FDA Designations for Therapeutics and Their Impact on Drug Development and Regulatory Review Outcomes AS Kesselheim1,2 and JJ Darrow1,2 New prescription drugs receive approval from the US Food and Drug Administration (FDA) based on tests establishing safety and adequate and well-controlled trials demonstrating “substantial evidence” of efficacy. However, a number of legislative and regulatory initiatives, the most recent being the breakthrough therapy designation created in 2012, give the FDA flexibility to approve drugs on the basis of less rigorous data in situations of greater clinical need. These expedited development and review pathways now contribute to a majority of all new drug approvals and have important benefits in encouraging efficient availability of transformative drugs. They also have a number of risks, including a heightened possibility that the drugs will be discovered to be ineffective or unsafe after widespread use, and confusion by patients and physicians over what it means for a product to be “FDA approved.” INTRODUCTION

In the US, the Food and Drug Administration (FDA) serves as the primary gatekeeper to the market for new prescription drugs by ensuring that they are proven to be both efficacious and safe enough before they can be made available to patients. However, the way the FDA applies these two key criteria can vary considerably depending on the particular drug in question. For example, in 2012, the FDA approved the anti-tuberculosis drug bedaquiline (Sirturo) on the basis of two pivotal studies involving a total of about 200 patients. Those studies showed that the drug significantly improved clearance of the Mycobacterium tuberculosis bacillus from infected patients’ sputum, but also revealed that patients receiving bedaquiline were about 2.5 times more likely to die from tuberculosis than control group patients.1,2 Despite these clinical trial data, bedaquiline was approved because multidrug resistant tuberculosis is a life-threatening condition with a limited number of available treatment options. Bedaquiline is illustrative of the flexible approach that the FDA takes in reviewing drugs deemed to have particular public health importance. In such circumstances, the FDA has a number of regulatory tools at its disposal to expedite drug development, approval, and early availability of the products, thereby tempering the high costs of pharmaceutical development and efficiently channeling the agency’s own limited resources. These tools include the orphan drug designation, the accelerated approval

pathway, the fast-track designation, and the priority review program. Indeed, bedaquiline was designated as an orphan drug because tuberculosis is a rare disease in the US, was put on the fast track, was granted accelerated approval status, and was ultimately given a priority review by the FDA scientific reviewers. This array of overlapping designations and programs has emerged over the past three decades in response to crises involving the urgent needs of seriously ill patients. Another major contributor has been political pressure on Congress and the FDA from pharmaceutical manufacturers and certain patient groups to expedite the premarket drug testing and regulatory review process. In addition, new pathways continue to emerge or be proposed. In 2012, Congress authorized a breakthrough therapy designation for investigational drugs that appear based on preliminary evidence to offer substantial improvements over currently available therapies. Originally envisioned to apply to a small number of the most promising drugs each year, the FDA has received over 150 applications, of which 46 have so far been designated breakthrough drugs. Proposed legislation would create yet another abbreviated pathway for urgently needed antibiotics and antifungal drugs. In the current US pharmaceutical market, more than half of all newly approved novel drugs now receive the benefit of at least one special expedited development or review designation. Some

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Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.; 2Program On Regulation, Therapeutics, And Law, Division of Pharmacoepidemiology and Pharmacoeconomics. Correspondence: AS Kesselheim ([email protected]). Received 15 August 2014; accepted 6 October 2014; advance online publication 00 Month 2014. doi:10.1002/cpt.1

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of the products prioritized via these early access and approval pathways have been potentially transformative agents like the hepatitis C virus-treating agent sofosbuvir (Sovaldi), which in combination with other drugs may for the first time offer some patients a cure for the condition. However, other drugs that have emerged from these pathways have been controversial or had less clear clinical utility, such as ponatinib (Iclusig), a treatment for chronic myelogenous leukemia that was temporarily withdrawn from the market in the wake of reports of greater than expected adverse events, or bedaquiline, for which mandated studies intended to confirm that the sputum clearance effect was associated with positive clinical outcomes were not required to be completed for another 10 years. The proliferation of programs raises the question of whether they have had their intended effect of promoting the efficient development and early availability of therapeutic advances, and to what extent their availability and frequent use have exposed patients to harmful or ineffective drugs and contributed to the misdirection of scarce agency resources. In this review, we survey special FDA designations intended to hasten the development and regulatory approval of qualifying prescription drugs and evaluate their impact on drug development, approval, and patient care.3 Of note, FDA pathways also allow patients to receive experimental treatments on an expanded access basis even before they are approved. Each year the FDA allows preapproval access to experimental treatments by granting permission for 10 largescale early access programs, 16 intermediate-size early access programs, and more than 600 individual patient requests.4–7 We focus on the expedited development and review programs and do not address preapproval access programs. THE FDA STANDARD OF REVIEW

The 1962 Kefauver-Harris Amendments to the federal Food, Drug, and Cosmetic Act gave the FDA its power to exclude new prescription drugs from the marketplace that had not been appropriately tested for efficacy and safety. The amendments set down the basic legal standard for new prescription drug approval, requiring manufacturers to provide “substantial evidence that the drug will have the effect it purports or is represented to have,” with substantial evidence being defined as “adequate and wellcontrolled investigations, including clinical investigations” demonstrating that the product has the effect represented. The 1962 amendments were primarily designed to address concerns over the proliferation of medications with poorly documented efficacy; over the next two decades, the Drug Efficacy Study Implementation program winnowed out hundreds of prescription drugs that could not meet reasonable standards of effectiveness. In addition, the amendments minimized the risk that new drugs with severe and unanticipated side effects would be prematurely approved or distributed, as nearly occurred with thalidomide, which at the time of the amendments had been distributed for investigational use (but not approved) in the US. One year after receiving this legislative mandate, the FDA promulgated regulations requiring manufacturers to file an investigational new drug (IND) application before human testing could begin.8 The FDA also divided post-IND clinical trials into three 2

phases: phase I are tests generally in healthy volunteers to establish a nontoxic dosage range; phase II are usually uncontrolled trials in patients to provide an initial glimpse of efficacy in the population intended to be treated with the drug; and larger phase III are controlled clinical trials to establish safety and efficacy.9 The FDA interpreted the Kefauver-Harris Amendments to encourage two phase III clinical trials for each investigational drug before it could be approved. (Three decades later, in 1997, legislators would amend the FDCA to confirm the FDA’s flexible approach that, in appropriate circumstances, allowed efficacy to be proven by “one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation).”) Soon after establishing the baseline processes for review and approval of new drug products, FDA regulators recognized the importance of flexibility in applying these rules. Adaptable application of these rules was most relevant for therapies treating serious or life-threatening diseases, as concern arose that the FDA’s new authority would prevent access to lifesaving medicines during the regulatory review period.10 In response, during the 1970s, the FDA began allowing cancer patients access to experimental cancer drugs for treatment purposes before evidence of efficacy and safety sufficient for FDA approval had been obtained.11 Pressure soon emerged from physicians, patients, and manufacturers to facilitate access to investigational drugs outside of the cancer context (Figure 1).

Expedited development and approval programs Orphan drugs. The first program legislatively enacted to help a particular category of drugs reach the market more efficiently was created by the Orphan Drug Act of 1983. Recognizing that pharmaceutical manufacturers might not invest in drugs for small therapeutic markets unless the costs of producing those drugs could be reduced, Congress created a number of financial incentives to bring drugs for rare diseases to market, including tax credits, research funding grants, and additional exclusive marketing rights.12 Rare diseases were originally defined as conditions for which there was “no reasonable expectation” that domestic sales could support the drug’s development, but when drug companies declined to submit their revenue models to the FDA, the statute was amended a year later to apply as well to all diseases with an annual prevalence of under 200,000 people in the US. Congressional hearings leading up to the Orphan Drug Act highlighted the lack of treatment options for patients with rare diseases and the legislation included an expanded access policy under which the FDA was required to encourage drug sponsors to design open protocols that would facilitate broad treatment access to orphan drugs even before their formal FDA approval.13 Such expanded access to investigational orphan drugs was justified, according to Congress, by the frequent absence of alternative therapies for such diseases and their more lengthy clinical trial periods resulting from the small patient populations.14 In creating the program, Congress directed the FDA to be flexible in seeking clinical trial data and in making approval decisions relating to designated orphan drugs, with recognition that “clinical VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary/cpt

tests for orphan drugs cannot be conducted under the same requirements as tests for drugs for common diseases.”15 The number of approved orphan drugs has grown consistently as a fraction of all new drug approvals, reaching about onequarter to one-third of new approvals in recent years.16 Naturally, many of these orphan drugs are tested on fewer patients than nonorphan drugs; indeed, between 2005 and 2012, pivotal efficacy trials for newly approved orphan drugs involved a median of only 98 patients in the intervention group, compared to 294 for nonorphan drugs.17 In addition, although the orphan drug statute does not directly alter the FDA approval criteria, subsequent experience has shown that in reviewing orphan drugs the FDA follows Congress’ guidance and consistently lowers its traditional standards for what is considered to establish the statutorily required levels of safety and efficacy.18 Orphan drugs are more likely than comparable nonorphan drugs to be approved on the basis of nonrandomized, unblinded, single-arm trials, and/or trials that consider only intermediate endpoints such as disease response rather than patient outcomes.19 Fast track. A second program, designated Subpart E or “fasttrack,” was formalized in 1988 during the height of the AIDS crisis to “expedite the development, evaluation, and marketing of new therapies” aimed at serious or life-threatening diseases.20 Under the fast-track pathway, drug sponsors could request a meeting with the FDA at the conclusion of phase I trials with the goal of designing phase II trials that would produce safety and efficacy data sufficient for approval.21 It allowed for the possibility of drug approval based on a single phase II trial without traditional phase III trials. The rationale for moving to a twophase process was that desperately ill patients and their physicians were generally willing to accept greater risks and uncertainty.22 The regulations allowed the FDA to seek agreement from the drug sponsor to conduct postapproval (phase IV) studies to collect additional risk and benefit information. Accelerated approval. In 1992, the accelerated approval pathway was created to expedite approval of certain investigational drugs in a different way, allowing the substitution of “surrogate endpoints” such as tumor shrinkage for hard clinical endpoints such as death. Clinical endpoints are variables measured in trials that reflect patient experiences, including how they feel, function, or survive. Clinical endpoints include mortality and resolution of symptoms of a disease. When surrogate endpoints are substituted for clinical endpoints, investigators are using other evidence, including laboratory measures (biomarkers) or other physical measures like blood pressure, to predict clinical benefit. Surrogate endpoints substantially shorten clinical trial duration by avoiding the need to wait for hard clinical endpoints to occur in sufficient numbers of study participants to produce statistically significant results. Under the accelerated approval program, surrogate endpoints had to be reasonably likely to predict patient benefit23 and the investigational drugs had to be indicated for serious or life-threatening illnesses and provide meaningful therapeutic benefit over existing treatments.24 Because surrogate endpoints may be measurable in most or all subjects, while the event rate for hard clinical endpoints such as CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014

mortality or hospitalization may occur in only a fraction of those subjects, accelerated approval also leads to smaller trial sizes. Between 2005 and 2012, pivotal efficacy trials for drugs approved via the accelerated approval pathway involved a median of only 142 patients in the intervention groups, compared to 289 for drugs approved via nonaccelerated pathways.15 The smaller size may be partially attributable to the nature of drugs studied, since drugs for rare diseases are more likely than other drugs to qualify for expedited designations. The FDA acknowledged that “reliance on surrogate endpoints almost always introduces some uncertainty into the risk/benefit assessment” and that consequently “the expected risk/benefit relationship may fail to emerge.”25 As with the fast-track pathway, evidence of safety and efficacy for drugs approved via the accelerated approval pathway must subsequently be confirmed in phase IV clinical trials. In one review of oncology drugs granted accelerated approval from 1992–2010, confirmatory evidence of safety and efficacy was eventually developed for about half of the drugs after postmarket studies (26/47), with three removed from the market and trials for the remaining 18 not yet completed at the time of the review.26 Priority review. The priority review program, also instituted in 1992, sought to expedite not the drug development and testing process, but FDA review of a completed new drug application (NDA). The FDA had previously prioritized NDAs into types A (important therapeutic gain), B (modest therapeutic gain), and C (little or no therapeutic gain), and distributed institutional resources appropriately to the most pressing products. In the 1980s, funding shortfalls had limited the FDA’s ability to conduct timely reviews of NDAs overall, although this problem was in the process of being corrected.27 The 1992 Prescription Drug User Fee Act (PDUFA) replaced the previous three-category framework with a dual classification system under which new drugs would receive either priority or standard review.28 The priority review designation was reserved for drugs treating serious or life-threatening conditions that offered “significant improvement[s] in . . . safety or effectiveness” compared to available therapies.29 The FDA interpreted significant improvement to include 1) evidence of increased effectiveness, 2) reduction of a treatment-limiting drug reaction, 3) enhancement of patient compliance, or 4) evidence of safety and effectiveness in a new subpopulation.30 Amendments to the FDCA in 2012 mandated a few categories of drugs to receive automatic priority review, including certain antiinfective agents for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection, multidrug-resistant tuberculosis, and Clostridium difficile enterocolitis, if designated as qualified infectious disease products by the FDA.31 Drugs designated as priority review were associated with congressionally specified review deadlines of 6 months, while the FDA had to complete its evaluation of standard review drugs within 12 months (shortened to 10 months in 2002).32,33 Breakthrough therapy. In 2012, Congress created the “breakthrough therapy” designation to focus even more FDA 3

resources on investigational drugs for which preliminary clinical evidence suggested the potential for substantial improvement over existing therapies on one or more clinically significant endpoints.34 What qualifies as substantial improvement is not further defined in the legislation. In June 2013, the FDA issued draft guidance on the breakthrough drug designation that offered examples of types of improvements likely to qualify an investigational drug as a breakthrough therapy: drugs for which no current treatment is available; therapies that offer a complete response where existing treatments provide only partial responses; drugs with similar efficacy to existing therapies that offer an important safety advantage for serious adverse events; and drugs that treat the underlying cause of the disease or reverse disease progression rather than merely treating symptoms. The statute provides a nonexhaustive list of five actions that the FDA might take to expedite development and approval: 1) holding meetings with the drug sponsor; 2) providing timely advice to the sponsor; 3) involving senior managers and review staff; 4) assigning a cross-disciplinary project lead to serve as a liaison between the FDA and the sponsor; and 5) taking steps to ensure that clinical trial design is efficient. Actions (1, 2, 3) and (5) overlap substantially with those already available under the fast-track process, and the FDA has stated that drugs qualifying for breakthrough designation would also meet the standard for fast-track designation.35 Action 5 also broke new ground by encouraging flexibility beyond that already associated with the fast-track designation. In accelerating evaluation of breakthrough therapies, Congress encouraged the FDA to “us[e] a broad range of surrogate or clinical endpoints and modern scientific tools earlier in the drug development cycle,” which it expected to result in “fewer, smaller, or shorter clinical trials,” although it did not formally change the approval standard.36 Implementing this directive, the FDA in draft guidance explained that acceptable evidence for the breakthrough designation could include an effect on a “pharmacodynamic biomarker” that strongly suggests the potential for a clinically meaningful effect on the underlying disease but that does not meet criteria for an acceptable surrogate endpoint under the accelerated approval standard.37 By specifically encouraging the use of trials that “minimize the number of patients exposed to a potentially less efficacious treatment,” Congress invited the broader use of trials with adaptive designs, or trials that randomize patients in an unequal (e.g., 2:1) ratio of intervention treatment to active control treatment. Adaptive or unbalanced designs can facilitate trial recruitment and reduce costs, but close regulatory attention may be required for statistical analysis of the results.38 FDA draft guidance expresses concern that adaptive trial design could introduce bias and “increase the possibility of erroneous positive conclusions and of positive study results that are difficult to interpret.”39 In addition, unequal randomization may be in tension with the principle of equipoise that is an ethical imperative for the conduct of a trial.40 MEASURING PROGRAM BENEFITS

One measure of the impact of expedited development and approval programs is their frequency of use. Available 4

information suggests that special designations have become the norm rather than the exception. Of the 312 new molecular entities (NMEs) approved from 2002 to 2013, 174 (56%) benefited from at least one designation that expedited either the clinical development or the regulatory review of the product. Of the 27 NMEs approved in 2013, for example, 2 (7%) benefited from accelerated approval, 3 (11%) from the breakthrough therapy designation, 9 (33%) from the orphan designation, 10 (37%) from the fast-track program, and 10 (37%) from priority review, with many drugs benefiting from multiple programs. The number of NMEs benefiting from more than one program has increased from under 20% in 1987 to more than 40% in 2013.41 Increased prevalence may be partially attributable to a shift in drug development toward so-called “specialty drugs” treating smaller patient populations, including drugs for rare diseases and molecular disease subtypes.42 Another way to measure the prevalence of expedited development or approval designations is by studying all investigational drugs, rather than just those approved. According to a Congressional Research Service Report, 74.5% of requests for fast-track drug designation were granted by the FDA since the fast-track program was initiated (63.6% in the case of biologics), although only 10.6% of these applications had been approved by the publication of the report in 2008 (17.7% in the case of biologics).43 Similarly, during fiscal year 2013, 31 (34%) of 92 requests to the FDA’s Center for Drug Evaluation and Research for breakthrough designations among investigational drugs were approved (nine were still pending).44 Drugs receiving special FDA designations have shortened development and review times. One older study found that the average clinical development time for drugs with a fast-track designation was 6.2 years—compared to 8.9 years for nonfast-track drugs—while drugs benefiting from accelerated approval averaged just 4.2 years.45 The priority review program was associated with a dramatic decrease in average NDA review times, from over 30 months in the 1980s to just 9.9 months for applications received in 2011.46 While the FDA was criticized in the 1980s for being much slower than its counterparts in Europe and Canada, from 2001 to 2010 regulators at the FDA approved 63.7% and 85.7% of novel therapeutic agents earlier than did European and Canadian drug regulators, respectively.47 While making new drugs available more quickly is an important benchmark of success, expedited development and approval programs benefit patients only to the extent that the newly approved drugs confer clinical benefits not already available from existing medicines. Transformative drugs48 approved under expedited pathways include protease inhibitors for the treatment of human immunodeficiency virus (HIV), infliximab (Remicade) for rheumatoid arthritis, and imatinib (Gleevec). The latter received fast track, accelerated approval, and priority review designations, leading to approval for chronic myelogenous leukemia after only 2.5 months of regulatory review.49 First-in-class status can be a sign of a drug’s novelty, and FDA designations related to expedited development and approval have been preferentially attached to first-in-class drugs. Using a definition of first-in-class offered by regulators at the FDA,50 we VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary/cpt

reviewed 778 NMEs and original therapeutic biologics approved between 1987 and 2013, and found that 45% of priority review drugs, 50% of fast-track drugs, and 42% of accelerated approval drugs were first-in-class products. But there is no systematic evidence that first-in-class drugs actually offer major advances in treatment as an adequate tradeoff for the shortcomings of their safety evaluations. Experiences in disease fields such as type 2 diabetes, hypertension, and cholesterol-lowering show that first-in-class drugs may not offer major advances in clinical benefit for conditions in which other effective treatments are already available. These measures of expedited development and regulatory approval programs reflect the popularity of these programs and suggest that the programs have succeeded in reducing development and approval times. How well these programs target approval of medications subsequently found to have high therapeutic value is not known, although it is clearly the case that some expedited drugs have become clinically essential. Possible disadvantages of expedited regulatory review

Expedited drug development and FDA programs come with important risks. These include drug safety concerns, insufficient or delayed studies to confirm preliminary evidence on which expedited approval was based, potential industry capture associated with the fees paid for expedited review, and public misperception of the therapeutic value of drugs approved via expedited pathways.

Figure 1 Timeline of formal enactment of special FDA designations for drugs. Description and chronology of five special regulatory designations for prescription drugs that can lead to expedited approval or accelerated testing. CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014

Drug safety. Perhaps the greatest risk of expedited development and approval of investigational drugs is that the products approved based on limited data will later turn out to lack real effectiveness, or worse, be dangerous to patients. One study showed that drugs approved in the 16 years after the 1992 PDUFA legislation had 35% greater odds of having a black-box warning—the FDA’s most stringent safety warning—or being withdrawn from the market for safety reasons (26.7%) than a cohort of drugs approved prior to PDUFA (21.2%, P < 0.05).51 The authors noted two possible explanations for the greater odds, including 1) that rushed approvals led FDA reviewers to miss potential risks and 2) that rushed development compromised the quality of evidence available for the FDA to review. In another study, patients receiving orphan drugs approved for cancer indications had about 70% increased odds of experiencing serious adverse drug events during clinical testing than did patients receiving a comparable cohort of nonorphan drugs.52 Olson and other investigators have reported that drugs receiving faster reviews have more drug-related adverse events.53,54 Carpenter et al. showed that drugs approved shortly before the PDUFA regulatory deadlines were associated with higher levels of safety concerns than drugs approved at any other time.55 Still, research on whether drugs approved via expedited pathways are in fact more dangerous than drugs approved via traditional pathways is not settled. Grabowski and Wang found no relationship between review speed and actual adverse effects among the 1992–2002 drug approvals, using a different way of counting adverse effects from Olson.56 Another data point, as indicated above, is that confirmatory phase IV evidence is eventually developed for at least about half of drugs granted accelerated 5

Figure 2 Stages of drug development process and impact of FDA special designations. Schematic representation of growth in knowledge about pharmaceutical products. Point 1 represents potential impact of the Accelerated Approval designation, which truncates phase III clinical trials by permitting reliance on surrogate endpoints. Point 2 represents potential impact of the Fast Track designation, which allows approval after phase II trials for certain drugs addressing serious or life-threatening conditions. Point 3 represents potential approval point of Orphan Drugs particularly those designated as and breakthrough therapies, the latter of which can be designated as such on the basis of effects on pharmacodynamic biomarkers.3 NDA, New Drug Application.

approval. Although expedited approval increases the risk of lateridentified safety problems or drugs being less effective than initially believed (Figure 2) more work is needed to define the relationship between development and review speed and safety. As the FDA has recognized, in the most serious and lifethreatening clinical circumstances, it may be ethical to allow wellinformed patients to voluntarily assume additional risks based on promising but unconfirmed evidence that benefits exceed harms. However, the expansion of expedited development and review programs over the past two decades has led to numerous examples of drugs that are not particularly unique or clinically essential receiving these designations. For example, four breakthrough therapy-designated drugs approved in 2013 and 2014 target chronic lymphocytic leukemia (CLL), a rare blood cancer that already has a number of approved therapies on the market.57 Under the breakthrough therapy standards, these drugs presumably demonstrated early clinical evidence of “substantial improvement” over existing therapies, but details of the FDA decision process in assigning designations are not made public. Delayed confirmatory data gathering on safety and effectiveness.

While expedited programs appear to have succeeded in shortening development and approval times, the gathering of confirmatory safety and efficacy information has been insufficient. Notably, mandatory postapproval studies have been a part of FDA regulation for decades, but the proportion of new molecular entities subject to postapproval study requests or requirements has increased from 36% in the late 1970s to 80% in the early 2000s.58 However, the FDA has had limited power to enforce timely conduct of confirmatory postapproval trials. Prior studies consistently show that a substantial fraction of phase IV studies are delayed or not completed,59 and the FDA has not removed drugs from the market or taken other remedial steps solely based on the absence of confirmatory trials.60 A study of the 20 new molecular entities approved in 2008 showed that, 4 years after approval, five (25%) drugs had acquired new or expanded boxed warnings, four (20%) had additional warnings or precautions, 6

and 60% of promised studies had not yet been completed.61 Delayed evidence development is particularly problematic because manufacturer promotion of new drugs is most intense in the years immediately after approval, when postmarketing evidence may not yet be available. Regulatory resources and industry capture. Expedited development programs are not without direct financial costs. FDA personnel are needed to promulgate regulations and guidance documents, receive and respond to public comments, maintain records, respond to public requests for information, and ensure that investigational drug development is appropriately managed according to the requirements of each program. The priority review program may be particularly costly, since additional personnel must be hired in order to ensure that NDAs can be processed within the statutorily prescribed time periods. To address the need to timely review applications, including those subject to priority review, the 1992 PDUFA legislation authorized the FDA to collect “user fees” from drug sponsors. User fees have been established on an annual basis and the amount authorized to be collected rose to $760 million in 2014 from $36 million in 1993 ($58 million in 2013 dollars).32 The success of the program led Congress to institute user fees in other areas regulated by the FDA as well; overall, the 2014 FDA budget request was $4.7 billion, including $2.1 billion (45%) in user fees.62 While user fees have expanded the institutional capacity of the FDA and allowed it to institute expedited development and review programs, FDA operations and personnel salaries have become more dependent on these funds. Although the FDA is not required to approve new drug applications simply because a sponsor has paid a user fee, paying user fees has given manufacturers more political justification to become involved in FDA decisionmaking. The 1992 PDUFA legislation included a single reference to “consultation” with industry as part of a feasibility study of animal drug user fees, but did not otherwise mention pharmaceutical industry involvement.31 The FDA Modernization Act of 1997 required the FDA to “consult” with industry with respect to the VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary/cpt

FDA’s obligations under the act, explicitly calling for industry input into numerous issues, including pediatric studies of approved drugs, radiopharmaceuticals, and dissemination of information on safety and effectiveness. The PDUFA reauthorization legislation in 2002 for the first time referred to “negotiations with the regulated industry”63 as part of the process for the anticipated 2007 renewal as well as “negotiated deadline[s]” for completing required postmarketing studies. The 2007 FDA Amendments Act (FDAAA) included six references to “negotiations with the regulated industry,” and required minutes of the “negotiation meetings” to be openly available on the Internet. Input from relevant stakeholders can contribute to more effective laws, and Congress has long required administrative agencies to solicit input from regulated parties and the public.64 However, commentators have expressed concern that too much industry influence could weaken regulatory independence and adversely affect the “fidelity of regulators to their statutory obligations.”65 Others have argued that the close relationship of the FDA and pharmaceutical manufacturers built over these years puts pressure on the FDA to approve new drugs.66,67 Perceptions of therapeutic benefit and risk. While expedited development and review programs offer patients the potential for earlier access to promising investigational therapies, some have argued that the nuances of the programs are not fully communicated to patients. When a new drug is approved via a fast-track or accelerated approval program, it is necessarily based on a more limited preapproval investigation, but the newness and the promise of the drug may be preferentially communicated over the riskiness of its use. For example, for the recently approved and breakthrough-designated lung cancer drug ceritinib (Zykadia), the secondary headline to the FDA’s press release announced: “Breakthrough therapy drug approved four months ahead of review completion goal date.” However, the release reserved mention that approval was based on a single uncontrolled trial of 163 patients until the eighth paragraph of text.68 The evidence supporting any drug’s approval can be found in the formal prescribing “label,” but patients rarely receive this document from pharmacies when they pick up their prescriptions. The FDA appropriately cautions that in many cases, early promise is not borne out by subsequent definitive studies,69 but manufacturer-sponsored advertisements to physicians and patients for brand-name drugs commonly tout the newness of the product in large font, relegating to less prominence any explanations of how recently the drug was approved or inherent limitations—such as reliance on surrogate endpoints—in the data underlying recent FDA approval.70 Physicians and patients commonly expect greater benefits and fewer risks than prescription drugs can deliver, and this misperception may be enhanced in the case of expedited development and review programs.

CONCLUSION

It is difficult to predict which drugs demonstrating early promise will ultimately be approved, and focusing efforts on drugs believed to be most likely to confer large therapeutic benefits can increase regulatory efficiency and promote the more rapid developCLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014

ment and evaluation of the small number of drugs that ultimately do provide dramatic benefits. Similarly, allowing the use of surrogate endpoints can facilitate the development of drugs that might not be developed if trials were required to continue until distant clinical endpoints were reached, and fewer or smaller trials may be appropriate where treatment effects are large and reliably detectable with such trials. Expedited development and review can promote the availability of valuable drugs to seriously-ill patients and can also promote drug development by lowering development costs and business risks, making investment more attractive. Nevertheless, these programs impose substantial risks and costs. They increase the likelihood that patients will be exposed to drugs that will ultimately be shown harmful or ineffective by loosening required evidentiary standards, postpone evidence development, and fuel premature enthusiasm for unproven therapies among vulnerable patient populations. Although there is a clear need to rapidly develop new and more effective drugs to address pressing medical needs, these needs should be met with intensified research efforts and therapeutic innovation, including increased government funding of research or prize funds for effective drugs that meet priority needs. Even if well-intentioned, policymaking that is focused on more rapid approval of new drugs through an ever more complex array of designations threatens to roll back the hardwon protections established in the 1962 Kefauver-Harris Amendments and can gradually alter the meaning of “FDA approved.” ACKNOWLEDGMENTS Dr. Kesselheim is supported by a Greenwall Faculty Scholarship in Bioethics, a Robert Wood Johnson Foundation Investigator Award in Health Policy Research, and an Ignition Award from the Harvard Program in Therapeutic Science. CONFLICT OF INTEREST The authors declare that there are no conflicts of interest. C 2014 American Society for Clinical Pharmacology and Therapeutics V

1.

Diacon, A.H. et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: longterm outcome, tolerability, and effect on emergence of drug resistance. Antimicrob. Agents Chemother. 56, 3271–3276 (2012). 2. Diacon, A.H. et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N. Engl. J. Med. 371, 723–732 (2014). 3. Darrow, J.D., Avorn, J. & Kesselheim, A.S. New FDA breakthroughdrug category – implications for patients. N. Engl. J. Med. 370, 1252– 1258 (2014). 4. FDA. Expanded Access Submission Receipts Report, October 1, 2012 – September 30, 2013. 5. FDA. Expanded Access Submission Receipts Report, October 1, 2011 – September 30, 2012. 6. FDA. Expanded Access Submission Receipts Report, October 13, 2010 – October 12, 2011. 7. FDA. Expanded Access Submission Receipts Report, October 13, 2009 – October 12, 2010. 8. 21 C.F.R. § 312.40(b) (2013). 9. 28 Fed. Reg. 179–180 (Jan. 8, 1963); 21 C.F.R. § 130.3(a)(2) (1964 ed.) (see paragraph 10 of Form FD 1571). 10. Beers, D.O. & Karst, K.R. Generic and innovator drugs 10.02[A] n.5 (8th ed. 2013). 11. 55 Fed. Reg. 20,857 (1990). 12. Orphan Drug Act, Pub. L. No. 97–414, 96 Stat. 2049, § 1 (Jan. 4, 1983). 7

13. Pub. L. No. 97–414, 96 Stat. 2049 (Jan. 4, 1983) (codified as amended at 21 U.S.C. § 360dd). 14. H.R. Rep. 97–840(I), at *10 (1982). 15. H.R. Rep. 97–840(I) (1983), at *10. 16. Kesselheim, A.S. Innovation and the Orphan Drug Act, 1983–2009: the regulatory and clinical characteristics of approved orphan drugs. In Accelerating Rare Diseases Research and Orphan Product Development (eds. Field, M.J. & Boat, T.F.) (National Academy Press, Washington, D.C., 2010). 17. Downing, N.S., Aminawung, J.A., Shah, N.D., Krumholz, H.M. & Ross, J.S. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005–2012. JAMA 311, 368–377 (2014). 18. Sasinowski, F.J. Quantum of effectiveness evidence in FDA’s approval of orphan drugs. Drug Inform. J. 46, 238–263 (2012). 19. Mitsumoto, J., Dorsey, E.R., Beck, C.A., Kieburtz, K. & Griggs, R.C. Pivotal studies of orphan drugs approved for neurological diseases. Ann. Neurol. 66, 184–190 (2009). 20. 53 Fed. Reg. 41,516 (1988). 21. 53 Fed. Reg. 41,523–24 (1988). 22. Investigational new drug, antibiotic, and biological drug product regulations; procedures for drugs intended to treat life-threatening and severely debilitating illnesses. Fed. Reg. 1988;53:41516–24. 23. Fed. Reg. 58,958 (1992) (codified as amended at 21 C.F.R. § 314.510). 24. 57 Fed. Reg. 58,958 (1992). 25. 57 Fed. Reg. 1992;57:58944. 26. Johnson, J.R., Ning, Y.M., Farrell, A., Justice, R., Keegan, P. & Pazdur, R. Accelerated approval of oncology products: the food and drug administration experience. J. Natl. Cancer Inst. 103, 636–644 (2011). 27. Carpenter, D., Chernew, M., Smith, D.G. & Fendrick, A.M. Approval times for new drugs: does the source of funding for FDA staff matter? Health Affairs Suppl Web Exclusives: W3–618–W3–624 (2003). 28. FDA. Drug classification and review policy. CDER Staff Manual Guide 4820.3, January 22, 1992. 29. CDER MAPP 6020.3, at 6 (June 25, 2013). 30. CDER MAPP 6020.3, at 6–7 (June 25, 2013). 31. Pub. L. No. 112–144, 126 Stat. 993 (2012) (codified in 21 U.S.C. § 355f(f)–(g) (2014)). 32. 138 Cong. Rec. H9095 (1992). 33. Prescription Drug User Fee Act, Pub. L. No. 102–571, § 102, 106 Stat 4491 (1992). 34. FDA Safety and Innovation Act. Pub. L. No. 112–144, 126 Stat. 993 (2012). 35. FDA. Draft guidance for industry: expedited programs for serious conditions: drugs and biologics. (2013). 36. Woodcock, J. Drug development in serious diseases: the new “breakthrough therapy” designation. Clin. Pharmacol. Ther. 95, 483– 485 (2014). 37. Food and Drug Administration. Guidance for industry: expedited programs for serious conditions—drugs and biologics. (2014). 38. Dumville, J.C., Hahn, S., Miles, J.N. & Torgerson, D.J. The use of unequal randomization ratios in clinical trials: a review. Contemp. Clin. Trials 27, 1–12 (2006). 39. Food and Drug Administration. Guidance for industry [draft]: adaptive design clinical trials for drugs and biologics. (2010). 40. Miller, F.G. & Joffe, S. Evaluating the therapeutic misconception. Kennedy Inst. Ethics J. 16, 353–366 (2006). 41. Kesselheim, A.S. & Darrow, J.J. Drug development and FDA approval, 1938–2013. N. Engl. J. Med. 370, e39 (2014). 42. Kesselheim, A.S., Tan, Y.T., Darrow, J.J. & Avorn, J. Existing FDA pathways have potential to ensure early access to, and appropriate use of, specialty drugs. Health Affairs (in press). 43. Thaul, S. FDA fast track and priority review programs. CRS Report for Congress. Feb. 21, 2008. 44. Food and Drug Administration. FY2013 CDER Breakthrough Therapy Requests as of Dec. 6, 2013. . 45. Shulman, S.R. & Brown, J.S. The Food and Drug Administration’s early access and fast-track approval initiatives: how have they worked? Food Drug Law J. 50, 503–531 (1995).

8

46. Food and Drug Administration. FY 2012 innovative drug approvals. (2012). 47. Downing, N.S., Aminawung, J.A., Shah, N.D., Braunstein. J.B., Krumholz, H.M. & Ross, J.S. Regulatory review of novel therapeutics: comparison of three regulatory agencies. N. Engl. J. Med. 366, 2284– 2293 (2012). 48. Kesselheim, A.S. & Avorn, J. The most transformative drugs of the past 25 years: a survey of physicians. Nat. Rev. Drug Discov. 12, 425–431 (2013). 49. Cohen, M.H., Moses, M.L. & Pazdur, R. Gleevec for the treatment of chronic myelogenous leukemia: U.S. Food and Drug Administration regulatory mechanisms, accelerated approval, and orphan drug status. Oncologist 7, 390–392 (2002). 50. Lanthier, M., Miller, K.L., Nardinelli, C. & Woodcock, J. An improved approach to measuring drug innovation finds steady rates of first-in-class pharmaceuticals, 1987–2011. Health Affairs 32, 1433–1439 (2013). 51. Frank, C. et al. Era of faster FDA drug approval has also seen increased black-box warnings and market withdrawals. Health Affairs 33, 1453–1459 (2014). 52. Kesselheim, A.S., Myers, J.A. & Avorn, J. Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA 305, 2320–2326 (2011). 53. Olson, M.K. The risk we bear: the effects of review speed and industry user fees on new drug safety. J. Health Econ. 27, 175–200 (2008). 54. Lexchin, J. New drugs and safety: what happened to new active substances approved in Canada between 1995 and 2010? Arch. Intern. Med. 172, 1680–1681 (2012). 55. Carpenter, D., Zucker, E.J. & Avorn, J. Drug-review deadlines and safety problems. N. Engl. J. Med. 358, 1354–1361 (2012). 56. Grabowski, H. & Wang, Y.R. Do faster Food and Drug Administration drug reviews adversely affect patient safety? An analysis of the 1992 Prescription Drug User Fee Act. J. Law. Econ. 51, 377–406 (2008). 57. Food and Drug Administration. FDA expands approved use of Imbruvica for chronic lymphocytic leukemia. (2014). 58. Steenburg, C. The Food and Drug Administration’s use of postmarketing (phase IV) study requirements: exception to the rule? Food Drug L. J. 61, 295–384 (2006). 59. Fain, K.M., Daubresse, M. & Alexander, G.C. The Food and Drug Administration Amendments Act and postmarketing commitments. JAMA 310, 202–204 (2013). 60. Harris, G. F.D.A. backtracks and returns drug to market. New York Times, 3 September 2010. 61. Moore, T.J. & Furberg, C.D. Development times, clinical testing, postmarket follow-up, and safety risks for the new drugs approved by the US Food and Drug Administration: the class of 2008. JAMA Intern. Med. 174, 90–95 (2014). 62. FDA FY 2014 Budget Request. 63. Public Health Security and Bioterrorism Preparedness and Response Act of 2002, Pub. L. No. 107–188, Sec. 505(a), 116 Stat. 594 (2002). 64. Administrative Procedure Act, Pub. L. No. 79–404, 60 Stat. 237 (1946). 65. Carpenter, D. Corrosive capture? The dueling forces of autonomy and industry influence in FDA pharmaceutical regulation. In Preventing Regulatory Capture: Special Interest Influence and How to Limit It (eds. Carpenter, D. & Moss, D.A.) (Cambridge University Press, New York, 2013). 66. Okie, S. What ails the FDA? N. Engl. J. Med. 352, 1063–1066 (2005). 67. Horton, R. Lotronex and the FDA: a fatal erosion of integrity. Lancet 357, 1544–1545 (2001). 68. Food and Drug Administration. FDA approves Zykadia for late-stage lung cancer. (2014). Accessed 8 August 2014. 69. Food and Drug Administration. Guidance for industry: FDA approval of new cancer treatment uses for marketed drug and biological products. (1998). 70. Schwartz, L.M. & Woloshin, S. Communicating uncertainties about prescription drugs to the public: a national randomized trial. Arch. Intern. Med. 171, 1463–1468 (2011).

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