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FDA Policy and Cardiovascular Medicine

2015; Lippincott Williams & Wilkins; Volume: 132; Issue: 12 Linguagem: Inglês

10.1161/circulationaha.114.010295

1524-4539

Joseph S. Ross, Aaron S. Kesselheim,

Health Systems, Economic Evaluations, Quality of Life

HomeCirculationVol. 132, No. 12FDA Policy and Cardiovascular Medicine Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBFDA Policy and Cardiovascular Medicine Joseph S. Ross, MD, MHS and Aaron S. Kesselheim, MD, JD, MPH Joseph S. RossJoseph S. Ross From Section of General Internal Medicine and the Robert Wood Johnson Foundation Clinical Scholars Program, Yale University School of Medicine; Department of Health Policy and Management, Yale University School of Public Health; and Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, CT (J.S.R.); and Program On Regulation, Therapeutics, And Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (A.S.K.). and Aaron S. KesselheimAaron S. Kesselheim From Section of General Internal Medicine and the Robert Wood Johnson Foundation Clinical Scholars Program, Yale University School of Medicine; Department of Health Policy and Management, Yale University School of Public Health; and Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, CT (J.S.R.); and Program On Regulation, Therapeutics, And Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (A.S.K.). Originally published22 Sep 2015https://doi.org/10.1161/CIRCULATIONAHA.114.010295Circulation. 2015;132:1136–1145The US Food and Drug Administration (FDA) is among the oldest agencies in the federal government. Its origins can be traced back to 1862, when President Abraham Lincoln appointed a chemist, Charles M. Wetherill, to serve in the Department of Agriculture.1 One of the key early pieces of legislation that initiated the evolution of the FDA into its modern form was the 1906 Pure Food and Drug Act, which prohibited interstate commerce in misbranded drugs, thereby giving the FDA its first regulatory oversight over medical product labeling.2 The transformation of the FDA took another major step forward in 1938 with passage of the Food, Drug and Cosmetic Act, which gave the FDA authority to require evidence of safety before new drugs could be marketed.3 Finally, in the 1962 Kefauver-Harris Amendments, the FDA's drug regulatory authority was expanded to require the FDA to certify drug efficacy and safety before marketing.4 The Medical Device Amendments in 1976 gave the FDA similar authority to certify the effectiveness and safety of high-risk medical devices before their approval.5Each of these points in the FDA's early history represented a broadening of its authority and occurred in the context of public health crises related to widely promoted unsafe or ineffective drugs or medical devices, justifying the need for greater government oversight. For example, the Kefauver-Harris Amendments were designed to address the proliferation of medications with poorly documented efficacy and the occurrence of severe side effects caused by some drugs, the most noteworthy example of which was the sedative-antinauseant thalidomide.6,7 The 1976 legislation was passed after >100 deaths of young women from a widely promoted, but largely untested, implantable intrauterine contraceptive device.8 Currently, the FDA describes its responsibilities as ensuring the safety, efficacy and security of the medical products for which it maintains oversight; advancing the public health by helping to speed innovations that make medicines more effective and safer; and helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health.9Given the FDA's central role in regulating and facilitating access to the medical products that make up physicians' therapeutic armamentarium, it is important that physicians be familiar with the processes and decisions made during drug and device development and evaluation. The purpose of this review is to discuss current FDA policies related to the approval and postmarket surveillance of new drug and biological therapies, generic drugs, and medical devices, along with the implications of these policies for clinical care, particularly in the context of cardiovascular care.New Drug and Biological Approval ProcessThere are essentially 3 phases to the development process for most new therapeutic drugs and biologics: preclinical, clinical, and FDA review. The preclinical phase involves assessments of safety and sometimes efficacy of a potential drug candidate in laboratory and animal models. When it becomes clear that the drug is not toxic to animals, the sponsor must submit an Investigational New Drug application to the FDA before human trials can begin. Investigational New Drug applications provide a comprehensive summary of results from animal testing, compound manufacturing, and composition information and describe planned clinical protocols and investigator information for human testing. In allowing an Investigational New Drug to proceed, the FDA makes a determination that human subjects will not be placed at unreasonable risk of harm during clinical testing.Human clinical testing has traditionally been divided into 3 phases. Phase I trials are focused on drug safety and typically enroll up to a few dozen healthy volunteers. The primary objectives of these dose-ranging studies are to demonstrate safety in humans and to assess the pharmacokinetic and pharmacodynamic properties of the drug such as half-life, metabolism, and excretion. Phase II trials typically enroll up to a few dozen to 100 patients, generating the first safety data in patients who have the disease or condition for which the drug is indicated, and may provide preliminary insight into the efficacy of the drug that can be used to plan subsequent trials. Phase III trials provide the first comparative testing of drug efficacy and safety and may enroll hundreds to thousands of patients with the disease or condition of interest. Higher-quality phase III trials are blinded and randomized, use a comparator, and test clinical end points (eg, mortality, hospitalization, relief of symptoms), as opposed to surrogate markers of disease activity (eg, systolic blood pressure, glycosylated hemoglobin level, tumor progression).At the completion of clinical trial testing, the manufacturer submits a formal application for approval, seeking FDA approval for marketing in the United States. This application includes all human and animal studies and information on clinical pharmacology, toxicology, microbiology, chemistry, and manufacturing. The FDA reviews the dossier to assess whether there is substantial evidence of efficacy based on "adequate and well-controlled investigations," as well as adequate evidence of safety, and makes a determination as to whether the benefits of the drug outweigh risks. The FDA also reviews the manufacturer's planned product labeling and decides to approve the New Drug Application or to request additional information from the manufacturer. The FDA also normally inspects the facilities where the drug will be manufactured.What defines adequate and well-controlled investigations remains controversial.10 FDA guidance suggests that 2 phase III trials are preferred, each providing independent evidence of efficacy—such studies are known as pivotal efficacy trials—but also provides flexibility, describing circumstances in which a single efficacy trial might be sufficient to support approval.11 Legislation in 2007 formally mandated that the FDA allow drug approval on the basis of a single adequate and well-controlled trial in appropriate cases.12 Research examining pivotal efficacy trials of new drug and biologics approved from 2005 through 2012 found wide variations in the quality of clinical trial evidence that served as the basis of FDA approval.13 More than one third of indications were approved on the basis of a single pivotal efficacy trial. In addition, only 40% were supported by at least 1 trial that used an active agent as a comparator (as opposed to placebo or no comparator), and 45% were approved on the basis of trials that were focused exclusively on surrogate markers of disease activity. Similarly, fewer than half of new drugs expected to be used for lifelong, continuous treatment were supported by at least 1 trial of ≥6 months. Among the 23 new drugs approved during this period for treatment of cardiovascular disease, the use of surrogate markers of disease activity was higher than for all non–cardiovascular disease drug approvals. These approval decisions influence clinical care. For example, several drugs that effectively lower low-density lipoprotein cholesterol, including ezetimibe, fenofibrate, and niacin, are now used among large numbers of the population, at great expense, on the basis of only evidence from trials focused on surrogate markers and without clinical trial evidence of their effectiveness for lowering the risk of clinical end points such as death or myocardial infarction.14–17When a drug is approved via a New Drug Application, it receives 5-7 years of guaranteed market exclusivity, during which time no generic versions of the product can be introduced in the market. This is commonly called the regulatory exclusivity period, and it is extended to a minimum of 7.5 years for nearly all new drugs when potential generic drug entrants bring legal challenges to enter the market (see the generic drug section below). In practice, drug patents maintain effective market exclusivity for new small-molecule drugs for ≈12 to 14 years before competition by generic drugs.18 As discussed in more detail later, most biological drugs (which are approved via Biologics License Applications) enjoyed indefinite protection from generic competition until recently because there were no clear pathways for approval of follow-on biological drugs.Important Features and Variations of the New Drug Approval ProcessesPrescription Drug User FeesThe Prescription Drug User Fee Act (PDUFA) passed in 1992 authorized the FDA to collect fees from manufacturers submitting new drugs for approval to supplement direct appropriations from Congress. These user fees were enacted at a time when there was widespread dissatisfaction among consumers, industry, and the FDA that the drug approval process was taking too long and that Congressional appropriations to the FDA were too small, although there is evidence that these appropriations had been growing in the years preceding PDUFA.19 Initially, the user fees were allowed only to support the review of applications and other industry submissions to the agency, but legislation in 2007 allowed some of the funds to also support postmarket safety surveillance activity. User fees now constitute more than $2 billion of the FDA's $4.5 billion total annual budget.20 As a quid pro quo, the legislation imposed regulatory performance review deadlines on the FDA such as review of 95% of priority drug applications within 6 months and 95% of standard drug applications within 12 months (shortened to 10 months in 2002). PDUFA requires, and has received, Congressional reauthorization every 5 years since its creation.After PDUFA was enacted, review times quickly fell from the pre-PDUFA average of 30 months, and there was a spike in new drug approvals after 1992 from the pre-PDUFA backlog that had built up.21 Annual drug approvals subsequently returned to their historic mean,22 although there has been an uptick in new approvals in the past 3 years. Currently, the FDA's approval times are the shortest among regulators worldwide. The average FDA regulatory review time for all new drugs and biologics approved from 2001 through 2010 was ≈10 months, whereas the regulatory review times at the European Medicines Agency and Health Canada were each ≈12 months.23 However, there is evidence that imposing arbitrary regulatory review deadlines on the FDA may pose a risk to public health. Research has found that the PDUFA requirements concentrated the number of approval decisions made in the weeks immediately preceding the deadline and that, compared with drugs approved at other times, drugs approved in the 2 months before their PDUFA deadlines were significantly more likely than drugs approved at other times to be later found to have important safety risks or to be withdrawn from the market for safety-related reasons.24 Furthermore, others have raised ethical concerns that the user fee system, whereby nearly half the FDA's budget is derived directly from manufacturers' payments, beholds the agency to the industry it regulates.20Orphan DrugsThe Orphan Drug Act was enacted in 1983 by Congress to encourage the development of new drugs for rare diseases likely to otherwise languish in development because they were anticipated to produce low revenues for manufacturers. In 1984, the definition of a rare disease was extended to include conditions that affect $1 trillion in the last decade alone.47 Moreover, there are clear clinical care benefits to generic drug use because their low cost is associated with improved patient adherence compared with brand-name drugs.48 A recent study comparing the efficacy of generic and brand-name statins found improved clinical outcomes among generic statin users, likely in part because of improved adherence to the lower-cost therapy.49In addition, despite generic drugs being cheaper, they remain equally effective. One systematic review and meta-analysis identified 38 head-to-head randomized, controlled trials that compared the clinical efficacy of generic and brand-name cardiovascular drugs among 9 subclasses of medications, the vast majority of which were conducted during the 1980s and 1990s.50 Clinical equivalence was demonstrated for 35 of these comparisons (92%), with only 1 of 11 comparisons of diuretic therapies and 2 of 7 comparisons of calcium channel blockers not finding equivalence.50 Currently, >8 in 10 prescriptions filled in the United States are for generic drugs,41 and this rate is likely higher for commonly prescribed cardiovascular medications such as cholesterol-lowering statins.51 Widespread use of generic drugs occurs in part because of state pharmacy laws that promote generic drug use by allowing substitution of FDA-approved generic drugs when a physician writes a prescription for a brand-name drug.52 Nearly all states also allow patients or the prescribing physician to request the brand-name formulation, although their health insurers may charge more for this choice.53Notable Features of the Generic Drug MarketBarriers to Generic CompetitionBrand-name manufacturers use many strategies to delay generic competition as long as possible, a practice called life-cycle management, and it would be impossible to review all of those strategies here.54 One of the most common of such strategies relies on the fact that all pharmaceutical manufacturers frequently patent peripheral aspects of their approved drug products, including metabolites, alternative crystalline structures, or the coating of the pill, and use these later-issued patents to block generic approval even after the patent on the original active ingredient has expired. The Hatch-Waxman Act included an incentive to encourage generic manufacturers to design around and challenge brand-name drug manufacturers' patents in court, reducing the chance that these secondary patents would excessively extend brand-name market exclusivity. That legislation provided a 180-day period of generic market exclusivity for the first manufacturer mounting a successful challenge that leads to generic drug approval, essentially creating a duopoly that would artificially inflate generic prices for that period.In the past decade, many of these Hatch-Waxman patent challenge cases have ended in settlements between the brand-name and generic manufacturers. Some of those settlements have come under scrutiny by the Federal Trade Commission because they involved massive payments from the brand-name company to the generic company in exchange for dropping its patent challenge and consequently delaying marketing of its generic drug until a date closer to the end of the patent term. These payments look like anticompetitive business deals between the 2 companies and have been referred to as pay-for-delay deals.55 Annual reports by the Federal Trade Commission indicate that generic versions of as many as 142 brand-name drugs have been delayed by pay-for-delay arrangements between drug manufacturers since 2005 and that these arrangements are expected to lead to $35 billion in excess drug spending over the 2010 to 2020 period.56 A focused review of the top 20 of these drugs, including well-known cardiovascular therapies such as aspirin and extended-release dipyridamole (Aggrenox), amlodipine/atorvastatin (Caduet), atorvastatin (Lipitor), and extended-release niacin (Niaspan), found that these agreements delayed generic drugs for 5 years on average and for as long as 9 years, during which time the brand-name drug companies made an estimated $98 billion in sales.57 In 2013, the Supreme Court ruled that settlements involving payments can be challenged by the Federal Trade Commission, although whether a particular settlement is actually anticompetitive will be determined by the circumstances of the case.58Biosimilar ApprovalThe foregoing discussion of the generic drug approval process has applied only to so-called "small-molecule" drugs, in part because the Hatch-Waxman Act did not apply to most biological drugs. Biological drugs are large-protein therapeutics such as monoclonal antibodies or enzymes usually made from living cells. There was no pathway for approval of follow-on versions of biological drugs in the United States until 2009, when Congress passed the Biologics Price Competition and Innovation Act, one of many components of the Patient Protection and Affordable Care Act.59 In Europe and other places where follow-on biologics (also called biosimilars) for products have been available since the mid-2000s, these products have led to anywhere between 2% and 73% reductions in prices.60 One of the primary concerns has been that biologics are much more complex than small-molecule drugs, and it is still an unanswered question whether biologics produced by different manufacturers, but not subject to the same clinical testing, can be confirmed to have similar efficacy or can be substituted in routine patient care without causing immunological or unexpected side effects. The act gives the FDA the option of approving follow-on biologics as interchangeable or noninterchangeable, and the preclinical testing required of follow-on biologics will be more extensive than that for small-molecule generics and will be based on the type of biological drug.61 In March 2015, the first follow-on biologic was approved by the FDA, filgrastim-sndz (Zarxio), a version of the granulocyte colony stimulating factor filgrastim (Neupogen), although its launch was delayed until September due to litigation.62Generic Drug User FeesUnder the Generic Drug User Fee Amendments (GDUFA), introduced in 2012, generic drug manufacturers have for the first time been required to pay user fees, akin to PDUFA. The purpose of these fees is to facilitate the review of the large backlog of generic drug applications that had developed and to provide additional funding to the FDA for inspections of generic drug manufacturing facilities, particularly overseas. Initially, several factors complicated GDUFA implementation, including slower-than-expected registration by generic manufacturers and difficulty knowing which overseas facilities need to register.63 Under GDUFA, the FDA's review time commitments are much shorter than the average pre-GDUFA review times for generic drug applications, so there is widespread expectation that generic drug applications will be approved more expeditiously.64Medical Device Approval ProcessThe Medical Device Amendments of 1976 established 2 major pathways through which the FDA could review novel medical devices: premarket approval (PMA) and 510(k) clearance pathways. The pathway through which a device is authorized for marketing depends on the risk associated with its use, the patient population that stands to benefit from the device, and the existence of similar devices on the market.65 Class I devices are the lowest risk and include products such as bandages, tongue depressors, and walking canes. Class II devices pose moderate/intermediate risk to patients but have established performance standards and include products such as contact lens solutions and hearing aids. Although neither class I nor class II medical devices are intended to be used in supporting or sustaining human life, several devices that might be interpreted as meeting this criterion, including hip and knee implants, have been classified as class II. Class III devices are the highest risk and include products such as implantable cardiac pacemakers, stents, and heart valves.The PMA pathway is intended to evaluate high-risk devices for which there are no commercially distributed precedents. Applications require clinical testing that provides reasonable assurance that the device is safe and effective for its intended use. The FDA reviews the planned product labeling and conducts manufacturing inspections before clearing the PMA or requesting additional information from the manufacturer. Notably, the strength of the evidence underlying PMAs can vary.65a In a study examining 78 high-risk cardiovascular devices that received market clearance by the FDA through the PMA pathway from 2000 through 2007, 65% were found to have been approved on the basis of a single trial.66 Moreover, only 27% of these trials were randomized, 14% were blinded, and half had a comparison group (one third of which were historical controls), and nearly 90% of end points were focused on surrogate markers of disease.66The 510(k) pathway generally provides clearance of moderate-risk devices. The 510(k) clearance does not require clinical trials that demonstrate safety and effectiveness. Instead, the manufacturer must demonstrate that the device is substantially equivalent in materials, purpose, and mechanism of action to another device already on the market, referred to as the predicate device. In fact, the pathway allows the use of multiple predicates, and reports have found devices cleared on the basis of predicates that have been voluntarily recalled.67 The 510(k) pathway can allow manufacturers to make small improvements on already marketed devices and allow companies with new products to compete with very similar devices without undergoing extensive clinical testing. The pathway has been criticized, including by the Institute of