








key: cord-267608-0odu8lus
authors: Chen, Daohong; Qi, Eric Yining
title: Innovative highlights of clinical drug trial design
date: 2020-06-03
journal: Transl Res
DOI: 10.1016/j.trsl.2020.05.007
sha: 
doc_id: 267608
cord_uid: 0odu8lus

Clinical trials serve as the gold standard to evaluate the efficacy and safety of tested drugs prior to marketing authorization. Nevertheless, there have been a few challenging issues well noted in traditional clinical trials such as tedious processing duration and escalating high costs among others. To improve the efficiency of clinical studies, a spectrum of expedited clinical trial modes has been designed, and selectively implemented in contemporary drug developing landscape. Herein this article presents an update on the innovated human trial designs that are corroborated through coming up with approval of notable therapeutic compounds for clinical utilization including delivery of several blockbuster products. It is intended to inspire clinical investigators and pharmaceutical development not only timely communicating with the regulatory agencies, but also insightful translating from cutting-edge scientific discoveries.

The randomized clinical trials (RCTs) of sequential three phases have been traditionally regarded as an official paradigm during drug development for decades. While phase I study is to define the tolerability, pharmacokinetics and adverse effects, subsequently phase II and then III studies are to examine the therapeutic efficacy in exploratory and confirmatory manners respectively [ 1， 2] . Although RCTs historically played and are still playing a decisive role in evaluating efficacy and safety of a therapeutic agent prior to the marketing authorization, the implementing practice also came up with several challenges including tedious processing duration, ever-escalating costs and lack of subgroup differentiation for maximizing clinical benefits [2, 3] . To circumvent these problems, the significant advancement in disease biology and clinical pharmacology has inspired emergence of a spectrum of innovated clinical trial designs in contemporary drug developing landscape [2, 3, 4] .

Overlapping with the essential principles of classic RCTs, these recently emerged clinical studying models are characterized by an impressive list of additional strengths such as improved time and cost effectiveness among others [3] . Based upon the progresses in bio-assays of clinical pharmacology, the USA Food and Drug Administration (FDA) made a policy change known as Hatch-Waxman Act in 1984, which officially determined the human pharmacokinetic bio-equivalence (BE) to replace traditional RCTs for developing generic medications [4] . As a result, the BE policy was also implemented for chemical generics by European Union in 2009 [4] . Consistently in 2016, Chinese State Council initiated a campaign requiring the quality of generic drugs be reevaluated through running clinical BE studies, compared to that of original reference products [5] .

In the field of innovative medicine, dramatic breakthroughs from life science have revolutionized our understanding in a number of aspects of disease biology, including therapeutic targets and diagnostic bio-markers [2，6], thus inspiring some flexible modification of traditional RCTs in order to deliver novel medicine to the patients in need more efficiently [3] . Accordingly in late 2016, the 21 st Century Cure Act was passed into law by USA Congress, and instructed FDA to update the adaptive design guidance for investigational drugs and biological therapies [7] . To date, certain modes of these updated trial protocols have exceptionally contributed to timely translating contemporary scientific discoveries into innovative drugs that addresses unmet clinical needs [ 2， 8] . In this light, the article herein highlights an array of outstanding developments in the perspective of drug trial design, being corroborated by notable successes in the clinical settings.

It has been well recognized that pharmacological effects of drugs are dependent on their targeting tissue concentration which is usually proportional to their distribution in circulation system, known as bio-availability. Of note, the latter can be affected by various pharmacokinetic-associated factors including active compound, formulation, manufacture, drug-drug interaction, among others [4, 9] . In this sense, major pharmacokinetic parameters, such as area under curve (AUC) and maximal concentration (Cmax), are utilized as the surrogate parameters to compared efficacy and safety of a generic agent with those of the reference product in clinical BE studies [9] . Most drugs are thereby accepted to be therapeutically equivalent when their AUC and Cmax fall in the range between of 80%-125% regarding limits of 90% confidence interval [4] . While having been significantly contributing to development of most chemical generics, BE is recently noted as an efficient approach that can not be completely replaced by in vitro methodology even in some high solubility and high permeability products [10] .

In parallel, BE study is frequently applied for comparing certain innovative agents in terms of formulation changes or fixed dose combinations; for example just being approved in 2018, Consensi consists of a combination of amlodipine and celecoxib to treat concomitant hypertension and osteoarthritis [11] . Realistically for evaluating a generic version of the polysaccharide drug heparin, the activities of anti-factors Xa and IIa instead of pharmacokinetic parameters are used to be the official standard for human BE trials [12] . In consistent with the policy of FDA, European Medicines Agency (EMA) has recently accepted the BE investigation in healthy human subjects for generic development of low molecular weight heparin (LMWH) without requiring RCTs in thromboembolism prone patients anymore [13] . Besides, utility of BE study is being expanded into the field of evaluating biosimilar products such as antibodies and fusion proteins which represent much larger and more complex molecules [4] . Interestingly based upon a human BE investigation in healthy volunteers and non-inferiority RCTs in the patients, the biosimilar version of etanercept, a medication of fusion protein neutralizing inflammatory cytokine tumor necrosis factor- (TNF), has just be approved for managing rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis [14] .

Contemporary pharmaceutic innovation is facing a serious realty of declined successful rates from research and development, in contrast to much more new compounds/new targets for examination in clinical investigation. In this regard to reduce a wast of the resources, FDA issued a guideline of an alternative approach for first-in-human trials in 2006, which was termed exploratory investigational new drug application (eIND, or phase 0) allowing a flexible amount of data needed for IND application based upon the specific circumstances of each proposed human trial [15] . Tending to bridge the gap between preclinical studies and traditional clinical development, phase 0 investigation differs from phase I trial in fewer human subjects, short processing time and no tolerability test. As a result, phase 0 study can accelerate the "goor-no go" decision making prior to a formal RCT, namely improving the efficiency of identifying drug-like candidates and terminating non-promising compounds [15, 16] .

The strengths of phase 0 study have been validated in various aspects of drug development including intra-target micro-dosing, clinical pharmacology, vulnerable populations, among others [15] . Interestingly, micro-dosing of insulin through limb artery injection was capable of achieving targeted control of local glucose level with minimal systemic exposure of the drug [17] ; it offered insights into local application of medications, in particular for those with narrow therapeutic windows, to deliver clinical efficacy precisely while remarkably diminishing the systemic toxic effects [18] . Impressively, an unique role of phase 0 trial has been recently highlighted in the drug development against brain tumor. As a cell cycle-associated kinase inhibitor, AZD1775 was revealed to have a strong anti-glioblastoma efficacy and poor blood-brain barrier (BBB) penetration in preclinical studies. It was through a phase 0 investigation demonstrating that the compound substantially crossed BBB and induced the expected biomarker alterations clinically, which thus made a moving-forward decision for this project [16] . Besides, microdosing study appears particularly beneficial for vulnerable populations in which new drug trials are restricted, including children, liver/kidney function impaired, mutipharmacy, among others [15] .

In contrast to a classical clinical trial of sequential three-phases with interval times in between for analysis to determine the next design, seamless development integrates the three phase-processing into a comprehensive clinical study without gaps [2, 3] . While reserving the core strength of traditional clinical trials in terms of defining efficacy and safety regarding tested compounds, seamless clinical study significantly improves time and cost efficiency to translate the scientific breakthroughs into innovative medicine [2] . A seamless phase I/II design is to examine the toxicity and efficacy in one trial, during which a reasonable dosing set need to be screened out at the first stage, and then forwarded to evaluate the efficacy at the second stage [3, 19] . In a similar sense, a seamless phase II/III trial is performed with multiple dosing levels of the investigated drug at the exploratory stage to define the most efficacious dose based upon some surrogate end-points such as objective response rate (ORR), and this dose is then continued into the confirmatory stage for further testing without a timing gap, to obtain more definitive end-points such as overall survival (OS) [8, 19] .

Given the flexibility for modification upon interim analysis, seamless development allows to study accumulating data from the ongoing clinical trial for early assessment of toxicity, efficacy or futility, and thus to decide the terminating or continuing/expanding treatment arms accordingly for further investigation [19] . It was through a well-designed seamless clinical trial that the programmed death 1 (PD-1)-blocking antibody keytruda achieved accelerated approval by FDA [2, 18] . In this scenario, a dosing-escalation study was carried out at the first stage of the trial, to evaluate safety, tolerability and possible efficacy (ORR) in a spectrum of patient cohorts with advanced cancer of various types [18, 19] . Based upon the interim analysis, the cohorts of melanoma and non-small cell lung cancer (NSCLC) were determined to be expanded for the continuing clinical trial on treatment with keytruda at the selected dosages of 2mg/kg or 10mg/kg [20, 21] . As a result, keytruda was demonstrated to confer a therapeutic benefit for the patients with melanoma (ORR: 38%~40%) and NSCLC (ORR: 19.4%); moreover, with the bio-marker stratification of PD-L1 + above 50%, an even better ORR (45.2%) was achieved in the subset of patients with NSCLC [21] . Additionally, beyond successful application for oncological drug development, seamless clinical study has substantially contributed to therapeutic innovation in other medical fields [3] . Of note, the efficiency of clinical developing inhaled indacaterol, a long-acting 2-agonist for treatment of chronic obstructive pulmonary disease (COPD), was clearly improved through a seamless clinical trial [3, 22] .

Historically human disease is categorized and managed according to anatomic location of body organs and histological types of pathology， which forms a solid basis for therapeutic indications designed in conventional clinical drug development [23] . However, since the rise of targeted medicine in recent two decades, the landscape of pharmaceutical innovation has been transformed to modulate an aberrant biological pathway that can contribute to pathogenesis across a number of diseases [24] , such as a gene mutation occurred in various neoplastic disorders [25] . Intriguingly, a mutational target is typically present only in a portion of the patients with each tumor type due to inter-personal heterogeneity, thus inspiring emergence of basket trials in the clinic [2, 23] . In this light, a targeted compound is simultaneously examined across numerous disease baskets, for example different cancer types, in order to determine not only whether the drug is efficacious but also what tumor types and more precisely which patient subsets are sensitive to this therapy [23, 25] . The first stage of a basket trial is to select the therapeutically sensitive disease types and patient sub-populations, with a bio-marker-based companion diagnosis if possible [19, 26] . Following interim analysis, the futile tumor type baskets are terminated, and the efficacious subjects are enriched from the responsive baskets, to be thus forwarded to further clinical investigation at the second stage [23, 26] .

As a selective tropomyosin receptor kinases (TRK) inhibitor, larotrectinib represents the newly approved medicine targeting a wide spectrum of tumor types, reflecting a dramatic success of basket clinical study [25, 27] . Aberrant TRK activation drives oncogenic pathogenesis, and is expressed in more than 20 distinct tumor types. Nevertheless, except a few types of rare neoplasms such as congenital fibrosarcomas, TRK alterations occur in very low frequencies in common cancers of various tissue/cell lineage origins, for instance below 5% in lung adenocarcinoma [26] . Based upon a basket trial design to investigate the clinical efficacy of larotrectinib, the subjects were selectively enrolled from patients with the aberrant TRK activity in tumors across 16 histological types. Impressively, larotrectinib was demonstrated to be well tolerated, conferring an ORR of 80% and a median progression-free survival (PFS) of 9.9 months [25, 26] . As such, this novel targeted agent stands out to address the unmet clinical need of combating the rare neoplasms and numerous common tumor types with the rare genetic mutations [26, 27] . Besides the validation in field of anti-cancer drug development, basket clinical has been proposed to go beyond oncology into cardiology, such as therapeutic innovation for preserved ejection fraction (HFpEF) across diverse etiologies, pathobiologies, and clinical presentations [28] .

To identify the best therapeutic benefit(s) of a testing drug, the flexibility of adaptive clinical trials can be implicated in indication changes based upon accumulating data or/and cutting-edge scientific discoveries [7] . Depending on bio-medical contexts, such dynamic updating of clinical applications may be pre-planned or inspired by certain serendipitous observations, through shifting from a therapeutic hypothesis to an alternative one or multiple ones [2, 29] . In this sense, a study design allows to examine beyond the intend-to-treat disease, thus being re-purposed to an alternative indication according to the initial assignment upon lack of efficacy or safety issues [7] ; otherwise, a clinical trial can also be optimized to cover more therapeutic directions with the emerged evidence of certain additional efficacy [24, 30] . In the era of precision medicine, there has been a consensus that therapeutic outcomes can vary significantly among subgroups of patients with differential genetic profiles [2, 27] . Accordingly taking the advantage of interim analysis based on novel biomarker approach for detecting the pathogenesis-specific molecular alteration(s), an adaptive clinical study can select the drug-sensitive sub-population from patients with initially targeted disease or an alternative indication, to continue the investigation for an optimized therapeutic efficacy [7] .

As a selective 5-phosphodiesterase inhibitor, sildenafil was designed to manage angina pectoris in the initial clinical trial. Disappointingly this compound appeared non-efficacious in relieving anginal pain, with a side-effect of inducing penile erection [31] . Inspired by this serendipity, the clinical development was successfully re-directed to come up with a major innovative product of anti-erectile dysfunction [29, 31] . In the field of oncology, crizotinib was initially identified as a potent inhibitor of mesenchymal-epithelial transition factor (MET), thus tending to treat the relevant neoplasms such as NSCLC and gastrointestinal tumors [2] . Whereas this compound was then revealed to suppress anaplastic lymphoma kinase (ALK) as well, and impressively to exert a clear efficacy of tumor shrinkage in the NSCLC with ALK rearrangement during a phase I clinical study. In this regard, the therapeutic indication of crizotinib was re-focused and successfully developed through following-up clinical trials, to be a precisely targeted medication for managing a subset of lung cancer patients with ALK aberrations [2, 32] . Interestingly in recent years, besides serving as an exceptional type of medicine for controlling tape 2 diabetes, the clinical trials of sodium glucose cotransporter 2 (SGLT2) inhibitors are being expanded or re-positioned to manage heart failure and protect renal function through blood glucose loweringdependent or/and -independent mechanisms [29, 33] .

Orphan drugs are developed to treat a particular spectrum of medical conditions with low morbidity, termed rare disease, resulting from genetically linked pathogenesis in most cases. Of note, definition of rare disease varies among different countries depending on epidemic incidence of each illness geographically [34, 35] . To address this largely unmet clinical need and meanwhile to deal with the challenging issue of limited market size for profits, FDA announced an incentive policy known as the Orphan Drug Act (ODA) in 1983, offering research & development funding, market exclusivity, among other attractive benefits [35] . Since then there were similar policies coming forth from other countries, encouraging an increased interest in this regard for pharmaceuticals; orphan drugs have been representing more than 40% of innovative medications marketed through last three decades [34] . Interestingly in recent years, certain orphan drugs are revealed to be overlapped with blockbuster products, which appear more notable in the field of oncology [18, 21] . In this scenario, a novel medicine can be initially approved for a rare disease, and subsequently go beyond to treat additional types of disease; vice versa a conventional drug may occasionally obtain orphan status upon expanding its therapeutic indications toward a rare medical condition [21, 34] .

Clinical development of orphan drugs often involves expedited trial designs described above, and may even be further simplified or alternatively designed under particular circumstances [35, 36] . For instance, the approval of orphan drug xuriden was based upon a minimal seamless trial for 6 weeks with only four patients, to treat hereditary orotic aciduria representing a rare disease of only 20 cases worldwide [37] . In addition, a viral inhibitor tecovirimat has recently been authorized to treat smallpox upon the waive of clinical efficacy study due to lack of patients with the naturally occurred disease. Setting the first record in regulatory history, this innovative medication was exceptionally approved based on positive results from the preclinical efficacy studies in animal models of rabbits and monkeys, along with a phase I trial of clinical pharmacology and safety in healthy human subjects [38] .

Impressively, certain orphan drug-based clinical trials can also come up with a broad spectrum of efficacy covering multiple indications. As a hallmark success of targeted medicine with orphan status, to combat Philadelphia chromosomepositive chronic myelogenous leukemia (CML) imatinib was launched onto the market through the accelerated approval following a phase II trial consisting of three open-label, single-arm clinical studies [6, 39] . Moreover, imatinib was subsequently evaluated in a basket clinical trial and demonstrated to be efficacious for an array of extra-therapeutic indications beyond CML, dramatically transforming this orphan drug toward being a blockbuster medication [40] . Besides, an interesting basket clinical study has recently been designed to investigate a target-specific monoclonal antibody for controlling an array of complement-mediated rare disorders, including bullous pemphigoid, antibody-mediated rejection of organ transplants and and warm autoimmune hemolytic anemia [41] .

Clinical trial plays an indispensable role in evaluating efficacy and safety of therapeutic agents prior to marketing for human use, and has been constantly co-evolving along with the dynamic interactions between cutting-edge scientific discoveries and regulatory policy updating [2, 3] . In this light, a number of agile clinical developing modes were designed through past decades, and impressively some of them have been further corroborated upon the contemporary achievements evidenced by successfully delivering innovative medicine to the patients in a more efficient manner [7] . While human bioequivalence study is increasingly contributing to evaluation of emerging formulation and bio-similar agents besides chemical generics [4] , several adaptive trial designs have been capable of translating the scientific breakthroughs into novel therapeutic benefits with shorter processing time and lower financial costs, to address the unmet clinical needs [3, 19] . Moreover with the assistance of bio-marker-based companion diagnosis, certain innovative trial designs have been streamlined to precisely confer selective therapeutic efficacy to the responding subgroups of patients with an array of serious diseases such as cancer and beyond [6, 27] .

Of note, to preserve the strength of clear defining efficacy and safety of tested drugs, the innovative designs of clinical study are substantially overlapped with classic trial protocols of three phases which still serve as the mainstream approach of clinical investigation [3, 7] . Realistically, the medications through expedited processing appeared having a higher rate of post-approval black-box warnings than that of regularly approved drugs in terms of safety issues [42] . It has accordingly been proposed that single-armed phased II studies to be accepted only for accelerated approval (AA) applications regarding refractory diseases. Otherwise, interim analysis of ongoing phase III trials may be able to support AA processes, with the follow-up studies required to provide further evidence for the drug's effects on human bodies [43] . Whereas precision medicine-inspired trials represent an unique highlight in contemporary clinical studies to optimize the therapeutic efficacy for preferable subsets of patients with certain diseases upon enrichment strategies [3, 27] , the validated biomarkers are limited and even much less than established drug-target molecules [2, 44] . Moreover, there still is a lack of the bio-markers to predict drugtriggered adverse events such as heparin-induced thrombocytopenia or immune checkpoint inhibitor-resulted hyper-progressive disease [45, 46] . Hence, it takes a dialectic perspective to appreciate the high efficiency of these innovated designs, with mindful efforts on circumventing their imperfectness. replaces RCTs biosimilar enoxaparin [12] biosimilar etanercept [14] Phase 0 trial Exploratory trial AZD1775 [16] with microdosing midazolam DDI [15] Seamless trial Integrated trial keytruda [18, 21] without phase gaps indacaterol [22] Basket trial One trial for numerous larotrectinib [27] types of disease tafamadis [28] Therapeutic Shifting therapeutic sildenafil [31] re-purpose indication during a trial crizotinib [2, 32] empagliflozin [33] Orphan drug Various expedited xuriden [37] trial designs tecovirimat [38] imatinib [6, 40] 

Assessing the gold standard--lessons from the history of RCTs

Cancer clinical trials: the rear-view mirror and the crystal ball

Adaptive designs for clinical trials

chemisimilars and biosimilars: is clinical testing fit for purpose?

Make up a missed lesson-New policy to ensure the interchangeability of generic drugs in China

Targeted therapy : resistance and re-sensitization

Adaptive design clinical trials: a review of the literature and Clinical Trials.gov

Adaptive clinical trials: advantages and disadvantages of various adaptive design elements

The new European Medicines Agency guideline on the investigation of bioequivalence

Investigating the discriminatory power of BCS-biowaiver in vitro methodology to detect bioavailability differences between immediate release products containing a class I drug

Consensi) for Hypertension and Osteoarthritis

Bioequivalence of a biosimilar enoxaparin sodium to Clexane ® after single 100 mg subcutaneous dose: results of a randomized, double-blind, crossover study in healthy volunteers

The introduction of biosimilars of low molecular weight heparins in Europe: a critical review and reappraisal endorsed by the Italian Society for Haemostasis and Thrombosis (SISET) and the Italian Society for Angiology and Vascular Medicine (SIAPAV)

Focus on biosimilar etanercept -bioequivalence and interchangeability

Microdosing and other phase 0 clinical trials: facilitating translation in drug development

Phase 0 trail of AZD1775 in first-recurrence glioblastoma patients

Intra-target microdosing-a novel drug development approach: proof of concept, safety, and feasibility study in humans

Cellular immunity augmentation in mainstream oncologic therapy

Adaptive clinical trial designs in oncology

Using model-based "learn and confirm" to reveal the pharmacokinetics-pharmacodynamics relationship of pembrolizumab in the KEYNOTE-001 trial

Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic

Intergrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design

An efficient basket trial design

Dual targeting autoimmunity and cancer: from biology to medicine

Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children

Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers

A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors

Innovative clinical trial designs for precision medicine in heart failure with preserved ejection fraction

The role of serendipity in drug discovery

Translating recent results from the Cardiovascular Outcomes Trials into clinical practice: recommendations from the Central and Eastern European Diabetes Expert Group (CEEDEG)

The serendipitous story of sildenafil: an unexpected oral therapy for erectile dysfunction

Development of crizotinib, a rationally designed tyrosine kinase inhibitor for non-small cell lung cancer

Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials

Orphan drugs and their impact on pharmaceutical development

Challenges in orphan drug development and regulatory policy in China

Clinical research for rare disease: opportunities, challenges, and solutions

FDA approves ultra-orphan drug on a 4-patient trial

Oral Tecovirimat for the Treatment of Smallpox

Gleevec for the treatment of chronic myelogenous leukemia: US. Food and Drug Administration regulatory mechanisms, accelerated approval, and orphan drug status

Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases

Combined integrated protocol/basket trial design for a first-in-human trial

Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study

Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs?

ANTXR1, a stem cellenriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer

Heparin-induced thrombocytopenia

Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy

We thank our colleagues for encouragement.

The authors declare no conflict of interest.

