicines Regulatory Network, such as the exchange of information and sharing of best practices ▸ Collectively being responsible for all areas of medicines regulation, including the Mutual Recognition and Decentralized Procedures ▸ Focusing on the development, coordination, and consistency of the Network ▸ Supporting the Network by providing high-quality professional and scientific resources ▸ Providing a focus for making the most effective use of scarce resources across the Network, such as developing and overseeing arrangements for work sharing

To fulfill these objectives, the HMA has been working on both general issues (i.e., strategy for telematics, and regulatory and scientific training) and technical and scientific topics (i.e., harmonization of clinical trials, coordination of products testing, and European Risk Management Strategy) is support of the European Medicines Regulatory Network. The HMA's website contains the MRI Product Index database, which includes all medicines approved in the Member States according to the Mutual Recognition Procedure. One interesting program that has been developed is the Benchmarking of European Medicines Agencies (BEMA). The BEMA program assesses the systems and processes in individual agencies against a set of agreed-upon indicators. This is a good opportunity to exchange best practices and ensure harmonization of practices (i.e., assessment, inspection, etc.) between regulators within the Network.

Coordination among the national competent authorities is not a simple task due to the heterogeneity of these national organizations. Indeed, these authorities differ in size, historic origins, roles, resources, expertise, and funding. Acknowledging these differences and also the legal, scientific, social, political, and financial challenges facing the Network, the HMA adopted a strategic paper that provides a plan of action for 2011-2015 [112] . This second plan (the first one covered 2006-2010), highlights a number of key themes and areas of focus (i.e., pharmacovigilance, clinical trials, and communication) and also the need for international cooperation.

The HMA is supported by the Heads of Medicines Agencies Management Group, the Permanent Secretariat, and working groups covering specific areas of responsibility. Iceland, and Liechtenstein) appointed for a renewal period of three years. Observers from the European Commission and accession countries also participate in the meetings. It also has many interactions with the EMA to facilitate harmonization in several areas (i.e., pediatric regulation, variation regulation, and pharmacovigilance). It holds monthly meetings at the EMA (which also provides the Secretariat of the CMDh). In practice, approximately half of the time of the CMDh meeting is dedicated to discussions on procedural and regulatory issues, development of guidance documents, and oversight of the activities of the various CMDh subgroups and working groups, while the other half is devoted to trying to reach agreement for applications referred to the CMDh in the case of disagreement between Member States.

The gradual harmonization of pharmaceutical regulation in the EU has been dictated by the development and expansion of the community. It represents a good example of successful harmonization and also demonstrates the influence of the political and economical decisions on the harmonization process and its outcomes.

▸ The Birth of the European Union:

The historical roots of the EU lie in World War II. Following this bloody, horrific war, several leaders in Europe wanted to ensure that war could never happen again. Their goal was to develop a peaceful Europe and to stop the frequent wars via the promotion of cooperative projects. This initiative has been critical but not easily accomplished due to the post-war geopolitical situation and the beginning of the 40-year-long Cold War that split Europe into East and West.

On September 19, 1946, Winston Churchill called for a "kind of United States of Europe" in a speech given at the Zurich University. Many attempts at cooperation were made in the following years (e.g., the Customs Convention between Belgium, Luxembourg, and the Netherlands, and the Organization for European Economic Cooperation). In 1949, West European nations created the Council of Europe. uu It was a first step towards cooperation between them, but some countries wanted to go ever further.

On May 9, 1950, France's Foreign Minister Robert Schuman presented a plan for deeper cooperation and for the creation of an organized Europe, which would prove indispensable to the maintenance of long-term peaceful relations. This proposal (known as the "Schuman Declaration") is considered to be the beginning of the creation of what is now the EU. May 9 has since been designated as "Europe Day" to celebrate this event. The idea of this plan (inspired by Jean Monnet, top advisor of the French government) was to promote European peace by (1) eliminating the age-old opposition of France and Germany, and (2) creating a framework and organization open to the participation of the other countries in Europe. It proposed that the Franco-German production of coal and steel be placed under a common high authority and that this new productive unit be open to all European countries willing to participate. The double objectives of this proposal were (1) to set up common foundations for economic development as a first step in the federation of Europe, and (2) to make war materially impossible [113] .

Based on the Schuman plan, six countries (Germany, France, Italy, The Netherlands, Belgium, and Luxembourg) signed the Treaty of Paris on April 18, 1951 to establish the European Coal and Steel Community (ECSC) in order to run their coal and steel industries under a common management. It is important to note that the independence and the powers of the high authority have been critical, and differentiated the EU from other traditional intergovernmental organizations. Indeed, the establishment of the ECSC was the first step towards a supranational Europe. For the first time the six Member States of this organization relinquished part of their sovereignty, albeit in a limited domain, in favor of the European Community.

Building on the success of their first treaty, the six countries decided to expand cooperation to other economic sectors. On March 25, 1957, under Belgian Minister for Foreign Affairs, Paul-Henry Spaak, they signed the Treaty of Rome, establishing the European Economic Community (EEC) (or "common market") allowing persons, goods, services, and capital to move freely across borders. The same day, they also signed a second treaty to create the European Atomic Energy Community (EURATOM).

Despite the construction of the Berlin Wall in August 1961, which increased the division between the East and the West, the cooperation between European countries continued to increase in different areas (e.g., food and agriculture, aerial navigation, the environment, etc.). On July 1, 1968, the six countries created the world's largest trading group by removing customs duties on goods imported from each of the six countries to the others, allowing free cross-border trade for the first time. They also applied the same duties on their imports from outside countries. This EU Internal Market was reinforced in 1986 with the adoption of the "Single European Act" (which entered into force on July 1, 1987) to remove the final obstacles. In 1993, the single market and its four freedoms (movement of goods, services, people, and money) had finally been fully established. Additional agreements, such as the Schengen Agreement in 1995, have since been signed to further facilitate movement within Europe. Today, this single market represents the core of the EU.

In 1991, following the collapse of communism across Central and Eastern Europe and the dissolution of the Pacte de Varsovie, a decade began that would be critical for the future of Europe. On December 13, 1997, EU leaders agreed to start the process of membership negotiations with 10 countries of Central and Eastern Europe (Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, and Slovenia). The Mediterranean islands of Cyprus and Malta were also included. In December 2000, treaty changes agreed to in Nice (France) and finally signed on February 26, 2001 were entered into force on February 1, 2003 and opened the way for enlargement of the EU by reforming its institutions and voting rules. This enlargement to the Eastern European countries became effective on May 1, 2004 and January 1, 2007. Six years later, on July 1, 2013, the accession of Croatia brought the number of Member States to 28 countries.

A single currency (Euro [€]) was introduced on January 1, 1999 in 11 countries (joined by Greece in 2001) for commercial and financial transactions only. Notes and coins were introduced in January 2002. This introduction of the single currency followed a long stepwise process that started in the 1970s with the creation of the "Exchange Rate Mechanism" to maintain monetary stability.

The next important step of integration (i.e., development of a political union with fully functioning institutions) took time and faced many challenges. The debate on the "constitutionalization" of Europe started in 1984 when the European Parliament adopted Altiero Spinelli's report proposing, in a "draft treaty on European Union," a fundamental reform of the European Community.

In the 1990s, two important treaties transformed the community:

▸ The Treaty on European Union (signed in Maastricht [The Netherlands] on February 7, 1992, entered into force on November 1, 1993) represented a new stage in European integration as it opened the way to political integration. It was a major EU milestone, introducing the concept of European citizenship and setting clear rules for the future single currency and for foreign and security policy. Under the treaty, the name "European Union" officially replaced "European Community." ▸ The Treaty of Amsterdam (signed on October 2, 1997, entered into force on May 1, 1999), built on the achievements of the treaty from Maastricht, laid down plans to reform EU institutions, gave Europe a stronger voice in the world, and concentrated more resources on employment and the rights of EU citizens.

Building on this transformation of the Community, the adoption of a European constitution and major institutional reform became an important topic of discussion for two reasons: ▸ Succeeding treaties have spurred progress in the building and reforming of Europe and its institutions. This long process marked by ever-closer integration progressively transformed Europe from an economic community to a political union. ▸ The combination of the various treaties and protocols signed over 50 years has made the European structure and legislation more and more complex. Although the EU will certainly continue to grow, it is difficult to predict the next steps of integration due to the current geopolitical situation and the instability caused by the financial crisis.

The evolution of pharmaceutical regulation harmonization and cooperation in Europe represents an excellent example and model that needs to be analyzed in detail as it shows the different important steps necessary for harmonization success.

A large body of legislation has been developed, with progressive harmonization requirements since the 1960s.

The first European Directive related to pharmaceutical products (Directive 65/65/EEC [114]) was signed on January 26, 1965. This text provides the European definitions of a "Medicinal Product" and a "Substance" and set up some fundamental principles for the creation of the European pharmaceutical system such as: ▸ No medicine may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities following the review of an application submitted by the person responsible for placing that product on the market. ▸ Quality, safety, and efficacy are the basis for the evaluation of an application by the competent authorities. ▸ The information included in the application should be updated on a regular basis.

Following this first Directive, many texts followed over the years to further detail the European principles and requirements led by Directive 65/65/EEC, to organize and structure the European system, and to add new requirements related to specific types of products or emerging problems. Major texts and important steps in the development of the European pharmaceutical system are discussed below. However, it is important to note that many other legislative texts, guidelines, and other recommendations (including harmonized quality, and nonclinical and clinical requirements) have been prepared and released over the years to support the major legislatives texts listed in this section.

Directive 65/65/EEC was complemented by two additional Directives (Directives 75/318/EEC and 75/319/EEC) in May 1975 to provide further details on the analytical, nonclinical, and clinical standards and protocols to be applied during the development of medicines, and how the results of such studies should be presented in the MAA. Directive 75/319/EEC also established the idea of Expert Reports (that would later influence the structure of the CTD), the CPMP (that would later be part of the EMA), and the first Multi-State Licensing Procedure, which would then evolve progressively to become the current Mutual Recognition Procedure (MRP).

Further clarification of requirements was provided by Directive 83/570/EEC (which also modified the Multi-State Licensing Procedure to facilitate its use), and Directive 87/21/ EEC (which established the notion of combination products and created a route for abridged applications in case of generics and literature-based applications).

In 1987, Directive 87/22/EEC established the Concertation Procedure, which provided a simple community-wide licensing opinion (via a mandatory referral to the CPMP) for all new biotechnology products and optionally for high technology medicinal products [115] . It was an important new step in building the European pharmaceutical system as this new procedure (the forerunner of the current Centralized Procedure) required further cooperation between National DRAs compared to the Multi-State Licensing Procedure previously established. However, both procedures were still based on voluntary cooperation between the relevant national authorities, and each Member State remained solely responsible for granting the Marketing Authorization.

In 1989, legislators extended the scope of the previous Directives to specific types of products: vaccines, toxins or serums, and allergens (Directive 89/342/EEC); radiopharmaceuticals (Directive 89/343/EEC); and products derived from human blood or human plasma (Directive 89/381/EEC). Additionally, on April 23, 1990, Directive 90/219/EEC laid down the first common measures related to genetically modified organisms (GMOs); several additional texts have since then been released on this topic over the years. Finally, extension of the scope of the harmonization of homeopathic products was only made in 1992 via the adoption of Directive 92/73/EEC.

In 1991, Directive 91/356/EEC, which laid down the principles and guidelines of GMP, was adopted.

In 1992, four new Directives covering the distribution of medicines were adopted to further establish the EU Internal Market and facilitate the free movement of products. They especially harmonized wholesale distribution (Directive 92/25/EEC), the classification of products as subject to medical prescription or not (Directive 92/26/EEC), the labeling of products (Directive 92/27/EEC), and advertising principles (Directive 92/28/EEC).

Despite all these texts adopted since 1965, the resulting progress of completing the single market in pharmaceuticals was not satisfactory. It was therefore decided to fundamentally improve the authorization procedures. A new European pharmaceutical system was then created in 1993 (but only implemented in January 1995). This new system, still in place today, is based on two major texts that established, for the first time, "European decisions" binding to the Member States:

▸ Following the adoption of these European procedures, it was necessary to harmonize the system to vary the terms of marketing authorization. This was done via the adoption of two Regulations in 1995: Regulation 541/95 (for the MRP) and Regulation 542/95 (for the Centralized Procedure).

Additionally, acknowledging the increased complexity of the European pharmaceutical legislation, it was agreed to assemble all previous Directives in one single text. This codifying Directive, Directive 2001/83/EC adopted on November 6, 2001, was necessary because all the Directives adopted since 1965 had been frequently and substantially amended. Therefore, this Directive regroups all legal requirements agreed-upon since 1965 (except requirements and legal provisions provided by Regulation 2309/93). This new Directive has already been amended several times since its adoption, some of these amendments being the result of a major general review of the legislation and system discussed below.

In 2000, as directed by Regulation 2309/93 (Article 71), the Commission conducted a major review of the operation of the new system implemented in 1995. The goal of this audit, contracted out to independent auditors, was to review the extent to which the results achieved over the first five years have met the objectives (namely to enhance the creation of a single market in medicinal products, while ensuring the protection of public health and the development of the pharmaceutical industry). The audit report [116] , known as the "Cameron McKenna Andersen Report," includes the results of the extensive consultation carried out involving individual companies, all DRAs responsible for the authorization of medicines and the EMEA, patient and professional associations, trade associations, and relevant ministries.

This audit highlighted the overall satisfaction with this new system, as both procedures had been perceived as contributors in both a qualitative and quantitative way to create a harmonized European Community pharmaceutical market. Ninety-two percent (92%) of companies and 97% of DRAs in the EU were satisfied or very satisfied with the Centralized Procedure. There was also general recognition of the very considerable contribution made by the EMEA and the EU telematics strategy to the successful operation of the system. However, this report also identified several issues and listed several possible improvements to the system. These criticisms were primarily directed towards the MPR for which it was agreed that the lack of real supervisory, management support, and liaison between Member States had altered the application of the central principle of mutual recognition. Concerned Member States were continuing to assess applications. Regarding the Centralized Procedure, it was felt that it should be opened up to a broader range of products and that the "decision-making process" of the Commission (post-CPMP opinion) should be reduced and improved. Finally, it was also interesting to note that the European procedures had not yet produced any real dividends in terms of cost efficiencies through economy of scale. There was also a need to reduce the administrative burden where there were no public health implications (e.g., in relation to minor variations to existing approvals).

This evaluation of the regulatory processes was not only very timely with the emerging technical challenges (e.g., gene therapies, etc.), but also with the political challenges in preparation for EU expansion [117] . Indeed, there was little doubt that the upcoming major enlargement of the EU (in 2004, and involving 10 additional countries) would accentuate the weaknesses of the system if both the structural and process issues were not resolved by then.

Based on this review of the EU pharmaceutical legislation and various public hearings, the EC concluded that on the whole the system had proven appropriate and suitable for its purpose and therefore it was recommended that it keep its main principles and structures. However, the EC also proposed several adaptations of the system and legislation in order to better achieve four major objectives [118]: ▸ Assure a high level of public health protection, notably by increased supervision of the market through the strengthening of inspection procedures and of pharmacovigilance. ▸ Complete the single market for pharmaceutical products, taking into account the stakes of globalization, and establish a regulatory and legislative framework that favors the competitiveness of European industry. ▸ Respond to the challenges of the future enlargement of the EU. ▸ Rationalize and simplify the system and improve its overall coherence and visibility and the transparency of its procedures.

These proposals, such as opening up the Centralized Procedure to a broader range of products, establishment of a fast track procedure and conditional authorization, improvement of the transparency of the system, strengthening pharmacovigilance and supervision requirements, abolition of the renewal, control of the effective use of marketing authorization with the "Sunset Clause," improvement of the decision-making process after CPMP opinion, re-organization and increase of the role of the EMEA and its committees, major modifications to the MRP and creation of the Decentralized Procedure, and harmonization of data protection periods [119,120], have been further debated with the Parliament and the Council over subsequent years. Most of them have finally been implemented via the adoption of new or revised legislation and/or guidelines. One of the major legislative impacts has been the adoption of Regulation ( Finally, in addition to these critical texts that created the European system and general requirements, it is worth mentioning the following additional legislative texts adopted over the past 10 years on important specific subjects (see Part I-2. 

The current European pharmaceutical system has progressively developed over the years via the adoption of agreed-upon policies. Since 1985 many texts have been adopted with the aim of achieving a single market for pharmaceutical products. As noted above, several European institutions and technical bodies, together with the EU Member States, are involved in the harmonization of European pharmaceutical regulation.

The European harmonization process lies in the adoption of EU laws [121] that can be categorized as follows:

▸ The "primary" legislation: The Treaties are binding agreements between EU member countries. They state EU objectives, rules for EU institutions, how decisions are made, and the relationship between the EU and its Member States. They also form the basis or ground rules for all EU actions. This means that every action taken by the EU is founded on treaties that have been approved voluntarily and democratically by all EU member countries. For example, if a policy area is not cited in a Treaty, a law cannot be proposed in that area.

▸ The "secondary" legislation: This is derived from the principles and objectives set out in the Treaties. It includes the following texts:

• Regulations are the most direct form of EU law. As soon as they are passed, they have binding legal force throughout every Member State and must be applied in its entirety across the EU. National governments do not have to take action themselves to implement EU regulations (i.e., regulations do not require any transposition by the national authorities). • Directives are legislative acts that set out a goal that all EU countries must achieve.

National authorities have to adapt their laws to meet these goals, but are free to decide how to do so. vv Directives are used to bring different national laws in line with each other, and are particularly common in matters affecting the operation of the single market (e.g., product safety standards). They may concern one or more Member States, or all of them. • Decisions are individual acts relating to specific cases and are addressed to specific parties. They are binding only on those to whom they are addressed (e.g., an EU country or an individual company), and are directly applicable (no need for implementation into national law). Decisions can come from the EU Council (sometimes jointly with the European Parliament) or the EC.

vv Each directive specifies the date by which the national laws must be adapted (giving national authorities room to maneuver within the deadlines necessary to take account of differing national situations).

• Recommendations are not binding, but allow the institutions to make their views known and to suggest a line of action (without imposing any legal obligation on those to whom it is addressed). • Opinions are not binding. They are an instrument that allows the institutions to make a statement in a nonbinding fashion; in other words, without imposing any legal obligation on those to whom it is addressed. They can be issued by the main EU institutions (Commission, Council, Parliament), the Committee of the Regions, and the European Economic and Social Committee.

The European Parliament and the Council of the EU share legislative power, which means they are empowered to adopt European laws (directives and regulations). In principle, it is the Commission that proposes new "legislative texts," ww but it is the Parliament and Council that adopt them. The Commission and the Member States then implement them, and the Commission ensures that the laws are correctly applied.

The vast majority of European laws are adopted jointly by the European Parliament and the Council using a procedure known as "co-decision." xx This means that the directly elected European Parliament has to approve EU legislation together with the Council (the governments of the 28 EU countries). In addition to this "ordinary legislative procedure," there are also other special legislative procedures (which apply only in specific cases) where the Parliament has only a consultative role.

The requirements and procedures for the marketing authorization of medicinal products, as well as the rules for variations to the terms of marketing authorizations and for the constant supervision of products after they have been authorized, are primarily laid down in Directive 2001/83/EC and Regulation (EC) No 726/2004 (and their subsequent amendments). These texts additionally lay down harmonized provisions in related areas such as the manufacturing, wholesaling, or advertising of medicinal products for human use. In addition, various laws have been adopted to address the particularities of certain types of medicinal products and promote research in specific areas.

In addition to the legal texts, many additional Community or international documents and recommendations have been developed and support the harmonization and cooperation in the EU. The "Introduction and General Principles" of Annex 1 of Directive 2001/83/EC, as ww The European Commission is the only institution empowered to initiate legislation. Before proposing a new text, it assesses the potential economic, social, and environmental consequences that they may have by preparing "impact assessments" (which set out the advantages and disadvantages of possible policy options) and by consulting interested parties. The Commission will propose action at the EU level only if it considers that a problem cannot be solved more efficiently by national, regional, or local action. This principle of dealing with things at the lowest possible level is called the "subsidiarity principle," and has been reaffirmed in the Lisbon Treaty. xx The co-decision procedure was introduced by the Maastricht Treaty on European Union (1992) , and strengthened and made more effective by the Amsterdam Treaty (1999) . With the Lisbon Treaty that took effect on December 1, 2009, this procedure has been renamed "ordinary legislative procedure" and has become the main legislative procedure of the EU's decision-making system. amended, acknowledged these scientific and technical recommendations (i.e., "The rules governing medicinal products in the European Community," ICH guidelines, and monographs of the European Pharmacopoeia).

All Community rules in the area of medicinal products for human (and veterinary) use are compiled in "The Rules Governing Medicinal Products in the European Union" (EudraLex), published by the EC. Volume 1 of this publication contains the body of the EU pharmaceutical legislation (i.e., Regulations, Directives, Decisions, etc.). The subsequent volumes include guidelines yy developed to support this basic legislation: zz ▸ Volume 2 (also known as "Notice to Applicants"), first published in 1986, contains all regulatory guidelines related to procedural and regulatory requirements (i.e., the presentation and content of the dossiers), and also the application forms. It was prepared and is regularly updated by the European Commission in consultation with competent authorities of the Member States and the EMA. This Notice has no legal power. In case of doubt, therefore, reference should be made to the appropriate Community Directives and Regulations. Also, in July 2012, the information contained in Chapter 7 of Volume 2A (concerning general information on procedures for marketing authorization) was transferred to EMA and CMDh websites. ▸ Volume 3 consists of all the scientific guidelines for medicinal products for human use prepared by the Committee for Medicinal Products for Human Use (CHMP) in consultation with the competent authorities of the EU Member States. The guidelines are intended to provide a basis for practical harmonization in the manner in which the EU Member States and the EMA interpret and apply the detailed requirements for the demonstration of quality, safety, and efficacy contained in the Community Directives. An updated list of scientific guidelines is accessible on the EMA website. ▸ Volume 4 contains guidance for the interpretation of the principles of GMPs for medicinal products for human and veterinary use. ▸ Volume 9 contained pharmacovigilance guidelines for medicinal products for both human use (Volume 9A) and veterinary use (Volume 9B). Volume 9A was replaced by the EMA "Guidelines on Good Pharmacovigilance Practice (GVP)" in 2012 [122] . ▸ Volume 10 contains guidance documents applying to clinical trials.

Finally, in addition to the published rules listed above, a lot of other documents that do not have the status of a law or guideline (i.e., questions and answers [Q&A], recommendations, public statements, position papers, reflection papers, etc.) are released by the EMA to provide additional guidance. Moreover, templates (e.g., assessment templates and guidance), internal standard operating procedures (SOPs), work instructions (WINs), and policy covering both general and specific topics (e.g., pharmacovigilance, inspection, etc.) have been developed by the EMA to improve consistency in activities and evaluations and to help ease the exchange of information.

Many technical requirements have been harmonized and published in Europe to ensure that medicinal products throughout Europe are of equal quality, safe, and efficacious. These are the three basic criteria that are always evaluated and taken into consideration when establishing the risk and benefit ratio. These criteria are evaluated through the quality, nonclinical, and clinical information included in all applications. Of course, the level of quality/nonclinical/clinical documentation varies depending upon the type of products and the level of development, but they are always the basis of approval for the registration of a clinical trial or a new product.

Legal provisions related to these technical requirements are included in Annex 1 of Directive 2001/83/EC and other relevant Regulations or Directives. In addition, scientific and technical guidelines are also prepared by the EMA's Committees (i.e. CHMP, COMP, PDCO, etc.) and its Working Parties (in consultation with the competent authorities of the EU Member States). Guidelines developed by other technical bodies (e.g., the European Pharmacopoeia) or international bodies are also used in Europe. For example, Europe is a founder and member of ICH, and therefore all ICH guidelines are also applicable in Europe.

▸ Quality: Many European requirements are in place regarding the quality of the products (active substance, excipients, and finished products). Detailed scientific guidelines have been developed to adequately cover pharmaceutical development, manufacture, packaging, control (i.e., specifications, analytical procedures and validation, and impurities), stability evaluation, and post-approval changes. Moreover, guidelines for certain types of products (i.e., biologics, radiopharmaceuticals, medicinal gases, or herbal medicinal products) have been specifically released to take into account their specific challenges.

These technical and scientific guidelines, together with the Q&A document, provide a common interpretation of the European legislation and ensure harmonization of quality requirements. Also, in addition to these guidelines, it is worth mentioning two other publications that have been critical in the harmonization of the quality aspect of medicinal products available on the European market:

• Good Manufacturing Practice (GMP) is one of the most important harmonized requirements that have been issued. As per Directive 2001/83/EC and Directive 2001/20/EC, all products (including investigational medicinal products) have to comply with the principles and guidelines of GMP. These GMP principles are laid down in Directive 2003/94/EC. In addition, the EC has published detailed GMP guidelines in line with those principles in EudraLex (Volume 4). This volume covers both the basic requirements for Medicinal Products (Part I) and for Active Substances used as Starting Materials (Part II). Particular considerations and conditions for specific products (biological products, radiopharmaceuticals, medicinal gases, products derived from human blood or plasma, herbal medicinal products, excipients, etc.) are also in place or under discussion. Under this EU system, manufacturers and importers of medicines located in the EEA are subject to a manufacturing authorization and come under the supervision of the competent authorities of the Member States (the Supervisory Authorities), who are responsible for issuing the authorizations for those activities taking place in their territories.

• The European Pharmacopoeia (EP), established on July 22, 1964 by eight countries, aaa is a collection of standardized specifications, so-called monographs, which define the quality reference standard for medicines. Today, the Convention has been ratified by more than 35 European countries and the EU. European Directive 2001/83/EC refers to the mandatory character of EP monographs in the preparation of dossiers for MAA in the EU. The EP is also applicable in all the signatory states of the Convention for the elaboration of an EP, and is used as a reference by many other countries (there are more than 20 Observers). The EP is published by the EDQM and covers active substances, excipients, substances or preparations for pharmaceutical use of chemical, animal, human or herbal origin, homoeopathic preparations and stocks, antibiotics, as well as dosage forms and containers. The texts of the European Pharmacopoeia also apply to biologicals, blood and plasma derivatives, vaccines, and radiopharmaceutical preparations.

▸ Nonclinical: All aspects of nonclinical testing and programs are covered under general guidelines (e.g., GLP) bbb or discussions on nonclinical strategies to identify and mitigate risks for first-in-human clinical trials or guidelines specific to a type of testing (i.e., pharmacology, aaa Belgium, France, Germany, Italy, Luxembourg, the Netherlands, Switzerland, and the United Kingdom. bbb The principles of Good Laboratory Practice define a set of rules and criteria for a quality system concerned with the organizational process and the conditions under which nonclinical health and environmental safety studies are planned, performed, monitored, recorded, reported, and archived. pharmacokinetics, single and repeat dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance). Most of these guidelines have in fact been developed under the auspices of ICH.

As for the quality requirements, specific nonclinical guidelines have also been developed for certain types of products.

Numerous clinical guidelines are available, which cover all phases of clinical development, from early on (i.e., clinical pharmacology and pharmacokinetics studies) to the design of Phase 3 studies (disease and patient characteristics, advice on selection of endpoint, duration, control groups, and choice of comparator, etc.). Due to the specificities of each group of products, guidelines have been organized by therapeutic area, and some focus on certain types of products (herbal medicinal products or radiopharmaceuticals and diagnostic agents). Additionally, general guidelines have also been released to provide advice on general considerations and topics during drug development that are not disease-specific (e.g., "Guideline on Missing Data in Confirmatory Clinical Trials," "Extrapolation of Results from Clinical Studies Conducted Outside Europe to the EU Population," "Clinical Trials in Small Populations," "Data Monitoring Committee," "Choice of a Non-Inferiority Margin," and "Excipients in the Label and Package Leaflet of Medicinal Products for Human Use").

In addition to these numerous scientific guidelines, it is worth mentioning the development and implementation of GCP in Europe for investigational medicinal products. This harmonization of GCP has been critical for the recognition of data between European countries, and therefore cooperation on clinical aspects of drug development. Directive 2001/20/EC is the framework legislation that provides for additional directives, accompanying guidelines, and detailed guidance documents. These guidelines and guidance documents are published in EudraLex (Volume 10).

Finally, it is important to note that there has been a lot of effort put forth in past years regarding harmonization of the European pharmacovigilance system. This system is coordinated by the EMA, but also involves national competent authorities ccc and the European Commission. It includes a broad range of activities such as the review of Risk Management Plans (RMPs) and PSURs, the development and maintenance of the EU reporting and data warehouse system for case reports (EudraVigilance), signal-identification activities in the EU, and the coordination of EU rapid alert and incident management systems for timely and adequate responses to new safety data.

The EU legal framework of pharmacovigilance was provided in Regulation (EC) 726/2004 and Directive 2001/83/EC. Additionally, relevant ICH guidelines have been implemented, and Volume 9 of EudraLex has been dedicated to this key public health function. It included a number of detailed guidelines, definitions, standards, and information regarding the precise execution of pharmacovigilance-related procedures.

ccc In some Member States, regional centers are in place under the coordination of the national competent authority.

In December 2008, following a public consultation, the EC decided to further harmonize the system (to ensure it is optimally effective, robust, and transparent) via the adoption of two additional texts [123, 124] . The final new legislation [125] was finally published on December 31, in the Official Journal of the European Union. On June 19, 2012, the Commission Implementing Regulation (EU) 520/2012 was adopted, complementing the 2010 pharmacovigilance legislation that started to apply in July 2012. Finally, some pharmacovigilance incidents in the Union have shown the need for further improvements of the 2010 legislation. These issues have been addressed by Directive 2012/26/EU and Regulation No 2012/1027/EU, which started to apply in 2013.

Due to the number and importance of improvements that need to be implemented [126, 127] , many observers consider this new pharmacovigilance legislation as the biggest change to the EU legal framework since the creation of the EMA in 1995.

The implementation of this new pharmacovigilance legislation required a lot of effort from the EMA [128]. This was a major activity because several processes needed to be established or amended (e.g., the establishment of a new Pharmacovigilance Risk Assessment Committee [PRAC] replacing the CHMP Pharmacovigilance Working Party). Also, an important change of the new legislation is the increased direct involvement of the EMA in the pharmacovigilance of nationally authorized products, in addition to the centrally authorized products. For example, the EMA has released the "Guidelines on Good Pharmacovigilance Practice (GVP)", which replace Volume 9 of EudraLex [129] . This new set of guidelines applies to all medicines authorized in the EU, whether centrally or nationally authorized.

The EMA is also working with other groups to continuously improve the safety monitoring of medicines. This includes its central coordinating role in PROTECT, ddd its support of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), eee its work with the US FDA on AE signal detection activities, and its notifications to the WHO of any measures taken in the EU on medicines that may have a bearing on public health protection in third-world countries.

Finally, the Heads of Medicines Agencies have also put in place a multi-annual program (called the European Risk Management Strategy [ERMS] ) which aims to strengthen European pharmacovigilance systems by putting in place efficient measures allowing for the early detection, assessment, minimization, and communication of a medicine's risk throughout its lifecycle.

These guidelines apply to more than one specific area and have been prepared through the collaboration of several working parties. They provide advice and guidance on specific ddd PROTECT is a project of the Innovative Medicines Initiative (IMI), which is aimed at strengthening the monitoring of the benefits and risks of medicines in Europe by developing innovative tools and methods that will enhance the early detection and assessment of adverse reactions. eee ENCePP is a network that supports independent, post-authorization studies on the safety and benefit/risk aspects of specific medicines.

important topics (i.e., pediatrics, cell therapy and tissue engineering, vaccines, biosimilars, gene therapy, and pharmacogenomics).

The EU harmonization activities related to certain of these topics are further discussed in the following sections.

It is also important to note that cooperation in the areas of inspection (e.g., GMP, GLP, GCP, or PhV) is critical. Although the responsibility for carrying out inspections rests with the national competent authorities of Member States, the coordination of these inspections by the EMA (and the agreement of common standards) has been an important step that allows for:

• Increased cooperation between Member States • Reduced duplication of work (due to the recognition of inspections performed by other Member States) • Ensuring the same level of quality of medicinal products, and the data generated during their development, wherever the location of the manufacturing site or studies

A European system for the authorization of medicinal products has been created with the objective of ensuring that safe, effective, and high-quality medicines can quickly be made available to all citizens across the EU.

Today, the European system offers several routes for the authorization of medicinal products:

▸ The Centralized Procedure (laid down in Regulation (EC) No 726/2004) is compulsory for certain types of products: products derived from biotechnology processes, advanced therapy medicines, orphan medicines, or products intended for the treatment of certain specific diseases. For medicines that do not fall within these categories (the "mandatory scope"), companies can also submit an application if the medicinal product constitutes a significant therapeutic, scientific, or technical innovation, or if it is in any other respect in the interest of public health. Applications for the Centralized Procedure are made directly to the EMA and lead to European marketing authorization. This authorization, binding in all Member States, is granted by the EC (based on the opinion of the relevant EMA committee). It is valid for the entire Community market, which means the medicines may be put on the market in all Member States. This is the ultimate integration model in this domain because there is a single application, a single evaluation, and a single authorization allowing direct access to the single market of the Community.

▸ The Mutual Recognition Procedure (MRP) (laid down in Directive 2001/83/EC), applicable to the majority of conventional medicinal products, is based on the principle of recognition of an already existing national marketing authorization by one or more Member States. Should any Member State refuse to recognize the original national authorization on the grounds of potential serious risk to public health, the issue is referred to the CMDh to find a consensus. In that case, the CMDh uses its best efforts to reach an agreement on the action to be taken (within the 60-day time period foreseen in the legislation). When this fails, the matter is then referred to the EMA/CHMP for arbitration (see below for details). At the end of the MRP and Decentralized Procedure, national marketing authorizations are granted in the Member States involved, whereas the Centralized Procedure results in a single marketing authorization (called a "Community marketing authorization") that is valid across the EU, as well as in the EEA-EFTA states (Iceland, Liechtenstein, and Norway). Purely national authorizations are still available, but are limited to medicinal products to be marketed in one Member State only.

In addition to the above registration procedures, another European procedure called "referral" has been established. This Community Referral Procedure is used to resolve disagreements (e.g. between Member States during an MRP or a Decentralized Procedure), address specific concerns relating to the safety or efficacy of a medicine or a class of medicines, or when there is a need to harmonize national decisions across the EU. In a Referral Procedure, the EMA is requested to conduct, on behalf of the European Community, a scientific assessment of a particular medicine or class of medicines. The problem is "referred" to the CHMP so that the Committee can make a recommendation for a harmonized position across the EU. Referral Procedures can be started by the EC, any Member State, or by the pharmaceutical company. At the end of the referral, the Committee makes a recommendation, and the European Commission issues a decision to all Member States reflecting the measures to take to implement the CHMP recommendation.

Finally, it is important to note that, in addition to the harmonization of procedures for the authorization of medicines, the system also ensures harmonization and coordination of the pre-and post-authorization activities:

▸ Pre-authorization activities: Companies can request scientific advice (or protocol assistance in the case of medicines for "orphan" or rare diseases) from the EMA at any stage of medicine development, whether the medicine is eligible for the Centralized Procedure or not. This European procedure helps the company to make sure that it performs the appropriate tests and studies so that no major objections regarding the design of the tests are likely to be raised during evaluation of the marketing authorization application.

▸ Post-authorization regulatory activities (i.e., variations or extensions and transfers of marketing authorizations, renewals, PSURs, and notifications) have also been harmonized and are coordinated via the Centralized, MRP, or Decentralized Procedures. This ensures that the same quality, safety, and efficacy of products are maintained during the entire lifecycle management of the products throughout Europe (e.g., availability of new formulations, extension of indications, etc.).

After years of extensive discussions involving ethical aspects [130] , the European Commission adopted a proposal on September 29, 2004 [131] . This proposal led to new legislation (Regulation (EC) No 1901/2006) that entered into force in the EU on January 26, 2007. Today, this amended text (and its several associated guidelines and other published information) [132] sets up a system of requirements, rewards, and incentives together with lateral measures to ensure that medicines are researched, developed, and authorized to meet the therapeutic needs of children (representing over 20% of the total European population [133]). In practice, this new regulation established an expert Pediatric Committee (PDCO) within the EMA, which is responsible for providing opinions on the development of medicines for pediatric use. The key objectives of the regulation are:

• To ensure high-quality research in the development of medicines for children aged 0 to 17 years of age • To ensure, over time, that the majority of medicines used by children are specifically authorized for such use • To ensure the availability of high-quality information about medicines used by children

In 2008, a communication from the EC (Communication 2008/C 243/01) provided guidelines on the format and content of applications for agreement or modification of a pediatric investigational plan. Many additional procedural and scientific guidance documents have also been released by the EMA to facilitate the implementation of this new regulation.

The EU introduced a new Orphan Medicinal Product legislation in 2000 in order to provide incentives for the development of medicinal products for rare disorders. Harmonization of requirements for these types of products is critical to allow for multinational clinical studies and to limit the development challenges due to the small number of patients. Prior to this European legislation, a number of Member States had adopted specific measures to increase knowledge on rare diseases and improve their detection, diagnosis, prevention, and treatment. However, these initiatives were few and did not lead to any significant progress in research on rare diseases.

Procedure for the designation of orphan medicines with the technical Committee for Orphan Medicinal Products (COMP), which is responsible for the scientific examination of applications. Designated orphan medicines are assessed centrally on a European level by the CHMP, rather than in each Member State separately. This regulation also put in place incentives for the research, marketing, and development of such products (e.g., fee waivers, a 10-year market exclusivity period postauthorization, and scientific assistance for marketing authorizations). Following its entry into force and its associated rules and guidelines, the number of orphan medicines authorized has increased significantly [134] . This Directive's aim is to protect public health while securing the free movement of herbal medicines within the Community. While most individual herbal medicines will continue to be licensed nationally by Member States, the process for licensing and information on herbal substances and preparations will be increasingly harmonized across the EU. For example, in order to further integrate these special medicines in the European regulatory framework, a Committee for Herbal Medicinal Products (HMPC) was established at the EMA in September 2004 (replacing the CPMP Working Party on Herbal Medicinal Products). The major tasks of this scientific Committee are to establish Community monographs for traditional herbal medicines, and to prepare and maintain a list of herbal substances that have been in medicinal use for a sufficient period of time, and so are not considered to be harmful under normal conditions of use [135] .

The procedures for clinical trials in Europe used to vary from one country to another. There were different national approaches regarding the approval and notification systems, documentation requirements, and timelines [136] . In October 2004, in order to coordinate the implementation of the new harmonized requirements across the Member States, the HMA established the Clinical Trials Facilitation Group (CTFG). The CTFG (attended by representatives from the National DRAs, EC, and the EMA) acts as a forum for discussion on the agreement of common principles and processes to be applied throughout Europe. It also promotes harmonization of clinical trial assessment decisions and administrative processes across the national DRAs. This group established a Voluntary Harmonization Procedure (VHP) for the assessment of multinational CTAs [138] . During this three-phase procedure, DRAs from all Member States involved assess the application, though each Member State remains ultimately responsible for the approval of the CTA in its own country. However, there is a coordinated validation phase (phase 1) and voluntary cooperation of the Member State during the assessment phase (phase 2) before the usual formal national process (phase 3). Phases 1 and 2 of the procedure are coordinated by a VHP coordinator. The "acceptability statement" obtained through this VHP procedure is then included in the subsequent national CTA applications.

From March 2009 to April 2010, 30 applications were evaluated through the pilot VHP procedure; 23 of these applications received a positive opinion [139] . The average procedural time was 52 days (which is significantly less than the average time of standard national procedures). The overall feedback from sponsors was positive, except that: Directive 2001/20/EC and its associated texts and guidelines are a very important step in the harmonization of procedure for the registration and conduct of clinical trials in Europe. Implementation of this Clinical Trials Directive into national legislation of all 27 EU Member States was completed in 2006. Principles like Clinical Trial Authorization by the national DRAs within defined maximum timelines led to significant harmonization of the clinical trial approval process. However, it has been agreed that this new system needs further harmonization in order to achieve the ultimate objective [142] . Indeed, the actual assessment of a request for authorization of a clinical trial is done independently by the Member States concerned. The legislation does not provide for a mechanism whereby the Member States are obliged to reach a common conclusion regarding a clinical trial involving different Member States. This lack of obligation and detailed direction implied different interpretation from Member States and therefore created implementation issues. As a consequence, sponsors have to respond to the various required changes and adapt their protocol in view of diverging assessments by the DRAs. This situation requires additional time and effort by the pharmaceutical industry (without added value for the patients).

In 2010, following a public consultation and a long and thorough impact assessment ( The proposal has been submitted to the European Parliament and the Council who engage in ordinary legislative procedure. This proposal, once adopted by the EU-legislator, is going to replace the 2001 Clinical Trials Directive. It is expected to come into effect in 2016 and to provide major revisions to the current system (e.g., single assessment outcome, simplified reporting procedures, etc.).

Finally, it must be noted that other important topics related to the regulation of medicines are also coordinated at the community level (by the EC and the EMA) in order to have harmonized regulatory actions and enforcements, and to complete the single pharmaceutical market. These harmonization initiatives are at different stages of development:

• 

To support cooperation and harmonization activities, the EU needed systems and knowledge management support. The implementation of this telematics (the integrated use of telecommunications and informatics) strategy, coordinated by the EMA, is critical to increase efficiency and transparency across the European Medicines Regulatory Network.

In addition to the standards for Electronic Submissions (eSubmissions) that were developed and published, a central set of Pan European systems and databases was created. These systems and databases exchange information with systems of external stakeholders and DRAs, while staying separate from them. They also help provide high-quality information on medicinal products to the general public and support the monitoring of the post-authorization risk and benefit balance of medicines in the EU.

The following critical projects and tools have been developed under this program (some of them are still under development):

▸ EudraCT: The Community's electronic database for clinical trials containing information submitted by sponsors. It informs DRAs of ongoing clinical trials in all Member States and EEA countries, enabling an overview of multi-state trials. The system also alerts DRAs in the case of early interruption or termination.

▸ EudraGMP: Community database on manufacturing and import authorizations and GMP certificates. The EMA launched the first release in April 2007. This system is used by EU GMP inspectors to share information (i.e., GMP authorization, noncompliance with GMP information resulting from inspection activity, planned inspection activity, and "rapid alerts" arising out of faulty manufacture). ▸ EudraNet: Private electronic network linking the members of the European Medicines Regulatory Network and EMA. It ensures that both electronic mail between members of the Network and their access to the EU telematics systems is secure. ▸ EudraLink: The European Medicines Regulatory Network's secure file transfer system used for exchanging information for regulatory purposes. It operates independently of EudraNet, so that it can be used by applicants and marketing authorization holders, as well as the regulatory organizations within the network to transfer files. ▸ EudraPharm: The Community's database of authorized medicinal products. Some functionalities of this database are still under development. ▸ EudraVigilance: System monitoring the post-authorization safety of medicines through safety reports (i.e., suspected adverse reaction reports). It is designed to receive, process, store, and make available information. One of the objectives of this system is the early detection of possible safety signals to facilitate the regulatory decision-making process (based on a broader knowledge of the adverse reaction profile of medicines).

the EMA to receive, validate, store, and make available information for review marketing authorization applications. The system's key benefit is its ability to take advantage of the lifecycle management functionality built into the eCTD by easily allowing the full extent of the current valid documentation as well as its submission history. ▸ EU Telematics Controlled Terms (EUTCT): Central repository and publication system for a controlled term list used in the European Medicines Regulatory Network.

The establishment of the EU has not been easy, but it has represented the desire to end conflicts in Europe. Since its creation, the EU has been successful in delivering peace between Member States and has reunited a fractured continent via the promotion of cooperative projects (i.e., economic and social). This cooperative initiative went beyond the initial objectives of its founders. Ever deeper integration has been pursued while embracing new members. The membership of the EU has grown from 6 to 28 nations, bringing the EU's population to half a billion people. It has created stable institutions, a single market, and a single currency. Despite numerous challenges, ggg the EU has survived, and is today a major economic and commercial power. Although improvements are still needed in certain areas, the EU represents a unique model of successful cooperation, harmonization, and integration between countries of different languages, cultures, history, and levels of development.

In the pharmaceutical sector, much has been achieved towards the consolidation of the European system of evaluation and supervision of medicines. Several challenges have already been overcome, but outstanding issues still need to be resolved to further support and improve public health in Europe, free movement and access to medicines in the community, and the competitiveness of the Union.

Taking into consideration its successes and challenges, this section provides a balanced evaluation of the current situation. It demonstrates that harmonization of pharmaceutical regulation in Europe can be considered a real and quick success in general (considering the major changes it required), but acknowledges some specific areas where work is still needed. For all these reasons, the development of the EU and its European pharmaceutical "regulation/ system" is a great example that needs to be further evaluated and discussed. Although this model of harmonization and integration may not be fully applicable to other cases, this experience can certainly help other regional or global harmonization initiatives.

Since the adoption of the first pharmaceutical directive in 1965, many topics have been harmonized. The past 50 years have seen a gradual convergence of pharmaceutical legislation in Europe. Today, a considerable package of harmonized legislation (in the form of the pharmaceutical "acquis communautaire") is in place to support two objectives: the protection of public health and the free movement of products. These provisions/texts applicable to medicinal products are included in EudraLex. They include binding legislation (i.e., Regulations and Directives), but also numerous technical guidelines and recommendations to facilitate the implementation of these common principles.

A well-structured European pharmaceutical system has also been established. In addition to the European institutions necessary to harmonize and create the European pharmaceutical legislation, technical European bodies have also been established. Today, the evaluation and supervision of medicines in Europe is shared between European and national bodies that form a complex but well-organized network of approximately 5,000 technical and regulatory experts. Words like "networking," "work sharing," and "harmonization" became common and remain crucial for the future.

The establishment of the EMA as a key coordinator of this system was an important decision for the integration and harmonization of practices and standards to support and promote the single European pharmaceutical market. The primary aim of this centralized system was to create conditions in which a single scientific evaluation of the highest possible standard would lead to rapid access to an integrated market of innovative and good cost-effective treatments. This objective, in large measure, has been achieved. The EMA, which is comprised of experts provided by national DRAs, has today established itself as a leading world agency for the evaluation of medicines. Its contribution to the effectiveness and efficiency of the EU system, and therefore to the protection of public health and to the achievement of an operational internal market, is well recognized by all stakeholders. The effectiveness of the system has been maintained despite its growing complexity. Indeed, the increase in the number of centralized applications hhh and other procedures, EU enlargement, and new regulations have led to an increased workload and an enlarged scope of responsibility for the EMA over the past 10 years. These changes have led to the creation of new committees (COMP, PDCO, CAT, HMPC, PRAC) that require the implementation of additional procedures and new tools. These structural changes and increased responsibilities should be monitored closely in the future to avoid risks of inconsistencies, overlapping, bureaucracy, and rigidity. Also, it is critical to continue to monitor financial compensation of national DRAs and to regularly assess the involvement of each Member State in the EU pharmaceutical system to ensure availability of appropriate resources and expertise [150, 151] .

Within this legal framework and European pharmaceutical system, community authorization procedures (Centralized, MRP, or Decentralized) have been in place since the mid-1990s. The centrally coordinated tasks include assessments led by rapporteurs and co-rapporteurs, inspections, and pharmacovigilance through the medicine's lifecycle. Although the national DRAs have prime responsibility for the efficient operation of MRPs and Decentralized Procedures, national marketing authorizations, and clinical trial authorizations for human medicines, the EMA has an important role in supporting these noncentralized functions. For example, the EMA maintains the Eudravigilance database and the EudraCT database, and supports a range of scientific committees and the coordination group for MRPs and Decentralized Procedures [152] .

The criteria for the approval of medicines and other technical topics have been extensively harmonized within the EU. Many technical and regulatory guidelines have been released in all areas (quality, nonclinical, and clinical). There has been a specific focus in recent years to improve the European pharmacovigilance system, to simplify the variation system, to harmonize the requirements for clinical trials, and to implement an advanced therapies regulation. The establishment of the European Pharmacopoeia has also been very important to ensure standardization of specifications and quality of medicines in the EU.

All these measures and actions described above have led to improved marketing authorization procedures, the harmonization of data protection in the EU, better access to medicines for children, orphan drug development, clinical trials, and a new regulatory framework for advanced therapies. Lifecycle management of products has also been improved (i.e., the revised legislation on variations to reduce the administrative burden by streamlining the circumstances obliging industry to file applications). The next review of the European system will be noteworthy because it will evaluate if new measures (developed following the last review in 2000) improved the system and produced real dividends in terms of cost efficiencies through economy of scale (via the reduction of the administrative burden where this did not have public health implications).

It is also worth mentioning that this European system is solid enough to stand the challenges of new therapeutics. The current structure, forum, and processes allow "proactive" harmonization. Indeed, most of the harmonization initiatives are created to discuss existing disharmonies on specific topics. At the beginning, the European harmonization effort, related to pharmaceutical regulation, was focused on disharmonies between countries. Today, even if disharmonies do still exist on some specific subjects, many topics have been successfully harmonized. The processes and structures that have formed over the years now allow the system to cover new subjects for which no national regulations and requirements have been developed yet. Developing this new regulation at the EU level automatically creates harmonized requirements (this can be called "proactive harmonization"). . This group, which included EMA staff and members of the CHMP and its working parties, generated recommendations on how the EMA should tackle these new emerging topics not covered by the existing national, regional, or global regulations and standards. ▸ EMA Innovation Task Force (ITF): In order to provide support for medicine innovation in the EU, the EMA established an internal horizontal cross-sectorial group to focus on emerging therapies and technologies. The ITF brings together competences from the areas of quality, safety, efficacy, pharmacovigilance, scientific advice, orphan drugs, and good practices compliance, as well as legal and regulatory affairs. One of the objectives of the ITF is to address the impact of emerging therapies and technologies on current scientific and regulatory requirements. Its scope also encompasses areas for which there are no established scientific, legal, and regulatory experience. One of their tasks is to identify areas for legal, regulatory, and technical guidance preparation and proposals for consideration by the EMA Committees and working parties, and to contribute to relevant EC initiatives and legislation [154] .

The EU today is recognized as a major player in the international harmonization of pharmaceutical regulations. It has developed privileged relationships and initiated cooperation projects with other countries outside the European Community (major developed countries and emerging markets). For example, the EMA cooperates with many of the world's largest regulatory bodies outside the EU iii in areas such as inspections, safety of medicines, and exchange of information on issues of mutual concern. The establishment of the International and European Cooperation Sector, formed in February 2012 and responsible for the development, coordination, and implementation of the Agency's international strategy and activities (including confidentiality arrangements with countries outside the EU), demonstrates the EMA commitment to international cooperation [155] . Also, collaboration has been initiated with China, India, and Russia on pharmaceuticals, and it is partnering with international organizations (i.e., ICH, WHO, and PIC/S). This work should continue and also be extended. It is indeed important to support the development of globally harmonized standards and requirements in order to ensure fair competition with other parts of the world for the development of medicines and to avoid delay in the availability of essential medicines for European patients. Ensuring against falsified medicines, resolution of pandemic issues, product development in emerging markets, and reliability of clinical data produced outside Europe are good examples where international cooperation is necessary to ensure adequate protection of public health in Europe.

In spite of all the above-mentioned major progress and regular improvement of legislation by the European Commission, there is still room to improve the EU pharmaceutical system. On the regulatory side, issues dealing with the implementation and interpretation of Community legislation by Member States continue to create obstacles to the free movement of medicines. Stakeholders continue to raise concerns regarding market fragmentation linked to disparities in national pricing and reimbursement schemes (despite the adoption of Directive 89/105/EEC in the early days of the European pharmaceutical system), unnecessary regulatory burdens caused by divergences in the implementation of Community legislation (e.g., clinical trials requirements), and a lack of commercial interest in national markets that are economically less attractive. European patients still suffer from inequalities in the availability and affordability of medicines. This situation could worsen and create significant inequalities between patients in accessing medicines if it is not resolved. Additionally, Europe has been losing ground when it comes to innovation and competitiveness in the pharmaceutical market.

In its communication of December 10, 2008 [156] , the EC recognized that further harmonization is necessary to resolve shortcomings in the EU pharmaceutical market in furthering increased globalization of this sector. To improve this issue, the EC confirmed its objective to continue to progress towards a single and sustainable pharmaceuticals market [157] .

To further support and improve the public health in Europe and free movement of medicines within the community, and to maintain its competitiveness, the EU needs further harmonization in several areas, such as: novel medicines by patients, mainly due to increased pressure to cut healthcare budgets. In certain countries, medicines are not made available due to administrative requirements and poor economic rewards. A lack of transparency and harmonization with regard to pricing, reimbursement, and relative effectiveness remains a challenge [158] .

In contrast to the benefit-risk assessment carried out by regulators, national HTA bodies compare the "relative effectiveness" of medicines and take their financial cost into account. This post-marketing national HTA evaluation can lead to national differences due to different country needs. The addition of different requests (i.e., different type of studies) from regulators and HTA bodies can also delay availability of new products.

To resolve this major issue, the European Network for Health Technology Assessment (EUnetHTA) was established to support effective collaboration between national HTAs. Also, the EC gave the political mandate to the EMA to begin interacting with HTA bodies when it published the conclusions of the Pharmaceutical Forum in October 2008. kkk Since then, the EMA has begun to collaborate with national HTA bodies and with EUnetHTA [159] . This interaction focuses on centralized approved products and aims to facilitate communication between EMA and HTA bodies early in a medicine's development and throughout the medicine's lifecycle.

As mentioned above, the harmonization of price and reimbursement evaluation is critical in supporting a European pharmaceutical market. However, it will be a very difficult and long process to implement due to political and budgetary aspects and differences in pharmaceutical markets and healthcare budgets existing between Member States.

The European Clinical Trials Directive (Directive 2001/20/EC) has been an important and necessary step in the harmonization of European pharmaceutical regulation. The principles defined in the Declaration of Helsinki (in 1964) and the ICH GCP E6 guideline (in 1996) allowed some harmonization of clinical practices and protection of clinical patients. But, before this Directive came into force, the rules for performing clinical trials (i.e., regulatory procedures and requirements) varied significantly in the European Community as they were based on differing regulatory approaches in the Member States. This new legislation promoted harmonization of clinical trial practices allowing important improvements related to the protection of patients (i.e., safety and ethical concerns) and reliability of data, and facilitated the exchange of information between DRAs.

However, despite this progress, important negative effects of this new legislation have been reported (e.g., the increase in bureaucracy and administrative costs). The number of clinical trials carried out in the EU has fallen by 15% in recent years, while administrative kkk The Pharmaceutical Forum was set up in 2005 by the European Commission as a three-year process in order to find relevant solutions to public health considerations regarding pharmaceuticals, while ensuring the competitiveness of the industry and the sustainability of national health care systems. More specifically, this forum analyzed three key themes: information to patients on pharmaceuticals, pricing and reimbursement policy, and relative effectiveness.

costs and delays have doubled [160] . It is still labor intensive and costly to duplicate largely identical administrative procedures for multinational clinical trials. Additionally, sponsors spend a great deal of time retrieving the relevant national information and requirements and preparing customized applications without added value for the patient and the regulators (the core scientific information is the same, but the format and administrative information and forms differ). It is indeed a problem for a large pharmaceutical company, as it usually requires additional dedicated departments with the necessary resources to track differences in national requirements and follow the many parallel procedures. But it is even more problematic for SMEs or academic sponsors for whom these costs can reach prohibitive levels.

This multiplication of parallel procedures also has an important impact on the DRAs. Indeed, available resources are used in multiple assessments of the same core information in different Member States, which clearly delays the start of clinical studies. It is important to note that this duplication of assessments does not necessarily increase the quality of the assessment, as the necessary specific expertise might not always be readily available in all the Member States concerned. This is a nonefficient use of national resources without added value for the patients or science.

This implementation problem is partly due to the legal framework that has been chosen for harmonization in this area. As with all Directives, the Clinical Trials Directive had to be transposed in national laws. Unfortunately, in this case, the objectives of the directive were transposed into divergent national legislations, somewhat missing the harmonization goal and making multinational trials difficult to perform.

In its 2009 consultation paper [161], the EC proposed options to improve the situation. One of the best options is to continue with the harmonization process. This would mean creating a real European system of authorization for clinical trials to avoid duplication of assessment. It would avoid the inconsistent assessment conclusions and requests, encourage appropriate use of resources and expertise (for both the sponsors and DRAs), and ensure common implementation of the principles laid down in the Clinical Trials Directive.

The VHP initiative seems to be a good first step. It allows for a better implementation of the EU Clinical Trials Directive principles and further harmonizes the conduct of clinical trials in Europe. However, this procedure cannot be considered as the ultimate solution because it does not resolve all issues [162] . More specifically:

• There are still parallel CTA assessments by multiple DRAs.

• There are still major differences between countries regarding the time it takes to issue approval. • This is a voluntary cooperation and there are differences in the level of interest and responsiveness between countries. • The current procedure does not remove specific national requirements or differences between national assessments (this is a cooperation effort, not a harmonization of requirements). • This process does not accelerate the First Patient Enrolled (FPE) in Europe.

To resolve these outstanding issues, the current VHP procedure should be revised to become a real MRP where the assessment will be conducted by only one reference Member State. The content of the dossier should also be fully harmonized between countries.

The establishment of a Centralized Procedure through a new Regulation (which will deliver a Pan-EU approval) would also be very helpful for certain types of products that require specific expertise not available in all EU countries (e.g., advanced therapies), for orphan drugs, and/or for pediatric medicines. This centralized process for CTA would be a good bridge between the EMA Scientific Advice process and the Centralized registration procedure.

The system for registration of clinical trials would then mimic the system already in place for the registration of medicinal products with a combination of three types of procedures:

• Centralized Procedure for specific products such as biotechnology and advanced therapies • Mutual Recognition Procedure for other multinational clinical trials • National Procedure for a clinical trial involving only one Member State This reorganization of the system and procedures, supported by the EC [163] and most of the shareholders involved in clinical trials [164] , would utilize the current structures and expertise in Europe, would build on the experience acquired with the registration process, and would facilitate patient access to clinical trials and to new technology within the community. It would allow the necessary flexibility and different levels of review for interventional trials (e.g., a small national study with a well-known entity does not need the same type of evaluation, organization, and bureaucracy as a Phase 1 study with a new fusion protein or a large multinational Phase 3 study). Measures should be put in place to ensure that such reorganization would allow this flexibility and avoid any further increase of delay and administrative costs and burdens. For example, "recognition" of other assessments should be the focus, and "nonrecognition" should be limited to major issues (that should be clearly defined). These "nonrecognitions" of assessment by another country should be rare to avoid regular arbitration or appeals that would further delay the start of the clinical studies. Selection of Reference Member States (RMS) should also be defined because many parameters are involved in such selection (i.e., expertise, resources, balanced workload between countries, etc.). Finally, this new cooperative system should not result in the simple addition of national requirements, but a harmonized scientific assessment that would be implemented equally in all Member States. This next step in the harmonization of a clinical trial in Europe would certainly be beneficial for patients, sponsors of clinical trials (pharmaceutical companies, but also small entities or academic centers), and DRAs. Some of the above proposals have already been recommended by the European Commission [165] . The recent adoption of a "Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC" [166] by the Commission represents an important step in the improvement of the current system. However, this process will take time to implement, and national interests will need to be overcome.

Finally, the assessments of Ethics Committees also need to be reviewed and improved. The Clinical Trials Directive is based on the concept of one Ethics Committee opinion per Member State concerned. However, several Member States maintain a decentralized system where the single Ethics Committee opinion is based on the opinion of several local committees. As a consequence, in the EU there are approximately 1,900 Ethics Committees involved in the assessment of clinical trials [167] . Also, better harmonization of responsibilities between DRAs and Ethics Committees must happen across Europe [168] . It is agreed that ethical issues fall within the responsibility of Member States. However, current practices need to be reviewed in order to smoothly integrate an improved harmonized system and to protect European clinical trials subjects. These programs are important to make new therapies available to patients as soon as possible. They should be handled on a European basis in order to ensure that every European person, wherever their location, has the equal right to access these new medicines at the same time. Today, this difference in access within Europe is clearly contrary to the overall European objective to ensure that all patients within the Community have the same access to the same quality products throughout Europe. Of course, the harmonization of these requirements and procedures should be carefully implemented to avoid the creation of delays compared to the current situation.

▸ Pharmacovigilance: The EU pharmacovigilance system demonstrates that cooperation and harmonization of regulations and practices in Europe is beneficial to patients. Indeed, merging the EU national pharmacovigilance systems into one network increases the quantity of data/reports/ information, which facilitates the early detection of possible safety signals, and therefore the monitoring of product safety. Unfortunately, the Mediator issue in France has shown that the EU pharmacovigilance system needs to be improved to be fully functional. This topic has been one priority of the European network. The ongoing implementation of the new legislation by the EMA and the Member States will be critical.

Although the Mutual Recognition and Decentralized Procedures have improved over time, challenges still exist, and the principle of these procedures (i.e., recognition of another country's assessment) is not always respected. In both these procedures, Member States can only refuse to recognize other countries' assessments if they feel that this recognition could have a "potential serious risk to public health." Unfortunately, this reason for disagreement is vague enough to allow flexibility for Member States. In 2006, a guideline was released [171] to further clarify how this risk should be defined. However, some national DRAs continue to have a broad interpretation of "potential serious risk to public health," and trigger EMA arbitrations for grounds that do not fall under this specific category [172, 173] .

In addition to the specific issues discussed above, more general challenges can also impact the harmonization of European pharmaceutical regulation. Although these general considerations are not specific to the pharmaceutical sector, they can influence the establishment and implementation of pharmaceutical regulation. Therefore, they need to be understood and integrated when developing implementation plans and timelines:

• . This major difference in workload between countries demonstrates a big gap in work sharing and certainly highlights differences in national DRAs' expertise and resources and pharmaceutical companies' interests for each national market. • One of the complexities and difficulties of the EU system is the division of activities undertaken at the national level (e.g., clinical trial responsibility, scientific advice handling, etc.) and at the EU level (e.g., equal scientific advice handling, assessment of pediatric investigational plans, etc.). This requires many communications and infrastructures between the EU and national players. • External economic or political factors could also influence the harmonization of European pharmaceutical regulation. For example, the modification of European borders via new enlargement of the EU (even if the EU leaders have agreed to mark a pause for now, discussion on the accession of countries such as Turkey, Iceland, and Serbia are still ongoing). Additionally, the possible creation of a "Mediterranean Union" desired by past French President Sarkozy could also impact the scope and timelines of the next steps of harmonization and integration. Finally, it will be important to see if and how the two new functions created by the Treaty of Lisbon (President of the EU Council and High Representative of the Union for Foreign Affairs and Security Policy) will benefit the EU. The first important dossiers after the creation of these two functions (global financial crisis, global security, and support to Greece) have indeed still been handled by the political leaders of major Member States (i.e., France and Germany).

It is clear that the European system is integrally linked to its own history. This model cannot fully fit every harmonization initiative in the world because every situation and need is different. However, it is worth reviewing the lessons learned from this 50 plus years old initiative. This first Regional Harmonization Initiative (RHI) overcame a lot of challenges, and has since developed into a strong regional harmonized pharmaceutical regulation and system. This success demonstrates that an organized cooperation and harmonization can facilitate the development of high standards and practices.

More specifically, the European initiative clearly demonstrates that a structured stepwise approach is necessary: ▸ First, it is necessary to set up major principles (Directive 65/65/EEC). ▸ Second, it is critical to provide specific detailed requirements and to further detail the agreed principles (Directives 75/318/EEC, 75/319/EEC, etc.). ▸ Third, a structured and organized system is needed to implement the principles and requirements. Technical bodies need to be established to control medicines and manage the establishment of common procedures (especially centralized types). In Europe, it was key that the national DRAs provide expertise and resources to European bodies not only to ensure appropriate availability of resources, but also to ensure full adhesion of the countries into the system and adequate communication between all players of the system (national and European). ▸ When all the basic principles and a system are in place, additional more specific requirements can be discussed so that the system can take into account particular needs (i.e., specific requirements for specific products, population, etc.) in order to have a more coherent system. ▸ Finally, it very important to monitor the system and regularly review the extent to which this system and measures support the harmonization goals and meet the predefined objectives. Evolution of the environmental impact (i.e., globalization, change of membership, change of political commitment, and need for new requirements due to emerging problems, etc.) also has to be taken into consideration, and the regulation and system needs to be carefully adjusted to ensure its longevity.

Another lesson learned from Europe is the importance of cooperation. To be successful and ensure effective functioning of this system, cooperation between the different entities of the system (EMA, HMA, National DRAs, EC) has been, and remains, critical. Even if the European pharmaceutical system is complex, it is well organized. The provision by the Member States of high-quality scientific resources for the evaluation and supervision of medicines is a critical factor for the success of the EU system. Indeed, scientific excellence (as a result of EU-wide pooling of expertise and data) has been a key strength. In this respect, it should be stressed once again that such excellent progress has been highly dependent on close collaboration between the EMA and the national DRAs within the context of the EU regulatory network, and in particular on the valuable input of high-quality specialist expertise provided by the Member States. This provision of national resources, coordinated by the EMA, is one of the features of the EU regulatory network.

This success also relies on political support for this European harmonization initiative in order to support the creation of the single market. Without this political commitment (and therefore associated funds and resources), it would have certainly been much more difficult and taken more time to create this system. It is recognized that other harmonization initiatives in the world are certainly suffering from the lack of such political commitment, especially when such harmonization is not driven by the willingness to create a single market (i.e., integration model).

Finally, the EU has also clearly demonstrated that better organization at the regional level is extremely critical to ensuring the success of global harmonization and cooperation. Even if all regions are not working towards integration like Europe, this example of better coordination and representation should be followed and discussed in other regions of the world. Indeed, this example demonstrates that a well-organized and coordinated regional structure is beneficial to all stakeholders [176]: ▸ Individual countries via better representation and better access to international activities/agreements/decisions through regional structure (this is especially true for small countries with less expertise and resources). Individual countries also benefit from the infrastructure (i.e., databases or training programs) and good practices developed at the regional level. ▸ Regions because they allow better representation of interests (Europe has more power than a combination of small countries' voices, and has an impressive network of experts). ▸ International cooperation and harmonization initiatives because they facilitate communication by reducing the number of contacts and seats at the international level (but provide a structure for dissemination of information). For example, having all EU countries represented at ICH would not be possible.

This regional coordination is very important for the future of global initiatives (such as ICH or WHO projects), but it is even more important in the management of a worldwide health crisis (e.g., pandemic influenza). This European coordination system should be implemented in other regions of the world because the coordination of rapid and efficient communication of information and actions during such a crisis helps the overall coordination of the situation. For example, in the recent case of pandemic influenza, it was critical to have central coordination (not only global, but regional). The EMA (using its "crisis management plan") allowed Europe to respond rapidly and efficiently to the challenges of an outbreak of pandemic influenza by: ▸ The fast-track review of vaccines (using its best experts) ▸ Monitoring the safety of centrally authorized pandemic-influenza vaccines and antiviral medicines ▸ Liaising and coordinating activities with critical partners, including the EC, EU Member States, other European Agencies (such as the European Centre for Disease Prevention and Control), and international partners (such as WHO and regulatory bodies of non-EU countries) to ensure timely exchange of information and coordination of activities relating to the pandemic ▸ Coordinating the communication of relevant information to the public, healthcare professionals, and the media All of these activities would be less efficient if performed by each individual country.

Political and economic development in the Pan-American region has resulted in interest in regional economic integration. Several subregional integration groups have emerged in this area since the 1970s. Harmonization of pharmaceutical regulations and technical standards is a component of this economic integration, but the degree of progress in this area varies a lot from one subregion to another (and even from one country to another). In light of these various economic integration initiatives, the need became evident for an entity in which the different countries of the region could share experiences and expertise.

The Pan-American Network for Drug Regulatory Harmonization (PANDRH) was created in November 1999. This is a regional initiative established to promote drug regulatory harmonization throughout the Pan-American region within the framework of national and subregional health policies. This continental forum is not a supranational entity, and its decisions represent recommendations to be assimilated into the subregional integration initiatives. The mission of this network is "to promote the harmonization of pharmaceutical regulation covering aspects of quality, safety, efficacy and rational use of pharmaceutical products, the strengthening of National Regulatory Authorities (NRA) capacity within the Region of the Americas based on the right of the population to access quality medicines, recognizing advances in science and technology and within the context of national and sub-regional realities" [177] .

The objective of this initiative is to facilitate regional harmonization of medicinal drug requirements and guidelines for specific regulatory issues. This objective is achieved by adopting recommendations for implementation at national and regional levels, and also by supporting the development of training on specific important topics.

However, this initiative also has broader objectives such as: ▸ Promoting and maintaining a constructive dialogue among DRAs, the pharmaceutical industry, and other sectors ▸ Strengthening the DRAs of the region ▸ Encouraging convergence of drug regulatory systems in the Pan-American region ▸ Facilitating technical cooperation among countries in collaboration with subregional integration groups.

Since 2003, PANDRH has been a member of the ICH Global Cooperation Group (GCG). This membership broadens PANDRH's role because this regional harmonization initiative is now also involved in global harmonization. PANDRH provides a way to disseminate recommendations on drug regulatory harmonization of global initiatives. It also ensures that regional specificities and challenges will be considered when new global recommendations are discussed.

▸ DRAs of all Pan American Health Organization (PAHO) Member States ▸ Regional pharmaceutical industry associations: Latin American Association of Pharmaceutical Industry (ALIFAR) and Latin American Federation of the Pharmaceutical Industry (FIFARMA). ▸ Academia ▸ Consumer groups and professional associations It also includes representatives from the five subregional trade integration groups within the Americas (Plate 2) that are themselves multinational cooperation initiatives but are working on a broader integration with emphasis on political and/or financial interest:

▸ The Andean Community is a Community established in 1969 (by the Cartagena Agreement) that currently regroups four countries (Bolivia, Colombia, Ecuador, and Peru). Chile and Venezuela have also been part of this initiative in the past and some others countries are observers. These countries decided voluntarily to join together for the purpose of achieving more rapid, better-balanced, and more autonomous development through Andean, South American, and Latin American integration. They also created a free trade area (including the four current members plus Venezuela). This integration initiative is broad and regroups several areas, one of them being health. The integration of health is governed by the Andean Health Body, which coordinates the actions aimed at improving the healthcare of member countries. It gives priority to cooperative mechanisms that promote the development of subregional supranational systems and methodologies. These actions are also coordinated with the other subregional, regional, and international organizations. Discussions include many topics such as the development of a pharmaceutical policy model, the evaluation of medicinal products, and a surveillance network.

▸ SICA (The Central American Integration System) is the institutional framework of subregional integration in Central America. This is the latest step of a long integration process in the region. It was created in December 1991 (by the signing of the Tegucigalpa Protocol) by the States of Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama. This initiative also involves the Dominican Republic as an associated State and some regional and extra-regional observers (Mexico, Chile, Brazil, China, Spain, and Germany). The headquarters of the General Secretariat is located in El Salvador. The first objective of this integration process in Central America was to transform the area into a region of Peace, Liberty, Democracy, and Development, based firmly on the respect, tutelage, and promotion of human rights (following a history of political crisis, conflict, and dictatorial rule in the region). Health topics are covered by the Executive Secretariat of the Council of Ministers of Health in Central America (SE-COMISCA). Several projects are under discussion in this subregion, such as the basis for quality assurance of drugs and a pharmacovigilance system.

▸ MERCOSUR (the "Common Market of the South") was created in 1991 (by the signature of the Treaty of Asuncion) and encompasses five Latin American countries (Argentina, Brazil, Paraguay [which is currently suspended], Uruguay, and Venezuela). The purpose of this agreement was to set up a common market and eliminate trade barriers among the signatory parties. MERCOSUR has been involved in several health projects (such as implementation of GMPs with training and joint inspections and development of programs on vaccine regulation and control) to promote cooperation between its members and harmonization of specific pharmaceutical regulations in this subregion. To date, there is no mutual recognition system.

▸ NAFTA (North American Free Trade Agreement) was implemented in January 1994 to remove most barriers to trade and investment among the US, Canada, and Mexico. The objective of this agreement was to establish procedures to facilitate trade and investment on the North American continent. This trade liberalization had some positive impact and created one of the largest trade blocs in the world, but some downsides have also been reported by economists (who have shown that NAFTA has not been able to produce an economic convergence). NAFTA has had a minor impact on the harmonization of pharmaceutical regulations in the region and has not been able to resolve the problem of parallel import of pharmaceutical products between Canada and the US.

One of the major components of this initiative is the Pan-American Conferences on Drug Regulatory Harmonization held every two to three years. These conferences are the highest instance of the PANDRH Network. They serve to define priority areas for harmonization and to endorse standards, guidelines, and other recommendations, including norms and procedures and Steering Committee membership. They also provide a forum for discussing issues of common interest in drug regulation. Participants include all interested parties such as the DRAs of all PAHO Member States, representatives of the regional pharmaceutical industry associations, academia, consumer groups, professional associations, and representatives from the five subregional trade integration groups within the Americas.

The 1st PANDRH Conference took place in November 1997 (in Washington, DC, US). PAN-DRH was then officially created during the 2nd PANDRH Conference in November 1999 (also in Washington, DC). Following these first two conferences, subsequent conferences took place to review ongoing activities of the Working Groups.

PANDRH mimics the ICH structure. It is organized around three major bodies:

▸ The Steering Committee (SC), which ensures operational management of this initiative between conferences, is composed of:

• Seven members from five national DRAs (one from each of the subregional economic groups) and two industry representatives (FIFARMA and ALIFAR) • Seven alternate members from five different national DRAs (one from each of the subregional economic groups) and two industry representatives (FIFARMA and LIFAR) • Regulators from other countries (not represented on the SC), representatives from nongovernmental organizations (NGOs) recognized by PAHO/WHO, and other stakeholders invited by the SC who may also participate in SC meetings as observers Members of the committee serve for a period of four years, with staggered rotation to maintain continuity. The SC meets at least twice every year. Its primary role is (1) to establish the agenda for the biennial Pan-American conferences, and (2) to follow up on conference recommendations by establishing and monitoring the progress of Working Groups. The responsibility of this group is to promote progress between conferences through the coordination, promotion, facilitation, and monitoring of the harmonization activities.

▸ The Technical Working Groups are specifically formed to work on topics and areas identified for harmonization. The members are experts in their specific subject matter. A Working Group may include the following categories of members:

• Main Members that represent the national DRA of a country in each of the five subregional blocs, the regional Industry Associations ALIFAR and FIFARMA, and those designated by the Secretariat • Alternate Members designated to attend the meetings instead of the principal members • Observers from any country generally nominated by a participating national DRA (the observers do not retain voting rights) • Expert resources (as needed) to support a specific activity of the group (expert resources do not have voting rights)

The national DRAs of countries not represented in the Working Group can designate focal points to follow the activity of the group. Each Working Group has a coordinator (and an alternate) who chairs and coordinates the meetings, leads the development of documents, and reports periodically to the SC on the progress of the group. In general, the first task of a new Working Group is to conduct a survey to identify the differences in regulatory requirements among countries in order to prepare a work plan. Then, the group reviews international and regional and/or national recommendations and guidelines and prepares a harmonized proposal. When the harmonized standard is developed, the Working Group is in charge of designing training and helping in implementation of this standard by assisting countries in the dissemination and education concerning this new rule. Technical Working Groups meet in conjunction with SC meetings or separately (determined by a work plan and resources).

▸ A Secretariat, provided by PAHO, supports the initiative technically and administratively. It monitors the PANDRH website, serves as a focal point for the coordination and dissemination of information, coordinates activities arising from recommendations of the conferences and SC, and acts as liaison and a representative of the Network in global and interregional harmonization organizations (ICDRAs, ICH, etc.)

As in other regions of the world, there is a need to promote harmonization of pharmaceutical regulations to facilitate the availability of safe, effective, and good-quality products and thereby protect public health. PAHO initiated communication among the different members of the pharmaceutical sector in the Americas in order to facilitate communication among the different subregional blocs (and also the countries not already covered by these blocs) and organize regional harmonization.

The first Pan-American conference took place in November 1997 (in Washington, DC, US). This conference was considered the first step towards the establishment of PANDRH. During this first conference, the scope and the term "harmonization" were defined (as the search for common ground within the framework of recognized standards, taking into account the existence of different political, health, and legislative realities among the countries of the Region). The structure and financial support of PANDRH were also discussed at this first conference. However, PANDRH was officially created during the 2nd Conference (November 1999 in Washington, DC) following a consultation in Caracas, Venezuela in January 1999, and also several ad hoc discussions and meetings (Meeting of Americas' Regulators in Washington, DC in November 1997, Regional Working Group on Bioequivalence in Caracas in January 1999, and Regional Working Group on GCP in Buenos Aires in May 1999). During this second conference, the mission statement and objectives of the SC were agreed upon.

This initiative was then officially recognized by the 42nd Directing Council of the PAHO in September 2000. Resolution CD42.R11, which was approved during this Council, provided strong support from Ministers of Health of the Member States in the region to PANDRH and to the process of drug regulatory harmonization.

During PANDRH Conference V (in Buenos Aires in November 2008), the regulations governing PANDRH (mission, structures, and procedures) that were originally created during the 2nd Conference were slightly modified to incorporate lessons learned during its first few years of establishment [178].

Harmonization proposals are developed by the Technical Working Groups. These groups primarily use WHO documents as the basis for developing regional guidelines. Other international guidelines including ICH and selected regional (e.g., EU, American subregional) or national technical documents are also used as the basis for harmonization proposals and as reference materials.

After a Working Group has agreed on a draft harmonized document, it is posted on the website for external comment. Comments are reviewed by the Working Group to prepare the final version of the document that will be presented for adoption by the Conferences through the SC. Conclusions and recommendations of the Conferences are to be adopted by consensus (if consensus cannot be reached, the different points of view have to be recorded).

During its seventh meeting (in June 2006 in Washington, DC, US), the SC established a system of phases and stages for its harmonization process. This system, which mimics the ICH process, is composed of five phases, with each having substages: Final technical documents are intended for use at the national level (through the subregional integration groups), but this implementation is at the discretion of each country. Members of the SC are responsible for monitoring implementation in their subregion. PANDRH is also discussing strategies to follow up the implementation of its recommendations at the national and subregional levels. In addition to the biennial Pan American Conferences on Drug Regulatory Harmonization that allow for communication and exchange, PANDRH is also committed to training all interested parties (including regulators and industry). Such training covers major topics such as GMP inspection, GCP, GLP, bioequivalence, etc.

The initial priorities that the PANDRH defined during the first conference were GMP (to facilitate the implementation of GMP in the region and ultimately to develop mechanisms for mutual recognition of inspection), bioequivalence, and GCP. Additional topics were then added, each of these considered critical in the development of the network and in the protection of public health in all concerned countries.

Currently, there are 13 areas of priority that have been selected by PANDRH (for which Working Groups have been established):

Several recommendations developed so far are based on WHO recommendations. For example, WHO Report 32 was the basis for the discussion on GMPs, and the WHO and ICH guidelines were used to build consensus on GCPs.

Most of the selected topics are technical and have been chosen in order to ensure the quality, safety, and efficacy of the products approved, and that these products are adequately promoted and maintained. The work on drug classification is also key to ensuring a common language and facilitating subsequent harmonization discussions. Combat against drug counterfeiting has also been selected, as this is a major issue in this region directly affecting public health in all countries and requiring a multidisciplinary, multi-sectorial, and crossborder perspective. Finally, the activity on drug registration is a broader project, and is very important for ensuring implementation of PANDRH recommendations and for reaching full harmonization of pharmaceutical regulations. This is critical in ultimately developing a collaborative regional or subregional registration process and system and sharing of expertise and resources between countries. This group drafted a proposed list of harmonized requirements for drug registration in the Americas [179] .

The current list of selected topics above will certainly be amended in the future if new emerging topics (creating potential health public issues in several countries of the region) need to be discussed and resolved at a regional level. For example, the Working Group on Biotechnological Products has been established following a roundtable session of the 5th PANDRH Conference. This roundtable session was organized to discuss biotechnological products (and also the specific issue of biosimilars). Biosimilars present a clear risk for the patient (if they are not well controlled), but also a major opportunity for increased access to cheaper essential medicines (if they are well regulated). These biotechnological/biologic products have unique technical challenges that require technical and specific expertise. PANDRH will have to work on this topic collaboratively with WHO, which has already released recommendations on this topic.

PANDRH's scope of harmonization and cooperation includes technical guidelines, regulatory processes, and the strengthening of national DRAs through harmonization of processes and standards to improve and assure drug quality. By adopting its recommendations and standards, countries in this region can clearly improve the quality of their regulatory system and provide access to quality, safe, and effective drugs.

Moreover, PANDRH plays an important role in the global harmonization of pharmaceutical regulations. It is an important link between global organizations/forums and the regions. Through its involvement in the ICH GCG, it increases: ▸ The integration of the regional challenges/priorities/vision in the development of international standards ▸ The implementation of such international standards in the region This regional initiative is one of the most difficult to operate because it includes very different regulatory systems and structures (from the most developed system such as the US FDA to the most undeveloped countries in the world). This initiative also has to take into account the existence of very different political, health, and legislative realities among the countries that correspond to very different priorities, interests, and resources. This reality creates difficulties in the management of projects and the establishment of consensus [180] . However, this disadvantage also provides opportunities and benefits as the most developed DRAs can help to mentor the less developed ones.

Recognizing preexisting asymmetries in the region, PANDRH has become a forum to discuss common issues on drug regulation and share knowledge and expertise. Not all the countries are involved in actually developing the proposals, but all of them participate in the decision of adopting them via the conferences. By promoting the collaboration of experts from different countries/subregions, and also from both the public sector (authorities and academia) and private sector (industry), PANDRH has developed quality recommendations (frequently based on WHO or other international reports and recommendations).

It must be noted that PANDRH is clearly dependent on PAHO/WHO. Without this support and investment, PANDRH would certainly not be viable. Indeed, this financial, technical, and administrative support from PAHO/WHO, which represents an important recognition (both in and outside the region), is critical for the following reasons:

▸ As for all such multinational initiatives, one of the challenges of PANDRH is funding. PANDRH's budget is primarily supported by PAHO, but additional funds also come from governments, the pharmaceutical industry, international organizations, and registration fees from training courses. ▸ Resources from involved countries are limited. PAHO, by providing a Secretariat, has structured this initiative and allows the practical development of the harmonization projects. ▸ WHO provides critical technical help for the preparation of PANDRH recommendations. Most PANDRH guidelines and documents are indeed based on WHO reports.

The 6th Conference of PANDRH, held in July 2011 (which included over 300 participants from 26 countries), focused its discussions on the theme "Strengthening National Health Regulatory Authorities." Several working groups presented the conclusions of their work and their recommendations and actions. The topics also addressed during this Conference included the role of PANDRH as coordinator of international cooperation, PAHO's recognition of national regulatory reference authorities (ANMAT-Argentina, ANVISA-Brazil, INVIMA-Colombia, and CECMED-Cuba), implementation of the PANDRH guidelines in the subregions, and innovative activities of the national DRAs in surveillance or in treatment compliance. This conference concluded with the approval of a strategic orientations document. The main recommendations were aimed at developing more effective cooperation among countries to guarantee, inter alia, the adoption and implementation of the different technical documents produced.

The major challenges for the future (what PANDRH will be assessed on) is the implementation of both its own and ICH's recommendations. This will determine if this initiative delivers on its promises and if the countries that form this initiative are committed to this harmonization. Because DRAs of all countries in the region participate in the conferences, it is expected that recommendations and guidelines will be adopted and implemented by the individual countries and incorporated in the discussion at subregional economic groups. However, it may not always be so straightforward/automatic, and the implementation of its recommendations may become one of the major challenges of this regional initiative because its members have no obligation to implement harmonized standards.

The decision to develop a 2013-2020 PANDRH strategic plan to guide future development of the network, and ensure flexibility, scientific rigor, and representation of all stakeholders in the network [181], will certainly strengthen this initiative.

The Gulf Cooperation Council (GCC), also known as the Cooperation Council for the Arab States of the Gulf (CCASG) is a political and economic union. Established in 1981, this trade bloc comprises six Arab states of the Arab Gulf. It represents one of the wealthiest country groupings in the world due to its extensive oil and gas reserves. Its population is approximately 42 million and its gross domestic product (GDP) is estimated at approximately US $917 billion [182] .

The GCC has been active in political affairs outside its territory. Due to the instability of the Middle East region, the GCC has been heavily involved in diplomatic discussions to solve the different conflicts and problems of the region (i.e., Iraq/Iran war, Iraqi invasion of Kuwait, Iraqi situation after the breakdown of the former regime, Israeli/Palestinian war, etc.). The objectives are to avoid the expansion of war and eliminate violence and terrorism in the region in order to support regional development and modernization.

In order to achieve unity, the GCC promotes the coordination, integration, and interconnection between its Member States in various fields. One of the first objectives of the GCC is to formulate similar regulations in different areas, including health. Cooperation and coordination in health are under the responsibility of the Council of the GCC Health Ministers (CHM). Under its oversight, the Gulf Central Committee for Drug Registration (GCC-DR) was established to provide Gulf States with safe and effective medicines at a reasonable cost. This committee works towards this objective by promoting cooperation and harmonization among Member States. This initiative covers prescription, nonprescription, generics, and biologics.

On the international side, the GCC represents the region at the ICH Global Cooperation Group (GCG).

The current GCC members are six Arab states of the Arab Gulf (Plate 3): Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates (UAE). Iran and Iraq are currently excluded although both nations have a coastline on the Persian Gulf.

Yemen is currently not part of the union. This country is, however, involved in some GCC initiatives (i.e., activities related to the health sector) in view of a future accession. For example, Yemen is a member of the Council of the GCC Health Ministers (CHM).

The Supreme Council is the highest authority of the GCC and is formed by the heads of the Member States. Presidency of the GCC Supreme Council rotates, and it convenes annually in a regular session, though additional extraordinary sessions may also be scheduled. This Supreme Council is supported by the Ministerial Council, composed of the Ministers of Foreign Affairs of Member States or other ministers acting on their behalf. The Ministerial Council proposes policies, lays out recommendations, and coordinates existing activities in all fields. Resolutions adopted by other ministerial committees are referred to the Ministerial Council, which in turn refers relevant matters to the Supreme Council for approval.

The CHM is the highest regional level of authority in the area of health. It consists of Health Ministers from each of the GCC Member States (plus Yemen, though presently not a member). It meets for two to three days twice a year, and these meetings are open to all regulators from the GCC Member States and Yemen. WHO (via its Regional Office for the Eastern Mediterranean, EMRO) also attends as an observer. The CHM is supported by an Executive Board to whom an Executive Office General Director reports. The Executive Office is located in Riyadh, Saudi Arabia.

At the working level, a GCC-DR was established to oversee the different activities in the pharmaceutical sector. The Steering Committee of the GCC-DR is composed of two members from each of the Member States (including Yemen), and meets at least four times per year. The membership is limited to government agencies or DRAs. The Executive Office also appoints two of its affiliates as advisors (nonvoting members) to the Steering Committee. This committee is responsible for the registration of the pharmaceutical companies and their products as well as for the preparation of technical regulations and guidelines.

To develop a new guideline, the GCC-DR Steering Committee uses the resources of the Member States by assigning the drafting of the specific guideline to either a single Member State or several Member States. Technical working groups can also be set up to help in developing the guideline.

Within the Executive Office, a permanent GCC-DR Secretariat was also created to support the organization. The role of this Secretariat is to facilitate the harmonization activities through administration, coordination, and communication. It is also responsible for receiving and reviewing registration files for completeness and for preparing Steering Committee meeting agendas.

The GCC was created on May 25, 1981, and its unified economic agreement was signed by its Member States on November 11, 1981 in Riyadh, Saudi Arabia. The primary objective was to achieve "coordination, integration and interconnection between Member States in all fields in order to achieve unity between them" [183] . This integration plan was developed in detail during the first 20 years following the establishment of the GCC.

On December 31, 2001, the GCC Supreme Council adopted, during its 22nd Session in Muscat, Oman, a revised economic agreement that accelerated this integration. This revised agreement enhanced and strengthened economic ties and increased harmonization among Member States.

In Chapter II, the agreement defined specific areas that needed to be harmonized in order to support the GCC common market, health being one of these areas. Article 12 also promotes joint projects and adoption of integrated policies between Member States.

Having finally completed all requirements, the GCC common market was declared in December 2007 and came into force as of January 2008. This launch of the common market removed barriers to cross-country investment and service trade.

GCC cooperation in the health sector began in the mid-1970s when the GCC health ministers held informal meetings such as the one held in Geneva (May 16, 1975) during the general assembly of WHO. Such cooperation was then formalized with the establishment of the Conference of the Health Ministers of the Arab Countries in the Gulf, which held its first meeting in February 1976. Since 1991, it has been called CHM. As mentioned previously, under the CHM, the GCC-DR was established in 1999 to provide the Gulf States with safe and effective medicines.

The scope of the GCC-DR's harmonization and cooperation efforts in the pharmaceutical sector covers technical guidelines and regulatory processes. This includes the registration of pharmaceutical companies and products as well as good manufacturing practice (GMP) inspection.

Under the oversight of the CHM, the GCC-DR Steering Committee is responsible for the selection and prioritization of topics, the assignment of the development of guidelines and policies, and the subsequent review and approval of the resulting recommendations.

When a new topic is selected for harmonization, the GCC-DR Steering Committee assigns the development of the guideline/policy to either a single Member State or several Member States, and a technical working group is then established. The membership of this working group is at the discretion of the assigned Member State(s). It may include regulatory, industry, and academic experts. Technical working groups meet regularly (independently of the Steering Committee meetings). An annual meeting is also held with both the Steering Committee and relevant invited experts to discuss policy and regulations.

ICH guidelines are often used as reference material when developing GCC-DR guidelines.

Other international guidelines (including WHO recommendations), available national technical documents, and guidelines from other regions (e.g., EU) are also used.

Once developed by a working group, the draft guideline is posted on the GCC and the Saudi Food & Drug Authority (SFDA) websites (http://www.sgh.org.sa and http://www.sfda.gov.sa/ en/Pages/default.aspx). They are also circulated to all Member States for comment. At the end of the consultation period, the working group reviews all comments received, finalizes the document, and proposes its adoption by the GCC-DR Steering Committee. Following its adoption, the General Director of the Executive Office submits the guideline to the CHM for final approval.

GCC-DR Steering Committee members are responsible for monitoring the implementation of the adopted guidelines in their countries. Each country reports whether it encounters any problems in implementing the guidelines during an annual meeting where the GCC-DR activities are evaluated.

Standard practices and operating procedures have been developed to govern all steps of the harmonization process (i.e., selection and prioritization of topics, solicitation of comments, approval/ implementation of guidelines and responsibilities of the different bodies, as well as funding). Additional procedures also cover the process in place for the registration of products and companies. The GCC-DR is financed by Member States (using established quotas of contributions) and by registration fees. The status of its activities is communicated through its website, and also through presentations at national and international meetings, workshops, and conferences.

Although the Executive Office organizes GMP training, there is currently no official structured training program within this initiative. Each Member State is responsible for providing training to their regulators.

The GCC-DR has initiated work on several general topics related to the development and registration of all medicinal products (GMP and GMP inspection, bioequivalence studies, stability, good laboratory practice [GLP] , and clinical trials). The group also decided to harmonize practices on post-marketing activities via the development of guidelines on post-marketing surveillance (covering the counterfeiting problem) and pharmacovigilance. Finally, recommendations on specific types of products (biosimilars, sera and anti-venom, vaccines, and blood products) are also under discussion.

The guidelines listed above are at different stages of development (under discussion, drafting in progress, approved, or implemented). They are all based on ICH, WHO, US FDA, and/or EMA recommendations.

In addition to these guidelines, the GCC-DR also established a common central procedure for the registration of both the pharmaceutical companies and the pharmaceutical products. The establishment of a common system of registration and control of medicines was discussed at the first meeting of the CHM in 1976. This subject was a recurrent topic of discussion until actual implementation of this procedure in 2001. Since its implementation, the registration of both medicines and pharmaceutical companies has slowly transitioned from the national to the GCC registration procedure as shown in the Table 6 . Under this procedure, dossiers (including fees) are submitted to the GCC-DR Secretariat. Each country reviews the dossiers and forwards its recommendations to the GCC-DR Steering Committee. The committee's resolutions are adopted by the majority of the attendant members' votes (four countries is the minimum that must be represented). GMP inspection and analysis of samples by the accredited laboratories are also part of this central procedure. After the central approval, each country must adopt this central approval nationally.

As mentioned above, the GCC-DR is responsible for GMP inspections, but also for the approval of quality control laboratories and for the review of technical and post-marketing surveillance reports. All these central activities increase the harmonization and integration of the pharmaceutical sector.

Since its creation and the signing of its initial unified economic agreement in 1981, the GCC has cooperated in many different fields (i.e., political, military, security, legal, economic, environment, and health) and developed common policies in support of achieving full integration. This integration goal was reemphasized in 2001 when the GCC Supreme Council adopted a revised Economic Agreement. In January 2008, the launch of the GCC common market marked an important step in the GCC's integration.

In the health sector, cooperation began earlier. Before the signature of the unified economic agreement in 1981, the Health Ministers had decided to cooperate in the area of health. Since the initial discussions by the Health Ministers, many objectives have been fulfilled. The development of common guidelines, cooperation in the domain of GMPs, and the establishment of a central registration procedure for companies and products are certainly the major achievements from this group.

The unified purchase of drugs (i.e., common tenders concept) is also one of the most important achievements of the CHM. It has ensured the purchasing of high-quality registered products from registered companies (national or international) for a more affordable price as it increased the amount of products purchased. But it has also ensured the use of the same products by all Member States, which is indeed an important step in the integration process and the creation of the common market. This cooperation allows the member countries to implement common drug policies and adopt an efficient drug quality surveillance reporting system to monitor the efficacy and safety of the registered drugs [184] .

Recognizing all the above achievements, and despite clear increases in cooperation, the GCC has, however, not yet fully achieved its goal of unity in the pharmaceutical sector. Indeed, this group has selected an integration model that will require stronger ties between countries. For example, the central registration procedure still involves national reviews and is longer than the national registration [185] . Moreover, approvals delivered via this central procedure still have to be adopted by each member country. This integration process is not as advanced as in Europe, where there is a rapporteur that conducts the review of the application on behalf of the group and where the EC approves drugs on behalf of all European countries.

Harmonization of the regulation (via both regional integration and international cooperation) is critical for this region for the following two reasons:

▸ First, this region is highly dependent on medicines developed and manufactured in other countries and regions. Even if pharmaceutical companies (both international and regional) are increasing their investment in the Middle East region, this region is still primarily an import-oriented market. All GCC countries share the same characteristic of being high importers of pharmaceutical products. More than 70% and 80% of pharmaceuticals consumed in Oman and Saudi Arabia, respectively, are imported [186] . It is critical for the region to ensure that products from other countries have been developed and manufactured following acceptable standards and requirements. ▸ Second, we have seen that most of the GCC-DR recommendations and guidelines are based on other international work (i.e., ICH, WHO, etc.). The GCC is therefore dependent on the resources and expertise of these international organizations to develop its own state-of-the-art requirements and standards.

The next step in the integration process of the GCC region will certainly be a better and bigger sharing of resources and expertise. The challenges of this next step will be the development of an organization and infrastructure to support such evolution. Today, the regulatory expertise in the different countries is varied, with Saudi Arabia being the leader in the region. This country represents the biggest pharmaceutical market of the region, with approximately 65% of the pharmaceutical sales of the GCC [187], and its regulatory system is recognized as the most developed of the region. In 2010, the regulatory agency in Saudi Arabia, the SFDA, employed 150 people in its drug sector with approximately 50 reviewers, compared to less than 10 in most of the other GCC countries. The ongoing development of a common and central system needs to ensure that the less developed countries of the regions will benefit from this cooperation without impacting the more developed countries in this sector. Another challenge for this group, like for all other harmonization initiatives, is the implementation of the agreed-upon standards. The GCC needs to work on measures, including the development of a structured training program, to facilitate the implementation and follow-up of recommendations.

Today, the Southern African Development Community (SADC) is comprised of 15 Southern Africa States, and its headquarters are located in Gaborone, Botswana.

Each of the SADC Member States is at varied stages of socio-economic development, but are predominantly underdeveloped. Its aggregated gross domestic product (GDP) is approximately US $457 billion, with South Africa representing a significant portion of this amount.

Its estimated total population is approximately 250 million [188] , with an average population growth rate of 2.2% and an average fertility rate of 4.9 births per woman of childbearing age. Approximately 50% of this population lacks sustainable access to affordable and quality essential medicines. The average life expectancy is 39.7 years (the lowest in the world) [189] .

The SADC objectives (listed in Article 5 of the SADC Treaty) support regional integration and increased economic, social, and political cooperation in order to promote peace and security, economic growth, well being of the population, and protection of the environment and natural resources of the region. To achieve this major and broad objective, the SADC has launched projects and defined specific actions (e.g., harmonization of policies and creation of appropriate institutions and mechanisms).

Additionally, the SADC has had major milestones, such as the formation of the SADC Free Trade Area (FTA) in 2008, and set future goals, including the establishment of the common market by 2015 and the creation of a single currency by 2018. The first achievement related to the formation of the SADC FTA took place on August 17, 2008 at Sandton, South Africa during the 28th Summit of SADC heads of state and government. Acknowledging that regional cooperation was critical to addressing the health problems of the region, the SADC decided to include health in its program of action. The need for harmonization of registration and control of medicines was further justified in 1999 when the disparities of legal systems and levels of development affected the implementation of a regional bulk purchasing initiative (involving five medicines used to treat tuberculosis) [190] .

The SADC health program was developed taking into account global and regional health declarations and targets. To enhance this regional health integration within a legally enforceable framework, a protocol on health matters was developed.

SADC also has access to the international network because it is part of the ICH Global Cooperation Group (GCG).

The 

The Summit, comprising all the heads and/or governments of SADC Member States, is the highest regional authority and therefore the supreme policymaking institution of SADC. It is responsible for the overall direction and control of the community. Its structure and functions are enumerated in Article 10 of the SADC treaty. The Summit usually meets in the Member State holding the deputy chairpersonship of SADC at the time (additional meetings can also be held if necessary).

The main objective of the Organ on Politics, Defense and Security, under the oversight of the Summit, is to promote peace and security in the region. The structure, operations, and functions of the Organ are regulated by the protocol on politics, defense, and security cooperation, which was approved and signed by the Summit at its meeting in August 2001 in Blantyre, Malawi. Since 1999, the SADC leadership has been based on the Troika system, which includes the chair, incoming chair, and the outgoing chair of SADC (other Member States may be co-opted into the Troika if necessary). The Troika represents the Summit between annual meetings and makes quick decisions on behalf of SADC that are ordinarily made during the Summit meetings. This system allows the organization to execute tasks and implement decisions expeditiously. It also allows the provision of policy direction to SADC programs and operations between regular SADC meetings. This Troika system is applied at the Summit level, but is also applicable for the Organ on Politics, Defense and Security, the Council, the Integrated Committee of Ministers, and the Standing Committee of Officials.

To support the SADC activities, a central Secretariat was formed. This body is defined as the principal executive institution of SADC responsible for the coordination of the harmonization of policies and strategies to accelerate regional integration. It is responsible for the management of SADC meetings, and financial and general administration. It is also involved in strategic planning, management of SADC programs, and the implementation of decisions of SADC policy organs and institutions. One of the characteristics of the SADC is its emphasis on a decentralized institutional arrangement ( Figure 2) . Following previous negative experiences and failures in regional discussions, the founder states agreed that Member States should be the principal players in the formulation and implementation of policy decisions. Therefore in addition to the central SADC institutions, SADC National Committees were established by the SADC treaty. These SADC institutions at the national level are present in each Member State and include key stakeholders from government, the private sector, and civil society. Their functions are (1) to provide national feedback and input in regional strategy and planning, and (2) to ensure the proper implementation of these agreed-upon regional strategies, protocols, and programs at the national level. 

This Southern African Union was created in 1980 by nine founding Member States (Angola, Botswana, Lesotho, Malawi, Mozambique, Swaziland, United Republic of Tanzania, Zambia, and Zimbabwe) with the adoption of the Lusaka Declaration on April 1, 1980 in Lusaka, Zambia. At that time, this alliance was called the Southern African Development Coordination Conference, and its main objective was to coordinate development projects in order to lessen economic dependence on South Africa, then under apartheid. The formation of this alliance was the culmination of a long process of consultations begun in the 1970s when it became clear to the leaders of the founder countries that the improvement of living standards would require regional cooperation. This cooperation was directed initially towards the political liberation of the region. Following the decolonization and the political independence of Southern African countries, and acknowledging the poverty and economic problems of the region, the leaders of these countries saw the promotion of economic and social development through cooperation/integration as the next logical step.

On August 17, 1992 (in Windhoek, Namibia) , a new declaration and treaty was signed during the Summit of Heads of State and Government. Article 2 of the treaty gave a legal basis to the organization and promoted it from a coordinating conference into a development community. The SADC was then established to spearhead economic integration of Southern Africa. This strengthening of the integration process in Southern Africa was aligned with the overall African continental efforts to promote closer economic relations (as defined in the treaty signed in 1991 to establish the African Economic Community).

In March 2001, SADC country Heads of State and Governments met in Windhoek, Namibia. During this extraordinary Summit, many important decisions were made that triggered an amendment to the SADC treaty. First, the Summit decided to restructure SADC institutions and to establish SADC national committees in order to facilitate the implementation of a more coherent and better-coordinated strategy. The extraordinary Summit also approved the preparation of the RISDP by the secretariat. The purpose of this 15-year plan (which was adopted in August 2003 and launched in March 2004) was clearly to deepen regional integration by providing SADC Member States with a consistent and comprehensive program of long-term economic and social policies. This plan reemphasizes the major objectives of the organization, reviews the socio-economic indicators and challenges of the region, and analyzes all the important domains for the integration process (including health). It also provides objectives and specific targets for priority intervention areas, and specifies plans and timeframes for implementation and monitoring of its important measures. For example, in the health domain, the plan proposes to coordinate, harmonize, and monitor the implementation of regional policies and to standardize the qualification and accreditation systems.

The cooperation in the health domain started in 1997 with the development of the SADC health program. Three key policy documents were important in the implementation of this SADC health program: 

As defined in Article 22 of the SADC Treaty, protocols were established in each area of cooperation. These protocols spell out the objectives and scope of, and institutional mechanisms for, cooperation and integration. Each protocol (which is approved by the Summit and is registered with the secretariat of the United Nations Organization and the Commission of the African Union) is binding for the Member States that are party to the protocol. More than 20 protocols have been developed in all domains of integration.

The protocol on health [192] covers all aspects related to health (from the control of major communicable and noncommunicable diseases to the health laboratory service and institutional mechanisms). Article 29 states that Member States should cooperate in the harmonization of procedures for pharmaceuticals, quality assurance, and registration, and also in the production, procurement, and distribution of affordable essential drugs. The implementation plan of this protocol (which further defines and prioritizes the actions to facilitate implementation of the protocol) fixes the integration of regional regulatory processes and the establishment of a mutual recognition as a 2011-2015 past, present, and future milestone [193] .

In line with the SADC Health Protocol, a pharmaceutical program was developed to address issues related to the access to quality medicines in all Member States. This program was approved in June 2004. This SADC pharmaceutical harmonization initiative and cooperative activities include the development of technical guidelines and policies relating to the registration and control of medicines across the SADC Member States. The initiative aims to improve the quality, safety, and efficacy of medicines circulating within the region, and to establish and maintain a regional shared network system for DRAs. The ICH and WHO guidelines, as well as other guidelines, form the basis as reference materials for the development of regional guidelines, with agreement on the adoption of international guidelines whenever possible. Potential topics for harmonization are identified at the level of the subcommittee of Ministers of Health, often with the input of senior ministerial health officials and MRA forum experts. The process of harmonization is initiated through the SADC Secretariat, which prepares and submits for decision an agenda to the Ministers of Health.

Within this context, the SADC Pharmaceutical Business Plan was released in June 2007. This 2007-2013 plan identified priority areas, objectives, and major activities that needed to be implemented both at regional and national levels to improve access to quality and affordable essential medicines (including African traditional medicines). For example, strengthening regulatory capacity (and ensuring that fully functional DRAs are in place with an adequate enforcement infrastructure) and facilitation of the trade in pharmaceuticals within the regions were key strategies developed in the plan. The monitoring and ongoing evaluation of this plan (its implementation was estimated at US $16 million) was also described (see Figure 3 , which explains the relationship between the different players of the plan). Under the oversight of the Ministers of Health, a group of designated senior officials monitored the implementation of the plan via the establishment of technical subcommittees or task teams. This group of senior officials (from the health departments of each Member State) was also supported by the Secretariat. The sector of the Secretariat responsible for supporting the operations of the pharmaceutical harmonization initiative takes place under the directorate of the SHD&SP. National Health Ministries also play a significant role (by coordinating and leading the implementation of programs at the national level), and report on progress through their SADC National Committees. Finally, other stakeholders (e.g., professional associations, research institutions, DRAs, etc.) are also involved and requested to provide expertise and feedback on specific actions of the plan.

In 2004, the Medicines Regulatory Forum was created as a technical subcommittee to promote the harmonization and enhancement of the pharmaceutical regulations in the region. This standalone committee is made of the heads of the national regulatory bodies.

The SADC has released guidelines on several topics. These guidelines regulate the following general areas:

▸ The conduct of clinical trials: these guidelines provide a framework (information to be submitted, review process, etc.) and refer to the entire ICH GCP (this is not a replacement or subimplementation of the ICH GCP). ▸ Registration of medicines: "Guidelines for Submitting Applications for Registration of a Medicine" were released in 2007. An application form is also available. ▸ Good manufacturing practices. ▸ Pharmacovigilance (only basic rules are provided). ▸ Advertising. ▸ Recalls. ▸ Registration of nutritional supplements, vaccines, and traditional medicines. ▸ Bioavailability and bioequivalence. ▸ Stability studies. ▸ Import/export (with an emphasize on GMP).

Most of the above guidelines are based on, or cross-reference, ICH and WHO guidelines and recommendations. These international bodies provide much of the technical assistance to SADC initiatives. When they exist, national rules and requirements are also used (e.g., the GCP requirements from South Africa).

Guidelines have also been developed to cover the following topics that are of specific interest for the region:

▸ Pharmaceutical wholesale ▸ HIV vaccine clinical trials ▸ Donations of pharmaceutical products It should be noted that the SADC efforts in the pharmaceutical area include African traditional medicines. These products are an important part of the healthcare environment of these countries. One of the cooperation projects is to establish a regional databank of traditional medicines and medicinal plants, and to develop regional policies and legal frameworks for the practice of these traditional medicines.

Finally, SADC is trying to establish a joint procurement system and to harmonize standard treatment guidelines/lists among countries. These two actions will facilitate the use of the same medicines within the region and therefore allow further harmonization of the pharmaceutical environment.

Since its inception in April 1980, SADC has demonstrated that regional cooperation and integration is possible and useful for Southern Africa. One of the foremost achievements of SADC has been to put in place a regional program (the SADC Programme of Action) with numerous projects covering cooperation in various economic sectors. The formation of the SADC FTA on August 17, 2008 was an important first step in this ongoing integration process.

The overall and ultimate goal of SADC is integration by 2020; this is a very ambitious plan. Presently, the level of cooperation varies for each area. In some areas, this cooperation only aims to coordinate national activities and policies. In others, the cooperation goes towards real integration. For example, on foreign policy, the main objective is coordination and cooperation, but in terms of trade and economic policy, a tighter coordination is in progress with a view to one day establishing a common market with common regulatory institutions.

In the health and pharmaceutical domain, many harmonization projects have been established despite challenges. Indeed, as recognized in the SADC pharmaceutical business plan, the region has many weaknesses, such as weak regulatory systems (leading to many unregistered products), lack of adequate capacity and trained personnel, outdated medicine and intellectual property laws, and noncompliance to GMP (leading to inadequate availability of medicines and poor and inconsistent quality of these medicines in some Member States). Even if there is a political will, it is very difficult for the authorities of this region to resolve this situation as they are confronted by two major problems: ▸ The management of major diseases (such as HIV/AIDS, tuberculosis, malaria, etc.) ▸ The lack of adequate resources and finances to support all health initiatives

The combination of the two above problems, common to all developing countries, slows down the development of other health activities. All the efforts and resources in the domain of health are rightfully dedicated to the prevention and treatment of the major public health concerns. Activities such as the development of adequate regulatory function and framework or the development and harmonization of pharmaceutical requirements are therefore negatively impacted. Even if all SADC Member States have national medicine policies, legislation, and regulation in place, some of these policies have been draft documents for many years (up to 15 years). A number of the laws date back from the 1960s (some even to the 1930s). It is clear that such policies and legislation need revisions to include recent developments and meet current standards in public health and medicines. Such revisions and updates would help the implementation of the SADC harmonized recommendations and guidelines.

However, despite the numerous weaknesses and problems that the region faces, the SADC was able to promote cooperation between Member States in order to improve access to quality medicines. There have been several major accomplishments in the development and harmonization of pharmaceutical requirements, such as the development of pharmaceutical guidelines for the registration and control of medicines, the establishment of the pharmaceutical business plan, and the establishment of the "Medicines Regulatory Forum."

Moreover, the SADC has now analyzed (with its pharmaceutical business plan) the weaknesses, opportunities, and overall priorities in the pharmaceutical domain (i.e., regulation and control of medicines). The road map includes the assessment and strengthening of DRAs (work performed in collaboration with the WHO), combat against the spread of counterfeit medicines, the development of regional training programs, and the establishment of accredited quality control (QC) laboratories.

To support this road map and other areas of harmonization, the structure of the SADC institution will certainly have to be modified (as done in the past). In order to be successful, SADC will also need to continue to work with external organizations. Support and technical assistance from ICH and WHO will continue to be critical. But, communication and cooperation with other groups and regions (e.g., the New Partnership for Africa's Development [NEPAD]) will also be necessary to coordinate the efforts on the entire continent and share the available resources, financial support, and expertise. This is especially important because some SADC members are also part of other African subregional initiatives.

Finally, the next important phase for SADC is the implementation of the agreed-upon standards, recommendations, and plans (e.g., How will the proposed actions to "strengthen national DRA capacity to implement harmonized SADC guidelines" be managed?). Implementation is a challenge for all harmonization initiatives. This is especially true for this region due to all the weaknesses carried by these countries and the lack of resources and finances. However, the lack of appropriate regulations in some countries may paradoxically become an opportunity; the coordination of the development of the regulation (based on the WHO and ICH recommendations) can be viewed as an a priori harmonization. Moreover, it is interesting to note that the SADC structure presents a specificity not found in other harmonization initiatives. In addition to the standard centralized bodies (i.e., Summit, Council of Ministers, Committee of Senior Officials, Central Secretariat, etc.), the SADC has established National Committees. These national SADC contact points could become critical for this implementation phase. This unusual model may also be useful for other worldwide initiatives.

The Association of Southeast Asian Nations (ASEAN), established in 1967, has very broad objectives. The aims and purposes of the Association, stated in its Declaration, include:

▸ The acceleration of economic growth, social progress, and cultural development in the region through joint endeavors in the spirit of equality and partnership in order to strengthen the foundation for a prosperous and peaceful community of Southeast Asian Nations ▸ To promote regional peace and stability through abiding respect for justice and the rule of law in the relationship among countries in the region ▸ To promote active collaboration and mutual assistance on matters of common interest in the economic, social, cultural, technical, scientific, and administrative fields ▸ To provide assistance to each other in the form of training and research facilities in the educational, professional, technical, and administrative spheres ▸ To maintain close and beneficial cooperation with existing international and regional organizations with similar aims and purposes, and explore all avenues for even closer cooperation among them

The ASEAN region has a population of approximately 590 million, a total area of 4.5 million square kilometers, a combined gross domestic product (GDP) of US $1,500 billion, and a total trade of about US $1,500 billion [194] . Its estimated annual pharmaceutical imports and exports is US $9.5 billion [195] .

Among the three pillars of the ASEAN Community (Political-Security, Economic, and Socio-Cultural) agreed upon by the ASEAN Leaders in the Declaration of ASEAN Concord II (signed on October 7, 2003 in Bali, Indonesia), the establishment of a single market by 2020 is an important goal. Its objective is to allow the creation of a stable and prosperous ASEAN economic region in which there is a free flow of goods, services, and investments in order to reduce poverty and socio-economic disparities. At the 12th ASEAN Summit in January 2007, the Leaders affirmed their strong commitment to accelerate the establishment of an ASEAN Economic Community (AEC) by 2015 and signed the Cebu Declaration on the Acceleration of the Establishment of an ASEAN Community by 2015.

In 1992, in moving towards this ultimate goal, ASEAN launched the ASEAN Free Trade Area (AFTA) and defined priorities (e.g., healthcare) where regional integration should be accelerated. One of the basic criteria to support AFTA, and ultimately a single market, is the harmonization of standards and regulations.

Therefore, recognizing the importance of the harmonization of standards to facilitate and liberalize trade and investment in the region, ASEAN has established the ASEAN Consultative Committee on Standards and Quality (ACCSQ) to harmonize national standards with international standards and implement mutual recognition arrangements on conformity assessment to achieve its end goal of "One Standard, One Test, Accepted Everywhere."

The ACCSQ monitors the harmonization of standards and regulations in many different areas (i.e., pharmaceutical products, but also cosmetics, medical devices, food, electrical and electronic equipment, automotive products, wood-based products, etc.). Harmonization in the pharmaceutical area is coordinated by the Pharmaceutical Product Working Group (PPWG). The objective of this group is to harmonize the technical procedures and requirements applicable to the ASEAN pharmaceutical industry in the region, taking into account other regional and international developments on pharmaceuticals.

Since 2003, ASEAN has been a member of the ICH Global Cooperation Group (GCG). This membership helps ASEAN to become an important component in the global harmonization process, as it constitutes a way to disseminate the ICH recommendations on drug regulatory harmonization. It also ensures that ASEAN specificities and challenges will be considered when new global recommendations are discussed.

The 

The highest decision-making body of ASEAN is the meeting of the ASEAN Heads of State and Government (the ASEAN Summit) that is convened annually. Additional ministerial meetings are also held regularly.

Committees of senior officials, technical working groups, and task forces have been created to support the ASEAN Summit and Ministerial meetings and conduct the agreed ASEAN activities.

The ACCSQ was established to coordinate the harmonization of national standards with international standards. This committee reports to the ASEAN Senior Economic Official Meeting (SEOM) that is under the supervision of the ASEAN Economic Ministers (AEM).

The PPWG, under the supervision of the ACCSQ, was created to coordinate the harmonization activities related to the pharmaceutical area. The scope of activities of the PPWG includes the following: ▸ Exchange information on the existing pharmaceutical requirements and regulations implemented by each ASEAN member country. ▸ Review and prepare comparative studies of the requirements and regulations. ▸ Review the harmonized procedures and regulatory systems currently implemented in others regions in order to develop harmonized standards, regulations, and procedures for the region.

For each specific topic selected for harmonization, the PPWG sets up ad hoc committees and assigns one of the Member States as the project leader. Membership of the Ad Hoc Committee is on a voluntary basis.

The core members of the PPWG are the chair and co-chair, representatives from the DRAs from each ASEAN Member State, a representative from the ASEAN Secretariat, as well as representatives from pharmaceutical industry associations. Delegates from additional Member States can also participate in PPWG meetings as observers. In addition, ACCSQ members and invited experts may attend the annual PPWG meeting. The Ad Hoc Committee meets prior to the PPWG meetings. Additionally, the PPWG operates through self-sponsorship (i.e., each Member State is responsible for its own funding for traveling or hosting meetings). WHO has also contributed to the process in the past.

PPWG activities are supported by the ASEAN Secretariat, which was established on Feburary 24, 1976 to coordinate the ASEAN branches and to implement ASEAN projects and activities.

In 1992, the mandate of the ASEAN Secretary-General was enlarged to initiate, advise, coordinate, and implement the agreed-upon ASEAN activities.

Finally, it should be noted that another working group, the ASEAN Working Group on Pharmaceuticals Development (AWGPD) (under the supervision of the ASEAN Health Ministers Meetings), also participates in the regional harmonization of pharmaceutical regulations through its activities on traditional medicines, good manufacturing practices (GMPs), good clinical practices (GCPs), counterfeiting drugs, and pharmacovigilance [196] .

ASEAN was officially established with the signature of its declaration (the Bangkok Declaration) on August 8, 1967 in Bangkok, Thailand by the five original Member Countries (i.e., Indonesia, Malaysia, Philippines, Singapore, and Thailand). Brunei Darussalam joined on January 7, 1984, Vietnam on July 28, 1995, Laos and Myanmar on July 23, 1997, and Cambodia on April 30, 1999.

The ACCSQ was formed in 1992 to facilitate and complement the AFTA. Efforts towards specific harmonization of pharmaceutical regulations have been initiated by the ACCSQ since 1992. The Pharmaceutical Product Working Group was then established in September 1999 in Kuala Lumpur, Malaysia following a decision by the ACCSQ during its 13th meeting (March 1999 in Manila) . During its inaugural meeting during September 6-7, 1999, the PPWG formulated its terms of reference and set up a work plan (i.e., goals, strategy, activities, expected output, and status). Subsequent meetings focused on the status review of ongoing harmonization activities, and discussion and adoptions of final recommendations.

The ASEAN also decided to develop relationships with other countries. They developed "bilateral agreements" with a number of countries (Canada, India, the US, the Russian Federation, Pakistan, etc.), other regions (Europe, GCC, SADC, Andean Group, Mercosur), and international organizations (United Nations, UNESCO). But one of the most important developments was the creation of the "ASEAN Plus Three" cooperation to promote the East Asia region. This cooperation began in December 1997 with the convening of an informal summit among ASEAN leaders and their counterparts from East Asia, namely China, Japan, and the Republic of Korea. It was then formalized in 1999 with the issuance of a joint statement on East Asia cooperation at the 3rd ASEAN Plus Three summit in Manila, Philippines. The ASEAN Plus Three leaders expressed confidence in further strengthening and deepening East Asia cooperation at various levels and areas, particularly in economic, social, political, and other fields. Public health and harmonization of standards are topics under discussion among others. Several bilateral economic arrangements have already been signed, and may be the basis for the possible establishment of an East Asia free trade area in the future [197] .

In November 2007, two important documents were ratified: ▸ First, the ASEAN charter which spells out the principles to which all 10 Member States adhere to was signed. This legal framework, which entered into force on December 15, 2008, serves as a firm foundation in formulating the ASEAN community by providing legal status and an institutional framework for ASEAN. It also codifies ASEAN norms, rules, and values, sets clear targets for ASEAN, and presents accountability and compliance. ▸ Second, the ASEAN leaders also signed the Declaration on the ASEAN Economic Community (AEC) blueprint that provides the elimination of forms of nontariff measures and market access limitations in order to transform ASEAN into a single market.

The draft guidelines developed by the Ad Hoc Committees are reviewed, discussed, and then adopted, by consensus, during the PPWG meeting. These standards are then endorsed by the ACCSQ.

The PPWG harmonization process includes the following steps: ▸ Exchange and review of information on existing pharmaceutical requirements and regulations of the Member States. ▸ Compare the requirements and regulations to identify key areas for harmonization. ▸ Create an Ad Hoc Committee (and assignment of a lead country) to prepare the draft "harmonized product," which most of the time is based on guidelines or recommendations already available (in one of the ASEAN countries, internationally, or in another regions). ▸ Circulate the draft to all Member States for comments. ▸ Consolidate comments into the revised draft. ▸ Discuss and adopt (by consensus agreement) the draft by the PPWG. ▸ Endorsement of the document and recommendation by the ACCSQ. ▸ Dissemination of the adopted documents (via the ASEAN website or seminars/ meetings). ▸ Compulsory implementation of the recommendation by the Member States.

In order to organize, coordinate, and monitor the implementation of the agreed-upon recommendations and guidelines, the PPWG set up a specific Task Force and working group to focus on a Mutual Recognition Arrangement (MRA) and implementation. They developed a standard operating procedure (SOP) and plan of action. They also assessed the status of the implementation of requirements (i.e., adoption into the national systems) in order to develop appropriate training (to government and industry) to increase understanding of the ASEAN guidelines and fill the gaps among the Member States.

The first project of the ASEAN PPWG was to compare the existing product registration requirements for pharmaceuticals of ASEAN member countries in order to help define key areas for harmonization. This report was finalized in 1999.

Following this assessment, the group developed the ASEAN Common Technical Requirements (ACTRs) for pharmaceutical product registration in the ASEAN region. These requirements are sometimes based on the existing national requirements, WHO guidelines and recommendations from other regions (e.g. the ASEAN guidelines for "The Conduct of Bioavailability and Bioequivalence Studies" were created from the EMA/CPMP Note for Guidance). But most of the ASEAN ACTRs have been developed via the adoption or modification of the ICH guidelines. They cover all the quality, nonclinical, and clinical aspects already developed by ICH. Labeling requirements, administrative data (i.e., Certificate of Pharmaceutical Product (CPP), Letter of Authorization, Application Forms, etc.), and the glossary have also been discussed. The final ACTRs were endorsed by the ACCSQ at its 21st meeting (in March 2003) . Guidelines to ACTR (e.g., Process Validation and Stability) have also been developed.

The group also developed an ASEAN Common Technical Dossier (ACTD) for pharmaceutical product registration. Like the ICH CTD, this initiative reduces the time and resources needed to compile applications for registration in different countries. Regulatory reviews and communication with the applicant is also facilitated by a standard document of common elements. This ACTD is based on the ICH CTD, but is organized into four parts only (the overview and summaries are included at the beginning of the relevant Parts I, II, and III instead of being grouped under a separate section as in Module 2 of the ICH CTD): ▸ Part I: Activities have also been conducted in the area of GMPs. On April 10, 2009, the ASEAN Economic Ministers (at the 14th ASEAN Summit and related summits in Pattaya, Thailand) signed the ASEAN MRA for GMP inspection of manufacturers of medicines. This arrangement establishes the mutual recognition of GMP certifications and/or inspection reports (issued by inspection bodies) that will be used as the basis for regulatory actions such as granting of licenses and supporting post-marketing assessment of conformity of these products.

The PPWG also worked on a bioavailability/bioequivalence study reporting format and a post-market alert system. The objective of the ASEAN post-marketing alert system is to share information relating to defective or unsafe medicines, and also cosmetics, health supplements, and traditional medicines. This pilot project was launched in April 2005 and then adopted by the PPWG in February 2006.

The two major accomplishments of the PPWG are the ACTD and the ATCRs. The ACTD is the common format for marketing authorization application dossiers, while the ATCRs are the set of written materials intended to guide applicants to prepare application dossiers in a manner that is consistent with the expectations of all ASEAN DRAs. A series of guidelines for the implementation of the ATCRs is being finalized.

Most of the ASEAN recommendations strictly follow the ICH guidelines and recommendations. Indeed, ASEAN is a good example of the influence of the ICH outside the ICH regions and of the integration and implementation of ICH standards outside ICH frontiers.

Beyond these harmonized technical aspects of the pharmaceutical product registration that need to continue, the ultimate goal of the ASEAN PPWG is clearly to implement a system where countries fully cooperate in enhancing mutual regulatory capacities and resources.

With the ongoing challenges posed by the globalized economy, and in particular the huge economic growth of China and India, which may have specific impacts on the region, this association of countries is clearly committed to full integration (with the goal to establish an ASEAN economic community by 2015) and moving towards the European community model. The ultimate steps in the pharmaceutical harmonization process will certainly be the development of ASEAN pharmaceutical directives, the development of a Pan-ASEAN registration process (with a centralized procedure), and the establishment of an ASEAN regulatory agency. But the full implementation of this supranational system will take time. It will only be possible when the ASEAN has developed common legislation and structure (i.e., commission, parliament, etc.), as in Europe. The harmonization of pharmaceutical regulations can, however, continue before such an organization is in place. The next logical step is the creation of an MRA procedure. Indeed, this type of procedure is not binding for the countries (and therefore does not require common legislation) and requests only a "facilitator body" and not a supranational evaluation agency. This procedure would be similar to the old "multi-state" procedure that Europe established in 1975 as a first step towards the creation of the system that we know today.

ASEAN is also committed to increased relations with external partners. The creation of the ASEAN Plus Three cooperation may indeed promote the harmonization of pharmaceutical regulations in the much broader Asia region. Outside the region, ASEAN and its PPWG clearly want to increase relationships and cooperation with other regional organizations, and also international bodies (i.e., UN, WHO, ICH). This development, which is outside its current framework, could indeed strengthen this initiative by increasing its exposure on an international basis, therefore allowing this organization to play a pivotal role in the international community.

The Asia-Pacific Economic Cooperation (APEC) is a forum, established in 1989, to facilitate economic growth, cooperation, trade, and investment in the Asia-Pacific region. This region accounts for approximately 40% of the world's population, approximately 54% of world gross domestic product (GDP), and about 44% of world trade [198] . Since its creation, this intergovernmental grouping has worked to reduce tariffs and other trade barriers across the Asia-Pacific region in order to liberalize trade and investment and facilitate business within the region. APEC also works to create an environment for the safe and efficient movement of goods, services, and people across borders in the region through policy alignment and economic and technical cooperation.

To support its "Three Pillars" (i.e., Trade and Investment Liberalization, Business Facilitation, and Economic and Technical Cooperation), APEC has been active in a broad range of more than 50 topics (from fisheries, agriculture, and tourism to terrorism, finance, and intellectual property). This broad range of topics, under which hundreds of specific projects have been developed, reflects the complex factors and issues related to economic development, growth, and the pursuit of open trade and investment for a region. Several of these topics can influence the health and pharmaceutical sector (such as Intellectual Property or Science and Technology), but two specifically focus on this area: ▸ The Health topic, managed by the "Health Working Group," focuses mainly on the prevention and management of infectious diseases (naturally occurring or due to bioterrorism) in the region. This working group is not involved in the discussion related to pharmaceutical regulation. ▸ The Life Sciences topic, managed by the Life Sciences Innovation Forum (LSIF), addresses key challenges in the health and pharmaceutical sector in order to create the right policy environment for life sciences innovation. The harmonization of standards and the regional and international cooperation are two of the tools used to achieve the objectives.

As a member of the ICH Global Cooperation Group (GCG) since 2003, APEC LSIF promotes the implementation of the ICH guidelines through its workshops. It also keeps ICH informed on the status of the different ongoing initiatives in the region.

APEC has 21 member economies from the broad Asia-Pacific region, which spans four continents (Plate The 21 members of APEC recognize that strong economies and harmonization initiatives are not built by governments alone, but by partnerships between government and its key stakeholders, including industry, academia, research institutions, and interest groups within the community. Therefore, APEC actively involves these key stakeholders in the work of the forum. At the working level, representatives from the private sector are invited to join many APEC working and expert groups. This process provides an important opportunity for industry to provide direct input into APEC's ongoing work.

APEC has official observers, the Association of Southeast Asian Nations (ASEAN) Secretariat being one of them. These observers participate in APEC meetings and have full access to documents and information.

APEC operates as a cooperative, multilateral economic, and trade forum.

APEC policy direction is provided by APEC Leaders from the member economies. The Life Sciences Innovation Forum (LSIF), under the Committee on Trade and Investment, is a tripartite forum involving representatives from government and academia, and also from industry. It brings together scientific, health, trade, economic, and financial considerations to create the right policy environment for life sciences innovation.

All the APEC activities are supported by the APEC Secretariat, which is based in Singapore and operates as the core support mechanism for the APEC process. It provides coordination, technical, and advisory support, as well as information management, communication, and public outreach services.

The idea of APEC as a cooperative to enhance economic growth and prosperity, and to strengthen the Asia-Pacific community, was first publicly mentioned by the former Prime Minister of Australia (Bob Hawke) during a speech in Seoul, South Korea in January 1989.

Later that year, 12 Asia-Pacific economies met in Canberra, Australia to establish APEC. In November 1994, APEC's vision was reiterated by APEC Economic Leaders during their meeting in Bogor, Indonesia. During this meeting, the Economic Leaders adopted what are referred to as the "Bogor Goals." These goals of "free and open trade and investment in Asia-Pacific no later than 2020" were based on a recognition of the growing interdependence of the economically diverse region, which comprises developed, newly industrializing, and developing economies. Due to the heterogeneity of the region, it was agreed that the pace of implementation would take into account differing levels of economic development among APEC economies.

In 1995, a framework for meeting the Bogor Goals (referred to as "the Osaka Action Agenda") was adopted. This action plan focused on three key areas: ▸ Trade and Investment Liberalization ▸ Business Facilitation ▸ Economic and Technical Cooperation

Following this first action plan, several other plans have been adopted over the years to support the implementation of the Bogor Goals. Specific topics (such as climate change and severe acute respiratory syndrome [SARS]) were also discussed. Recognizing the global financial crisis as one of the most serious economic challenges ever faced, the leaders highlighted the importance of reducing the gap between developed and developing members. This meeting included discussions related to regional economic challenges (implementing a structural reform and food supply and price), the social dimension of globalization, the enhancement of human security in the region, and the problem of climate change.

The LSIF and the Health Working Group held their first joint meeting in March 2011 in Washington, DC, US to explore possible areas of cooperation. This meeting followed the 2010 recommendations of the APEC Senior Official endorsing a new Terms of Reference for the Steering Committee on Economic and Technical Cooperation. It was then agreed that the role and operations of the Health Working Group would be reviewed with a view to merge, disband, or reorient this body.

The LSIF leads the activities related to the regulatory convergence in the pharmaceutical area within the Asia-Pacific region.

Both APEC and the LSIF have recognized the benefits of convergence related to the pharmaceutical standards within the region. To achieve this goal, these two groups rely on other regional and global harmonization initiatives. Indeed, the LSIF is working towards the adoption and implementation of existing harmonized international guidance and regulatory best practices. It also provides the ability to access funds to advance projects. Unlike ASEAN, the objective is not to proactively develop specific regional harmonized guidance. This practice is in line with the overall APEC goals to facilitate cooperation and trade in the region, and to operate on the basis of nonbinding commitments and open dialogue. As already mentioned, APEC has no treaty obligations required of its participants, and there is no plan for integration (unlike ASEAN, which follows an integration model like Europe). Recognizing this specific context, the objective of LSIF is "regulatory convergence" with gradual alignment over time between member economies. The distinction with "regulatory harmonization" is that "regulatory convergence" does not typically involve or require active harmonization of regulations that would be unrealistic within the APEC environment.

The objectives and priorities of the LSIF, listed in its strategic plan approved by the APEC ministers in 2004, are very broad. This plan includes recommendations on four different sectors: Research, Development, Manufacturing and Marketing, and Health Services. The goal was to develop recommendations that would contribute to a more efficient, effective, and coordinated policy approach to support innovation and health in the region. These recommendations have applications in many different areas (legal, finance, scientific, regulatory, infrastructures, etc.).

One of the recommendations from this strategic plan follows: "harmonization of standards for life sciences products and services and mechanisms for collaboration and exchange of information among economies were recognized as critical elements" [199] . The principle was to review policies, standards, and regulatory mechanisms against international best practices in order to move towards regional convergence. The objective was also to achieve close collaboration and to facilitate the use of international standards and global best practices through collaboration with outside bodies such as the ICH GCG.

The LSIF has been very active in sponsoring a series of workshops on anti-counterfeiting, ICH quality guidance, clinical trials, and good clinical practice (GCP) inspection. However, it has been recognized that the LSIF has not been used to its full potential to promote regulatory convergence and cooperation compared to some other RHIs [200] . What was missing was the engagement of regulators and the appropriate industry people in this equation, together with the lack of a more focused strategic framework and multiyear plan for medical products.

In 2008/2009, acknowledging the lack of strategic and effective approaches, the LSIF decided to react and strengthen its organization: ▸ In June 2009, the LSIF took an important step towards harmonization by establishing, in Seoul, South Korea, the APEC Harmonization Center (AHC). This followed a proposal from South Korea in August 2008 (at the APEC LSIF VI in Lima, Peru) that was endorsed by the APEC leaders in November 2008 in a Joint Ministerial Statement. As an LSIF organization, this center has its own structure (including a Director, a Secretariat, and an Advisory Board of LSIF Experts), and also its own website (www.apec-ahc.org). This organization includes representatives from government, industry, and academia. Its mandate is to provide a platform to address and solve priority concerns of APEC members on regulatory convergence. Following the establishment of the AHC, several workshops took place. In general, they focused on the regional regulatory convergence, but also discussed specific problems such as multiregional clinical trials and the biosimilar concept. The purpose of these workshops is to allow government, regulators, academics, and the pharmaceutical companies to discuss and exchange information and views on the harmonization of standards. Funding and support from the AHC has allowed for the delivery of more than a dozen workshops since June 2009. ▸ In addition to the AHC, APEC also decided to establish a Regulatory Harmonization Steering Committee (RHSC) within the LSIF structure to strategically coordinate regulatory convergence in the region. The RHSC brought together senior officials from regulatory authorities and representatives from industry coalitions. This committee provides leadership and direction on regulatory priorities. During its inaugural meeting in Seoul, South Korea in June 2009, the RHSC discussed and finalized its Terms of Reference and started to identify priority projects. Since then, the RHSC has initiated several projects and developed a Strategic Framework on Regulatory Convergence of Medical Products by 2020 to coordinate activities [201] .

Since the creation of the APEC AHC and RHSC, considerable progress has been made with the design, development, and implementation of a more strategic, coordinated, and sustainable approach. This includes the Strategic Framework and the creation of priority work areas (PWAs), each of which is associated with a roadmap that defines an overall strategy to achieve the ultimate goal of greater regulatory convergence by 2020 in the area of medical products. Each project or activity undertaken must now support the roadmap and in turn move APEC closer to the 2020 goal. This is a better-structured organization that moves away from individual, uncoordinated activities and workshops to a more directed, coordinated approach with parties and individuals that are in a position to effect change and commit resources.

The workshops, organized and funded by the AHC and led by the RHSC membership, are now tied to a directed roadmap and strategic framework representing the collective efforts and commitment of many economies. These workshops served as a diagnostic of issues, challenges, and opportunities associated with a particular area of focus, with recommendations coming back to the RHSC for consideration. All workshops are championed by the regulators of various APEC economies (for example, the US for medical product quality and supply chain integrity, Korea for biotechnological products and pharmacovigilance, Singapore for cellular-and tissue-based therapies, Chinese Taipei for good review practices and combination products, and Thailand for GCP inspections).

Finally, this organization is partnering with other regional and international players in an effort to promote synergy and more effective use of resources. A good example here is the supply chain roadmap. This is a global issue and requires a global, coordinated approach. The RHSC roadmap is being implemented through the direction of an oversight committee that includes the WHO, EMA, EDQM, and the DRA of Nigeria. In doing so, APEC takes account of and complements like initiatives, and can serve as a catalyst to global action.

Up to now, the APEC did not proactively develop guidance or harmonized standards and requirements. The objective is to promote convergence via the dissemination of international harmonized information and recommendations (i.e., ICH guidelines). To achieve these goals, the group has developed and funded several projects.

In 2008, the LSIF released an "Enablers of Investment Checklist," a voluntary guidance tool for member economies to assess and improve their innovative life sciences sector investment opportunities. One of the six principles covered by the checklist is "Efficient and Internationally Harmonized Regulatory Systems." Under this principle, the LSIF promoted the development and implementation of focused efforts on harmonization towards international standards through recognized international organizations (i.e., ICH). Moreover, to support this objective, the LSIF also proposed development of the following: ▸ A regulatory framework (transparent, predictable, and science-based) that allows for the quick introduction of new innovative products ▸ An efficient clinical trial regulatory system focused on safety, efficacy, and ethical standards ▸ An adequate number and level of training programs for regulatory personnel ▸ The publication of proposed regulations for stakeholder comments (which should be taken into account) ▸ Laws providing for stakeholder consultation throughout the regulatory drafting and review process ▸ Participation in international joint clinical trials Performance metrics have also been defined to assess the implementation of the recommendations. Finally, some of the other principles on this checklist also support cooperation and convergence as they assess the resources, exchange programs, intellectual property rights, and interagency coordination of life science policy and regulation.

In addition to the "Enablers of Investment Checklist," LSIF has also developed projects focusing on specific topics of interest, such as:

▸ Clinical Trials: The area of clinical trials was selected as one of the LSIF priorities in its strategic plan. Assessment and improvement of the clinical trial system and regulation in each country has also been recommended in the LSIF "Enablers of Investment Checklist."

The goal was to put in place an effective regulation infrastructure (by harmonizing regulatory practices and policies according to international best practices and standards). This activity includes work on regulatory process and framework (incorporating interagency review of new policies, guidances, and regulations), implementation and promotion of good clinical practices (GCPs)/good manufacturing practices (GMPs), protection and enforcement of intellectual property, establishment of clinical trials registries, and implementation of ICH recommendations. To implement this goal and strengthen the DRAs' capacity to harmonize practices, a first workshop on "Review of Drug Development in Clinical Trials" was held in March 2008. Several additional workshops concerning clinical trials and GCP (including clinical research inspection) have since been set up on this subject. The first workshop organized by the AHC in 2009 focused on the opportunities and challenges of multiregional clinical trials. Each of the workshops serves to refine recommendations and showcase the China-Japan-Korea Tripartite Research Initiative that is exploring possible ethnic differences between the three countries. As a result of workshops, two roadmaps have been developed: one for GCP inspection (under the leadership of Thailand), and one for multiregional clinical trials (under the leadership of Japan) [202] . The focus will address gaps and needs not addressed by any other institution or regulatory authority to date.

▸ Counterfeit Medicines: Another area of interest for LSIF has been the increase in counterfeit medicines in the region. A series of seminars and workshops have been organized since January 2008 to examine ways to combat this problem. The LSIF has also developed an Anti-counterfeit Medical Product Action Plan. The objective of this plan is to share best practices in the detection and prevention of counterfeits to both DRAs and industry professionals, and organize systems to reduce the threat and occurrence of counterfeit medicines. Finally, it is important to note that APEC also promotes capacity building for its members. This objective is met through the organization of workshops, training courses, and seminars that enable people, businesses, and government departments to improve their skills and knowledge [204] .

The primary focus of APEC is clearly the economy, and its objectives center on the facilitation of trade and business between member economies (with no integration plan). The Asia-Pacific region has consistently been one of the most economically dynamic regions in the world. Since the establishment of APEC in 1989, the total amount of trade has grown significantly [205] . APEC's work under its three main pillars of activity has helped drive this economic growth. In 2010, APEC conducted an assessment to determine what progress has been made against the Bogor Goals of free and open trade and investment. The results were positive, showing that member economies have taken concerted action and progressed in a wide array of economic, trade, investment, and social areas. Average tariffs in the region have been reduced from about 17% in 1989 to approximately 5.8% in 2010. Nontariff barriers have also been reduced thanks to APEC's work on trade facilitation. This progress by APEC towards the Bogor Goals contributed to a more than five-fold increase in members' total trade (goods and services) between 1989 and 2010 (from US $3.1 trillion to US $16.8 trillion). Finally, these activities contributed to real benefits for people across the entire Asia-Pacific region. Over the span of 10 years, from 1999 to 2009, poverty was reduced by 35% (poverty levels are measured by calculating the population living on less than US $2 a day) [206] .

APEC represents a large region and approximately 40% of the world's population. This is obviously an advantage in facing the challenge of globalization. However, this size and magnitude can also be a disadvantage in terms of management. Indeed, this region is very heterogeneous with countries at the two extremes of the development spectrum (i.e., very developed and very undeveloped countries). Due to this disadvantage and the heterogeneity of this large region, it is difficult to adopt a treaty and to impose obligations on these members. For this reason, APEC operates on the basis of nonbinding commitments where each country has the choice to implement the decisions. The implementation of economic measures (i.e., reduction of taxes and trade barriers to increase trade between members) is possible since it can quickly benefit all members. However, the lack of a treaty or obligations on members can sometimes be more challenging for more drastic long-term reforms (i.e., the harmonization of standards), as member economies have different priorities. The diversity of the APEC region means that member economies will gradually move closer together in requirements and approaches, but not everyone will implement the measures at the same time. Capacity and local realities must be taken into account.

Though technical cooperation is part of APEC's objectives (i.e., APEC is very involved on specific topics such as climate change), it is the second priority behind economic development.

The health topic, managed by the Health Working Group and the Life Science Innovation Forum, has clearly been funded because this topic has an impact on the economy. As stated on the APEC website, "Life sciences innovation is critical to growth and socio-economic development as healthy people produce healthy economies. Efficient and effective delivery of patient focused products and services can improve a population's longevity, wellness, productivity and economic potential" [207] .

However, even if the above challenges are important, very positive outcomes have to be noted in terms of regulatory convergence in the pharmaceutical area. Indeed, this organization supports convergence via the funding of projects and workshops. LSIF was able to focus its effort on projects that impact all member economies (developed or developing), such as the coordination of multicountry clinical trials, the implementation of GCPs, the quality of medicines, the counterfeit medicines problem, and the emergence of biosimilars. LSIF also creates a forum that allows exchange of information between very different countries and between all the players (regulators, industry, and academia). This communication and dissemination of harmonized standards is very important, and is as essential as the development of the standards itself.

In 2008/2009, acknowledging a lack of strategic coordination, APEC and LSIF decided to better organize the activities. First, they established the AHC to facilitate the exchange of information and the creation of a network. Second, they created the RHSC to strategically coordinate regional convergence. Since this revision of LSIF's structure and the creation of these two supporting bodies, significant progress has been made and APEC has since declared that further harmonization to "achieve convergence on regulatory approval procedures" is targeted for 2020 [208] . To support this goal, many important projects have been initiated on critical topics, such as product quality and supply chain integrity [209] , good review practices [210], GCP inspection [211], pharmacovigilance [212] , biotechnology products [213], etc. All these changes and projects today represent great promise for this region, and the tools to be developed could also support global cooperation and convergence. The challenge is now to implement the plan and to continue to coordinate the projects in order to achieve the desired objectives. The recent establishment of the RHSC Regulatory Network (including DRAs not currently part of the RHSC) will certainly support the implementation of agreed-upon measures.

Many different types of bilateral cooperation have been established over the years. lll It would be difficult to list and discuss them all as several dozen exist. However, all these types of bilateral cooperation and agreements can be grouped into three categories based on their scope and objectives: ▸ Cooperation between Two Developed Countries: The objective of such cooperation is to exchange good practices and harmonize standards to avoid duplication of efforts (e.g., for orphan drugs). For example, the EU and the US developed a privileged relationship and the exchange of officials and staff between US FDA and EU Authorities allow for a closer collaboration, exchange, and therefore better understanding of each other. ▸ Cooperation between One Developed Country and One Developing Country: This type of cooperation focuses on training, mentoring, and support from the developed country to the developing country. The objective is indeed to build expertise and capacity in the developing country based on the experience of the developed country. For example, the US FDA has established several agreements with developing countries (e.g., Brazil, Mexico, South Africa, Taiwan, etc.) ▸ Cooperation between Two Developing Countries: By pooling experience and resources, two countries can better tackle issues of common interest. This type of cooperation allows for better allocation of sparse resources, and also increases interest for pharmaceutical companies (two small markets with different requirements would be less attractive to industry). For example, Brazil has cooperation projects with Cuba, Dominican Republic, Mozambique, and several other countries [214, 215] .

One of the most advanced bilateral collaborations is between Australia and New Zealand. It represents a good example of a bilateral cooperation and harmonization model working towards a full integration of systems. Indeed, after several years of convergence and harmonization, Australia and New Zealand agreed to establish a joint Australia New Zealand lll Bilateral cooperation can involve two countries, but it can also mean the collaboration of a regional entity with another party. For example, the European Union has been collaborating with Australia, Canada, the US, and Japan, but also with the GCC group.

Therapeutic Products Agency (ANZTPA). This new Agency will ultimately replace Australia's Therapeutic Goods Administration (TGA) and the New Zealand Medicines and Medical Devices Safety Authority (Medsafe). During the first meeting of the ANZTPA Implementation Ministerial Council (Melbourne, January 28, 2012), Ministers from both countries agreed on key elements to establish the joint Trans-Tasman Agency, and also how the joint regulatory scheme will be organized over a five-year period [216-1]. Since then, the framework of the ANZTPA is under discussion .

This cooperation/harmonization initiative was begun with the objective of sharing expertise and resources in order to provide health benefits for consumers by creating a world-class scheme. It is also expected that this single approval process for both countries will increase efficiency, improve the standards of medicines produced in the two countries, reduce regulatory costs for industry, and facilitate further economic integration [217] .

This initiative is a great example of successful bilateral harmonization and cooperation, and emphasizes the importance of a staged approach for this type of project. It also shows that such ultimate integration of systems is challenging. Indeed, the agreement for a joint regulatory scheme was first reached in 2003, but this project was not able to proceed because New Zealand was unable to pass enabling legislation. Negotiations between the countries were also suspended in July 2007 [218] .

The increased collaboration between Europe and the US in the pharmaceutical domain is another interesting example of bilateral cooperation. Though this cooperation does not follow an integration model, it is a well-developed bilateral initiative. It is a stepwise and structured program that is interesting as it provides a clear example of what such bilateral collaboration can achieve in a nonintegration process, and also outlines its limitations. It also provides examples of the measures and organization necessary to support such bilateral work.

The European Union (EU) and the United States of America (US), in addition to their collaboration within the scope of multilateral frameworks such as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), have also established strong regulatory and scientific bilateral cooperation in the pharmaceutical sector. This bilateral cooperation promotes public health, safer trade of products, and harmonization of regulations.

Over the years, the scope of this transatlantic collaboration has increased, and today represents a good example of what bilateral cooperation can achieve.

This collaboration mainly involves the European Commission (EC), the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA). However, it is important to note that the US FDA also maintains an active relationship with national DRAs throughout Europe.

Confidentiality arrangements with the US have been signed at the European level (EC and EMA) and also at the national level with Austria, Belgium, Denmark, France, Germany, Ireland, Italy, the Netherlands, Sweden, and the United Kingdom. This is particularly important for collaboration in the area of inspections. It also allows the US FDA to exchange information on products not approved via the Centralized Procedure (this exchange is done through the relevant Reference Member States [RMSs]).

The leaders of the EU and the US agreed on a framework for advancing transatlantic economic integration and established the Transatlantic Economic Council (TEC) to oversee the efforts outlined in the framework, with the goal of accelerating progress and guiding work between EU-US Summits. Moreover, confidentiality agreements have been established to create a framework allowing the exchange of confidential information between the EU and the US FDA as part of their regulatory and scientific processes. They include information on advanced drafts of legislation and regulatory guidance documents, as well as nonpublic information related to ensuring the quality, safety, and efficacy of medicinal products for human (and veterinary) use. An implementation plan has also been agreed upon between all parties to allow for a successful exchange of information and documents between the EU and the US FDA in accordance with the terms of the confidentiality agreements. The objective of this implementation plan was to describe the processes by which each party will undertake information and document exchange as envisioned by the confidentiality agreements. Also, to facilitate this transatlantic pharmaceutical cooperation, the US FDA and the EMA have established "liaison officials." These liaison officials remain employed by their home organizations, but their physical location in the partner agency is designed to facilitate collaboration. Their role is to facilitate regulatory and scientific cooperation between the US FDA and the EMA, and to coordinate information exchange. They also increase awareness of interaction opportunities with the EMA and the US FDA, and potential new areas of common interest [219,220]. In 2003, the scope of this bilateral cooperation intensified with the establishment of confidentiality arrangements between the parties. These agreements signed on September 12, 2003 were then extended on September 15, 2005. In September 2010, these confidentiality agreements were extended again, and are now in effect for an indefinite period without the need for further renewal. These two 2010 official statements of authority and confidentiality commitment [223, 224] restate the agreement to pursue in-depth collaboration and exchange of confidential nonpublic information between the US FDA and the EMA. It is interesting to note that these statements reiterate that the shared information includes confidential commercial or trade secret information (the US FDA is required by current legislation to ask pharmaceutical companies before sharing trade secret information with counterpart DRAs).

At the EU-US Summit on April 30, 2007, further momentum was given to regulatory collaboration with the signature of the Framework for Advancing Transatlantic Economic Integration between the European Union and the United States of America by EC President José Manuel Barroso, German Chancellor Angela Merkel, and US President George W. Bush. This document called for more effective, systematic, and transparent regulatory cooperation, and the removal of unnecessary differences between regulations. It also specifically requested the promotion of "administrative simplification in the application of regulation of medicinal products."

The objective of this bilateral process is more towards cooperation than harmonization per se. Exchange of information between the parties allows for a better understanding of each other's systems and requirements, and therefore builds confidence and recognition facilitating convergence. This EU-US cooperation also tries to avoid future disharmony by upstream regulatory cooperation on new medicines legislation [225] .

The exchange of information and practices are well structured and occur on a regular basis, but the exchange can also be done on an ad hoc basis if necessary. ▸ Regular Exchange: The EMA and US FDA exchange a list of specific information on applications (both pre-authorization of new molecules and post-authorization of marketing products), including decisions made for such applications on a quarterly basis. They also exchange other information such as a list of Good Clinical Practice (GCP) inspections or pharmacovigilance topics (either product-or nonproduct-related issues).

▸ Ad Hoc Exchange: In addition to the exchange of new drafts of final legislation or guidelines (prior to publication), the EU and US FDA also exchange information relating to scientific advice, difficulties in relation to the evaluation of applications, and urgent drug safety issues and other issues impacting public health. These types of information are exchanged prior to their release into the public domain.

Meetings or workshops on regulatory issues of mutual concern are also organized on an ad hoc basis.

Finally, the EMA and the US FDA publish an annual report summarizing their interactions under the confidentiality arrangements. These arrangements also provide for annual meetings between the US FDA, the EMA, and the EC to monitor the operation of activities within the scope of the agreed-upon implementation plans. However, it should be noted that the sharing of product-related information is limited to medicinal products evaluated or authorized in accordance with the EU Centralized Procedure, as well as medicinal products authorized at the national level by the EU Member States, which are subject to arbitration or referral in accordance with European Community procedures [226].

Initiatives related to general topics are reported below. In addition to these initiatives, cooperation has also been established in certain specific scientific areas or for a specific type of product (i.e., oncology, pharmacogenomics, nanotechnology, Advanced Therapy Medicinal Products [ATMP], blood products, and vaccines).

Under the auspices of the Transatlantic Economic Council, on November 28, 2007 the EC hosted the "Transatlantic Administrative Simplification Workshop" in Brussels, Belgium, which was co-chaired by the EC and the US FDA and organized in collaboration with the EMA and the Heads of the EU National Medicines Agencies (HMA). The key objective was to identify opportunities for administrative simplification through transatlantic cooperation in the removal of unnecessary burdens of administrative practices and guidelines. This would allow more human and fiscal resources to be focused on greater innovation and efficiency in the development of quality products. It was agreed that this project should not require change to legislation, and of course, the simplifications should maintain or increase current levels of public health protection.

As a follow up to the Transatlantic Administrative Simplification Workshop, a "Medicines Regulation Transatlantic Administrative Simplification Action Plan" was published in June 2008, outlining administrative simplification projects to be taken forward. This document promoted further cooperation and pilot collaboration programs in major areas such as inspections, biomarkers, counterfeit medicines, risk management (content and format), scientific advices, biosimilars, pediatrics, and advanced therapies.

During the annual EC/EMA-US FDA bilateral meeting in September 2010, it was agreed that the majority of projects in the original plan had been successfully completed and that most of the pilot projects had been extended and became "standard" cooperation [227] . Ongoing developments and new initiatives in transatlantic administrative simplification are now included in the annual reports on interactions between the US FDA and the EMA.

Several projects have been initiated to increase collaboration on GMP and GCP inspections. Ad hoc exchanges on specific products, quality defects, product shortages, and on draft guidelines also took place.

▸ GMP Inspections: Several pilot projects were first initiated in the context of the Transatlantic Administrative Simplification Workshop deliverables. An initial project (established in cooperation with the European Directorate for the Quality of Medicine and the Australian Therapeutic Goods Agency) was conducted between December 2008 and December 2010 and related to GMP inspections of Active Pharmaceutical Ingredients (API) manufacturers [228] . The project's objective was to determine whether greater international collaboration and information sharing could help to better distribute inspection capacity, thus allowing more sites to be monitored and reducing unnecessary duplication.

The second project, related to finished products, allowed EU-US FDA joint inspections and was aimed at developing ways of working together on joint inspections of routinely scheduled sites in the territory of the US or EU, to reduce duplicate inspections and the resulting burden on both the pharmaceutical industry and the DRAs.

This pilot phase, conducted under confidentiality agreements, allowed the development of new tools for work sharing and the exchange of information in order to share inspection reports and to organize joint inspections. Increased transparency and visibility of inspections performed by participating authorities allowed a successful collaboration between authorities on manufacturing sites of common interest. It also increased the number of inspections performed that were of value to more than one authority. This pilot phase confirmed that such collaboration in the area of GMP inspections led to a reduction in duplicate inspections, more efficient use of combined inspectional resources, and wider global inspectional coverage. Following the successful conclusion of the pilot, it was agreed to maintain the cooperation established [229] .

In December 2011, the US FDA and the EMA decided to further enhance their GMP inspection cooperation by moving from confidence building to reliance upon [230] . This initiative, launched in January 2012, allows the EMA and the US FDA to share inspections of manufacturing sites in each other's territories. This important step follows the positive experience acquired through the pilot joint inspection programs and other information sharing projects that have occurred over several years. This strategy allows some inspections on each other's territories to be deferred or waived completely based on a number of considerations and on a risk-based approach [231] . This strategy is applicable to GMP inspections related to manufacturing sites located in the US and the European Economic Area (EEA), mainly focusing on routine post-authorization and surveillance inspections as a first step [232] . The result of this arrangement could free up inspection resources that would then become available for inspections to other regions.

Ongoing EMA-US FDA joint inspection pilot projects will continue according to the agreedupon procedures [233, 234] as it remains important to maintain mutual confidence and build further mutual understanding of GMP inspection approaches. Some successful pilot programs will also be expanded to new partners such as the ongoing collaboration on GMP inspections of active substance manufacturers [235] .

Due to the increased globalization of pharmaceutical product clinical development, and based on previous positive experiences in the GMP field, the EMA and US FDA agreed to launch a pilot EMA-US FDA GCP initiative. The objective of this GCP initiative, conducted between September 2009 and March 2011, was to reinforce and systematize periodic information exchanges on GCP-related activities between the US FDA and EMA. These included the exchange of GCP inspection plans to improve inspection coverage, the exchange of information on applications to help identify candidates for collaborative inspections, and the exchange of inspection outcomes and reports (both negative and positive) and their potential impact. Conduct of collaborative GCP inspections and the sharing of information on interpretation of GCP (such as draft guidelines or policies) were also part of this project.

The pilot initiative has been very productive. A considerable amount of information has been exchanged on many products [236] , and this communication (which included 23 teleconferences and four face-to-face meetings) has facilitated improvements in the inspection coverage and decision-making processes of the agencies. The 13 collaborative inspections conducted under the initiative have contributed greatly to each agency's understanding of the other's inspection procedures. They have also led to the identification of potential improvements to these procedures. Both agencies have learned several general lessons during the process [237].

In addition, exchanges of views on interpretation of GCP documents have also been organized. During the pilot initiative, the EMA and the US FDA have shared different pieces of GCP-related guidance documents, position papers, and policies in order to harmonize the agencies' understanding of GCP and to standardize the requirements for industry wherever convergence would be beneficial for the clinical research process.

At the end of the program, both parties considered this pilot initiative very successful and agreed to continue this collaboration, incorporating lessons learned with the broader aim of moving from "confidence building" to the mutual acceptance of inspectional findings. The agencies will also expand the scope of the initiative to sites outside the US and EU [238].

Although not defined as a cluster, interactions in the area of safety continue to play an important part in the ongoing collaboration between the US FDA and the EMA.

▸ Videoconferences take place on a bimonthly basis and include product-related issues and issues related to risk management. Usually five to six products are discussed at these teleconferences. ▸ Regular informal teleconferences in order to exchange information on emerging safety and strategic issues. ▸ EMA shares the Early Notification System on a monthly basis and the US FDA sends advance notice of publication of its quarterly update reports on potential safety signals. ▸ Joint projects have also been established, such as the collaborative project on the Progressive Multifocal Leukoencephalopathy Research Agenda to stimulate research into this important safety issue that affects some biological agents.

The objective of this program is to allow interaction between the EMA and the US FDA assessors and sponsors during product development. This dialogue between the two agencies' assessors and sponsors on scientific issues [240] aims to optimize product development and avoid both unnecessary testing replication and unnecessary diverse testing methodologies.

Such a procedure can be valuable for products developed for indications for which development guidelines do not exist, or if guidelines do exist, the EMA's and the US FDA's recommendations differ significantly. Experts from the EMA and the US FDA exchange views and discuss draft responses to questions from the applicants on their clinical development programs or on new biomarkers.

General principles for this voluntary parallel scientific advice were published in 2009 by the EMA and the US FDA [241] . It is important to understand that this is a parallel procedure, and unfortunately, not joint advice. The goals of the EMA and US FDA are primarily to share information and perspectives, rather than specific harmonization of study or regulatory requirements (although they recognize that harmonization is a beneficial outcome). After this procedure, the two agencies conduct their individual regulatory decision-making process regarding drug development issues and marketing applications. Each agency provides independent advice to the sponsor regarding questions posed according to their own usual procedures and timelines. The advice of each agency may therefore still differ after the joint discussion. However, in many cases, these discussions between regulators achieved a high degree of alignment and helped industry move closer to a global development plan [242] .

In 2010, following a rather slow acceptance in previous years (due to hesitation from industries to use this procedure that does not commit the two agencies to issue common advice), the EMA and the US FDA discussed seven new parallel scientific advice procedures. WHO experts were involved in two of these procedures, due to the therapeutic area covered by the request. In addition to the formal parallel scientific advice exchanges between the US FDA and the EMA, ad hoc informal scientific advice teleconferences between the agencies took place for five products in 2010 [243].

"Clusters" or specific areas of mutual interest have been identified, and a more structured working relationship has been established. These clusters (i.e., oncology, pediatrics, orphan medicines, pharmacogenomics, blood products, biosimilars, and vaccines) facilitate the exchange of information through teleconferences relating to applications for marketing authorization and extensions of indications, including risk management plans [244] .

The latest cluster established, with a focus on biosimilars [245], significantly increased cooperation between the agencies. The recent announcement from the EMA stating that the agency will now accept data from reference product batches sourced outside the EU for biosimilar product applications [246] will certainly boost the EU-US cooperation in this domain and the global development of biosimilar products. This decision follows the US FDA proposal to also accept comparative data referencing a product that is not approved in the US [247].

The EU-US FDA collaboration on orphan drug development has been important. Discussions between the EMA and the US FDA usually include sharing of information on applications submitted in order to approach and discuss criteria for designation. A common application form has been designed and agreed to so that sponsors can apply for orphan designation (of the same medicinal product for the same use) in both jurisdictions using this common form, facilitating the exchange of information. Since 2010, discussions have also included analysis of different opinions.

On February 26, 2010, the US FDA and the EMA announced that they had agreed to accept the submission of a single annual report mmm from sponsors of orphan products designated for both the US and the EU [248] . Each regulatory body continues to conduct their own review of the annual report to assure the information meets their own requirements. The use of one single report benefits both the sponsor and the two regulatory agencies. The sponsors benefit from the elimination of duplication of efforts to develop two separate reports, and the regulators can better identify and share information throughout the development process of an orphan product.

Collaboration in pediatrics is governed by the principles agreed to in 2007 [249] . This framework includes information exchange (product-specific and general issues) and invitation of the other party to relevant pediatrics meetings. The two main objectives are (1) to avoid exposing mmm These reports provide information on the status of the development of orphan medical products, including a review and status of ongoing clinical studies, a description of the investigation plan for the coming year, any anticipated or current problems in the process, difficulties in testing, and any potential changes that may impact the product's designation as an orphan product.

children to unnecessary trials, and (2) to facilitate the development of global pediatric development plans that are based on scientific grounds and that are compatible for both agencies.

In practice, the cluster on pediatrics organizes monthly teleconferences between the EMA's pediatric team and the US FDA during which Pediatric Investigational Plans (PIPs) are discussed in detail and information between the two agencies is exchanged. In addition, more general questions have also been addressed, such as extrapolation, choice of endpoints, and patient/parent reported outcomes. From September 2009 until September 2010, 42 products and four general topics were discussed [250] . Since the end of 2009, US FDA representatives have been able to participate in certain EMA PDCO discussions and vice versa. The EMA has also provided the US FDA access to its internal database that includes scientific details on all PIPs.

Several guidelines have been developed at the ICH level (ICH Q8, Q9, Q10) in order to facilitate the implementation of "Quality by Design." Taking into account the global perspective of pharmaceutical manufacturing, the EMA and US FDA agreed that it would be beneficial if at this early stage of implementation assessors from the US and EU could exchange their views on the implementation of ICH concepts and relevant regulatory requirements using actual applications.

A three-year pilot program, operating under the US-EU Confidentiality Arrangements, started in April 2011. This program allowed parallel evaluation of "Quality by Design" aspects of applications submitted to the EMA and the US FDA at the same time [251-1]. On August 20, 2013, the EMA and US FDA published the lessons learned and Q&A resulting from the first parallel assessment. Both agencies found the pilot program extremely useful to share knowledge, facilitate a consistent implementation of the ICH guidelines, and harmonize regulatory decisions to the greatest extent possible [251-2].

The bilateral collaboration between the EU and the US has been extremely productive, and today it is recognized as a very successful initiative. Its scope has increased over the years, from the basic exchange of information and harmonization of format to close collaboration and discussion of divergent positions. The liaison placement in each organization has also been an important decision to facilitate such cooperation. This increase in interaction, in a relatively short period of time, has been driven in part by reaction to crises and in part by proactive measures to enhance EMA-US FDA communication and collaboration [252] . The establishment of the Transatlantic Administrative Simplification project in 2007 has also been beneficial as it initiated several pilot projects that further demonstrated the need for, and benefits of, such collaboration.

In general, activities in all the clusters have increased over time, and there has been an overall increase in the number of ad hoc requests for teleconferences on specific products and topics. Following a significant increase between 2008 and 2009, the total number of monthly US FDA and EMA interactions (i.e., teleconferences, document exchanges, etc.) now averages about 55 per month, excluding document exchanges relating to cluster and pilot activities.

Significant achievements have also been made in several critical areas for public health such as orphan medicinal products (with the agreement on a single annual report), drug development (with the establishment of the parallel scientific advice procedure and collaboration on pediatric development), GCP and GMP inspections (with several successful pilot projects that increased collaboration), and safety of products (with close collaboration and regular exchange of safety information, risk management, and safety alerts). Exchange of draft regulation (before release in the public domain) has also facilitated harmonization of practices and exchange of opinions. Finally, tools for more effective tracking have also been developed. All these achievements confirm that collaborations between countries have a positive impact on public health. It is particularly evident in certain areas such as orphan drug development (for diseases affecting a small population) or the exchange of information relating to urgent drug safety issues (to better assess and understand risks).

It is also important to note that this successful collaboration allows not only for the convergence of practices, but more importantly, this exchange of information and communication builds confidence in each other's systems, practices, and evaluations, allowing for a sharing of activities in certain areas. This is already the case in the area of inspection. In December 2011, EMA spokesperson Monika Benstetter stated that "each agency is now relying on its partner for drug manufacturing facility inspection data." [253] The success of this transatlantic cooperation is partly due to the fact that it has been well structured and organized over the years. The establishment of clusters and then the creation of the liaison officials' positions nnn strengthen regulatory cooperation between the agencies. These decisions have been extremely beneficial from the perspective of education and timely communication. A large number of staff visits and exchanges also took place, and there is now more routine involvement in the scientific work of both agencies. The US FDA representatives take part as observers in Committee for Medicinal Products for Human Use (CHMP) discussions, and the EMA representatives are provided with access to webcasts of US FDA Advisory Committees.

However, other parameters such as those listed below have also been critical for this success, and clearly demonstrate their importance of this type of cooperation and harmonization initiative: ▸ First, it is clear that the political commitment to increased cooperation has been important. Indeed, closer collaboration was evident after the signing of the "Framework for Advancing Transatlantic Economic Integration between the European Union and the United States of America" in 2007 by EC President José Manuel Barroso, German Chancellor Angela Merkel, and US President George W. Bush. ▸ Second, the establishment of confidentiality agreements, which since 2010 are effective for an indefinite period, allow both parties to exchange inspection reports or other nonpublic product-related information. This was critical in the establishment of collaboration as this communication on specific practical cases allowed the parties to nnn Since 2009, the FDA has seconded a permanent representative to the EMA's office in London. Since early 2010, the EMA has seconded a representative to the FDA's offices.

discuss the similarities and differences of opinion when assessing product applications and documentation. Although necessary, sharing only public information (i.e., new regulations and guidelines) does not provide this opportunity. ▸ Third, this bilateral collaboration benefited from the fact that both parties had the same level of maturity and development of their systems and regulations, and similar public health needs and challenges (even if they were not always identical). ▸ Lastly, the step-by-step approach established has been helpful because it provided clear priorities (with the clusters), allowed progressive exchange of information (from ad hoc requests to regular teleconference and nonpublic product information exchange), and time for each party to evaluate the partner agency's system and practices (with several specific pilot projects and visits/exchange of staff). Although it took some time and a lot of effort, these different steps were beneficial as they facilitated transparency and confidence building. This clear understanding of similarities and differences of practices is a prerequisite to foster a culture of convergence of each agency's assessments and evaluations.

To conclude, this bilateral collaboration is now very developed and has moved from confidence building and exchange of information, to recognition of each other's information and data for decision making. Its success so far supports the continuation of this collaboration and even its extension, as confidence in each other's system continues to increase. Although it is recognized that each party will remain ultimately responsible for public health in their territories, closer cooperation and convergence are obviously possible in many domains. Finally, it would be beneficial to continue to expand successful projects to additional partners (as has been the case for GMP inspections of active substance manufacturers [254] ) in order to foster greater international collaboration and information sharing.

In addition to the bilateral, regional, and global regulatory initiatives described in previous sections, other technical and scientific harmonization projects have also been initiated. Although these projects do not enter in the scope of this research (as they do not specifically relate to regulatory harmonization), it is important to mention them, as the standards they develop are often used by the regulatory harmonization initiatives.

The following organizations and projects ooo have indeed supported the harmonization of standards in the pharmaceutical domain:

▸ The Pharmacopoeial Discussion Group (PDG) involves (since 1989) the European Pharmacopoeia (EP), the Japanese Pharmacopoeia (JP), and the US Pharmacopeia (USP) to harmonize pharmacopoeial standards (i.e., excipient monographs and selected general chapters). It works in collaboration with ICH, and WHO became an observer in May 2001.

ooo This list of organizations/projects below is provided as an example and does not represent an exhaustive list.

▸ The International Organization for Standardization (ISO) is the world's largest developer and publisher of international standards (with a network of the national standards institutes of 163 countries and a central secretariat in Geneva, Switzerland). This is a nongovernmental organization that today has more than 19,000 international standards and other types of normative documents covering many technical areas.

▸ The Pharmaceutical Inspection Co-operation Scheme (PIC/S) facilitates (since 1995) ppp cooperation and networking in the field of good manufacturing practice (GMP) in order to lead the international development, implementation, and maintenance of harmonized GMP standards and quality systems of inspectorates in the field of medicinal products. The PIC/S activities include the development and promotion of harmonized GMP standards and guidance documents, the training of inspectors, and the assessment of inspectorates. This initiative currently includes more than 40 worldwide pharmaceutical inspection authorities.

▸ The Council for International Organizations of Medical Sciences (CIOMS) is an international, nongovernmental, nonprofit organization that was established jointly by WHO and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949. It includes over 55 international, national, and associate member organizations representing many of the biomedical disciplines, national academies of sciences, and medical research councils. One of the objectives of CIOMS is to facilitate and promote international activities in the field of biomedical sciences, and its activities include programs on drug development and international nomenclature of diseases.

▸ The World Medical Association (WMA) is an international organization founded in 1947 to represent physicians. Today, it includes 100 National Medical Associations, and its goal is to achieve consensus on the highest international standards of medical ethics and professional competence. The Declaration of Helsinki (developed in 1964) is the WMA's best-known policy statement.

Finally, other groups of experts have also worked and released recommendations on specific topics related to the harmonization of pharmaceutical regulations (e.g., the PhRMA's [Pharmaceutical Research and Manufacturers of America] Simultaneous Global Development project [255] or the nonprofit TransCelerate BioPharma project [256] ). All these projects contribute to the global convergence and harmonization of pharmaceutical regulations.

Many harmonization initiatives have been established over the past several decades because regulators understand that cooperation can help in resolving the new challenges brought on by globalization. Understanding the importance and advantages of cooperation and ppp The Pharmaceutical Inspection Convention (PIC) had been operating since 1970.

harmonization in supporting their mandate to promote and protect public health, many countries and regions have strongly enhanced their collaboration with other countries bilaterally and multilaterally at the regional and global levels.

The globalization of the pharmaceutical market has highlighted several problems that have been associated with data generated from foreign countries and with imported products. For example, in 2008, deaths associated with heparin imported from China into the US was due to contamination of its pharmaceutical ingredients at a Chinese plant, and in Panama, the diethylene glycol found in cold and fever medicine killed many people [257] [258] [259] . These problems have been a wake-up call, and they further increased the recognition of benefits to be derived from leveraging the activities and resources of foreign counterpart DRAs [260] .

For example, the US has strongly increased their international collaboration in the pharmaceutical domain. US legislators decided that such international cooperation and harmonization activities are an integral part of the US FDA's mission. Indeed, the Food and Drug Administration Modernization Act of 1997 stated that one of the missions of the FDA is to "participate through appropriate processes with representatives of other countries to reduce the burden of regulation, harmonize regulatory requirements, and achieve appropriate reciprocal arrangements" [261] . Since then, the US FDA's international work has grown exponentially, especially over the past decade, to respond and adapt to the new global society [262] . It has increased communication qqq and developed regulatory cooperation with other countries (bilaterally and multilaterally). The US FDA's role in harmonization and multilateral relations is to coordinate and collaborate on activities with various international organizations (i.e., WHO, ICH, PANDRH, and APEC) and individual countries on international standards and harmonization of regulatory requirements. In pursuit of appropriate international collaboration, the US FDA utilizes a wide variety of International Arrangements, including "Confidentiality Commitments" rrr and "Memoranda of Understanding and other Cooperative Arrangements." sss

The EMA is one of the US FDA's closest regulatory partners. with China, uuu the US FDA must increase its capacity for inspecting and analyzing Chinese products before they are shipped to the US. In order to accomplish this, the US FDA established an office in Beijing, China in November 2008 and employed 14 people (with additional employee hiring planned in the following years [263] ). It has allowed for solid relationships with Chinese regulators and exporters, and has trained more than 1,600 manufacturers and regulators on US safety standards in two years [264] . Finally, there has been increasing recognition within the US FDA of the need to strengthen regulatory capacity and provide technical and scientific expertise to developing countries to ensure that products exported to the US meet US FDA standards and adequate levels of patient protection. Many cooperative initiatives have been established to meet this goal [265] .

other countries and regions, including the US, EU, Australia, Canada, Singapore, and China. These bilateral collaborations are based on confidential agreements vvv and include information sharing. Proactive exchange of staff has also been agreed upon with some DRAs ( ). Japan's PMDA has also developed privileged relationships with China and South Korea following the pandemic influenza crisis [271, 272] . Since 2007, this tripartite initiative has specifically cooperated on clinical research and promoted regional clinical trials [273, 274] .

In February 2009, the Advisory Council approved the PMDA International Strategic Plan as a framework for its international activities [275] . This plan outlined the strategies for bilateral, regional, and global cooperation, and established an internal office in charge of international affairs. In line with this International Strategic Plan, further goals (to be attained by 2020) were published in November 2011 . Finally, a Roadmap for the PMDA International Vision was released in April 2013. In this roadmap, the PMDA defines more specific actions to support its international vision .

The primary objective of this increase in international collaboration was to urgently resolve the "drug lag" www that has impacted the Japanese pharmaceutical market in the past (2.4 years in 2006). Many measures have been taken to improve the clinical testing environment (including the promotion of global clinical trials) and expedite drug approval decisions (via, among other measures, the increase of collaboration with the other worldwide DRAs). A global, simultaneous drug development approach has also been strongly recommended. Many actions, including release of guidelines, have been taken to facilitate such global development [277] .

In addition to the US and Japan, other major DRAs of developed countries (such as Health Canada and the Australian TGA) also recognized the important added value of global cooperation and therefore increased their involvement in international activities. The EU, based on its prior experience of harmonization and cooperation from the establishment of its own system, has also developed external bilateral and multilateral collaborations and is today an important international partner.

Although these diverse, coexisting, bilateral, regional, and global initiatives create complexity, it is important to note that they are complementary. Global harmonization does not preclude having regional harmonization and regional harmonization does not preclude bilateral agreements. In fact these three levels of harmonization and cooperation bring about different added value:

▸ Bilateral agreements allow for a bigger exchange of information, including productspecific data, through confidential agreements and the development of privileged relationships (and trust) between regulators as they allow for assessment of one another's vvv In the case of China, a cooperative agreement has been established. www Drug lag is defined as the difference of availability of new medicines between the US and Japan.

systems and practices. xxx These assessments are indeed critical for confidence building and can ultimately support the signing of agreements, allowing for recognition of inspection or the exchange of nonpublic information (e.g., EU/US collaboration and confidentiality agreements). Bilateral collaboration also helps strengthen relationships, which would be more difficult in the context of a multilateral initiative, and facilitates training and mentoring activities between developed and developing countries.

▸ Regional harmonization allows for the harmonization of policies between countries that are usually closer in term of systems, cultures, and levels of development. It is indeed easier to harmonize closed systems and policies between countries of similar culture and environment (for example, it is more difficult to harmonize systems and policies between Asia and North America because they have very different medical practices and cultures). This level is essential for global harmonization because it provides a structure. Achieving global harmonization without a supporting regional organization structure is impossible. This regional level allows for inclusion of regional realities and difficulties in global discussions, and eases the diffusion and implementation of the global recommendations.

▸ Global harmonization is the highest level of harmonization. Compared to regional harmonization, the global harmonization initiative is not driven by economic objectives; the goal is not to create a free trade area or a single market, but to develop global consensus and standards in order to allow the world's population to have access to medicine and innovative therapies.

To conclude, these bilateral, regional, and global cooperative activities have been beneficial as they supported the harmonization of requirements globally and therefore facilitated the availability of safe and efficacious medicines, critical in promoting global public health, on a worldwide basis. Many topics and standards have already been partly or fully harmonized at a bilateral, regional, or global level. For example, most of the requirements regarding the conduct of nonclinical studies, and also the GMP and good clinical practice (GCP) principles, have been agreed on, allowing for joint inspection projects. A common format of application has been developed, and many technical aspects have been harmonized through the ICH's work. Collaboration has also been increasing in resolving major topics requiring global interaction, such as orphan drug evaluation yyy and development of medicines for the pediatric population. zzz Confidence and trust have been built between developed countries through pilot projects, but xxx For example, bilateral collaboration allows two countries to assess their respective inspection systems or systems to control critical information (such as trade secrets). Such assessments of each other systems could be possible in the case of multilateral collaboration, but would be more complex. yyy Because only a small number of the population is affected by these life-threatening diseases or serious conditions, it is critical to have global requirements in order to facilitate global clinical studies. Moreover, the pharmaceutical industry has been reluctant to invest in the research and development of medicinal products to treat these conditions. The development of global requirements allows quick access to the global market and therefore allows a better return on investment. zzz It is critical that countries cooperate in this area to avoid exposing children to unnecessary trials.

also through the location of official liaisons in other DRAs to facilitate collaboration. This has been positive, and this new type of interaction is very promising as it increases relationships and allows for the better exchange of experiences and information. aaaa The establishment of liaisons in other countries also allows more proactive measures and risk analysis in the area of quality systems and inspections [278] . Exchanges of information between DRAs have also dramatically increased. This regular communication between regulators facilitates evaluation of risk (e.g., via exchange of safety alerts) and assessment of new medicines. Finally, systems have been put in place to help developing countries (e.g., CPP scheme, prequalification of medicines, Article 58 of European Regulation (EC) No 726/2004, etc.).

However, without underestimating all these important positive outcomes, it is clear that differences still exist and that further efforts will be required to support this ongoing harmonization process. There are still differences between countries in terms of standards and strategies to assess compliance against standards. The conduct of global clinical studies continues to present many challenges (i.e., related to registration, conduct of the studies, and also the use of data), and there are still several clinical trial registries and databases in use. The safety of medicines has been one of the main focuses of DRAs in the past due to major problems and events, but there has not been a real effort toward worldwide harmonization regarding risk-mitigation strategies. Additionally, new standards continue to be developed by different bodies (i.e., ICH vs. regional organizations) in parallel that not only duplicate efforts, but also create disharmony (e.g., biosimilars requirements had first been developed by individual countries and also by WHO). There is also a significant difference in the level of implementation of harmonized standards (i.e., the ICH recommendations/guidelines) between countries, and the CTD format has still not been implemented in all countries. It has also been reported that differences between developed and developing countries has in fact continued to increase in the past several years due to the increased complexity of technologies associated with the development of new therapies. Even between two close partners like the US and EU, which have developed a privileged partnership and strong cooperation, there are still important differences in standards. For example, the US is still requiring two placebo-controlled studies to determine efficacy of a new medicine, while the EU is more interested in comparative studies using an active comparator. This difference is due to different legal requirements and scientific opinions regarding the value of such comparative data [279] . This situation may change in the future with the growing interest in the US for "comparative effectiveness" promoted by the Obama administration.

Finally, this complex worldwide harmonization context (with increased communication and exchange of experience, information, and good practices) requires good communication and coordination between all these ongoing initiatives. Even if such communication was initiated by WHO and ICH (with the GCG group), further improvement would still be needed. This enhanced coordination of international cooperation would indeed be beneficial, as it would provide the necessary transparency regarding the focus and responsibility of each initiative (i.e., development of standards, coordination of implementation of recommendations, etc.).

aaaa Exchange of information and best practices has been one of the most important outcomes of the EU/US bilateral collaboration.

It would also facilitate the appropriate use of resources and expertise, and therefore avoid duplication of efforts or conflicting recommendations and actions. Overlapping membership between the initiatives bbbb may not be fully efficient, and can create confusion and duplication of work.

Although the increased coordination of these diverse initiatives would be beneficial, it will certainly be challenging. It will need to be thoroughly structured and implemented, and it will also be critical that the coordinated body is a recognized and experienced entity, with appropriate mandate and power.

Under this Directorate, the US FDA's Office of International Programs serves as the agency's focal point for all international matters and is responsible for maximizing the impact of the US FDA's global interactions. Additional US FDA reorganizations were also announced in 2012 to further respond to drug industry globalization [268]. Also, in addition to China, the US FDA now has staff stationed permanently in India

the total number of shipments of US FDA-regulated products from China increased from approximately 1.3 million to 2.1 million. Of the 2.1 million entry lines arriving in 2011, 30% were drugs and devices, and 12% were human food products