key: cord-003118-58ta20fg authors: Van Norman, Gail A. title: Expanding Patient Access to Investigational New Drugs: Overview of Intermediate and Widespread Treatment Investigational New Drugs, and Emergency Authorization in Public Health Emergencies date: 2018-06-25 journal: JACC Basic Transl Sci DOI: 10.1016/j.jacbts.2018.02.001 sha: doc_id: 3118 cord_uid: 58ta20fg Individual patients with life-threatening or severely debilitating diseases can petition the U.S. Food and Drug Administration (FDA) through their physicians to have expanded access (EA) to drugs that are in clinical trials but have not reached full FDA approval (the “single-patient” investigational new drug [IND] application). Additionally, recent state and federal laws—so-called “right to try legislation”—allow patients to approach drug companies directly for access prior to FDA approval. While these pathways provide potential access for individual patients to investigational drugs, different EA pathways permit entire groups of certain patients to access investigational drugs prior to FDA approval. This review focuses on special categories of EA INDs intended for multiple patients—the intermediate-group IND and the widespread-treatment IND—as well as emergency authorization for use of investigational drugs and biological products (e.g., vaccines) in public health emergencies. For patients with life-threatening or severely debilitating disease, the wait for approval is simply too long, and can both abolish hope for those who diseases will be quickly fatal, and lead to sustained or even permanent disability for those whose diseases linger but are without effective proven therapies. Spurred by patient advocacy during the early days of the acquired immunodeficiency syndrome (AIDS) epidemic in the late 1980s, and facilitated by subsequent legislative efforts over the next 20 years, regulatory initiatives permit the FDA to release drugs for use in individual patients through expanded access (EA) INDs (4, 5) , in many cases allowing emergency treatment with nonapproved drugs within hours of application, and nonemergency treatment within an average of 4 days (6) . Further, most states have enacted so-called "right to try" legislation, permitting "compassionate use" of investigational drugs by individual patients through applications directly to the manufacturer (6) . It should be noted that although the terms "compassionate use" or "preapproval access" are often used informally to refer to the use of an investigational drug to treat a patient outside of a clinical trial, these terms are not defined or described in FDA regulations, which simply refer to expanded access to investigational drugs. The call for EA is not limited to individual patients. Advocacy organizations have pressed for groups of patients with rare and/or "orphan" diseases, for example, to be able to access promising new therapies prior to their approval. Indeed, social media is increasingly becoming a consumer/patient advocacy tool for implementing FDA regulatory changes and promoting access to investigational therapeutics (7) . In addition, once a drug has completed phase 3 testing and is awaiting approval, patients who have benefited from in-trial treatments may want continued therapy, and such use requires some form of "bridging approval" from the FDA to allow potentially large groups of patients to continue treatment while final FDA approval is pending. A previous review discussed individual patient emergency and nonemergency access to investigational drugs (6) . This review will focus on FDA EA for intermediate-sized groups of patients (the "intermediate-sized IND") and EA for entire classes of patients (the "widespread treatment use" IND), as well as emergency release of investigational drugs and biologics for use in public health emergencies. Releasing investigational new drugs to individual patients who are facing certain death or disability seems to be a relatively uncomplicated decision, but allowing EA to entire groups of patients for treatment with an investigational new drug presents more complex regulatory, logistical, and ethical challenges for scientists, commercial entities, and the FDA. The current regulatory process from IND filing to drug approval has evolved and includes not only the FDA's historical primary mission of ensuring patient safety, but also, since the latter half of the 20th century, the newer mission of ensuring that marketed drugs are actually efficacious for their advertised/approved use. EA for a single patient may not present much of a challenge to the assertion that a drug's benefits outweigh the risks, because as presumably the patient requesting compassionate use faces an otherwise dismal clinical future, taking even significant risks with a new drug still presents potential benefits to a patient without other options. Early in a drug's regulatory pathway, however, it is not usually possible to ensure that a drug has a reasonable risk/benefit ratio for all patients, including those in the early stages of disease. Drug companies face bigger issues when the seeker of EA is a group of patients or an entire class of patients. Before marketing, manufacture of the drug for clinical studies is nearly an "all cost" proposition for the commercial entity; the drug cannot be marketed to cover its costs. Thus, companies generally only manufacture sufficient quantities (plus a small margin) to cover the requirements of clinical studies, rather than devote resources to manufacturing large quantities of a drug which has a <10% chance of ever making it to market (1, 2) . The FDA approval process begins with the filing of an investigational new drug (IND). Making the drug available to groups or classes of patients who might then deplete the supply of drug for clinical studies could compromise the very research that would more completely disclose a drug's risks and benefits; thus, it could possibly impede full market approval that would make the drug more widely available. Companies have also expressed concern about how data from such "compassionate use" may be applied in the approval process. for CMV infection (9) . Later studies also showed that ganciclovir patients were living longer (10). The FDA refused approval of ganciclovir for treatment of CMV retinitis, because they had no animal studies for that use, nor significant human placebocontrolled trials on which to base a marketing application. Many questioned whether the use of ganciclovir was wise, or safe (11, 12) . But, because of ganciclovir's known efficacy, it became paradoxically impossible to carry out human controlled trials, because such trials are only ethically justifiable if investigators are honestly uncertain about whether net positive benefits over placebo exists (13) . Furthermore, neither patients nor doctors were willing to risk assignment to placebo and further loss of eyesight after the results were published. Syntex then sought approval to study ganciclovir for treatment of CMV colitis, knowing that once marketing approval of the drug was obtained, FDA rules would allow "off-label" use for retinitis (14) . At this time, EA of nonapproved drugs for treatment of more than 1 patient at a time is achievable only through the FDA, in contrast with access for individual patients, which technically can be legally obtained without the FDA by applying to the manufacturer directly (6) . As with individual EA INDs, specific conditions for group patient access apply: 1) the patients must have a serious or immediately life-threatening disease or condition with no comparable therapy or satisfactory alternative therapy; 2) the potential benefit must justify the potential risks of the treatment; and 3) providing the treatment must not compromise or interfere with the ongoing FDA drug development program, such as by critically depleting a limited supply of investigational drug that is also needed for an ongoing study or a future study that is in the planning stages (4). An "immediately life-threatening condition or disease" is defined by the FDA as "a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment." A serious disease or condition is defined as being "associated with morbidity that has substantial impact on day-to-day functioning." Furthermore, while short-lived or self-limited morbidity will usually not be a sufficient qualifying condition, the morbidity "need not be irreversible, provided it is persistent or recurrent." The FDA states that whether a condition is serious or not "is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one" (15) . and other animal species such as cats, armadillos, guinea pigs, swine and ferrets in which thalidomide had been tested, teratogenic effects had been induced only occasionally" (18) . In fact, when human birth defects began to appear in the offspring of women who had ingested thalidomide during pregnancy as a sedative and to treat nausea, researchers pointed out that thalidomide had failed to demonstrate teratogenicity in rats, and at first insisted that thalidomide could not be the culprit. In Germany, where the drug was first developed, thalidomide was held to be so safe that no prescription was required for its use, it was advertised for use in pregnant women (19) , and the drug company distributed free samples to its factory employees (18, 19) . given the most severe rating for drugs that contribute to fetal deformities, and for drugs whose risks prioritizing those who should receive treatment, such as women and children (36) . The fact that the treatment was made available to 2 U.S. citizens and not to Africans, who comprised most of its victims, engendered anger over the social justice of such decisions, providing, as Enserink (35) points out, a tragic validation to the satirical yet somewhat prophetic paper that had appeared in The Onion only weeks before titled "Experts: Ebola vaccine at least 50 white people away" (37) . As of now, 12 products have been approved under the Animal Rule, 7 of which were issued quickly after the guidance was published ( Table 3 There is a reasonably well-understood pathophysiological mechanism of the toxicity of the toxic substance and its prevention or substantial reduction by the product. The effect is demonstrated in more than 1 animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans. The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans. 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Accessed Experts: Ebola vaccine at least 50 white people away FDA product development under the animal rule: guidance for industry Working with the U.S. Food and Drug Administration to obtain approval of products under the Animal Rule Food and Drug Administration Ebola virus disease survivors: clinical and immunologic follow-up PREVAIL IV: double-blind, randomized two-phase, placebo-controlled phase II trial of GS-5734 to assess the antiviral activity, longer-term clearance of Ebola virus and safety in male Ebola survivors with evidence of Ebola virus persistence Expanded Access (Compassionate Use): IND submissions Medicine, University of Washington, 2141 8th Avenue West, Seattle, Washington 98119. E-mail: lbsparrow@ yahoo.com.