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RESTRICTIONS ON DISTRIBUTION OR USE OF PRESCRIPTION DRUGS: CURRENT PRACTICES AND FUTURE PROSPECTS Monica R. Gerber Harvard Law School Third Year Paper and Paper for Food and Drug Law May 10, 2003 ABSTRACT FDA must continually balance its dual missions of protecting the public from unsafe and ineffective drugs and expeditiously allowing access to new and beneficial medications. While most risks associated with approved drugs are addressed by appropriate labeling, in the case of certain drugs this approach appears insufficient to ensure an appropriate risk-benefit profile. To avoid the stark choice between permitting a drug with significant risks to remain freely available for prescription and withdrawing the drug from the market, thereby depriving those who would benefit from it, FDA has sought an alternative approach. Under this alternative approach, FDA allows certain drugs to be marketed subject to restrictions on distribution or use. The Clozaril Risk Management Program and the issuance of the Subpart H regulations, both in the early 1990s, heralded the emergence of this more nuanced framework for managing the risks of prescription drug products. This paper describes and compares risk management programs of the ten drugs currently marketed with restrictions on distribution or use, discusses the circumstances under which the rism management programs were adopted, and situates these programs within the broader context of FDA’s evolving attitude towards risk management. I. INTRODUCTION "All drugs have risks. It's FDA's job to balance the need for access to effective medications with those risks."1 On June 7, 2002, the Food and Drug Administration announced that for the first time it was allowing a drug to go back on the market after it had previously been withdrawn for safety reasons.2 The drug, Lotronex, had been removed from the market in November 2000 by its manufacturer, GlaxoWellcome, less than nine months after its approval for the treatment of irritable bowel syndrome (IBS), following reports linking its use to severe gastrointestinal adverse events, including some that resulted in death.3 In its press release FDA announced that the drug was returning under a risk management program designed to maximize its risk to benefit ratio, in part by assuring that only appropriate patients receive prescriptions.4 Lotronex thus joined a small but growing number of medications that are marketed under risk management 1 Lester M. Crawford, FDA Deputy Commissioner, announcing reintroduction of Lotronex, FDA Press Release P0219, June 7, 2002, available at http://www.fda.gov/bbs/topics/NEWS/2002/NEW00814.html, hereinafter Lotronex Reintroduction FDA Press Release. 2 Denise Grady, U.S. Lets Drug Tied to Deaths Back on Market, New York Times, June 8, 2002. 3 The Lotronex NDA was submitted by GlaxoWellcome, which subsequently merged with SmithKline Beecham to become GlaxoSmithKline prior to the reapproval of Lotronex. For purposes of convenience, both GlaxoWellcome and GlaxoSmithKline will be referred to herein as GSK. 4 See Lotronex Reintroduction FDA Press Release. 1 programs (RMPs) that impose restrictions on distribution and/or use.5 The medications form a diverse group as do the reasons why they are subject to restrictions. In addition, while sharing certain common features many of the elements of individual programs differ. Risk management is assuming an ever more prominent profile at the FDA. In a speech before the Food and Drug Law Institute on April 1, 2003, FDA Commissioner Mark McClellan highlighted efficient risk management as one of five top priority areas for the agency. 6 An economist and physician by training, McClellan emphasized that not only is risk management intended to improve health outcomes but it is also expected to reduce the cost of medical care. Traditional approaches to risk management have centered on educational efforts, primarily including appropriate labeling and communications to health care providers. When such efforts have proven insufficient, FDA has resorted to withdrawal of the offending drug. During the past several years FDA has been adopting a more comprehensive and nuanced approach to risk management. More and more drugs are entering the market with a “risk management program” already in place, and such programs are also being adopted in the case of approved drugs when new safety concerns emerge following marketing. One approach to improving the risk-benefit profile of a drug that poses safety concerns when marketed under usual conditions is to impose restrictions on the distribution or use of the drug. Such restrictions have been imposed either as part of the approval process, under a set of regulations issued by FDA a decade ago or have been adopted as a condition for allowing a drug to remain on the market. In both cases, the process involves extensive negotiation between FDA and the company, with the result that the restrictions are adopted on a “voluntary” basis. This paper explores the nature of risk management programs that impose restrictions on the distribution or use of a drug and the legal and policy issues that they raise. Part II outlines the evolution of FDA’s New Drug Approval process, focusing on policies and initiatives the agency has taken in the direction of imposing restrictions on distribution or use. Part II also describes FDA’s promulgation of the “restrictions on distribution or use” regulations under the supplemental New Drug Application that allowed the reintroduction of Lotronex was approved. These regulations are part of a larger group of regulations referred to as Subpart H. Part III 5 Programs whose goal is to manage risk are referred to interchangeably as risk management programs or risk management plans. 6 Text of prepared remarks by Mark B. McLellan before the Food and Drug Law Institute, April 1, 2003, available at http://www.fda.gov/oc/speeches/2003/fdli0401.html. 2 describes the medications that are currently subject to restrictions, some of which were approved under the regulations and some of which were not. Part III discusses the circumstances that led to the imposition of restrictions, the nature of the restrictions, and risk management programs of which they are a part. Part IV attempts to set the specific examples described in Part III within the context of FDA’s evolving risk management policies. II. THE NEW DRUG APPROVAL PROCESS AND RESTRICTIONS ON DISTRIBUTION OR USE A. The Approval Process for New Prescription Drug Products The passage of the Food, Drug, and Cosmetic Act (FDCA) in 1938 marked the beginning of federal regulation of new drug approval in the United States.7 The act was passed in response to a public health tragedy in which dozens of individuals died as a consequence of ingesting a formulation of elixir of sulfonilamide that contained the poisonous substance diethylene glycol as a solvent.8 The FDCA imposed, for the first time, a requirement that companies apply to the FDA prior to introducing new pharmaceuticals to the market. Data demonstrating safety in humans was a required component of the new drug application (NDA), and the FDA was empowered to reject applications that it determined did not meet the statutory standard for safety.9 A second major expansion of the federal government’s role in drug regulation occurred in 1962, with the passage of the Kefauver-Harris amendments.10 Like the original FDCA, these amendments responded to a public health catastrophe, albeit one that was largely averted in the 7 See Peter Barton Hutt & Richard A. Merrill, Food and Drug Law, Cases and Materials (2d. ed. 1991), Ch. 3, Human Drugs, for discussion of the history of new drug regulation and the current framework for approval of new drug applications. Prior to 1936 drugs had been regulated under the Food and Drug Act of 1906, which banned the sale of adulterated and misbranded drugs. This act, however, did not provide for any pre-market review or require demonstration of safety and did not impose regulate claims of efficacy. 8 See Hutt & Merrill, supra, at p. 476. 9 See 21 U.S.C. 355(d), stating that the drug must be “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof” and that there must be “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof”. 10 Pub. L. No. 87-781, 76 Stat. 780 (1962), codified with subsequent amendments in various sections of 21 U.S.C. 3 United States through the vigilance of FDA regulator Dr. Francis O. Kelsey.11 Dr. Kelsey was in charge of considering a new drug application for thalidomide, which was widely prescribed in Europe as a treatment for insomnia and morning sickness. Thalidomide proved to be a potent teratogen12, and its use led to severe birth defects in thousands of children in Europe before the danger was discovered. Concerned that the company had not adequately addressed various safety issues, and despite intense pressure from the company and from within FDA, Kelsey had refused to permit marketing to proceed, thus preventing a similar tragedy from occurring in the United States.13 Notwithstanding the fact that Kelsey succeeded in preventing thalidomide from becoming commercially available, the near miss drew attention to the issue of drug regulation, highlighted deficiencies in the existing scheme, and led to calls for reform. The Kefauver-Harris amendments made a number of important changes to the FDCA that established the modern framework under which the approval of new drugs is regulated.14 The amendments altered and expanded the role of the FDA in two major ways. Under the original FDCA, if the agency did not reject an NDA within 60 days of submission the company was free to commence marketing.15 However, under the amended Act, affirmative approval of the NDA was necessary. The amendments also required companies to demonstrate efficacy of the new drug for its intended use, in addition to safety, as a prerequisite to approval.16 While the Kevauver-Harris amendments set forth a broad statutory mandate, the details of its implementation emerged largely through the subsequent promulgation of regulations by FDA. These regulations establish the major elements of the system for pre-market approval that FDA continues to employ, commencing with submission of an investigational new drug application (IND) and culminating with an NDA. The regulations also set forth the standards by which FDA will judge safety and efficacy and establish the controlled clinical trial as the mechanism by which these features are to be demonstrated. 11 See Thalidomide: Potential Benefits and Risks, An Open Scientific Workshop, Sept. 9-10, 1997, supra. available at http://www.fda.gov/oashi/patrep/nih99.html and http://www.fda.gov/oashi/patrep/nih910.html. 12 A teratogen is a compound capable of causing birth defects. 13 See Thalidomide: Potential Benefits and Risks, An Open Scientific Workshop, Sept. 9-10, 1997, supra. See also Herbert Burkholz, Giving Thalidomide a Second Chance, FDA Consumer magazine (September-October 1997). 14 Pub. L. No. 87-781, supra.. 15 Technically an NDA can be filed by any party, not necessarily a company. Thus it is more correct to refer to the applicant as the “sponsor”. However, since the great majority of applicants are companies, for convenience the terms will be used interchangeably herein. 16 See 21 U.S.C. 355(d) 4 An approved IND is required before testing a new drug in humans can begin. The IND typically contains information regarding preclinical studies, including toxicology, and protocols for the planned clinical studies.17 If FDA does not reject the IND within 30 days of submission the company is free to begin testing the drug in humans. Clinical testing is usually divided into four phases (Phases I – IV), of which the first three occur prior to submission of the NDA. Phase I typically involves testing the drug in a small number of “healthy volunteers”18, primarily to gather safety-related information, including pharmacologic and toxicology data.19 Common side effects and dose-limiting toxicities are frequently discovered at this stage. If Phase I results are satisfactory, testing proceeds to Phase II, in which the drug is administered to a small number of patients suffering from the target disease.20 The goals of Phase II are both to obtain further information related to safety and to provide a limited assessment of efficacy. Generally the number of patients studied in Phase II is insufficient to establish statistically significant evidence of efficacy as required by the FDA. If results from Phase II appear promising, the drug proceeds to Phase III testing.21 In this phase testing of the drug is expanded to include many more subjects, typically hundreds to thousands. Testing generally consists of controlled clinical trials, in which the drug is compared to a placebo or sometimes to an accepted therapeutic agent. Information on efficacy is collected, and monitoring for adverse events is performed. All the data gathered during clinical testing, as well as data from pre-clinical testing, is submitted to the FDA as part of the NDA together with statistical analyses and a variety of additional required components.22 Both the review process and FDA’s role in the stages prior to submission of the NDA have evolved considerably over the years and continue to do so. These changes have come about through a combination of external pressures, agency initiative, and new statutory requirements. For example, FDA regulators now meet regularly with company representatives to discuss any of a wide range of issues ranging from clinical trial design to proposed labeling.23 17 See 21 C.F.R. 312.23 (1999), describing the requirements for an IND. See 21 C.F.R. 312.21 (1999), describing the phases of clinical investigation. 19 For drugs with an unacceptably severe toxicity profile, such as most cancer chemotherapeutic agents, Phase I (sometimes referred to as Phase I/II in this context) is performed in patients as a form of experimental therapy rather than in healthy volunteers. 20 21 C.F.R. 312.21 (1999) 21 See 21 C.F.R. 312.21 22 See 21 C.F.R. 314.50, setting forth the requirements for an NDA. 23 See 21 U.S.C. 355(b). 18 5 Deciding upon appropriate labeling is an extremely important element of the approval process. The label, also called the package insert, sets forth the intended conditions of use under which the drug must be safe and efficacious. The intended uses, as well as any contraindications, warnings, and other information useful to physicians, are required to be included in the label, also called the package insert. Companies are not permitted to include indications in which safety and efficacy have not been shown, since such inclusion is considered “false and misleading” within the meaning of the misbranding provisions of the FDCA.24 Prescription of a drug for such indications came to be known as “off-label” use. Absence of any particular indication from the list of approved uses does not carry an implication that the drug is not suitable for that indication. Instead, the list of approved uses typically reflects many factors.25 A notable feature of the approval process is FDA’s use of Advisory Committees composed of experts in particular therapeutic areas or disciplines such as pharmacology.26 FDA convenes these committees to seek advice on a range of issues including approval of new drugs, particularly those that pose concerns. The committees conduct public hearings at which company representatives and clinical investigators as well as members of the FDA review team present information about the drug, including results of the clinical trials, and answer questions. Other individuals, including members of professional organizations, consumer groups, patient advocacy groups, etc., may also participate. FDA typically asks the committee to address a variety of questions, and meetings frequently culminate in a vote to recommend approval or rejection of the NDA. In addition to making recommendations regarding approval, committees frequently consider whether and how the company should be requested to address areas of concern. For example, committees may suggest labeling requirements, advise additional pre- or post-marketing studies, or make any of a range of other suggestions. FDA convenes expert committees not only as part of the NDA review process but also to obtain advice on other matters, including the appropriate response to safety issues that emerge after the drug has been placed on the market. The committee’s 24 See 21 U.S.C. 351 and 352. Given the time and expense of conducting clinical trials and the fact that once a drug is approved its use is not limited to the labeled indications, pharmaceutical companies may choose to study the drug in indication(s) where it seems efficacy will be shown most easily. Although expanding the list of approved indications may increase use of the drug, the company also runs the risk that it will encounter negative results. Thus incentives are mixed. 26 See 21 U.S.C. 355(n). 25 6 recommendations are not binding on FDA, but it typically accords them considerable weight. Committee views have been influential in the development of a number of the risk management programs discussed herein. Once a drug is launched, i.e., introduced onto the market, the post-marketing phase, also referred to as Phase IV begins. Companies may perform formal studies, either on their own initiative or as part of an agreement reached with FDA during the NDA approval process.27 In the former case, companies may attempt to gain evidence to support additional indications for the drug or particular claims such as superiority to competing products. Post-marketing studies agreed upon between FDA and the sponsor typically address safety concerns that emerge during review of the NDA. For example, sponsors may agree to study potential drug interactions or the effects of the drug in subpopulations of patients in which parameters such as the risk-benefit ratio or the appropriate dose may differ from those determined in the total population studied in Phase III trials. Phase IV also includes studies conducted by independent investigators, which may be aimed at testing any of a variety of hypotheses about the drug. Despite the importance of formal studies, perhaps the most significant element of Phase IV is the informal data that accumulates as a result of physicians prescribing the drug for the actual treatment of patients. Rather than the limited number of carefully screened subjects that are studied in Phases II and III, once the drug is approved it typically used in a much larger and more heterogeneous population. Patients may have multiple diseases in addition to the condition for which the drug was approved and may be taking multiple other medications. They are not subject to the carefully designed protocols that attempt to ensure that the drug is studied only in patients who fit specific diagnostic criteria and is given at the correct dose, in the appropriate manner, and for the correct period of time. Companies are required to send copies of adverse event reports that they receive to FDA.28 In addition, patients and physicians can submit reports of adverse events directly to FDA through FDA’s MedWatch system.29 Since submission of See Draft Guidance for Industry Reports on the Status of Postmarketing Studies – Implementation of Section 130 of the Food and Drug Modernization Act of 1997, available at http://www.fda.gov/cder/guidance/index.htm 27 28 See Guidance for Industry Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report. See also 21 C.F.R. 310.305, 314.80, 314.98, and 600.80. FDA has recently issued a proposed rule modifying the adverse event reporting requirements. See Fed. Reg. March 14, 2003 (Volume 68, Number 50), pp. 12405-12497, available at http://www.fda.gov/OHRMS/DOCKETS/98fr/035204.html 29 See http://www.fda.gov/medwatch/index.html 7 reports by physicians and patients is voluntary, it is estimated that only a small percentage of serious adverse events (approximately 10%) are actually reported.30 B. The Early Debate Over FDA’s Authority to Regulate Conditions of Use of Approved Prescription Drugs Following the Kefauver-Harris Amendments The efficacy requirement imposed by the Kefauver-Harris amendments has led to a greatly expanded role for FDA in reviewing NDAs and has significantly increased the complexity and length of the approval process. Although these developments may not have been entirely foreseen when the amendments were enacted, nevertheless the efficacy requirement engendered considerable controversy. It replaced the existing system, in which the physician was free to prescribe any medication that met the statutory safety requirement, with a regime in which only those drugs that FDA accepted as efficacious for their intended use would be available. This was seen by some as an unwarranted intrusion into the practice of medicine – in effect replacing the personalized decision-making of the physician with the generalized, impersonal judgment of a federal agency. The extent to which the Kefauver-Harris amendments give FDA authority over pharmaceutical companies’ marketing efforts and physician’s freedom to prescribe, and the appropriate exercise of whatever authority exists, have been subjects of ongoing debate. Because risk management programs that impose restrictions on distribution or use of approved drugs often attempt to regulate or at least strongly influence physicians’ prescribing decisions and almost always involve substantial constraints on the conditions of marketing, it is worthwhile to consider this debate. The legislative history of the amendments is open to differing interpretations. Although the FDA was given the authority to disapprove drugs that could not be shown efficacious for any intended use, as long as a company could show both safety and efficacy for at least one use, the drug could be marketed. David Kessler, Commissioner of the FDA from 1991-1997, in an 30 See The Clinical Impact of Adverse Event Reporting, A MedWatch Continuing Education Article, CDER, October 1996. The reader is cautioned that the descriptions of reporting requirements for industry contained in this article have subsequently been revised and are currently the subject of a recently issued proposed rule. Fed. Reg. March 14, 2003. See also Barbara H. Noah, Adverse Drug Reactions: Harnessing Experiential Data to Promote Patient Welfare, 49 Cath. U. L. Rev. 449, 2000 for extensive discussion of adverse events in the context of FDA’s pre and postmarketing regulation of drugs. 8 article written long before he was appointed to that position, has suggested that the legislative history of the Kefauver-Harris amendments suggests that Congress intended FDA to have the authority to regulate uses.31 Kessler argues that this authority goes beyond regulation of manufacturer’s promotion of approved drugs for nonapproved uses, which has been held to be an exercise of the agency’s authority under the misbranding provisions of the FDCA.32 According to Kessler, FDA’s authority extends also to physician prescribing decisions. In support of this position, Kessler points to a section of the Senate report that accompanied the bill, in which the Senate Judiciary Committee, responded to Senator Kefauver’s concern over whether the bill would adequately address the situation in which a drug is promoted for non-approved indications. The Committee stated that the words, “for use under conditions prescribed, recommended, or suggested in the labeling thereof” in section 505(d) and section 201(p) meant that “it is the use claimed for a drug that determines whether or not it is a new drug and that a new drug application under section 505 with respect to any drug is limited to the particular use or uses presented in the application...” The Committee cited an FDA regulation asserting that a drug could be new by reason of “the newness of use of such drug...even though such drug is not a new drug when used in another disease...” According to Kessler, although the report discussed FDA’s authority to regulate uses only with regard to manufacturers, the logic under which a new use of an approved drug constitutes a “new drug” applies equally to the situation in which a physician prescribes a drug for a nonapproved use. Applying this reasoning FDA could argue that each new indication for a drug requires an NDA (or presumably an IND) to avoid violation of section 505(a). Although Kessler conceded that the Senate Report is not conclusive, he maintained that, “the FDA must be empowered to regulate uses in order to achieve the congressional intent to protect the public health.33 Opponents of this view argue that the Kefauver-Harris amendments did not mark a departure from an existing status quo under which FDA could not regulate uses. Instead, they struck a careful balance under which the public would be protected from the medical and economic consequences of treatment with drugs that could not be proven effective for any condition. Once approved, however, drugs would be freely available for physicians to 31 David A. Kessler, Regulating the Prescribing of Human Drugs for Nonapproved Uses Under the Food, Drug, and Cosmetic Act, Harvard. J. Legis, Vol. 15:4, pp. 693-760, 1978. 32 See 21 U.S.C. 352. 33 Kessler, supra, at p. 718. 9 prescribe for any indication, thus fostering innovation and leading to the discovery of new beneficial uses for approved drugs. In fact, FDA long maintained the position that “the physician was free to prescribe the drug as he saw fit”.34 FDA has grappled with the issue of how much authority it may exercise over distribution and/or use of approved new prescription drugs since shortly after passage of the amendments. Kessler recounts much of the early history of this struggle, describing the pressure Congress placed on FDA to regulate off-label usage. Kessler quotes from a congressional hearing held in 1971, in which FDA was criticized for being “grossly remiss in not formulating and enunciating a firm but reasonable policy” on off-label usage. In evident response, in 1972 the agency issued a proposed regulation setting forth its position on the issue of prescribing for unapproved uses. 35 Although it has never been adopted, this rule is significant because it appears to represent the first instance in which FDA formally asserted the view that it was authorized to impose restrictions on the distribution or use of drugs. In the proposed rule FDA affirmed that once a drug is no longer in interstate commerce, e.g., after it reaches a local pharmacy, a physician may lawfully vary the conditions of use from those suggested in the approved labeling without filing an IND or otherwise informing the agency.36 In support of this position FDA alluded to the legislative history of both the 1938 Act and the 1962 amendments, which included numerous statements to the effect that Congress did not intend the FDA to interfere with or regulate medical practice.37 In enacting the new drug provisions, Congress intended FDA to determine which drugs would be available on the market, but not the way they were prescribed by physicians for their patients. FDA appeared to recognize the limits placed by the Interstate Commerce Clause on Congressional power as an important constraint on its authority, implying that once a drug’s interstate shipment is finished, FDA’s authority ends. In fact, it is unclear whether the Interstate Commerce Clause does actually limit FDA’s power to regulate intrastate activities.38 Nevertheless, without citing specific statutory language or legislative history, FDA contended that, “where the unapproved use of an approved new drug becomes widespread or endangers the 34 Kessler, supra, at p. 698, quoting from a speech delivered by former FDA Commissioner H.L. Hey in 1971. 37 Fed. Reg. 16,503 (1972). Proposed rule entitled Legal Status of Approved Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration. 36 Id. 37 Id. 38 See Kessler, supra, at pp. 719-722, discussing relevant cases and describing FDA’s shifting position regarding the constraints the Commerce Clause places on its authority. 35 10 public health, the Food and Drug Administration is obligated to investigate it thoroughly and to take whatever action is warranted to protect the public.”39 The proposed rule described the various courses of action available in such circumstances, including, among others, imposing a requirement that the drug be distributed only through special channels and/or prescribed, dispensed or administered only by physicians with specified qualifications.40 FDA invoked the IND provisions in support of its authority to impose restrictions, making the argument described by Kessler, i.e., that any use of the drug not falling within the terms of the approved labeling made the drug a “new drug”. Thus the proposed rule itself appears to contradict FDA’s assertion that once a drug was approved a physician was free to prescribe it as he or she saw fit. In effect, FDA appeared to be saying that it would not regulate off-label use absent evidence that such use was endangering the public, but that if such danger became apparent FDA’s options were not limited to requiring revisions in the labeling of withdrawing approval of the drug. Although the proposed rule was never made final, it has never been disavowed by FDA and “remains an important statement of Agency policy”.41 As perhaps the first time FDA had formally asserted its authority to impose restrictions on the distribution and/or use of approved drugs, it may be seen as the forerunner to Subpart H. Although the proposed rule appears to limit itself to imposing restrictions on unapproved uses while Subpart H would seem to apply to both approved and unapproved uses, this distinction is illusory. In effect, the restrictions imposed by Subpart H are an effort to control uses of the drug that are not consistent with the labeling. If FDA could be sure that a drug was always being used as suggested in the labeling there would never be a need to impose restrictions. Any desired modification in use achievable by restrictions could be achieved more simply by incorporating particular conditions of use into the approved labeling. Imposing restrictions of the sort envisioned under Subpart H constitutes 39 Id. Id. Other options listed by FDA included requiring revision of the package insert, requiring the sponsor to conduct clinical trials to determine the safety and effectiveness of the drug for the unapproved use, and requiring that the package of the drug dispensed to the patient contain appropriate information for the safe and effective use of the drug by the layman. 41 Margaret Gilhooley, When Drugs are Safe for Some but not Others: the FDA Experience and Alternatives for Products Liability, 36 Hous. L. Rev. 927, 938, quoting David G. Adams, The Food and Drug Administration’s Regulation of Health Care Professionals in Fundamentals of Law and Regulation, an In-Depth Look at Therapeutic Products 423, 426 (David G. Adams, et al. eds, 2d ed. 1997). 40 11 an admission that the drug is not being used in accordance with its labeling and is an effort to bring its use into conformity. C. FDA’s Early Attempts to Impose Restrictions on Distribution or Use of Prescription Drug Products FDA’s first initiative in the post-approval regulation of prescription drugs involved an attempt to impose restrictions on the distribution of methadone in an attempt to control improper distribution of drug intended for maintenance treatment of heroin addiction. In 1974 FDA issued a regulation restricting distribution of methadone to direct shipment from the manufacturer to approved treatment programs, approved hospital pharmacies, and select community pharmacies in communities lacking access to an approved hospital pharmacy.42 At the same time FDA withdrew the existing NDAs under which methadone had been approved while also asserting that retaining it on an investigational basis (under which it had been used for maintenance treatment prior to issuance of the regulation). In American Pharmaceutical Association v. Weinberger the court held that the regulation exceeded FDA’s authority in that it purported to restrict distribution of a drug that was not solely investigational.43 FDA argued that use of the drug would only be “safe”, as required under 21 U.S.C. 355(d), if the drug’s distribution was restricted so as to prevent misuse made possible by drug diversion. In rejecting this argument, the court held that the term “safe” in the FDCA was “intended to include only the inherent safety or lack thereof of the drug when used in the manner intended.”44 The Court of Appeals affirmed without opinion. In a concurring opinion, Judge McGowan endorsed the lower court’s interpretation of the term “safe” and stated that if FDA’s view of its authority were adopted the agency would might establish “a comprehensive registration scheme, complete with detailed record-keeping, security, and inspection requirements.”45 McGowan did not believe that FDA’s authority encompassed establishing “far- 42 See 21 C.F.R. § 130.44 (1973). American Pharmaceutical Association v. Weinberger ,377 F. Supp. 824 (D.D.C. 1974), aff’d sub nom. American Pharmaceutical Ass’n v. Mathews, 530 F.2d 1054 (D.C. Cir. 1976). 44 Id. at 829. 45 American Pharmaceutical Ass’n v. Mathews, 530 F.2d 1054, 1056 (D.C. Cir. 1976). 43 12 ranging regulation of that sort”.46 American Pharmaceutical Association v. Weinberger would thus appear to cast considerable doubt on FDA’s authority to impose restrictions of the sort envisioned by Subpart H. As described in Part III, many of the RMPs adopted under Subpart H include the elements Judge McGowan found that FDA lacked the authority to require. FDA’s attempts to distinguish American Pharmaceutical Association are discussed in Part IV, infra. The court’s interpretation of “safe” seems somewhat at odds with a slightly later decision upholding FDA’s power, through an order of the Secretary of Health, Education, and Welfare (HEW) to remove the drug phenformin from the market by withdrawing approval of its NDA under §505(e) of the FDCA.47 This provision authorizes withdrawal of approval if FDA finds that the drug is either not safe or is not effective under the conditions that the drug is unsafe for use under the conditions of use upon the basis of which the application or abbreviated application was approved (emphasis added)48. FDA’s authority to revoke approval would appear to be limited to situations in which a drug proved to be unsafe or ineffective when used in accordance with its approved labeling. Nevertheless, in 1977 the Secretary of HEW invoked the imminent hazard provision of §505(e) and suspended the NDA for phenformin in a situation where improper prescription of the drug rather than lack of safety or efficacy for the approved indication presented a danger to public health. Phenformin had been approved as an oral hypoglycemic agent for treatment of diabetes in 1959 and soon began receiving reports of fatal lactic acidosis in patients taking the drug.49 Regulatory actions included five revisions of the labeling, which by January 1977 limited the 46 Id. 21 U.S.C. 355(e). 48 See 21 U.S.C. § 355(e). This section provides (in part) that the Secretary shall, after due notice and opportunity for hearing, withdraw approval of an application with respect to any drug under this section if the Secretary finds (1) that clinical or other experience, tests, or other scientific data show that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved; (2) that new evidence of clinical experience, not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved; or (3) on the basis of new information before him with respect to such drug, evaluated together with the evidence available to him when the application was approved, that there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling thereof. This section further provides that if the Secretary...finds that there is an imminent hazard to the public health, he may suspend the approval of such application immediately. 49 See Kessler, supra, at pp. 734 – 737, describing the withdrawal of phenformin. 47 13 drug’s indication to patients who failed to respond to diet and other drugs. In addition, a “Dear Doctor” letter was sent to physicians to warn them of the danger. However, deeming these measures insufficient, the Secretary suspended the NDA for phenformin on July 25, 1977. The Secretary was convinced that unless the distribution system for phenformin was changed, physicians would continue to prescribe the drug for patients in whom the risks outweighed the benefits. In keeping with his recognition that a small patient population could benefit from the drug, the Secretary sought to create a voluntary system of limited distribution to such patients.50 In Forsham v. Califano, the Secretary’s authority both to suspend the phenformin NDA and to establish a limited distribution system were upheld in a suit filed by physicians and diabetic patients.51 Notwithstanding the court’s evident approval of a limited distribution system, the manufacturers of phenformin refused to agree to such a system or to FDA’s definition of the appropriate patient population.52 This outcome represents one of the inherent limitations on FDA’s ability to prevent prescription of drugs to patients whom it believes should not be receiving the drug while making the drug available to patients in whom the benefits outweigh the risks under the current regulatory framework. The manufacturer always has the option of removing the drug from the market if it decides that marketing under restrictions is not economically justified, and the threat that the company will do so weakens FDA’s position as it tries to fulfill both prongs of its statutorily defined mission.53 Despite the favorable view of restricted distribution systems expressed by the Fordham court, for more than a decade following American Pharmaceutical Association FDA’s only other effort at imposing postmarketing controls (other than the required reporting of adverse events) was a surveillance system to monitor patients treated with L-dopa for Parkinsonism.54 FDA 50 Forsham v. Califano, 442 F.Supp. 203 (D.D.C. 1977). FDA had decided to commence withdrawal proceedings for phenformin in May 1977. 51 Id. at p. 210. The court held that the Secretary’s dual concerns of an orderly withdrawal of use of the drug from the majoriy of patients now using it, and of accommodating the small number of patients in whom the benefits outweighed the risks were eminently reasonable and that the power to deal with them in the manner in which he did could fairly be implied from his power to suspend. 52 See Kessler, supra, at p. 736. 53 In the Food and Drug Modernization Act of 1997 Congress defined FDA’s mission for the first time. FDA’s mission statement, now codified at 21 U.S.C. § 393, states in relevant part: (b) MISSION. - The Administration shall(1) promote the public health by promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner; (2) with respect to such products, protect the public health by ensuring that (B) human and veterinary drugs are safe and effective; 54 See Kessler, supra, at p. 739, describing the system. 14 granted conditional approval to the drug based on short-term studies showing safety and efficacy and established a Phase IV surveillance system that required the manufacturer to keep records on patients receiving the drug so that the agency could evaluate long-term effects. During this period FDA unsuccessfully sought passage of legislation that would have given it the power to limit the distribution of drugs.55 This fact may suggest that FDA interpreted the American Pharmaceutical Association court’s holding broadly, not as limited to situations in which the main goal of restrictions is to prevent drug abuse or drug diversion entirely outside the bounds of legitimate prescribing activity. Together, Fordham and American Pharmaceutical Association seem to suggest that while FDA could not, by regulation, establish a restricted distribution scheme, the existence of such a scheme may legitimately be a de facto requirement for allowing a drug to enter or remain on the market. Fordham endorses such a “voluntary” system, at least in a situation in which the drug poses clear hazards that suggest that its risk-benefit ratio is favorable in only a limited subset of patients and in which labeling has failed to appropriately modify prescribing behavior. D. FDA’s Response to the Need for Access to New Prescription Drugs The relatively rigid framework of clinical testing phases and the de facto requirement for two controlled clinical trials described above resulted in a lengthy and costly drug development process.56 Seemingly unable to manage risk by means other than refusing to approve a new drug, FDA adopted a conservative regulatory approach. It is not surprising that a regulatory agency like the FDA would impose a high standard for the approval of new drugs and prefer to err on the side of refusing to approve, particularly if there were questions as to the drug’s safety. 55 See Id. at 740, referring to 9 Wash. Drug & Device Letter 1 (Dec. 9, 1977), S. 2697 § 405(a), and H.R. 11,617 § 104 (1976) 56 Frustration with this state of affairs was cited as a major motivation for passage of the Food and Drug Modernization Act of 1997. See 105 S. Rpt. 43, stating as follows: b. need for the legislation Over the years, and particularly with the enactment of requirements that the FDA determine that drugs and devices are effective as well as safe, the FDAs requirements for clinical testing and its premarket reviews of new products have grown increasingly complex, time-consuming, and costly. From the 1960s to the 1990s, for example, the time required to complete clinical trials for new drugs has grown from 2.5 to nearly 6 years. Applications for the approval of new drugs typically run to hundreds of thousands of pages in length. According to a recently published study, from the beginning of the process to the end, it takes an average of 15 years and costs in the range of $500 million dollars to bring a new drug to market. (DiMasi, Trends in Drug Development, Costs, Times, and Risks, 29 Drug Information Journal 375, 382, April-June 1995.) 15 The agency and the individual decision-makers bear a very obvious cost in terms of public outrage and Congressional scrutiny an unsafe drug is allowed to enter the marketplace. However, the consequences of failure to approve a drug that would be safe and effective are much less clear, and the costs fall largely on those patients who may have benefited from the drug. In addition, the agency has long been committed to a rigorous scientific approach and takes its statutory mandate to protect the public from unsafe and ineffective drugs very seriously. Even allowing a safe yet ineffective drug on the market may be deemed unacceptable for at least two reasons in addition, of course, to the statutory mandate. First, no drug is completely safe, so in the absence of any potential benefit its use places an unjustifiable risk on the patient. Second, a person being treated with an ineffective medication may be deprived of the benefit of an effective therapy that he or she might otherwise receive. During the 1980s FDA came under increasing criticism as it was perceived as contributing to a “drug lag” between the United States and other countries. The agency was accused of creating unwarranted impediments to the development of new and beneficial therapeutic agents. Much of the criticism came from patients with conditions such as terminal cancer or AIDS.57 Not only did these individuals object to the lengthy approval process, they also resented FDA’s refusal to relax its standards in the case of diseases for which no effective therapy had been approved. They argued that a fundamental rethinking of the risk-benefit calculus is necessary when the choice is between certain death and incurring the risk of taking a medication of unproven efficacy. In response to these critiques, particularly those of the activist AIDS community, FDA took a number of steps aimed at increasing availability and accelerating access to new drugs. It is perhaps inevitable that efforts to expand access would involve increased risk in that they are likely to expose individuals to drugs that have not undergone all the rigors of the FDA approval process. By allowing access subject to restrictions, FDA can attempt to minimize the risk. The development of risk management programs involving restrictions on distribution or use occurred in parallel with expanded access. The following description of the expanded access programs is provided to establish the context in which the Subpart H regulations were issued. See Hutt & Merrill, supra, pp. 552-566, for discussion of the drug lag and FDA’s efforts to expand and expedite access. See also Michael D. Greenberg, AIDS, Experimental Drug Approval, and the FDA New Drug Screening Process, 3 N.Y.U. J. Legis. & Pub. Pol’y 295 describing the influence of AIDS activism on FDA policies. 57 16 1. Initiatives Prior to Enactment of Subpart H The first set of initiatives involved increasing access to unapproved drugs. FDA had long maintained a strict attitude opposing the import of unapproved drugs, both for personal use and for commercial purposes, and had frequently exercised its enforcement powers to seize such compounds. However, FDA relaxed this policy, allowing individuals to import unapproved drugs for personal use without the threat of seizure.58 Another initiative involved a modification of the compassionate use IND exemption, under which FDA had for many years been willing to permit access to unapproved drugs intended for the treatment of serious illnesses upon request of the patient’s physician.59 FDA considered applications for the compassionate use exemption on a case-by-case basis, and approval was conditioned on the manufacturer’s agreeing to supply the drug free of charge. The compassionate use IND exemption, requiring individualized review and cooperation on the part of the manufacturer, and the personal import exemption were inadequate to address the growing need.60 In 1987 FDA issued the first of a series of regulations designed to enhance and/or expedite access to new drugs, culminating in the issuance of Subpart H. While a detailed discussion of most of these regulations is beyond the scope of this paper, they will be described briefly in order to provide context for the Subpart H regulations.61 Under the Treatment IND regulations, pharmaceutical companies may make experimental drugs intended for treatment of serious or immediately life-threatening diseases available to patients outside the clinical trial context, while the drug is still undergoing clinical trials. The regulations require that initial results are promising, that the sponsor is applying for approval of the drug, and that no satisfactory therapy for the disease is available. Once FDA approves a treatment IND any patient with the disease can receive the drug. Furthermore, companies can charge for the medication. 58 Id. Id. 60 Id. 61 See Greenberg, supra, for a more detailed description of the Treatment IND, Expedited Development, and Parallel Track programs. See also Sheila R. Shulman & Jeffrey S. Brown, The Food and Drug Administration’s Early Access and Fast-Track Approval Initiatives: How Have They Worked? Food and Drug L. J. 503 (1995) (describing the programs and reviewing drug approval under them) 59 17 Another initiative, referred to as “Parallel Track”, was enacted under regulations issued in 1992. 62 Parallel track is directed only towards drugs for treatment of AIDS and HIV-related conditions and like the treatment IND permits patients access to experimental drugs outside the clinical trial context before completion of clinical trials. The program is notable in that it involves panels from other federal agencies in the review of applications for the fact that it claims to require even less evidence of effectiveness than the treatment IND and also.63 A more broadly applicable set of regulations, known as Subpart E and originally proposed in 1988, was also enacted in 1992.64 These regulations, intended to expedite approval of drugs for treatment of life-threatening or seriously debilitating diseases, encompass a series of measures designed to make the review process more efficient and streamlined. They provide for early and frequent consultations between FDA and the manufacturer prior to and during clinical trials in an effort to ensure that the trial design will satisfy FDA requirements and permit approval based on Phase II trials if appropriate data has been acquired.65 Notably, Subpart E states FDA may seek agreement from the sponsor to conduct post-marketing (Phase IV) studies to “delineate additional information about the drug's risks, benefits, and optimal use.”66 However, FDA did not claim authority to condition approval on performance of such studies, and there is no mention of potential consequences if a sponsor fails to perform the studies agreed upon.67 2. Enactment of Subpart H FDA’s efforts towards expanding access and expediting approval of new drugs culminated in December 1992 with the issuance of a set of regulations that have come to be known as Subpart H, or the Accelerated Approval regulations.68 The subpart “applies to certain new drug products that have been studied for their safety and effectiveness in treating serious or 62 See Expanded Availability of Investigational New Drugs Through a Parallel Track Mechanism for People with AIDS and other HIV-Related Disease, 57 Fed. Reg. 13,250 (1992). 63 See Id. Parallel track seems to have fallen by the wayside. Based on a search of the FDA Web site it appears that only one drug, stavudine, has been approved under Parallel Track. Thus its impact has been limited, and it is difficult to predict how FDA would apply the standard for assessing evidence of effectiveness. 64 See 21 C.F.R. §§ 314.80-88 (2002) 65 21 C.F.R. § 314.82 (2002) 66 21 C.F.R. § 314.85 (2002) 67 Id. 68 See 21 C.F.R. §§ 314.500-560 (2002) 18 life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments”.69 Subpart H contains two distinct components. The first component (hereinafter “surrogate endpoint component”) provides that FDA will accept an effect on a “surrogate endpoint” (commonly known as a surrogate marker) in clinical trials designed to gain approval of a drug intended for treatment of severe of life-threatening disease.70 The second component (hereinafter “restrictions component”) states that FDA may approve a drug with restrictions to ensure safe use.71 The regulations contain essentially identical provisions that apply to biological products.72 a. The Surrogate Endpoint Component of Subpart H The surrogate endpoint component appears to have garnered the most attention when the regulations were issued. In Subpart E FDA had expressed its recognition that, “it is appropriate to exercise the broadest flexibility in applying the statutory standards” in performing a riskbenefit analysis for drugs intended to treat persons with life-threatening and severely debilitating illnesses.73 However, the statutory standards were still be to be applied to controlled trials with traditional endpoints which, for severe or life-threatening diseases, typically implied improved survival or a decrease in irreversible morbidity. A surrogate endpoint, in contrast, is a 69 21 C.F.R. § 314.500. Meaningful benefit includes, e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy. 70 21 C.F.R. §314.510. Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. The section reads: FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence. 71 Sec. 314.520 Approval with restrictions to assure safe use. The section reads: (a) If FDA concludes that a drug product shown to be effective can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the drug product, such as: (1) Distribution restricted to certain facilities or physicians with special training or experience; or (2) Distribution conditioned on the performance of specified medical procedures. (b) The limitations imposed will be commensurate with the specific safety concerns presented by the drug product. 72 See 21 C.F.R. §§ 601.40-45 (1999). To date no biological products have been approved under these regulations. 73 21 C.F.R. §§ 314.80 and 314.84 (1999) 19 “laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and that is expected to predict the effect of therapy.”74 The surrogate endpoint may be causally related to the disease or the relationship may be merely a correlation. In either case, since an effect on the surrogate endpoint may be detectable much earlier in the course of a disease than an effect on the ultimate outcome of the disease, the time required for clinical trials can be greatly reduced. As FDA pointed out in its response to comments on the proposed rule, the use of a surrogate endpoint was not in fact the major departure from previous practice that it seemed.75 The agency had previously allowed an effect on a surrogate endpoint to be used as a basis for approval of a new drug. For example, drugs for hypertension (high blood pressure) had been approved based on their effect on blood pressure rather than on survival or stroke rate, the clinical endpoints of interest.76 Similarly, drugs for hypercholesterolemia (elevated cholesterol level) had been approved based on their ability to lower cholesterol rather than on coronary artery disease (e.g., heart attack).77 However, in these instances there was good evidence from clinical trials, epidemiological studies, or animal studies to show that a favorable effect on the surrogate marker would correlate with reduced morbidity or mortality. Where the new regulations departed from past practice was in the degree of evidence of such a correlation that the agency would require in order that an effect on a surrogate endpoint could be used as a basis for approval. Under the new rules FDA would accept surrogate markers whose validity was less well established but was “reasonably likely” to predict clinical benefit.78 However, approval would be conditioned on the sponsor’s agreement to conduct post-marketing studies to validate the surrogate endpoint. FDA based its authority to require post-marketing studies on sections various portions of sections 505 and 701 of the FDCA.79 Whether these sections can be interpreted to permit FDA to require additional studies once a drug is approved remains open to question. However, in the Food and Drug Modernization Act of 1997 Congress essentially codified the surrogate endpoint component of Subpart H in a provision known as 74 See 57 Federal Register 13234 at 13235. 57 Federal Register 58942 76 Id. 77 Id. 78 Id. 79 57 Federal Register 13234 at 13236. 75 20 “Fast Track” and gave FDA specific authority to require post-marketing studies.80 In addition, the Fast Track provisions allow FDA to employ a streamlined withdrawal process (discussed further below) if the sponsor failed to perform the studies, or if the studies did not demonstrate actual clinical benefit of the drug81 b. The Restrictions Component of Subpart H The surrogate endpoint provisions of Subpart H addressed the need to provide access to promising drugs before absolute proof of clinically meaningful benefit was available, in situations in which such proof might take much longer to obtain than proof of an effect on the surrogate endpoint. The second component of Subpart H was designed for drugs that “are so inherently toxic or otherwise potentially harmful that it is difficult to justify their unrestricted use”.82 According to FDA such drugs could only be used safely if distribution and use are modified and restricted.83 FDA sought to expand access to these drugs, but only in situations in which the benefit justified the risk. FDA believed that for this class of drugs the traditional means of managing risk, namely appropriate labeling and physician and patient education, would not be sufficient to -ensure an acceptable risk-benefit ratio. The type of restrictions envisioned by FDA included restricting distribution to certain facilities or physicians with special training or experience or conditioning distribution on the performance of specified medical procedures.84 FDA emphasized that it expected such measures to be imposed only rarely and that most safety concerns would continue to be addressed by traditional patient management by health care professionals and appropriate labeling. In responding to comments on the proposed rule, FDA made it clear that the restrictions component of Subpart H may be applied to any drug intended for treatment of a severe or life-threatening disease, not just drugs approved on the basis of surrogate endpoints.85 80 See 21 U.S.C.356. Under regulations adopted in 1977, FDA had previously asserted its authority to condition approval of a new drug on an applicant’s agreement to perform postmarketing studies to assess long-term safety for drugs intended to be given over a long period of time. See 21 C.F.R. § 310.303 Continuation of long-term studies, records, and reports on certain drugs for which new drug applications have been approved. (1999) This regulation did not mention possible agency responses if a sponsor failed to perform the study. 81 Id. 82 57 Federal Register 13234 at 13236. 83 Id. 84 Id. at 13237. 85 57 Federal Register 58942. 21 FDA based its authority to impose restrictions on distribution on a broad interpretation of sections 501, 502, 503, 505, and 507 of the FDCA, alluding to congressional intent to “protect the public health by requiring safety and effectiveness of new drugs under the conditions of actual use”.86 FDA did not explicitly cite statutory provisions under which it would have authority to impose restrictions on use as distinct from restrictions on distribution. As discussed further below, whether any of these sections should be interpreted as conferring authority on FDA to restrict distribution or use of approved new drugs is open to question. Furthermore, in an important sense the restrictions are voluntary rather than imposed. Companies are always free to submit an NDA under the traditional approval mechanisms rather than under Subpart H. Furthermore, limitations are agreed upon with the manufacturer at the time of approval rather than after marketing has already begun. Thus sponsors can choose whether to accept the limitations or risk foregoing approval of the drug. Indeed despite the epithet “accelerated approval”, it appears that the restrictions component of Subpart H does not so much speed approval of a new drug as to simply alter the risk-benefit profile in a manner that makes an otherwise nonapprovable drug approvable. As the case studies in Part III reveal, the rule establishes a structure under which a regime of restrictions is arrived at through a process of negotiation between FDA and the sponsor. It would appear that this is a situation of extremely unequal bargaining power since FDA has complete freedom to refuse approval entirely, and in the case of a drug that is inherently very toxic the sponsor would be very unlikely to mount a successful challenge to FDA’s position. In addition, since pharmaceutical companies are repeat players at the FDA and have major incentives to remain in the agency’s good graces, such a challenge either to the rules themselves or to any specific application of them would seem very unlikely. A further provision, under which FDA may employ a streamlined, expedited withdrawal procedure, lends teeth to both the surrogate endpoint and restrictions components of Subpart H. FDA may employ the procedure if (1) A postmarketing clinical study fails to verify clinical benefit; (2) The applicant fails to perform the required postmarketing study with due diligence; (3) Use after marketing demonstrates that postmarketing restrictions are inadequate to assure safe use of the drug product; (4) The applicant fails to adhere to the postmarketing restrictions agreed upon; (5) The promotional materials are false or misleading; or (6) Other evidence demonstrates 86 See Id. 22 that the drug product is not shown to be safe or effective under its conditions of use.87 It would appear that the first two conditions would apply to drugs approved under the surrogate endpoint component, the third and fourth would apply to drugs approved with restrictions on distribution or use, and the fifth and sixth would apply to all drugs approved under Subpart H. Note that the sixth criterion is broader than the corresponding provisions of the regulations under which withdrawal had heretofore been performed. As described above, these regulations state that FDA may withdraw approval of an NDA if FDA finds that the drug is either not safe or is not effective under the conditions that the drug is unsafe for use under the conditions of use upon the basis of which the application or abbreviated application was approved (emphasis added)88. Under Subpart H, however, FDA may withdraw approval if postmarketing experience shows postmarketing restrictions are inadequate to ensure safe use or if evidence demonstrates that the drug is not shown to be safe or effective under conditions of use (emphasis added). Thus withdrawal under Subpart H does not appear to be limited to situations in which drugs are not safe or effective when used as intended but rather encompasses situations in which the drug as actually used is not safe or effective. When the withdrawal procedure of Subpart H was enacted into law under the FDAMA, Congress retained the language of the regulation.89 The FDAMA thus seems to broaden the scope of FDA’s withdrawal authority for drugs approved on the basis of surrogate endpoints beyond that which the agency enjoys for drugs approved under the traditional approval mechanisms. Since there is no discussion of this provision in the legislative history it is unclear whether Congress intended this effect or merely adopted the language of the corresponding regulation without realizing that it departed from the previous standard. The expedited withdrawal process under Subpart H involves a single hearing that constitutes final agency action, from which an applicant may petition for judicial review.90 FDA also stated in response to comments on the proposed rule that the burden is on the applicant to ensure that the conditions of use under which the applicant’s product was approved are being followed.91 Where those conditions mandate particular tests or conditions of 87 See 21 C.F.R. 314.530 See 21 U.S.C. § 355(e). See also 21 C.F.R. § 314.150, supra 89 See 21 U.S.C. 506(b)(3)(C), providing that expedited withdrawal procedures may be applied if, “other evidence demonstrates that the fast track product is not safe or effective under the conditions of use” (1999). 90 21 C.F.R. §314.530. (2002) 91 57 Fed. Reg. 58942 (1992) 88 23 administration (e.g., in hospital), this responsibility would appear to involve manufacturers becoming involved in controlling physician decision-making. This type of challenge to physician autonomy was a considerable source of resentment in the case of clozapine, although the subsequent rapid growth of managed care may have to some extent eroded physicians’ traditional view of themselves as autonomous decision-makers. In addition, it runs counter to the “learned intermediary” theory, which has served to insulate pharmaceutical companies from the duty to warn. It is unclear how FDA would determine whether the conditions of use under which a drug was approved are being followed. In particular, where a drug is approved for a particular indication, does prescription for a different indication violate the conditions of use? FDA has stated that the rule “does not itself prevent a physician from prescribing a drug granted accelerated approval for an unapproved use”, however “such off-label use would, of course, be carried out under the restrictions”.92 This statement seems ambiguous and potentially at odds with the notion that restrictions may be imposed to ensure that the drug is only used in situations where the benefits justify the risks. If a drug has not been studied for a particular indication, how is that determination to be made? What does it mean for the off-label use to be carried out under the restrictions? If one of the restrictions requires that doctors participate in an educational program that teaches the indications for which the drug is approved, is it a violation if the doctor prescribes the drug for a different indication? What about if the doctor has agreed only to prescribe the drug for indicated conditions? The answers to these questions emerge may emerge only in the context of specific risk management programs implemented under Subpart H. In response to comments on the proposed rule FDA added a provision describing conditions under which the restrictions on distribution or use would terminate.93 For drugs approved on the basis of a surrogate endpoint any restrictions would typically terminate following completion of the required postmarketing study confirming the drug’s clinical benefit, i.e., when the drug would be appropriate for approval under traditional procedures.94 For other drugs approved with restrictions (i.e., drugs approved based on studies using traditional endpoints), the restrictions would no longer apply when FDA determines that safe use of the 92 Id. 21 C.F.R. §314.560. (2002) 94 Id. 93 24 drug can be assured through appropriate labeling.95 In the case of some drugs, the restrictions might be applied indefinitely.96 As of March 2003 FDA had approved 37 drugs under Subpart H. Thirty-one had been approved using surrogate endpoints while six had been approved with restrictions on distribution and/or use. To date no drug approved using surrogate endpoints has also been subjected to restrictions. Not surprisingly, most of the drugs approved using surrogate endpoints have been intended for treatment of AIDS, HIV-related conditions, or cancer. The drugs approved with restrictions form a heterogeneous group, and the concerns that led to the restrictions vary widely. Four additional drugs are currently subject to restrictions on distribution or use as agreed upon by FDA and the manufacturer either as a condition for approval or in an effort to mitigate risks that became apparent postmarketing, as an alternative to withdrawal of the drug. The next section considers the drugs that are currently subject to risk management programs that impose restrictions on distribution and/or use. It describes the drugs and the indications for which they are approved, the factors that led to the adoption of the risk management programs under which they are currently marketed, and the features of the risk management programs themselves. The section focuses on the risk management program for It devotes most attention to Clozaril (clozapine), Accutane (isotretinoin), and Lotronex (alosetron) since these cases well illustrate the spectrum of risk management programs involving restrictions and highlight most of the issues that are involved. III. DRUGS WITH RISK MANAGMENT PROGRAMS INCLUDING ESTRICTIONS ON DISTRIBUTION OR USE A. Restrictions Before Enactment of Subpart H – the Case of Clozapine As described above, during the 1980s much attention was focused on attempts to address the contention that FDA’s stringent criteria were impeding access to new and beneficial medications. However, the agency continued to struggle with how to regulate drugs that posed particular safety concerns suggesting that their use should be limited to specific circumstances or 95 96 Id. 57 Federal Register 57842 25 patient populations. This struggle led the agency to return once more to the notion of restricted distribution system, this time in the case of the NDA for Clozaril (clozapine). Issues that arose during and after the approval of clozapine for schizophrenia may well have influenced and guided FDA as it developed Subpart H. Schizophrenia is a severe psychiatric disorder that affects approximately 1% of the world’s population. The disorder is characterized by a constellation of symptoms that typically include psychotic symptoms (delusions, hallucinations, and other disturbances of thought content) as well as so-called “negative symptoms” such as social withdrawal and emotional unresponsiveness.97 The disease is usually chronic and results in significant functional impairment. A variety of medications (referred to as antipsychotics) are available to treat schizophrenia.98 However, their efficacy is limited, and all of them are accompanied by a variety of serious side effects. Clozapine is a member of a class referred to as “atypical antipsychotics” because these drugs do not generally produce a constellation of particularly troublesome responses known as extrapyramidal side effects (EPS).99 In addition, clozapine proved uniquely effective in a subset of patients (approximately 20%) who failed to improve on other medications.100 Though lacking many of the severe side effects characteristic of other antipsychotic agents, clozapine has a potentially fatal side effect rarely seen with the other medications used for schizophrenia. Approximately 1% to 2% of patients taking the drug develop agranulocytosis, a rapid and severe reduction in the number of white blood cells (WBC), which play a key role in the immune response.101 Once it has developed, agranulocytosis is frequently irreversible, often leading to death from infection. However, early detection and cessation of therapy can halt progression. Thus while it remains impossible to predict in advance which patients will develop agranulocytosis, regular monitoring of the white blood cell count allows the drug to be stopped early enough in the course of the condition that most patients recover. In addition, it is important 97 Diagnosis of schizophrenia is based on clinical criteria, as defined in Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR (Text Revision), Task Force on DSM-IV, American Psychiatric Association, Amer Psychiatric Pr; 4th edition (June 15, 2000) 98 See Chapters 13 and 35 of Benjamin J. Sadock, and Harold I. Kaplan, Kaplan and Sadock's Synopsis of Psychiatry, 8th Ed., Williams & Wilkins, 1998 for general discussion of schizophrenia and medications used in its treatment. 99 See, id. at Ch. 35. See also Matthew J. Kleinerman, “Controversy Grows Over Monitoring System for New Schizophrenia Drug”, JAMA, 264 (November 21, 1990): 2448. 100 Kleinerman, supra. 101 Id. 26 to avoid reexposure of those who have proven susceptible since agranulocytosis can recur rapidly. As a result of the substantial risk associated with clozapine, approximately 20 times as high as the risk with other antipsychotics, FDA required a demonstration of clinical superiority rather than simply efficacy before it would approve clozapine.102 In addition, FDA indicated that it would expect the sponsor, Sandoz Pharmaceutical Corporation (now Novartis) to develop a mechanism to manage the risk. Accordingly, Sandoz presented plans for a mandatory WBC monitoring system along with the NDA that it submitted for Clozaril (the brand name for clozapine) in 1987. The system, known as the Caremark Patient Management System (CPMS), was to be run exclusively by Caremark Homecare. Under the terms of the program each patient was assigned to a case administrator who would ensure that WBC counts were performed weekly and that their results were analyzed, keep track of patient appointments, act as a liaison, and help maintain a national database of patients. All analyses were to be performed by a single national laboratory (Roche Laboratories), which would rapidly and reliably return the results. The product labeling contained specific guidelines regarding when treatment was to be halted based on the results of the CBC. The medication was distributed by Caremark on a weekly basis, and without an acceptable CBC Caremark would not provide the next week’s supply. Sandoz was committed to making Clozaril available even in remote, sparsely populated areas in which the actual cost of the service would have been prohibitively expensive. To address this issue the company established a single nationwide price for clozapine, which included both the price of the medication and the price of participation in the CPMS. The safeguards of the CPMS evidently satisfied FDA’s qualms about clozapine’s risk, and the drug was approved on September 26, 1989. In its Summary Basis for Approval FDA stated that restricted distribution was not specifically a condition for approval of clozapine. However, since the restrictions were incorporated into the labeling, FDA warned Sandoz that, “It is understood that, should Clozaril at some time become available outside of this carefully monitored distribution system, Clozaril could be considered misbranded.” The CPMS 102 See Jeffrey I. Zaref, The Controversy Over the Clozaril Patient Managements System, Undergraduate Thesis, Harvard University Department of the History of Science, 1996, Chapter 2, for a discussion of the approval process, the adoption of the original RMP, the Clozaril Patient Risk Management System. The following discussion relies heavily on this source, hereinafter referred to as Thesis. 27 established an entirely closed system for clozapine distribution. The drug would not be available through any wholesale or retail pharmacy or directly from physicians or health care institutions. Sandoz itself had come to believe that traditional modes of warning physicians of risks would not suffice to ensure that rigorous monitoring was performed. The company feared the possibility of product liability suits and felt that complacency would develop as physicians and patients became familiar with the drug. The CPMS was extremely successful, resulting in a compliance rate of more than 99% (versus 75% when physicians were responsible for monitoring during clinical trials).103 CPMS detected a number of cases of developing agranulocytosis during the first year of marketing, but no deaths resulted. Despite the evident success of CPMS in managing the major risk of clozapine treatment, a storm of controversy, involving patients and patient advocates, the professional medical and psychiatric communities, publicly funded health programs such as Medicaid, Congress, and the courts, soon surrounded the program. It is beyond the scope of this paper to discuss the sources and strands of the controversy in detail. Briefly, much of the debate centered on the cost of the program, antitrust concerns resulting from the exclusive relationship between Sandoz and Caremark, and the fact that patients were required to participate in the extremely expensive CPMS in order to have access to the drug. Of more relevance to this paper were the attacks from the professional community, which resented the intrusion of the company into what was viewed as physicians’ responsibility for managing their own patients. Both the American Psychiatric Association (APA) and the American Medical Association (AMA) passed resolutions criticizing Sandoz and FDA for their implementation of CPMS. The resolutions expressed the AMA’s “deep concern regarding the disenfranchisement of physicians..., the unconscionable high cost... and the resultant barrier to needed treatment and hazard to good patient care...” and resolved to pursue all avenues “to prevent the imposition of the FDA limitation on medical judgment and responsibility.”104 The resolution went on to maintain that, “any system that alters or circumvents the prescribing physician’s responsibility or autonomy is...an unwarranted intrusion into the physician-patient 103 Kleinerman, supra. Thesis, supra, quoting from “Resolution No. 136, “Food and Drug Administration Interference With Medical Practice and Decisionmaking,” Proceedings of the American Medical Association House of Delegates, 139th Annual Meeting (24-28 June 1990): resolutions. 104 28 relationship.”105 The head of the AMA stated that FDA had probably exceeded its regulatory authority when it mandated weekly monitoring.106 Zaref sees the extreme resentment aroused by CPMS as a manifestation of physicians’ fear of increasing loss of autonomy and independence that accompanied the rise of managed care. In another resolution the AMA revealed its apprehensions about what CPMS might portend for future regulation of pharmaceuticals. AMA resolved to study “the implication of the Food and Drug Administration and the pharmaceutical manufacturer’ interference in medical decisions by placing restrictions on future drugs, and the impact such interferences may have in medical practice.”107 It is notable that physicians for the most part did not question the necessity of weekly monitoring. Instead, what they objected to was the limits that FDA and Sandoz, through the CPMS, imposed on their freedom to prescribe medications and manage their patients. Under pressure from the press, Congress, impending antitrust litigation, and the professional community, Sandoz unbundled the CPMS in May 1991, replacing it with a system in which physicians and pharmacists formed independent alliances by signing mutual contracts and registered their individual system as a Clozaril treatment system (CTS). The drug was thus available through regular wholesale drug distributors and retail pharmacies, and responsibility for ordering and analyzing the weekly blood tests rested with the treating physician. The package insert continued to require that drug dispensing be linked to the receipt of WBC test results. Patient information continued to be entered in a national Clozaril registry to allow tracking of patient populations and prevention of re-exposure of patients who had at any time experienced signs of impending agranulocytosis. The revamped system proved highly effective.108 Clozaril’s manufacturer, Novartis (the successor to Roche) continues to coordinate and manage the patient registry and the establishment of Clozaril treatment systems, which register 105 Id. Kleinerman, supra. 107 Thesis, quoting from “Resolution No. 238, “Opposition to the Current Clozaril Funding Package”, Proceedings of the American Medical Association House of Delegates, 139th Annual Meeting (24-28 June 1990): resolutions. 108 See Gilbert Honigfeld, “Effects of the Clozaril National Registry System of Incidence of Deaths Rleated to Agranulocytosis,” Psychiatric Services 47 (January 1996) at p. 53, reporting that of a total of 99,502 patients exposed to Clozaril through the end of 1994 a total of only 12 deaths from agranulocytosis had been reported, as compared with an expected number of 149. Most of these deaths occurred in association with other medications and could not be attributed with certainty to clozapine. 106 29 with the company.109 The requirements are essentially unchanged except that biweekly rather than weekly monitoring is now considered acceptable. Implementation differs slightly depending on whether the treatment system is being operated by a facility with an on-site pharmacy or by a facility or individual treating physician without an on-site pharmacy. In either situation, a medically responsible individual (either medical director of a facility or treating physician) and an individual responsible for the pharmacy (director of pharmacy or designated pharmacy services provider) complete a Patient Safety Understanding Form and send it to Novartis. The form for medical personnel attests to the fact that the facility or physician has a system in place that meets the package insert requirements, that the signer is completely familiar with Clozaril package labeling including warnings concerning the risk of death associated with agranulocytosis, that patients will be enrolled in the Clozaril National Registry, and that Clozaril will not be prescribed until the patient has been assigned a clearance number from the Registry. The physician or medical director also agrees to submit results of the weekly WBC count and evaluation to the pharmacy for submission to the Registry within 7 days of collection, to notify the Registry of discontinuation, and to submit results of four weekly blood tests after discontinuation. The pharmacist or director of pharmacy fills out the other side of the form, committing the pharmacy to participation in the CTS, attesting to familiarity with Clozaril package labeling and warnings, agreeing to require the clearance number, and agreeing to submit results and evaluation of WBC count and dosage to the Registry within 7 days of collection. Both medical and pharmacy personnel agree to utilize the services of a local Quality Assurance Committee responsible for overseeing and enforcing compliance. Novartis operates a Clozaril Treatment System Support Program that provides reports from the Registry to the local committees, physicians, and pharmacists and evaluates the data. If a CTS fails to meet the quality standards despite remedial efforts by the local Committee, Novartis removes the CTS from registration. Once Novartis receives the completed registration forms, it informs Clozaril wholesalers of the newly registered pharmacy, which can then order a supply of Clozaril. To initiate treatment, the physician orders an initial WBC count and differential to be analyzed at a 109 Novartis kindly supplied a package of the materials currently (as of March 2003) used to establish a Clozaril treatment system. Treatment System Requirements Clozaril, Novartis 2002. The following description is based on the author’s review of these materials. 30 physician-designated lab and reported to the physician.110 The physician then completes a Patient Safety Assurance Form, which is used to obtain a clearance number (authorization code) from the Clozaril National Registry. Assuming the number is received (i.e., Registry check confirms that patient has not previously developed agranulocytosis or severe white blood cell depletion while taking clozapine) and the blood test results meet the requirements set forth in the labeling, the physician sends the first prescription, a Clozaril National Registry WBC Count Reporting Form, and the Patient Assurance Form including the authorization code to the pharmacy. The pharmacy may, but need not, verify the existence of the authorization code. The pharmacist checks the WBC count and, if acceptable (>3,500), dispenses the first weekly or biweekly supply of the drug. The pharmacy sends the test results and dosage to the Registry. This process is repeated on a weekly/biweekly basis. If there is no WBC count the pharmacist does not fill the prescription. In the event that the weekly WBC count ever falls below 3,500, or if any of a variety of other warning signs are present, the pharmacist is supposed to check with the physician before filling the prescription. Guidelines in the package insert specify in considerable detail what steps the physician should take if any of these warning signs occur, including repeating the test, increasing the testing frequency, interrupting therapy, checking for symptoms of infection, and permanently discontinuing therapy (and informing the Registry). The program includes provisions to handle emergency situations, patient or physician vacations or travel, patient discharge or transfer of care to a new provider, standing orders for prescriptions (though submission of the WBC count to the pharmacy is always required), etc. There are also provisions designed to ensure patient privacy, e.g., no use of patient names in the Registry and no release of patient-specific information. In addition, Novartis has developed computer software to assist physicians and pharmacists with WBC reporting. Notwithstanding the development of a variety of newer antipsychotic agents, including other atypical antipsychotics that do not pose the threat of agranulocytosis and thus do not require a RMP, clozapine retains an important place in the treatment of schizophrenia.111 Indeed 110 The differential count quantifies the percentage of different types of white blood cells. The total white blood cell count, the absolute neutrophil count (ANC), and the presence of immature WBCs are important parameters in determining the onset of agranulocytosis. 111 See Tuunainen A, Wahlbeck K, Gilbody S., Newer atypical antipsychotic medication in comparison to clozapine: a systematic review of randomized trials, Schizophr Res 2002 Jul 1;56(1-2):1-10, concluding that effectiveness and tolerability of the new atypical drugs compared to clozapine is not yet established. 31 the drug was recently approved for a second indication, namely the treatment of patients with schizophrenia or schizoaffective disorder at risk for emergent suicidal behavior.112 Suicide is the major cause of premature death in patients with schizophrenia, and treatment with clozapine is estimated to result in a potential decrease in suicide among these patients estimated to be as high as 85%.113 Given clozapine’s unique benefit profile, it appears likely that the drug and its RMP will continue to be important in the treatment of schizophrenia for the foreseeable future. Several generic versions of clozapine have been approved during the past several years, with similar RMP requirements. It remains to be seen whether the success of the clozapine RMP in its various incarnations will be maintained once responsibility for organizing and running the programs no longer rests with a company having exclusive rights to the drug. Clearly universal participation in the National Registry, or close coordination between multiple similar registries, will be required in order to maintain the effectiveness of the reexposure prevention component of the program. After overcoming a rocky beginning the system in place for clozapine appears to be highly effective and well accepted. It actively engages both physicians and pharmacists, as well as the company, in ensuring that the drug is not given to those in whom its use is contraindicated while preserving a significant amount of flexibility in all areas except for the required blood count monitoring. Any physician can prescribe the medication, and although the drug is only indicated for patients who have failed to respond to standard antipsychotics or have experienced intolerable side effects, physicians may use the drug off-label, provided they comply with the monitoring. There is thus no effort to control the physician’s decision about which patients fall within appropriate diagnostic criteria. The drug is available through normal wholesale and retail channels. In many respects the clozapine RMP may serve as a model for other programs involving restrictions on distribution and/or use. However, the nature of the risk posed by clozapine has a number of features that have contributed to the success of the program and which may not be present in the case of other drugs. Most significant is the fact that a simple test can effectively identify patients at risk of developing agranulocytosis at a time when the condition is still reversible by ceasing therapy. In addition, it is possible to readily identify a subset of patients 112 See Clozapine approval letter, available at http://www.fda.gov/cder/foi/appletter/2002/19758s048ltr.pdf Meltzer, H.Y., Suicide in schizophrenia: risk factors and clozapine treatment, J Clin Psychiatry 1998;59 Suppl 3:15-20. 113 32 who experience clear and substantial benefits from clozapine that would not be available with alternative medications. B. Approval With Restrictions Under Subpart H Thalomid™ (thalidomide) and the S.T.E.P.S. Program Although FDA rapidly started approving new drugs using surrogate endpoints, no drugs were approved with restrictions on distribution or use for the first six years following enactment of Subpart H. When FDA at last considered an NDA under the restrictions component of Subpart H, it could scarcely have selected a more controversial drug than thalidomide. As discussed above, FDA never approved the original NDA for thalidomide, thus preventing marketing of the potent teratogen in the United States.114 However, research on the drug never ceased, and evidence of its therapeutic potential in a number of different conditions continued to mount.115 Thalidomide is an immunomodulatory agent that exerts a variety of effects on cells involved in the immune response. Its mechanism of action is not fully understood but may be related to suppression of excess tumor necrosis factor (TNF-) production and downmodulation of certain cell surface adhesion molecules involved in migration of white blood cells.116 In addition, thalidomide has anti-angiogenic effects (i.e., it inhibits growth of new blood vessels). Thalidomide’s unique spectrum of effects led to its study as a treatment for a variety of conditions. In particular, U.S. Public Health Service studies over the course of 30 years (under an IND) confirmed thalidomide’s potential to treat the cutaneous (skin) manifestations of erythema nodosum leprosum (ENL). ENL is a complication that results from therapy of Hansen’s disease (leprosy), a chronic infectious disease caused by the bacillus Mycobacterium leprae. ENL is an inflammatory condition thought to be caused by deposition of immune complexes following death of M. leprae bacteria. The most common clinical manifestation is 114 See Thalidomide: Potential Benefits and Risks, An Open Scientific Workshop, Sept. 9-10, 1997, available at http://www.fda.gov/oashi/patrep/nih99.html and http://www.fda.gov/oashi/patrep/nih910.html. See also Herbert Burkholz, Giving Thalidomide a Second Chance, FDA Consumer magazine (September-October 1997) 115 Id. 116 See Thalomid™ (thalidomide): Balancing the Benefits and the Risks, Celgene Corp., hereinafter Balancing, available at http://www.celgene.com/images/pdf/$FILE/Balancing.pdf (1999). This document provides a substantial amount of information about the clinical pharmacology, therapeutic use in erythema leprosum leprosum, safety considerations and adverse events, prescribing information, and the S.T.E.P.S. program. 33 painful erythematous (red) nodules of the skin and subcutaneous tissues, which can lead to ulcers and scarring.117 The condition is associated with excessive production of TNF-and the ability of thalidomide to suppress this excess production provides a plausible explanation for its therapeutic effects. In addition to ENL, thalidomide appears to be effective in a number of other conditions associated either with excess TNF- production or inappropriate angiogenesis. Based on the finding that HIV-infected patients display elevated levels of TNF-a, thalidomide has been studied as a treatment for HIV cachexia (wasting), HIV-associated aphthous ulcers, and Kaposi’s sarcoma. Its immunomodulatory properties have led to its study as a therapy for various autoimmune conditions such as lupus and rheumatoid arthritis. Since tumor growth requires development of new blood vessels, thalidomide’s anti-angiogenic properties have led to its study in a variety of solid tumors and in multiple myeloma. Prompted by thalidomide’s evident efficacy in ENL and, more likely, its potential efficacy in a number of more common conditions discussed below, Celgene Corporation submitted an NDA for thalidomide to the FDA in 1996, as growing numbers of individuals were obtaining the drug from abroad. At its meeting in September 1997, FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee considered Celgene’s application and voted to recommend approval of thalidomide (under the trade name Synovir, changed to Thalomid) for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum.118 FDA approved Thalomid in July 1998 under the restrictions component of Subpart H after working extensively with Celgene to develop a RMP that would prevent exposure of women to the drug during pregnancy.119 Six years after enactment of Subpart H, thalidomide thus became the first drug to be approved under it with restrictions on distribution and use. Thalomid’s RMP is known as S.T.E.P.S., standing for System for Thalidomide Education and Prescribing Safety. The multicomponent S.T.E.P.S. program includes comprehensive physician, patient, and pharmacist education, mandatory pregnancy testing prior to initiation of 117 Id. Systemic manifestations of ENL include fever, neuritis, anorexia, malaise, weight loss, leukocytosis, and anemia. 118 See transcript of meeting of Dermatologic and Ophthalmic Drugs Advisory Committee, September 4-5, 1997, available at http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3321t1.pdf and http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3321t2.pdf 119 See Thalomid Approval Letter (NDA 20-785), July 16, 1998, available at http://www.fda.gov/cder/foi/appletter/1998/20785ltr.pdf. 34 therapy and throughout its duration, registration of prescribing physicians and pharmacies that wish to dispense thalidomide, and patient informed consent and participation in a confidential surveillance registry, for which they must complete a mandatory survey.120 Physicians interested in prescribing Thalomid obtain a S.T.E.P.S. folder from the company and register in the prescriber registry by completing a registration card, thereby attesting that they agree to prescribe the drug in accordance with the requirements specified in instructions. These include appropriate selection of patients, provision of patient education on the risk of birth defects and other side effects of thalidomide, counseling on contraception and emergency contraception, and pregnancy testing. Prior to initiating therapy the prescriber must provide comprehensive counseling on the risks of birth defects and the need for contraception. Female patients of childbearing potential must understand that two forms of contraception must be used at the same time beginning four weeks prior to therapy, throughout therapy, and for four weeks after stopping therapy. Contraceptive methods must include one highly effective method and one additional effective method. The only exception to these requirements is for women who maintain complete abstinence. Men must be instructed to use a latex condom every time they have sexual intercourse with a woman, even if they have had a previous successful vasectomy, since it is not known whether exposure of sperm to thalidomide can cause birth defects. Female patients of childbearing potential must have negative results of a highly sensitive pregnancy test performed within the 24 hours prior to initiating Thalomid therapy and must comply with an ongoing pregnancy testing regimen throughout therapy. If a woman misses her period she must receive pregnancy testing and additional counseling. If any pregnancy occurs during treatment the drug must be discontinued immediately. The patient must be referred to a specialist experienced in reproductive toxicity, and reports must be filed with FDA and the company. Patients of both sexes must be given a patient quiz, and the physician must assess the patient’s understanding of the requirements for taking the drug based on the results. If the patient cannot answer all the questions correctly, the physician must review the material with the patient and readminister the quiz until the patient answers all the questions correctly and the physician is satisfied that the patient understands the risks. Either the patient or a legal guardian 120 See Balancing, supra. See also http://www.celgene.com/steps/ 35 must then initial an informed consent form in multiple places to indicate that the patient understands and accepts the risks and required terms of thalidomide treatment. The statements to be initialed differ for women and men, reflecting the need for different precautions. The requirements include those described above and others. Copies of the initialed and signed informed consent form must be placed in the patient’s chart, retained by the patient, sent to the survey coordinator, and presented to the pharmacy when the first prescription is filled. Finally, patients must complete the survey. The physician completes the prescriber’s portion of the survey and sends it to the Slone Epidemiology Unit of Boston University School of Public Health, which maintains the patient registry and manages the data to allow evaluation of the program. Female patients must return to the physician for repeat counseling and have a negative pregnancy test each week for the first four weeks and should be given prescriptions for only a week’s supply of drug during this time. After the first four weeks women must have a negative pregnancy test every four weeks. Patients should receive repeat counseling at each physician visit and should never receive a prescription for more than a four week supply of thalidomide. Female patients must complete a follow-up survey form every month. Men must complete the follow-up survey at least every three months. Retail and hospital pharmacies desiring to dispense Thalomid must register by completing a registration card signed either by the head pharmacist of director of pharmacy. Pharmacies must agree to a rather complex set of requirements. They must refuse prescriptions written more than seven days prior to presentation, to collect and retain a signed informed consent form with an initial prescription, register Thalomid patients, dispense no more than a four week supply at a time with no automatic refills, to dispense subsequent prescriptions only if fewer than seven days of therapy remain on the previous prescription, to verify patient registry information and record subsequent prescriptions online or by phone, and accept unused drug returned by patient. No phone prescriptions are permitted. Thalidomide is currently in clinical trials for a number of the indications mentioned above.121 Given thalidomide’s potential in numerous disorders it is not surprising that an 121 Streicher HZ, Vereshchagina LA, Schoenfeldt M., Clinical trials referral resource. Current clinical trials of thalidomide, Oncology (Huntington) 2003 Mar;17(3):369-71, 374-5, 379-80. 36 estimated 90% of thalidomide use occurs off-label.122 While S.T.E.P.S. requires physician and patient registration in order to gain access to the drug, it does not limit the indications for which Thalomid can be prescribed to the approved indication. It does not require physician qualifications or specialty. Thus within the framework of a rigorous and comprehensive program with multiple safeguards to prevent fetal exposure, S.T.E.P.S. seeks to maintain sufficient flexibility so that patients will prefer to obtain the drug within the health care system rather than outside it. S.T.E.P.S. engages patients, physicians, and pharmacists, assigning responsibilities to each. It incorporates the innovative feature of a patient quiz, thus providing a more meaningful way of assessing patient comprehension of the information necessary to use the medication safely. In addition, the informed consent form must be initialed in next to each of a series of statements of patient understandings and commitments, thus increasing the likelihood that the patient will not overlook important elements. The mandatory patient survey allows an evaluation of the effectiveness of the program and serves to motivate and remind both physicians and patients to follow the requirements. S.T.E.P.S. appears to have been highly successful thus far in that there have been no reports of fetal exposure to thalidomide.123 It is, of course, difficult to be certain that this has truly been the case. In addition, the success of S.T.E.P.S. may be as much a reflection of the patient population and the notoriety of thalidomide as a consequence of the design of the program. C. Adding Restrictions After Approval By its terms, Subpart H applies only to the approval of new drugs and cannot be used to impose restrictions on distribution or use of drugs that are already on the market. However, safety concerns are as likely, or perhaps more likely, to arise postmarketing as during clinical trials. Thus the same considerations that have prompted the imposition of restrictions in conjunction with approval have led to the adoption of RMPs with restrictions for several approved drugs, through a process of negotiation between FDA and the sponsor. This section considers these drugs and their RMPs. The type of restrictions imposed under these RMPs do 122 123 Accutane House Hearings, infra, at p. 39. Id. 37 not appear to differ significantly from those that apply to drugs approved with restrictions under Subpart H. 1. Trovan™ and the Trovan Risk Management Program Trovan (trovafloxacin mesylate or alatrofloxacin mesylate injection) is a member of the fluoroquinolone class of antibiotics and, as such, has a different mechanism of action to that of many commonly prescribed anti-infective agents.124 The FDA approved Pfizer’s NDA for Trovan in December 1997. Like many other drugs in its class, Trovan is effective against all four important bacterial groups: gram-positive aerobic, gram-negative aerobic, anaerobic, and atypical pathogens.125 The drug was approved for more than a dozen indications, the largest number ever included in an initial drug approval in the United States.126 Among these indications were such common respiratory tract infections as community and hospital-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute sinusitis.127 Although the approved labeling mentioned that the drug can cause elevation of liver enzymes after prolonged therapy (≥ 21 days)128 and suggested hepatic monitoring in such circumstances, there were no reports of hepatic failure, liver transplant, or death due to possible hepatic etiology during the clinical trials.129 However, shortly after the drug’s U.S. launch in February 1998, FDA began receiving reports of patients who experienced serious hepatic reactions including both raised liver enzymes and symptomatic hepatitis in association with both short and long term use. In July of 1998, FDA and Pfizer agreed on the addition of information about hepatic toxicity to the Precautions section of Trovan’s package insert. Despite this action, FDA continued to receive reports of hepatic toxicity characterized as “strongly associated with Trovan exposure. The over 140 reports included 14 cases of acute liver failure, leading to 6 124 See Trovan final approved labeling at p. 8, available at http://www.fda.gov/cder/foi/nda/97/020760a_appltr_prntlbl.pdf. 125 See Appelbaum PC, Hunter PA., The fluoroquinolone antibacterials: past, present and future perspectives. Int J Antimicrob Agents 2000 Sep;16(1):5-15, discussing and comparing a number of fluoroquinolone antibacterials. 126 Medical Industry Today April 15, 1998,Pfizer Reports Revenue Growth Driven by Higher Sales Volume. 127 Trovan Approval Letter, available at http://www.fda.gov/cder/foi/nda/97/020760a_appltr_prntlbl.pdf. Trovan was also approved for uncomplicated urinary tract infections; gonorrhea; chlamydial cervicitis; uncomplicated and complicated skin infections, including diabetic foot infections; prostatitis; prophylactic use in various kinds of surgery; and post-surgical infections. 128 Trovan final approved labeling at p. 16. 129 Trovan Public Health Advisory, available at http://www.fda.gov/cder/news/trovan/default.htm. 38 deaths and 4 liver transplants.130 This rate was significantly higher than would be expected among the general population, and given the fact that adverse events are underreported probably represented an underestimate of the actual incidence. Although longer duration of therapy appeared to increase the risk, Trovan-associated liver failure was reported after as little as 2 days of treatment, indicating that monitoring of liver enzymes may not effectively manage the risk since only one or two doses is sufficient to cause irreversible damage. On June 9, 1999, FDA issued a public health advisory alerting physicians and the public to the risk of severe liver injury associated with Trovan.131 FDA advised physicians that Trovan should be reserved for patients having one of several types of infection, judged by the treating physician to be serious and life- or limb-threatening, and in whom the treating physician believes that, even given the new safety information, the benefit of the product for the patient outweighs the potential risk. FDA also advised that patients should receive their initial therapy in an inpatient health care facility (i.e., hospital or long-term nursing care facility) and that the duration of therapy should not exceed 14 days. Pfizer sent letters to doctors and pharmacies informing them that Trovan's use was restricted to in-patient health care facilities and that its distribution would be limited to such facilities, and offering to reimburse the pharmacies for any Trovan they had in stock.132 Approximately 2.5 million prescriptions for Trovan had been written since the drug’s launch133, and at the time the restrictions were implemented doctors were prescribing Trovan to approximately 300,000 patients a month, indicating the vast magnitude of the potential risk.134 Balanced against this risk was the possibility that Trovan would prove particularly appropriate for a subset of patients, to whom FDA did not wish to deny access to the drug. FDA stated its belief that the RMP “will better ensure that Trovan is used in clinical situations in which its benefits can be expected to outweigh its presently known risks”.135 On June 3, 1999, shortly before issuance of the public health advisory, Public Citizen had petitioned FDA to remove Trovan from the market.136 The petition alleged that evidence of 130 See Id. for discussion of events leading up to the issuance of the Public Health Advisory. Id. 132 Melody Petersen, Unforeseen Side Effects Ruined One Blockbuster, The New York Times, August 27, 2000. 133 Trovan Public Health Advisory, supra. 134 Melody Petersen, Unforeseen Side Effects Ruined One Blockbuster, The New York Times, August 27, 2000. 135 Trovan Public Health Advisory. 136 Letter to the Food and Drug Administration to immediately ban the antibiotic trovafloxacin (Trovan). (HRG Publication #1485), available at http://www.publiccitizen.org/publications/release.cfm?ID=6684. 131 39 liver toxicity was available from both the animal and human trials, and that FDA had been aware that Trovan was associated with a higher degree of liver-related adverse events than any other quinolone antibiotic on the market within six months after its launch. Pointing out that 8 other fluoroquinolones were already on the market, the petition alleged that Trovan posed no advantages over previously available drugs while having unacceptable, life-threatening risks. FDA, in denying the request, emphasized that Trovan’s broad spectrum anti-bacterial activity made it an important agent for a critically ill patient in situations in which treatment is given empirically, i.e., where the identity of the pathogen is unknown, and where the treating physician wishes to give broad spectrum monotherapy.137 The Trovan RMP includes both a traditional educational component directed primarily to physicians (the public health advisory and revised labeling) and restrictions on distribution. The restrictions are essentially those outlined in the Public Health Advisory. The drug is supplied only to in-patient health care facilities (hospitals and long-term nursing facilities), and the label warns physicians of the risks of hepatotixicity, recommends monitoring liver enzymes, advises that patients should receive their initial therapy in an in-patient facility and that the duration of treatment should be limited to 14 days. There is no physician or patient registration, no requirements for physicians to complete educational programs or possess other qualifications, no mechanism to ensure that the drug is prescribed only for patients in whom it is indicated or that patients receive the suggested monitoring and limited course of therapy, and no mechanism to assess effectiveness of the RMP. The Trovan RMP thus relies largely on restricting distribution to in-patient health care facilities. Given the large number of patients suffering from or at risk of infection who are seen by physicians authorized to prescribe medications supplied by the pharmacies in these facilities, it seems quite likely that use of Trovan will not be limited to those with serious and life- or limbthreatening infections. By failing to require an assessment of Trovan prescribing patterns after implementation of the restricted distribution system, FDA may tacitly be acknowledging that substantial off-label use is expected to occur. The limited nature of the Trovan RMP contrasts Letter to Drs. Wolfe, Sasich, and Barbehenn at Public Citizen’s Health Research Group, available at http://www.fda.gov/ohrms/dockets/dailys/00/feb00/021000/pdn001.pdf. The letter did not describe what sort of circumstances might make monotherapy with Trovan more desirable than combination therapy with alternative agents that, together, would cover the same spectrum of bacteria and would not be associated with Trovan’s risk of liver toxicity. 137 40 with the more extensive RMP Pfizer has implemented for Tikosyn, another medication whose initial administration is restricted to in-patient care facilities. 2. Tikosyn and the Tikosyn Risk Management Program Pfizer’s NDA for Tikosyn (dofetilide) was approved in 1999 for the conversion of certain cardiac arrhythmias, i.e., atrial fibrillation and atrial flutter, to normal sinus rhythm and for maintenance of normal sinus rhythm in patients suffering from these conditions.138 Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia found in clinical practice.139 It is characterized by rapid and irregular activation of the atria at up to 400-600 pulses per minute, leading to ineffective atrial activity with irregularly irregular ventricular contractions.140 Unlike the normal situation, in which each atrial impulse is transmitted to the ventricles and leads to their contraction, in AF most such impulses are filtered out, resulting in irregular ventricular beats at approximately 150 pulses per minute. While generally not acutely lifethreatening, the resulting alterations in blood flow may cause a variety of clinical manifestations. Atrial flutter (AFL) is broadly similar to AF except that the mechanism causing the arrhythmia is different, the atrial rate is considerably lower, and the condition is much less common. Potential complications of sustained AF include stroke, congestive heart failure (CHF) and tachycardia-induced cardiomyopathy. Although AF affects fewer than 1% of individuals in their fifties, up to 11% of 80 year olds suffer from the condition, with a total incidence of 2.2 million cases per year in the United States. AF increases the risk of stroke by a factor of approximately 5 (due primarily to blood clots that form in the atria as a result of pooling of blood) and is the single factor most commonly associated with stroke in those over 75 years of age. In contrast to most other arrhythmias, for which effective nonpharmacological therapies (such as pacemakers and ablation of foci that generate arrythmias) are presently available, AF 138 See Tikosyn Approval Letter, available at http://www.fda.gov/cder/foi/nda/99/20-931_Tikosyn_Approv.pdf. See Khariy and S. Nattel, New insights into the mechanisms and management of atrial fibrillation, CAMJ, 167(9), pp. 1012-1020, 2002, and S. Nattel, New ideas about atrial fibrillation 50 years on, Nature, Vol. 415, pp. 219-226, 2002, for excellent recent reviews on the pathophysiology and management of atrial fibrillation and recent advances in understanding the mechanisms responsible for it. 140 The atria are the upper chambers of the heart, which fill either with deoxygenated blood returning from the systemic venous system (right atrium) or freshly oxygenated blood from the lungs (left atrium). Contraction of the atria pumps blood into the more powerful ventricles, which contract to pump blood either to the lungs for oxygenation (right ventricle) or into the systemic arterial system to supply the body with oxygenated blood (left ventricle). 139 41 management remains difficult and controversial. While a variety of antiarrhythmic agents can be effective in converting AF/AFL to normal sinus rhythm and for maintaining it for extended periods of time, a number of them have actually been shown to increase mortality because they increase susceptibility to more severe, life-threatening arrhythmias, particularly in patients with underlying structural heart disease. In addition, certain of these agents have a variety of potentially severe noncardiac side effects. In clinical trials, Tikosyn was shown to be significantly more effective than placebo both in converting AF/AFL to normal sinus rhythm and in maintaining normal rhythm in patients who continued taking the drug for up to a year (the duration of the longest study). Most importantly, Tikosyn was not associated with an increase in mortality and appears largely free of noncardiac side effects. However, Tikosyn is associated with an increased incidence of an often fatal arrhythmia known as Torsades de Pointes (TdP). The likelihood that TdP will occur increases with increasing blood levels of the drug, which is more likely to occur in patients whose renal (kidney) function is impaired. Patients at particular risk may be identified by measuring renal function with a creatinine clearance study. Low blood levels of certain electrolytes (potassium and magnesium) also predispose to TdP as does treatment with a variety of medications that interact with Tikosyn. Patients with elevation of an electrophysiological parameter known as the QTc interval are more likely, and the drug is contraindicated in such patients. Patients at particular risk for developing TdP can thus be identified by performing a number of screening tests, and steps can be taken to reduce the risk (e.g., stopping interacting medications, providing electrolyte supplements). In addition, most cases of TdP occur within the first three days of starting therapy. Keeping patients in the hospital under continuous cardiac monitoring for arrhythmias and with immediate access to emergency care during this period can substantially reduce the risk of fatal TdP. To improve Tikosyn’s risk-benefit profile by minimizing the likelihood of TdP, FDA and Pfizer agreed on a comprehensive RMP, which was implemented in 2000.141 As the discussion above indicates, physicians must be aware of the TdP risk factors and must be committed to monitoring parameters of kidney and cardiac function both prior to and during Tikosyn therapy. The RMP requires that the prescribing physician complete an extensive educational program and register with the company to attest completion and understanding of the indications and 141 A comprehensive description of the RMP is available at http://www.tikosyn.com. 42 monitoring requirements, which include obtaining baseline measurements of renal, cardiac, and electrolyte parameters and ongoing monitoring of these parameters while the patient is in the hospital. The drug is supplied directly to hospitals for inpatient use. Once the patient is discharged, the drug is supplied directly to the patient from a single mail order pharmacy, which obtains the drug from single wholesaler. Tikosyn’s RMP contains a number of features not found in other RMPs described herein. The RMP extends beyond physicians, patients, and pharmacists to include other health care providers and the health care institution itself. For Tikosyn to be available at a health care institution, the RMP requires the institution to complete a staff education process and submit an Education Confirmation Form for Institutions to Pfizer after all staff members who will care for patients receiving Tikosyn are trained in dosing and treatment initiation.142 Each institution must designate one or two “hospital authorizing agents” or certified Tikosyn educators who coordinate and manage the training. Physicians are certified individually, either by attending a hospital inservice training program or other educational meeting, reading the product monograph, viewing an educational video, or completing the Tikosyn education program on the product’s Web site.143 After completing Tikosyn education the physician completes an education confirmation form for prescribers and faxes or sends it to the program administrator who reviews the information and enters it into the Tikosyn prescriber database. The prescriber is then sent a confirmation letter that contains information on product distribution and patient enrollment. Other health care providers (pharmacists, nurses, physician assistants) are certified as a group either via a hospital inservice training session or continuing education program. The hospital authorizing agent must complete an education confirmation firm certifying that all appropriate staff have been trained and that procedures are in place to train new staff and submit the form to the company for certification of the institution. Following certification, in order to acquire the drug, the institution must establish an account with the sole wholesaler, which verifies that the institution is authorized to provide Tikosyn. 142 See A. Tran, et al., Practical approach to the use and monitoring of dofetilide therapy, Am J Health Syst Pharm, 58(21):2050-9, 2001, describing the procedures involved in meeting the requirements for adding dofetilide to the formulary at a large, university-affiliated hospital and commenting on obstacles encountered and impediments to effectiveness of the RMP. 143 Id. 43 Prior to initiation of therapy, the patient must be screened as described above. If the patient meets all the criteria, the prescriber sends a completed patient enrollment form to the mail order pharmacy, which enrolls the patient in the mail order pharmacy’s database to ensure that there are no drug interactions and to allow refills of Tikosyn after discharge. The prescriber’s status is verified by access to the list of certified prescribers and pharmacy DEA numbers either by phone or via the Tikosyn Web site. The prescriber then orders the first dose for in-hospital administration. The institution should have procedures in place to ensure that the prescriber is certified, that the patient is not taking any contraindicated medications, and that the appropriate lab tests are performed and checked prior to administration of the first and subsequent doses. These steps require participation by and coordination of the hospital pharmacist and nursing staff as well as the prescribing physician and any other physicians who may be responsible for care of the patient during his or her hospital stay. Appropriate use of Tikosyn may require development of institution-specific protocols.144 Discharge planning requires the prescribing physician to complete two prescriptions. One is filled by the hospital pharmacy to provide the patient with an initial supply of medication. The second is sent or phoned in to the mail order pharmacy for subsequent supplies to be directly to the patient. In addition, the patient must receive medication teaching from a pharmacist and have a follow-up visit scheduled for monitoring. The mail order pharmacy sends one month’s supply at a time, following monthly patient request, and the pharmacy notifies the patient if the patient fails to request the next month’s supply. Refills are permitted. In addition, the patient’s outpatient physician(s) must be notified that the patient is taking Tikosyn. In summary, the Tikosyn RMP appears extremely comprehensive, incorporating extensive physician and hospital staff education, patient and physician registration, institutional certification prior to receipt of the drug by the inpatient pharmacy, and centralized mail order pharmacy distribution for outpatient prescriptions. Despite all of these features, the complex requirements leave the system vulnerable at a number of points. For example, as Tran points out, failure to obtain required test results prior to administration of the next scheduled dose or delays in administering required electrolyte supplementation may require alterations in the 144 See A. Tran, supra. 44 dosing schedule.145 Since the initial prescribing physician is typically not on duty throughout the entire hospital stay of the patient, other physicians must be trained and certified in Tikosyn administration. This may pose difficulties in institutions in which there is frequent rotation of staff. In addition, if a patient taking Tikosyn is readmitted with either a cardiac or noncardiac diagnosis, there is a risk that administration of the drug will be interrupted or that patients may be inappropriately continued on the drug (e.g., if they bring their supply from home).146 Tran also points out that lengthy intervals between staff training and actual treatment of patients may result in failure to recall the educational material.147 A regime in which only a small number of physicians and institutions are certified to prescribe and dispense the drug raises the general issue of how to coordinate care when patients change providers or institutions. D. Application of Subpart H to Drugs Subject to the Controlled Substances Act Long before the enactment of Subpart H Congress recognized the need to limit the distribution of drugs that are subject to widespread abuse. Many of these drugs are of great therapeutic value when used appropriately for certain conditions in certain patient populations. To address the need to allow use of these drugs for legitimate therapeutic purposes while minimizing the potential for drug diversion, Congress enacted the Controlled Substances Act. 148 Although they share the broad goal of ensuring that drugs are appropriately prescribed, the Controlled Substances Act is primarily concerned with limiting drug diversion rather than improving the risk-benefit profile of a drug, the primary concern of Subpart H. In certain cases these concerns overlap. This section considers two drugs of abuse that are subject to the Controlled Substances Act but were also approved with restrictions under Subpart H. The nature of the restrictions differs significantly. As suggested below, these differences may arise from the fact that the active ingredient in the first medication considered, is a member of a class of drugs (opioids) with which the medical community already has considerable experience. Many members of this class are already used clinically under the conditions imposed by the CSA and the dangers of drug diversion and addiction are well known to physicians. However, the medical community 145 Id. Id. 147 Id. 148 84 Stat. 1236, codified in 21 U.S.C. § 801 et. seq. 146 45 does not have comparable experience with the active ingredient in the second medication, Xyrem, which may seem inherently less dangerous. FDA may have felt that Xyrem would be more likely to be prescribed inappropriately, thus justifying the need for additional restrictions. 1. Actiq and the Actiq Risk Management Program Anesta Corporation’s NDA for Actiq (oral transmucal fentanyl citrate) was approved under the restrictions component of Subpart H in 1998 for the management of severe cancer pain in patients who are tolerant to opioid therapy. Approval followed the recommendation of FDA’s Anesthetic and Life Support Drugs Advisory Committee.149 The medication is a solid formulation of fentanyl citrate, a potent opioid analgesic (pain reliever) that is listed as a Schedule C-II controlled substance. Like other members of this class, fentanyl can cause serious or fatal respiratory depression and is addictive. Actiq is intended to be delivered by uptake across the oral mucous membranes.150 This mechanism of delivery provides extremely rapid absorption of the drug and also allows the patient to control the timing and amount of the dose, features of particular importance to patients having severe pain associated with cancer. Actiq has been shown to be more effective than either placebo or an “immediate release” formulation of morphine in treating breakthrough cancer pain (defined as episodes of moderate to severe pain occurring in patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications).151 Since adequate pain control is one of the main determinants of a cancer patient’s quality of life, there was considerable enthusiasm for approving Actiq. However, the Advisory Committee expressed considerable concern that the format of the medication, which is shaped like a lollipop and is sweetened to make it palatable to the patient, would also make it particularly attractive to children and individuals seeking drugs of abuse that do not require injection.152 The company sought to allay those fears by providing special child-resistant packaging and patient educational materials regarding the importance of keeping the medication away from children and properly disposing of unused portions. In addition, the company 149 See Hearing of Anesthetic and Life Support Drugs Advisory Committee, Sept. 17, 1997, transcript available at http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3327t1.pdf, hereinafter Actiq Hearing. 150 Actiq package insert, available at http://www.actiq.com/physicians/information/prescribeactiq.asp. 151 P.H. Coluzzi, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain, 91(1-2):123-30, 2001. 152 Actiq Hearing. 46 emphasized that the patient population for whom the drug is indicated is already using large amounts of Schedule II drugs and therefore there is no more reason to fear drug diversion than in the case of other such drugs used to treat cancer pain. Although approved under Subpart H, Actiq’s risk management program does not seem greatly different to that for other Schedule C-II controlled substances. There is a patient package insert and patient educational materials as well as special packaging. In accordance with the drugs scheduled status, distribution is limited to DEA (Drug Enforcement Agency) hospital and distribution registrants. The label contains a black box warning, indicating that the drug is intended to be prescribed only for opioid-tolerant cancer patients and only by oncologists and pain specialists skilled in the use of Schedule II opioids to treat cancer pain.153 Ultimately this risk control strategy relies primarily on the traditional approaches of the Controlled Substances Act and the widespread awareness of physicians of the dangers of opioids. 2. Xyrem™ and the Xyrem Risk Management Program Xyrem (sodium oxybate; gamma hydroxybutyrate) was approved in 2002 under the restrictions component of Subpart H for treatment of cataplexy associated with narcolepsy. Narcolepsy is a disorder characterized by chronic sleepiness and a disorganization of sleep/wake behavior.154 Additional clinical manifestations occurring as a result of sleepiness include inattention, poor memory, blurry vision, double vision, and automatic behaviors. The incidence of narcolepsy is estimated to be approximately 1 in 2,000 individuals. While most cases are sporadic, genetic factors are also important. The cause remains uncertain, but there is evidence to suggest that loss of certain neurons in the hypothalamus, resulting in decreased secretion of the neuropeptide orexin, which promotes wakefulness, may play a key role. Narcolepsy sufferers often display abnormal features of rapid eye movement (REM) sleep that intrude into wakefulness, among which are cataplexy, dream-like hallucinations, and sleep paralysis. Cataplexy is sudden onset of muscle weakness, generally without loss of consciousness, and can lead to injury and embarrassment. The condition occurs in approximately 60% of narcolepsy patients and is found almost exclusively in this population. Some patients experience up to several episodes of cataplexy a day. 153 154 Actiq package insert, supra. Scammell, T., The Neurobiology, Diagnosis, and Treatment of Narcolepsy, Ann. Neurol., 53:154-166, 2003. 47 GHB, the chemical name for the active ingredient in Xyrem, occurs naturally in the brain and is a metabolite of the neurotransmitter gamma hydroxybutyrate (GABA). GHB has been shown to both reduce the frequency and severity of cataplexy and reduce daytime sleepiness in narcoleptics, possibly through interaction with GABA receptors, although its mechanism of action remains unclear. GHB has become notorious as a “date-rape” drug. The drug causes central nervous system (CNS) and respiratory depression, a particular risk when the drug is taken together with alcohol or other agents that have similar depressant effects. In addition, it is addictive. GHB had been scheduled in the drug laws of at least 20 states by early 2000, and on February 16, 2000, Congress passed the Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000, designating the compound as a “date rape drug” and amending the Controlled Substances Act (21 U.S.C.S. §§ 801, et seq.) to add it to Schedule I.155 Recognizing that GHB was in development for treatment of cataplexy associated with narcolepsy, the Act provided that when contained in a drug subject to either an IND exemption or an approved NDA, the drug should be scheduled in the same schedule as that recommended by the Secretary of HHS.156 Xyrem was scheduled as a Schedule III drug, meaning that sale or distribution of the drug or use except as medically indicated is punishable under federal and state law by jail and fines.157 Orphan Medical submitted an NDA for Xyrem Oral Solution on September 30, 2000 for the treatment of cataplexy associated with narcolepsy. On March 12, 2002, pursuant to an agreement with FDA, Orphan requested review under the provisions of Subpart H for restricted distribution.158 On July 17, 2002, FDA approved the NDA under Subpart H, with marketing to be subject to the restrictions on distribution and use described in the Xyrem Risk Management Program. The major concerns to be addressed by the RMP were the various possibilities of drug diversion and the need for considerable patient education regarding the appropriate way to take the medication.159 155 Public Law 106-172, Feb. 18, 2000. Id. 157 See Xyrem Medication Guide, available at http://www.fda.gov/cder/drug/infopage/xyrem/medicationguide.htm 158 Approval letter for Xyrem Oral Solution, NDA 21-196, available at http://www.fda.gov/cder/foi/nda/2002/21196_Xyrem_Approv.pdf 159 See Xyrem Medication Guide. The drug must be mixed with water and taken in two doses, the first immediately before bedtime and the second between 2.5 and 4 hours later. 156 48 The key components of the Xyrem RMP are implementation of a restricted distribution scheme under which the drug is dispensed only from a single central pharmacy, the maintenance of patient and prescribing physician registries, and physician and patient education (including a black box warning, Medication Guide, special physician and patient educational materials, and a toll-free Helpline).160 Every patient and prescribing physician is registered with the central pharmacy in a secure database which contains the physician’s name, address, phone and fax numbers, specialty, DEA and state license numbers, and prescribing frequency.161 The database, which is available for review by federal and state agencies, allows retrieval of prescriptions by physician specialty, by patient name, by volume (frequency) and dose. Under the RMP prescriptions are communicated by the prescribing physician to the central pharmacy, which then contacts the physician and identifies the physician’s name, license and DEA registration number and verifies the prescription. The pharmacy then verifies that the physician is eligible to prescribe Xyrem by consulting the National Technical Information Services (NTIS) to confirm that the physician has an active DEA number and that there are no pending actions against the physician. If the physician is a first time prescriber of Xyrem the pharmacy sends educational materials which the physician must acknowledge having read by returning a form to the pharmacy. Before filling the initial prescription the pharmacy verifies the patient registry information, provides educational materials to the patient, confirms by phone that the patient has read the educational materials, and records the confirmation. The pharmacy then verifies the patient’s home address and availability for shipping and arranges shipment via Federal Express or a similar shipper. Receipt is confirmed by requiring the patient or his designee to sign for the package, by the courier’s tracking system, and by a phone call to the patient from the pharmacy within one business day of delivery. The initial prescription is limited to a one month supply, and patients are never to receive more than a three month supply. The program includes provisions for investigating reports of lost or stolen prescriptions. In summary, the Xyrem RMP represents a stringent set of regulations aimed primarily at minimizing the risk of drug diversion rather than optimizing the risk-benefit profile for the patient. The program places burdens on physicians and patients, which will surely be reflected 160 See Xyrem Risk Management Plan, available at http://www.fda.gov/cder/foi/label/2002/21196lbl.pdf The DEA registration number allows the physician to prescribe drugs subject to the provisions of the Controlled Substances Act. 161 49 in the cost of the drug, in order to minimize risks to the public. Evidently in the case of Xyrem, concerns such as patient privacy and access to beneficial medications take second place to maintaining the precautions associated with Xyrem’s status as a controlled substance. E. Mifeprex™ and the Mifeprex Risk Managment Program: Application of Subpart H to a Politically Controversial Drug Perhaps no currently marketed drug has had a more tortuous pre-approval regulatory history than Mifeprex (mifepristone or RU-486). It is beyond the scope of this paper to consider this regulatory history in detail, but suffice it to say that the end result was approval of the Population Council’s NDA for Mifeprex under the restrictions component of Subpart H.162 In accordance with the recommendation of FDA’s Reproductive Health Drugs Advisory Committee, Mifeprex was approved on September 28, 2000, for the medical termination of intrauterine pregnancy through 49 days’ pregnancy. 163 Approval of Mifeprex, which offers women an alternative to surgical abortion, marked a milestone in the ongoing struggle between pro-life and pro-choice forces in the United States. Mifepristone is an antiprogesterone agent that blocks the action of progesterone on progesterone receptors in the uterus, thereby preventing the uterine lining from developing in a manner that remains hospitable to a developing embryo and leading to miscarriage or preventing implantation.164 Mifeprex is more effective when used in conjunction with a second agent 162 See Lars Noah, A Miscarriage in the Drug Approval Process?: Mifepristone Embroils the FDA in Abortion Politics, 36 Wake Forest L. Rev. 571 (Fall 2001), which describes the history of FDA’s review of the mifepristone NDA. Noah argues that the FDA’s actions were considerably swayed by political considerations, resulting in possibly inappropriate regulatory decisions. The reader is cautioned that a number of Noah’s statements and conclusions are open to question. He appears to ignore the distinction between the surrogate endpoint and restrictions component of Subpart H and to take certain portions of statutes or regulations out of context. In addition, a large part of his thesis is based on the assumption that agencies should maintain complete political neutrality when making regulatory decisions. However, the feasibility of desirability of such an approach is not selfevident. Terms such as “safe” are open to differing interpretations, and society’s collective judgment about how they should be interpreted may change. Perhaps agencies, as components of the politically accountable Executive Branch, should take this fact into consideration as they fulfill their statutory mandate. 163 Mifeprex Approval Letter, available at http://www.fda.gov/cder/foi/appletter/2000/208=687appltr.htm. The meeting at which the Advisory Committee voted to recommend approval was held July 19, 1996, but approval was delayed due to a variety of events and circumstances beyond the scope of this paper. 164 See Ettiene-Emile Baulieu, RU-486 as an Antiprogesterone Steroid, 262 JAMA 1808 (1989); Beatrice Couzinet et al., Termination of Early Pregnancy by the Progesterone Antagonist RU-486 (Mifepristone), 315 New Eng. J. Med. 1565 (1986); Remi Peyron et al., Early Termination of Pregnancy with Mifepristone (RU-486) and the Orally Active Prostaglandin Misoprostol, 328 New Eng. J. Med. 1509 (1993), hereinafter Mifipristone articles. 50 administered approiximately two days after administration of Mifeprex, typically a prostaglandin (misoprostol) that triggers contractions that help expel the uterine lining and gestational sac.165 The labeling for Mifeprex states that it is to be used with misoprostol.166 Anticipated effects of Mifeprex include cramping and bleeding. Significant hemorrhaging requiring medical attention occurs in a small number of patients. The procedure fails in a few percent of patients, requiring a surgical abortion if the patient still chooses not to continue the pregnancy.167 It would appear that the risk of hemorrhaging and possible need for surgical intervention, as well as the desirability of ensuring that patients take misoprostol as recommended, could amply justify FDA’s decision to require a RMP. In particular, it seems important to ensure that a patient is evaluated after the treatment to determine whether termination of the pregnancy did indeed occur. The RMP that was agreed upon by FDA and the sponsor may be more restrictive than necessary to achieve these goals. FDA may well have been influenced by political considerations to make access to the drug more difficult than might be justified by the risks. If so, FDA’s motivations are unclear. It may have viewed restrictions that would limit access as a necessary price to pay in order to achieve sufficient political acceptability to avoid a future ban on the drug via the political process. Or it may have felt that easy access to the drug would discourage use of contraceptive methods, thus subjecting women to the arguably more traumatic (both physically and psychologically) decision to medically terminate an unwanted pregnancy. On the other hand, by making access to Mifeprex difficult, the Mifeprex RMP may be causing more women to opt for surgical abortions outside the health care system, possibly under unsafe conditions. FDA justified its decision to consider the Mifeprex NDA under Subpart H by stating that it had determined that “termination of an unwanted pregnancy is a serious condition within the scope of Subpart H”, and the “meaningful therapeutic benefit over existing surgical abortion is the avoidance of a surgical procedure”.168 FDA had determined that safe use of the drug could only be assured by restricting its distribution to physicians meeting certain qualifications.169 In 165 Id. Methotrexate can also be used for this purpose. See also FDA Talk Paper: FDA Approves Mifepristone for the Termination of Early Pregnancy, available at http://www.fda.gov/bbs/topics/NEWS/NEW00737.html. 166 FDA Memo to Population Council, September 28, 2000, available at http://www.fda.gov/cder/drug/infopage/mifepristone/memo.pdf 167 Mifipristone articles, supra. 168 FDA Memo to Population Council, supra. 169 Id. 51 addition, as described below, FDA required provisions to ensure the physical security of the drug. Such provisions appear to be unprecedented except in the case of drugs subject to regulation under the Controlled Substances Act. Under the Mifeprex RMP, Mifeprex must be provided by or under the supervision of a physician who meets a lengthy list of qualifications.170 The physician must have the ability to accurately assess the duration of pregnancy and to diagnose ectopic pregnancy. The physician must either have the ability to provide surgical intervention in cases of incomplete abortion or severe bleeding or have made plans to provide such care and must be able to assure patient access to medical facilities equipped to provide blood transfusions and resuscitation. These qualifications appear in effect to restrict eligible physicians to specialists in obstetrics and gynecology and, perhaps, a small subset of family practitioners who have training in these areas. Physicians must register with the sponsor by returning a form on which they certify that they have read and understood the Mifeprex prescribing information and agree to provide each patient with a Medication Guide and Patient Agreement (both of which are required under the RMP), to fully explain the procedure to each patient, to obtain the patient’s signature on the Agreement, and to sign it also. Physicians must further agree to notify the sponsor in the event of an ongoing pregnancy that is not terminated and must report any serious adverse event including hospitalization, transfusion, etc., to the sponsor. The Mifprex package and serial number must be recorded in the patient’s chart. Mifeprex is distributed exclusively to, and administered by, physicians who are certified as described above. The drug is to be given at the physician’s location, and patients are to return on Day 3 to receive the dose of misoprostol. Patients agree to return on Day 14 to confirm that pregnancy has been terminated. The requirements for physician qualifications and access to emergency services and administration of both Mifeprex and misoprostol under the direct supervision of the prescribing physician may seem excessively stringent (as opposed, for example, to allowing patients to take the misprostol at home). FDA justified these requirements by stating that they replicate the conditions that were employed in a number of the clinical trials that formed the basis of approval.171 Nevertheless, FDA rarely requires that marketed drugs be prescribed or administered under conditions that replicate clinical trial conditions. 170 171 Id. Id. 52 In addition to the above, the sponsor must assure secure manufacturing, receiving, and holding areas for the drug; secure shipping procedures; secure packaging; a controlled returns procedure; a tracking system to allow tracing of individual packages to the patient level while maintaining patient confidentiality; use of authorized distributors having expertise to handle distribution requirements; and a mechanism to ensure that only certified physicians receive the drug for administration to patients. The sponsor agreed to conduct a number of postmarketing studies including a study to monitor the adequacy of the distribution and credentialing system, a study to ascertain the frequency with which women follow the complete treatment regimen and the outcome of those who do not, and a study to ascertain the effect of the regimen on children born after treatment failure. Data from these studies may permit a determination of whether the rigid requirements of the Mifeprex RMP are justified by the risks posed by the medication.172 However, if the past is any guide to the future regulation of this drug, political factors may play a more significant role than would likely be the case for virtually any other drug. F. Tracleer™ and the Tracleer Access Program Actelion Pharmaceutical’s NDA for Tracleer (bosentan) for the treatment of pulmonary arterial hypertension (PAH) was approved under the restrictions component of Subpart H in November 2001. Pulmonary arterial hypertension is a progressive disease characterized by an abnormally high blood pressure in the arteries of the lung.173 It is a rare disorder, affecting 1 to 2 out of 1,000,000 people. PAH can occur in the absence of other diseases of the heart or lungs (primary pulmonary hypertension) or as a consequence of other diseases such as scleroderma and systemic lupus erythematosus. In either case, elevation of pulmonary vascular resistance occurs as a result of vascular constriction, other alterations in the vessels, and blood clots. The disease almost invariably leads to right ventricular failure and death as the right ventricle is no longer able to pump blood adequately through the lungs in the face of increased resistance to blood 172 Id. Briefing document provided by Actelion for Tracleer (NDA 21-209), August 10, 2001, meeting of Advisory Committee on Cardiovascular and Renal Drugs (July 2001). Available at http://www.fda.gov/ohrms/dockets/ac/01/briefing/3775b2_09_Tracleer%20Briefing%20Book(red).pdf 173 53 flow.174 For unknown reasons the great majority of victims are women, frequently in their 20s or 30s. PAH clearly meets the definition of a serious or life-threatening disease as required for Subpart H to apply. None of the existing therapies for PAH is even moderately effective. Prior to the approval of Tracleer, epoprostenol (prostacyclin) was the only approved therapy known to be effective in patients with PAH. This drug must be delivered by continuous infusion into a central vein. In addition to its inherent complexity, this delivery mode leads to numerous complications, including life-threatening infections. Furthermore, tolerance to the drug develops, leading to a decline in efficacy over time. Bosentan is an orally active agent that inhibits receptors for endothelin, an endogenous peptide that causes vascular constriction, deposition of extracellular matrix molecules, and cell proliferation, all of which may contribute to the pathogenesis of PAH.175 In clinical trials, bosentan was shown to reduce pulmonary arterial pressure and to produce a modest increase in exercise tolerance although there was no evidence that it alters the course of the disease. In a situation in which the only approved alternative therapy is of limited efficacy and is associated with serious complications, even a relatively modest benefit, coupled with a greatly preferred route of administration, can be seen as a major therapeutic advance. The major side effects of bosentan that emerged during clinical trials were a decrease in hemoglobin concentration and an elevation in liver enzymes, which occurred in approximately 11% of patients treated with the drug.176 In addition, evidence from animal studies indicated that bosentan is a teratogen and also causes severe testicular toxicity. FDA’s Advisory Committee on Cardiovascular and Renal Drugs unanimously recommended approval of Tracleer notwithstanding considerable concern, particularly regarding the side effects mentioned above.177 Although the raised liver enzymes had been reversible and had not led to any instances of severe liver toxicity, projections based on experience with other drugs suggested that the drug would cause hepatic failure with an incidence on the order of one 174 Id. Median life expectancy following diagnosis is two to five years, and quality of life is poor. Id. 176 See Tracleer Package Insert, available at http://www.tracleer.com/tracleer_website/hcp/pi.asp. The 11% figure refers to 3-fold elevation above the upper limit of normal. 177 See transcript of August 10, 2001, meeting of Advisory Committee on Cardiovascular and Renal Drugs (July 2001), available at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3775t2_01.pdf, http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3775t2_02.pdf, and http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3775t2_03.pdf. 175 54 in a thousand. The Committee grappled with the question of whether this risk, and the risk of birth defects, justified the relatively small symptomatic improvement resulting from treatment, in a disease in which there were no good therapeutic alternatives. To address the Committee’s concerns, Actelion unveiled a comprehensive RMP, the Tracleer Access Program (T.A.P.) The program, which Actelion had developed with input from FDA, is aimed primarily at preventing fetal exposure and liver toxicity. Company representatives seemed eager to show their willingness to implement the plan, appearing to view it as an opportunity to optimize therapeutic outcomes rather than a requirement to be avoided if at all possible. The main elements of the program included physician and patient registration, restricted distribution, and acceptance of a regime under which both pregnancy and liver function test (LFT) monitoring would be required in order for patients to receive the drug. The ready acceptance of the program, both by the sponsor and by the Committee (despite misgivings as to whether monitoring of liver function tests and cessation of therapy if results were abnormal would actually prevent development of liver failure, given the speed with which liver failure can develop and the fact that liver function tests may provide only a crude indicator), may be due in part to their realization that patients with PAH are already well integrated into the health care system. They undergo careful monitoring and follow-up on a regular basis, usually by specialists, because of the complicated nature of their condition. In addition, they were characterized as a highly compliant patient population. Thus the extra monitoring and physician and patient registration requirements would pose only an incremental burden. Concerns about imposing requirements to avoid fetal exposure may have been minimized because pregnancy is contraindicated in patients suffering from PAH as it is highly dangerous. Thus most patients are likely to avoid pregnancy regardless of the requirements of T.A.P. Concerns about preventing testicular toxicity were also probably minimized by the fact that the great majority of victims of PAH are women. The Tracleer Access Program (T.A.P.) includes the following elements: (1) registration of all patients and practitioners who prescribe Tracleer, (2) distribution of Tracleer through a restricted distribution network, (3) distribution of a Medication Guide to patients with each shipment of drug, (4) initial distribution of Tracleer only after receipt by distributor network of written certification by practitioner for the patient, stating that the drug is being prescribed for a medically appropriate use in the treatment of PAH and that the physician has reviewed the liver 55 and pregnancy warnings with the patient and is committed to undertaking the appropriate monitoring of LFTs and pregnancy tests. T.A.P. also includes an ongoing, comprehensive program to (1) track and report to FDA all fetal exposures to Tracleer and the results of such exposures, (2) track and report to FDA all adverse events related to liver injury and the outcomes, (3) a notification program that collects data from patients about their receipt of liver function tests and pregnancy tests in the previous month and provides feedback to prescribing physicians about patients who are not compliant. Finally, the program requires annual review by the sponsor and FDA of the program’s effectiveness. The program works as follows. There is a toll-free line to Actelion, through which patients and physician can obtain program information, ask questions, report adverse events, and request enrollment materials. Actelion sends program materials, including educational materials, to the physician. The physician sends a completed Patient Enrollment Form, which the physician certifies as described above, to T.A.P. T.A.P. enrolls the physician and patient in a central database and assigns the prescription to an approved specialty distributor. Specialty distributors must agree to a set of rules in order to sell Tracleer. These include (1) distribution of a Medication Guide and LFT and pregnancy testing reminder card with each prescription, (2) entering the prescription information into a database, sending a letter to the prescribing physician to indicate that the initial prescription has been filled and reminding the physician of the need for monthly LFTs and pregnancy testing, (3) calling the patient prior to the next scheduled shipment of Tracleer to ask if the patient is continuing on the drug and to determine whether the patient has had the required tests within the past month, and (4) informing the physician if the patient reports that he or she has not been tested. If a prescription is not refilled, the distributor notifies T.A.P., which then investigates the reason. As least as initially described, T.A.P. has considerably fewer requirements and safeguards than the comparable program for thalidomide. There appears to be no mechanism to ensure that the patient actually has the liver function and pregnancy tests or that they are appropriately evaluated. There are no specific requirements for contraception. It appears that the pharmacy will ship the next months supply of medication based simply on the patient’s verbal request. Although the distributing pharmacy is supposed to ask the patient whether the required tests have been performed, it is not even clear whether a negative answer would preclude shipment. After enrolling the patient, the physician seems to play a minimal role in the 56 program. Most of the responsibility for ensuring that the program goals are met appears to rest with the patient. The only area in which T.A.P. is stricter than S.T.E.P.S. is in its requirement that the prescribing physician specifically attest that Tracleer is being prescribed for PAH by checking a box next to the diagnosis and entering a diagnostic code. Neither S.T.E.P.S. nor most of the other RMPs described herein Perhaps FDA’s willingness to accept a program for Tracleer that seems much less stringent than S.T.E.P.S. is due in part to the fact that pregnancy is highly dangerous in patients suffering from PAH, so patients already have a strong incentive to avoid pregnancy. This, together with the fact that PAH patients already undergo extensive monitoring, are typically cared for by specialists, and are highly compliant, may have led FDA to accept a less stringent program than S.T.E.P.S. In addition, FDA was doubtless aware that the results of S.T.E.P.S. would be watched closely, given thalidomide’s notorious history, whereas T.A.P. will probably be much less subject to scrutiny. G. Accutane and the S.M.A.R.T. Program: The Next Candidate for Restricted Distribution? Probably no currently marketed drug has had a more troubled post-approval regulatory history than Accutane (isotretinoin). The drug, marketed by Roche Pharmaceuticals, was approved in 1982 for the treatment of severe, recalcitrant cystic acne.178 Approval was granted despite the fact that both the manufacturer and FDA knew from animal studies that the drug, like thalidomide, was a potent teratogen. Accutane proved capable of causing a range of severe birth defects including mental retardation, fatal heart abnormalities, and various facial abnormalities.179 The estimated rate of birth defects among live births is at least 25%, and the severity of the defects leads to a high rate of spontaneous abortion among women who are exposed to the medication when they become pregnant or early in gestation. As of the end of 2002, FDA was aware of 2,350 pregnancies in which Accutane exposure had occurred. Of these, close to 1,400 resulted in termination, 260 ended in miscarriages, 196 178 See Full Revised Accutane label, available at http://www.fda.gov/medwatch/SAFETY/2002/accutane_PI_602.pdf. 179 See Issues Relating to the Safety of Accutane, a Hearing Before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, House of Representatives, 107th Congress, Second Session, December 11, 2002, Serial No. 107-143. Available at http://www.access.gpo.gov/congress/house, hereinafter Accutane 2002 House Hearing. Much of the pre- and post-approval history of Accutane is recounted in the transcript of this hearing. 57 resulted in normal babies, and 172 children with birth defects were born. 180 It was estimated that since Accutane’s introduction there had been between 15,000 and 18,000 pregnancy exposures to Accutane, with 11,000 to 13,000 Accutane-related abortions and between 900 and 1,000 birth defects. Given the increased prescription rate for Accutane, an FDA official estimated that as of 2002 there were approximately 2,000 Accutane-exposed pregnancies annually, of which approximately 95% ended in abortion.181 While Accutane’s teratogenicity has long been a source of concern and regulatory attention, more recently it has become apparent that the drug may be linked to a variety of adverse psychiatric manifestations including depression, spontaneous acts of violence, and suicidal behavior.182 Accutane is an oral retinoid and is a derivative of Vitamin A. It is uniquely effective in the treatment of acne and the prevention of scarring, being of particular value in cases that have failed to respond to any of the other remedies available, which include cleansing, antibiotic agents, and various topical treatments such as benzoyl peroxide and salicylic acid. A single four to five month course of treatment can be curative. In contrast to other available agents, Accutane appears to exert its effect by altering the size and differentiation state of glands in the skin and by exerting anti-inflammatory properties. That Accutane would have these effects is not surprising, since the retinoid family includes a number of compounds known to exert profound effects on development and differentiation.183 That Accutane would also affect the developing embryo and fetus is therefore also not unexpected. Shortly after marketing of Accutane commenced, Roche and FDA began to receive reports of birth defects associated with use of the drug. During the 1980s Roche and FDA undertook a number of efforts to address this problem. These efforts were largely focused on educating physicians and the public and included labeling changes, letters to pharmacists and physicians, patient brochures to be given to the patient by physicians, warning stickers to be affixed to the drug receptacle by pharmacists, articles in FDA publications, and press releases. 184 The goal was to prevent pregnancy in women taking the drug by encouraging the use of appropriate contraceptive methods. 180 Id. at 43. Id. at 38. 182 Id. 183 Id. 184 Accutane House Hearings, supra. 181 58 Despite these efforts evidence accumulated that pregnancies and birth defects were continuing to occur and that the drug was being prescribed for patients whose acne was only mild to moderate rather than severe. FDA convened a meeting of its Dermatologic Drugs Advisory Committee to consider the situation. The Committee supported continued marketing of Accutane but made a number of recommendations to reduce the risks that accompanied its use including yet more revisions to the label and packaging to incorporate more effective warnings, and signed informed consent forms. Other proposals considered by the Committee and FDA included a requirement that women have a negative pregnancy test before receiving the drug and restricting prescribing to only certain physicians (e.g., dermatologists or physicians who had undergone specialized training).185 In 1989 Roche implemented the Pregnancy Prevention Program (PPP). The program, which was voluntary, instructed physicians that women of child-bearing potential should have two negative pregnancy tests, use two forms of birth control simultaneously starting one month before prescription, be capable of carrying out instructions, and receive verbal and written warnings of the risks of exposing the fetus to the drug. Results of a survey of women treated with Accutane, designed to measure the effectiveness of the program revealed that although most women were made aware of the risks, compliance with the recommendations was relatively poor. For example, only two thirds of the women waited for the results of a pregnancy test prior to starting therapy. In addition, Roche and FDA continued to receive reports of Accutaneexposed pregnancies and birth defects. Concerned about the ongoing risks associated with Accutane, coupled with the fact that the number of prescriptions to women of child-bearing potential had tripled between 1989 and 2000 and mounting evidence that considerable off-label use was occurring, FDA convened another meeting of the Dermatologic and Opthalmic Drugs Advisory Committee in September 2000. The Committee considered a number of proposals and recommended a program that included educational components for physicians and patients, mandatory informed consent, registration of both physicians and patients, monitoring of Accutane-exposed pregnancies using a registry, and patient surveys. The Committee stopped short of recommending a restricted distribution scheme. 185 Id. 59 Roche and FDA agreed upon the implementation of a new program to prevent Accutane exposure during pregnancy. The program, known as the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.), was launched in April 2002.186 The program adds considerably to the requirements of the PPM though it does not contain all the elements recommended by the Advisory Committee.187 Women must take two pregnancy tests prior to receiving an initial prescription and a monthly pregnancy test is required thereafter for the patient to receive the next month’s supply of the drug. Women are supposed to use two forms of contraception simultaneously beginning one month prior to the first dose of Accutane. Physicians interested in prescribing Accutane must register with Roche by completing a letter signifying that they have read and understood the educational materials provided by the company, and certify that they are able to diagnose and treat the various presentations of acne. They are encouraged to take a Continuing Medical Education course that provides further information. Following registration Roche send the physicians yellow qualification stickers to be affixed to prescription forms to signify that the patient has had negative pregnancy tests, education about Accutane risks, and counseling regarding contraception. Pharmacists are instructed to fill only prescriptions that bear a sticker, to dispense no more than one months’ supply, and to provide the patient with an FDA-approved Medication Guide. Phone-in prescriptions are not allowed. While its requirements are more rigorous than those of the PPP, S.M.A.R.T. has a number of limitations. There is no enforcement mechanism for physicians who fail to register or for physicians or pharmacists who do not follow the guidelines. Patients are strongly encouraged but not required to participate in the patient survey. There is a goal of 60% participation. Other than the patient survey, there is no formal mechanism for assessing the degree of compliance and specifically identifying and addressing violations. Participation in the patient survey is voluntary, and there is no way to track patients that do not participate since there is no mandatory patient registration. It is estimated that less than half the women receiving Accutane participated in the surveys conducted under the PPM program. It would not be surprising to find that those patients who fail to participate in the survey are those most likely to have been prescribed 186 Id. The S.M.A.R.T. program is described on FDA’s Web site at http://www.fda.gov/cder/drug/infopage/accutane.smart.pdf. 187 60 Accutane by physicians who do not adhere to the guidelines or who fail to follow the instructions themselves. There is no pregnancy registry to track the outcomes of any Accutane-exposed pregnancies that do occur. Finally, although prescribing guidelines recommend that Accutane should only be prescribed by physicians with special competence in diagnosing and treating severe recalcitrant nodular acne and have experience in the use of systemic retinoids, since any physician can prescribe the drug and physicians can self-attest to their knowledge it is virtually certain that this condition is not being met. Although the number of Accutane prescriptions has dropped by approximately 20% to 30% since introduction of S.M.A.R.T., it appears likely that off-label use is continuing, even among dermatologists. Thus in comparison with the clozapine RMP and several others discussed herein, S.M.A.R.T. has some very obvious deficiencies. In parallel with growing recognition of the large number of Accutane-exposed pregnancies and inappropriate prescriptions came increased concern that use of Accutane might be linked to an increased risk of depression and suicide. This possibility had not been foreseen prior to marketing, but during the 1980s there were post-marketing reports of depression in Accutane users, and Roche added a statement to that effect in the labeling. During the 1990s reports of suicide in some patients on Accutane caused the FDA to begin investigating whether Accutane treatment was associated with suicide. While a causative link between depression and suicide and Accutane use could not be established, at FDA’s behest Roche again revised the label in 1998 to draw attention to Accutane’s possible potential to cause depression and suicide and sent another letter to physicians. The issue of Accutane’s potential psychiatric side effects was catapulted into the spotlight when the 17 year old son of Congressman Bart Stupak committed suicide while on Accutane, seven months after receiving a prescription to treat a mild case of acne. Like many of the other patients who had committed suicide while on Accutane, Stupak’s son lacked evident risk factors, and his suicide was completely unexpected. Accutane’s possible link to adverse psychiatric events was the subject of a hearing before the House Government Reform Committee, of which Stupak was a member, in December 2000. Stupak currently serves on the House Subcommittee on Oversight and Investigations, which held a second hearing in December 2002 focusing both on Accutane’s teratogenic and psychiatric risks and FDA’s responses thereto. By that point in time Accutane had been the subject of five Advisory Committee meetings, numerous letters to 61 health care professionals, multiple label revisions including addition of black box warnings addressing both the pregnancy-related and psychiatric risks, numerous educational efforts directed to physicians, patients and the public, signed informed consent, and the voluntary PPM and S.M.A.R.T. programs aimed at preventing Accutane exposure during pregnancy. In addition to the reports of Accutane-exposed pregnancies and birth defects, FDA had received 173 reports of Accutane-associated suicide.188 FDA was sharply criticized on a number of grounds by virtually all Committee members, with Stupak referring to FDA’s response to birth defects and psychiatric events as “inadequate, irresponsible, and unacceptable”.189 Dr. Janet Woodcock, the Director of FDA’s Center of Drug Evaluation and Research, testified and responded to questions. Committee members wanted to know why the incidence of Accutane-exposed pregnancies in Europe is 8 to 10 times lower than in the United States and questioned why FDA had not implemented a restricted distribution scheme (as in Europe) in response to the recommendation of the Advisory Committee in 2000. The Committee demanded an explanation of why Accutane’s RMP seemed to be much less stringent than that for thalidomide, despite the fact that Accutane is prescribed for a patient population much more likely to become pregnant than patients on thalidomide. A number of Congressmen recognized that FDA’s authority to impose restrictions on an approved drug might be limited. Indeed Congressman Deutsch stated that, “A central question is whether the FDA can forcibly implement an effective risk management plan over a problem drug that has already been marketed.”190 Congressman Brown complained that FDA was taking a head-in-the-sand approach, was overly influenced by industry, and suggested that “things have got to change”. He expressed hope “that the FDA will return to its mission of promoting public health, not promoting the drug industry...”191 Woodcock’s testimony and that of other FDA officials shed light on the complexity of the issues with which FDA grapples when deciding what degree of oversight to exercise over marketed drugs. Similar considerations are relevant to decisions regarding restrictions associated with approval, although the availability of Subpart H at least provides FDA with ostensible 188 Accutane House Hearings, supra, at 59. Id. at 12. 190 Id. at 8. 191 Id. at 21-22. 189 62 authority to impose such restrictions. Nevertheless, it appears evident that extra-legal factors are likely to assume a more significant role in the decision-making process. Stating that, “FDA must constantly balance the public need for access to effective therapies against the risks associated with their use”, Woodcock acknowledged that Accutane “continues to be one of FDA’s most difficult challenges in the area of post-approval management”.192 She defended FDA’s decision to allow continued marketing of Accutane under S.M.A.R.T. rather than imposing more stringent requirements such as a restricted distribution system, mandatory patient and/or physician registries, etc. In particular, Woodcock drew attention to the issue of gray/black market distribution of Accutane, alluding to the ready availability of the drug in Mexico and via Internet sales. Two days before the hearing had FDA announced that it was strengthening the controls designed to restricting imports of all of the drugs that are subject to restrictions on distribution and/or use193. FDA's action entailed adding the drugs to an existing Import Alert194 and issuing a Consumer Advisory warning the public not to purchase these drugs over the Internet because doing would bypass important health safeguards.195 However, other than sending “cyber-letters” to a number of Internet sites advising them to stop selling the drug and issuing the Import Alert and Consumer Advisory, FDA had taken no additional action. By making access to Accutane more difficult, FDA feared that patients would turn to alternate sources, thus depriving them of any benefits that the health care system and S.M.A.R.T. might provide and exposing them to drug manufactured under unapproved conditions. Although appropriate risk management for both thalidomide and Accutane includes prevention of exposure during pregnancy, as Woodcock pointed out, there are fundamental differences that make regulation of Accutane much more difficult. Unlike thalidomide, which is generally prescribed to treat physician-diagnosed diseases such as leprosy and cancer, Accutane treats a condition that is self-diagnosed and for which other therapies are available over-the- 192 Id. at 27. See FDA Talk Paper: FDA Strengthens Controls, Issues Consumer Alert on Importing Certain Prescription Drugs, available at http://www.fda.gov/bbs/topics/NEWS/2002/NEW00856.html 194 See IA #66-41 - 9/28/00 REVISION OF IMPORT ALERT #66-41 "UNAPPROVED NEW DRUGS PROMOTED IN THE U.S." ATTACHMENT REVISED 4/4/03, available at http://www.fda.gov/ora/fiars/ora_import_ia6641.html, accessed April 12, 2003. 195 See Important Consumer Safety Alert, available at http://www.fda.gov/oc/buyonline/consumeralert120902.html, accessed April 12, 2003. 193 63 counter. Therefore patients are much more likely to order the drug themselves than is the case with thalidomide. Any effective effort to improve the risk-benefit profile of Accutane would almost certainly include elements to restrict prescription to those patients in whom the drug is indicated, i.e., those with severe, recalcitrant nodular acne. Such restrictions would encroach on physician autonomy and make it likely that many patients who desired the drug would not be able to obtain a prescription, given that an estimated 90% of current usage is off-label.196 In contrast, the thalidomide RMP does not attempt to regulate the indications for which physicians prescribe the drug, and most use of thalidomide is off-label.197 Significant off-label usage might be tolerable if an effective risk control program could be developed. While this is extremely difficult in the case of pregnancy (Woodcock conceded that it would be virtually impossible to achieve a rate of zero pregnancy exposure198), it is at least theoretically possible to achieve compliance with an extremely stringent pregnancy prevention program. However, in the case of the psychiatric side effects it appears very unlikely that it will be possible (at least in the near future) to identify a group at risk and take appropriate precautions. Many of the patients who committed suicide had no history of psychiatric illness and did not exhibit any warning signs.199 Under such conditions there may be no way to reduce the psychiatric risks posed by the drug other than limiting the exposed population. Clearly it is in the interests of the manufacturer to allow off-label usage to continue as long as the costs in terms of negative publicity and legal liability remain relatively low. Woodcock alluded to the possibility that Roche might decide to withdraw Accutane from the market if FDA attempted to regulate in a manner that the company deemed too restrictive. Finally, the treatment populations for Accutane and thalidomide are markedly different. Thalidomide is prescribed largely for adults, and women of child-bearing potential comprise a much smaller percentage of the treatment population. Accutane, in contrast, treats a condition found largely in adolescents, a group perhaps least likely to have the ability and responsibility to manage stringent contraceptive measures. 196 Accutane House Hearings, supra, at 39. Id. at 36. 198 Id. 199 See id. at numerous places, detailing case histories of suicide victims. 197 64 The considerations raised by Woodcock are compelling and problematic. Committee members expressed dismay that FDA had not taken stronger action to address Internet sales and foreign (Mexican) sources of Accutane. Yet dealing with these problems would seem to exceed the limits of a reasonably feasible post-marketing regulatory effort for any specific drug. They are issues that require a concerted and unified response rather than a piecemeal approach focusing on particularly problematic drugs. The concerns posed by these issues extend beyond drugs that are subject to restrictions on distribution or use. Woodcock also mentioned that there were doubts as to whether FDA had the authority to require mandatory registration and/or restricted distribution. Congressman Greenwood directly asked Woodcock whether she believed FDA did have such authority and, if not, whether FDA was seeking it.200 A representative of FDA’s Office of Chief Counsel responded that FDA had achieved most success in developing such registries by working with sponsoring companies since registries require participation of patients and physicians, while FDA’s authority extends only to companies. He went on to say that if the sponsor refused to cooperate, FDA’s only recourse would be withdrawal of approval. In response to a request for specific statutory authority, FDA later supplied a letter citing the restrictions component of Subpart H, i.e., 21 C.F.R. § 314.20.201 As discussed elsewhere herein, this regulation applies only to drugs that are not yet approved, whereas the question was not limited to such drugs. As a marketed drug, Accutane is clearly beyond the reach of 21 C.F.R. § 314.20. FDA appears to have foregone an opportunity to lobby for increased regulatory power. On the other hand, perhaps FDA felt that it would be better to avoid making any statement that might be interpreted as acknowledging a limitation on its authority on the public record. Or perhaps FDA feels that such authority would be of little use since the sponsor can always opt to withdraw the drug if the FDA’s requirements seem too onerous. If Congressional pressure continues, Accutane seems like a prime target for implementation of a more stringent regulatory scheme, probably involving mandatory physician and patient registries. Such an effort will test the limits of FDA’s authority to impose postmarketing regulations. It will also test the feasibility of efforts to greatly limit access to a drug that is readily available via the Internet and from abroad, approved in generic form in the United 200 201 Id. at 63. Id. at 64. 65 States, and of considerable appeal to a large patient population. It is also possible that continued pressure will lead to Accutane’s withdrawal from the market. Tellingly, Congressman Stupak stated that, “We’re hoping that this drug isn’t even on the market 10 years from now.”202 H. Lotronex™ and the Lotronex Risk Management Program: Watering Down Subpart H? Lotronex (alosetron) is the most recent drug to be approved under the restrictions component of Subpart H. In addition, it is the first drug to be approved with restrictions that is intended for use in a very common disease, irritable bowel syndrome (IBS) albeit in a select subset of patients. Irritable bowel syndrome is a very common disorder that is characterized by a combination of abdominal pain and altered bowel function, typically featuring a pattern of diarrhea alternating with periods of constipation.203 Other symptoms include abdominal bloating and distention. IBS is estimated to affect 14% – 24% of women and 5% to 19% of men. The disease is chronic and can cause significant interference with patients’ daily lives but does not increase susceptibility to other gastrointestinal (GI) disorders, directly result in serious health consequences, or affect lifespan. IBS is classified a functional disorder because no structural or biochemical abnormalities that are consistently associated with the disease have been identified. Current treatments, which include various antidiarrheal agents, antidepressants, and anticholinergic agents, are all classed as either “adjunctive treatment” or “possibly effective”, and all of them have undesirable side effects.204 Given the large patient population and the lack of satisfactory therapy, there was considerable reason for FDA to feel that rapid action was justified, and considerable reason why the agency might feel pressure to approve the drug. Alosetron (brand name Lotronex™ is a member of a class of compounds known as 5hydroxy-tryptamine (5-HT, also known as serotonin) receptor subtype 3 antagonists. 5-HT3 receptors have been implicated in the mechanisms controlling various GI functions, especially 202 Id. at 53. See Medline Plus Encyclopedia, entry on Irritable Bowel Syndrome, available at http://www.nlm.nih.gov/medlineplus/ency/article/000246.htm. See also Lotronex™ (alosetron hydrochloride; GR68755), NDA 21-107, Secondary, Multidisciplinary Review and Recommendations for Regulatory Action at pp. 7 - 9, available at http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3627b2bg.pdf, hereinafter Multidisciplinary Review. As described therein, “IBS has been defined using symptom-based criteria (e.g., the “Rome criteria” or the “Manning criteria”), as a “combination of chronic or recurrent GI symptoms not explained by structural or biochemical abnormalities”, which is “attributed to the intestines and associated with symptoms of pain and disturbed defacation and/or symptoms of bloated (sic) or distension.” 204 Multidisciplinary Review at pp. 12-14 203 66 motility and sensation, and the 5-HT3 receptors on certain nerves are believed to be involved in the pathophysiology of IBS. 205 In addition, elevated levels of 5-HT have been found in the GI tract of certain patients suffering from IBS. Thus IBS has been attributed either to inappropriate activity of 5-HT3 receptors (possibly due to increased levels of 5-HT), or an inappropriate response to such activity. Lotronex was hypothesized to exert its therapeutic effect by preventing or reducing this response. GlaxoSmithKline (GSK) submitted an NDA for Lotronex in June 1999. FDA granted GSK’s request for an accelerated review (6 months) based on the consideration that in comparison with existing therapies for IBS, alosetron represented a “significant therapeutic advance (with an acceptable safety profile)…for the significant population of female patients with non-constipating IBS.206 The FDA’s Gastrointestinal Drugs Advisory Committee considered the NDA later that year. GSK presented data that suggested a modest benefit with Lotronex therapy, previously characterized by FDA as between 10 and 15% therapeutic gain for the primary endpoint, subjective relief of IBS symptoms.207 The benefit was particularly great in a subset of female patients who had diarrhea as a predominant symptom. The Committee devoted considerable attention to two adverse events identified in the clinical trials – constipation and ischemic colitis. Constipation was the most frequent AE, occurring in 28% of the treated patients and causing significant numbers of patients to drop out of the studies, versus 5% of the patients who received placebo. Of greater concern were four reports of possible ischemic colitis among the patients who received Lotronex versus none in the placebo treated group. Colitis is an inflammation of the colon (large intestine) that may be caused by many different disease processes, including acute and chronic infections, primary inflammatory disorders (ulcerative colitis, Crohn's disease, lymphocytic and collagenous colitis), lack of blood flow (ischemic colitis), and history of radiation to the large bowel. Symptoms typically include abdominal pain, diarrhea, dehydration, abdominal bloating, increased intestinal gas, and bloody stools. Diagnosis involves imaging, visualization using sigmoidoscopy or colonoscopy, 205 Multidisciplinary Review at p. 7. Three drugs of this class had previously been approved for treatment of chemotherapy-induced nausea and vomiting. None of these drugs has proven to be associated with severe GI side effects. 206 Multidisciplinary Review at p. 12. 207 Multidisciplinary Review at pp. 2 and 11. 67 pathological evaluation of biopsies, and culture for infectious agents. Treatment and prognosis depend on the underlying disorder and the severity of the colitis.208 Ischemic colitis is caused by a reduction of blood flow to the colon, most commonly involving an episode of systemic hypotension (low blood pressure) or surgical disruption of blood flow to the colon such as during or after aortic surgery.209 Risk factors include a history of peripheral vascular disease, history of stroke, low blood pressure, congestive heart failure, aortic surgery, and several others. However, many cases are idiopathic (i.e., no definitive cause can be identified). The symptoms include crampy lower abdominal pain, nausea, vomiting, and bloody diarrhea, typically occurring several hours to days after the episode of low blood flow. The symptoms can thus overlap substantially with those of IBS. With early diagnosis and appropriate supportive care most cases resolve. All four of the patients diagnosed with ischemic colitis during the Lotronex trials recovered without sequelae. However, the death rate is high if one of the major complications, which include gangrene of the bowel, perforation (hole in the intestine), peritonitis (inflammation of the lining of the abdomen), or sepsis develops. During the hearing GSK’s representative, Dr. Mangel, suggested that the diagnosis of ischemic colitis was probably incorrect in three of the four cases, notwithstanding the fact that all four patients had received this diagnosis based on both clinical features (e.g., signs and symptoms) and endoscopic examination.210 GSK presented an academic pathologist who had reviewed the biopsy specimens and opined that in one case no evidence of pathology consistent with colitis was evident and that the two remaining cases were most likely not true ischemic colitis but rather a colitis caused by infection with one of a number of agents that can cause colitis, such as E. coli serotype O157:H7 or C. difficile.211 Dr. Mangel then went on to state GSK’s belief that there was no evidence for existence of a causal relationship between development of ischemic colitis and alosetron therapy.212 GSK’s less than straightforward presentation appeared to engender some frustration among the committee members. Indeed near 208 See Medline Plus Encyclopedia, entry on colitis, available at http://www.nlm.nih.gov/medlineplus/ency/article/001125.htm#Definition. 209 See Medline Plus Encyclopedia, entry on ischemic colitis, available at http://www.nlm.nih.gov/medlineplus/ency/article/000258.htm#Definition. See also Multidisciplinary Review. 210 Statement of Dr. Mangel at November 16, 1999, meeting of FDA Gastrointestinal Drugs Advisory Committee Meeting, at p. 86. Available at http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3565t1a.pdf. 211 Statement of Dr. Kay Washington at November 16, 1999, meeting of FDA Gastrointestinal Drugs Advisory Committee Meeting, at pp. 86-95. 212 Statement of Dr. Mangel at November 16, 1999, meeting of FDA Gastrointestinal Drugs Advisory Committee Meeting, at p. 95. Available at http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3565t1a.pdf. 68 the end of the meeting one committee member stated, “I used to know what ischemic colitis is; I’m not sure I understand it now.”, to which the chairman replied, “You used to know what IBS was until today.”213 Dr. John Senior, FDA’s GI medical reviewer responsible for the safety review of the Lotronex NDA, presented data on the unexpectedly high incidence of constipation and the disturbing occurrences of ischemic colitis and argued that these findings should not be ignored.214 Dr. Senior also drew attention to one patient who had experienced a reversible elevation in liver enzymes, a finding that may predict serious hepatotoxicity will develop in some patients once the drug is administered to a larger population.215 In his medical review of the Lotronex™ NDA Senior had expressed dismay “that the applicant has chosen to downplay so strongly the important issue of constipation induced commonly and predictably by alosetron, and has totally ignored the potentially very serious although uncommon problems of ischemic colitis and perhaps rare alosetron-induced hepatitis”216 However, the multidisciplinary review team, with the evident concurrence of Dr. Senior, recommended approval of the drug, with safety issues related to constipation, ischemic colitis and liver toxicity to be addressed through appropriate labeling.217 Summarizing the safety data before the GI Drugs Advisory Committee, Dr. Gallo-Torres, leader of the FDA multidisciplinary review team that evaluated the safety and efficacy of Lotronex, commented, “One will have to wonder what will happen if one approved this compound when the conditions are no longer controlled, and so one will have to raise potential additional risks, such as uncontrolled settings, such as the drug being taken by sicker patients, longer use, other medications, concurrent diseases such as liver disease, variable follow-ups, and other risk factors…Uncommon or rare events may become serious public health problems when 213 Comments of committee members Dr. Wald and Chairman Hanauer at November 16, 1999, meeting of FDA Gastrointestinal Drugs Advisory Committee Meeting, at p. 194. Available at http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3565t1c.pdf 214 Statement of Dr. John Senior, GI medical reviewer, at meeting of FDA Gastrointestinal Drugs Advisory Committee Meeting, at pp. 156-7. Available at http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3565t1b.pdf, at pp. 145-155. 215 Id. GSK also maintained that the raised liver enzymes had resolved while the patient was still taking the drug, which would have suggested that the drug was not responsible. 216 Medical review by Dr. John Senior, GI medical reviewer, NDA21-107 Medical Safety Review at p. 62, available at http://www.fda.gov/cder/foi/nda/2000/21107a_Lotronex_medr_P10.pdf. 217 Multidisciplinary Review at pp. 54-55. 69 hundreds of thousands or millions of patients are exposed to the drug.”218 Despite the relatively modest benefit and the potential for severe toxicity, the GI Drugs Advisory Committee voted unanimously to approve Lotronex while recommending careful surveillance of post-marketing adverse events, particularly ischemic colitis, and an independent review of the pathology specimens from the patients with suspected colitis.219 On February 9, 2000, FDA approved Lotronex “for the treatment of IBS in women whose predominant symptom is diarrhea.”220 The labeling reported that constipation was a common side effect of Lotronex, warned physicians that acute ischemic colitis had been infrequently reported in patients receiving Lotronex during clinical trials and that the drug should be stopped in patients experiencing worsening of abdominal pain or rectal bleeding, and advised that such patients be promptly evaluated.221 The package insert included a detachable portion to be given to patients by the pharmacist. This portion cautioned patients to stop the medication and seek medical advice if they experienced worsening of abdominal pain or blood in the stool as such symptoms might be a sign of a serious medical condition.222 As part of the approval package GSK committed to performing a variety of post-marketing studies including a large, one year risk trial to assess the incidence of colitis in patients receiving Lotronex.223 After Lotronex went on the market FDA began to receive reports of serious adverse events including surgical complications of constipation, ischemic colitis, and liver toxicity. These reports suggested an estimated incidence rate of 1/100 to 1/1000 for ischemic colitis and raised continued concerns regarding liver toxicity and new concerns regarding constipation, which in severe cases can result in fecal impaction and perforation of the bowel wall.224 An independent review of the pathology specimens from the patients who experienced colitis 218 Comment by Dr. Hugo Gallo-Torres, leader of FDA multidisciplinary team responsible for evaluation of Lotronex NDA, at meeting of FDA Gastrointestinal Drugs Advisory Committee Meeting, at pp. 156-7. Available at http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3565t1b.pdf 219 See transcript of November 16, 1999, meeting of FDA Gastrointestinal Drugs Advisory Committee, at pp. 201206, available at http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3565t1c.pdf. 220 Lotronex approval letter, available at http://www.fda.gov/cder/foi/appletter/2000/21107ltr.pdf. 221 See Lotronex package insert, February 2000, at p. 7, available at http://www.fda.gov/cder/foi/label/2000/21107lbl.pdf. 222 Id. at p. 18. 223 Lotronex approval letter, supra, at p. 2. 224 See Overview and Risk Management Issues for Lotronex™ Tablets, a briefing document prepared for June 27, 2000 meeting of FDA Gastrointestinal Drugs Advisory Committee available at http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3627b2bb.pdf. 70 concluded that three of the four cases were consistent with ischemic colitis.225 Furthermore, review of the records indicated that the case of hepatotoxicity did indeed resolve after discontinuation of Lotronex, suggesting an association with the drug. FDA therefore convened another meeting of the GI Advisory Committee for the purpose of reviewing the risk-benefit profile of Lotronex and how it might be optimized through adoption of a risk management plan.226 GSK proposed a risk management program comprising three main elements: risk definition, risk communication, and evaluation. The evaluation component included independently conducted tests to assess message comprehension and awareness among physicians, patients, pharmacists, and sales representatives.227 The program contained no requirements for physician or patient registration. Thus there was no way to confirm that physicians and/or patients had actually read and understood the educational materials, and there was no way to perform effective follow-up. There was no attempt to determine whether the RMP actually altered behavior. Following the meeting of the Advisory Committee GSK made labeling changes and produced a Medication Guide to be distributed together with the drug by pharmacists.228 Physicians and pharmacists were informed of the labeling changes, and FDA issued a press release highlighting them. However, within the next several months FDA received additional postmarketing reports of serious adverse events. 229 Reports of five cases with a fatal outcome were received between September and November 2000, leading FDA to question the efficacy of the risk management efforts. In addition, FDA received a petition from Public Citizen urging withdrawal of the drug. On November 28, 2000, FDA met with GSK and offered the company the options of (1) voluntarily withdrawing the drug, (2) temporary suspension of marketing pending an advisory committee meeting, and (3) restricted distribution to patients currently receiving the drug who Overview and Risk Management Issues for Lotronex™ Tablets, supra. See transcript of hearing of Gastrointestinal Drugs Advisory Committee, June 27, 2000, available at http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3627t2a.pdf, http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3627t2b.pdf, http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3627t2c.pdf 227 Id. 228 See Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science Background Package (hereinafter Background Package), available at http://www.fda.gov/ohrms/dockets/ac/02/briefing/3848B1_01_GSK%20Briefing%20Pkg.pdf. The section entitled Highlights of Regulatory History presents an overview of events beginning with consideration of the Lotronex NDA. 229 Background Package, Executive Summary and Highlights of Regulatory History. 225 226 71 signed an informed consent form. GSK decided to withdraw the drug and within a month had ceased all sales and distribution of Lotronex worldwide. Following withdrawal of the drug, a number of patients contacted both FDA and GSK seeking access to the drug, describing their inability to control their debilitating symptoms with other therapies. FDA received a petition from the Lotronex Action Group, a patient advocacy group formed in the wake of the withdrawal, requesting that marketing of Lotronex be permitted to resume. GSK declined to make Lotronex available under an IND, an option that has been pursued in the case of other drugs such as cisapride that have been withdrawn because of safety concerns. However, GSK indicated its willingness to consider marketing the drug under restricted conditions. In light of the patient requests and the fact that substantial amounts of additional safety data from clinical trials and postmarketing reports had become available since withdrawal, GSK and FDA agreed that GSK would submit a revised RMP, the new data, and revised product labeling as part of a supplement to the NDA for consideration of re-introducing Lotronex to the market.230 FDA convened a joint meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science in April 2002 to consider the whether the risk-benefit profile of Lotronex had changed, whether an appropriate RMP could be established for Lotronex, and what the characteristics of such a program would be. By the time of the meeting FDA had received 113 reports of serious complications of constipation, 84 of ischemic colitis, 143 admissions to hospital, 50 cases of surgery, and 7 deaths.231 The briefing package provided to the panel contained information about approaches to risk management compiled by FDA’s Office of Drug Safety.232 The document presented selected features of restricted distribution programs and their advantages and disadvantages, summarizing FDA’s experience with the restricted distribution schemes described above. The production of this document represents an important milestone since it indicates that FDA is developing an analytical framework with which to evaluate RMPs with restricted distribution schemes and an approach to the selection of appropriate elements of such schemes. 230 Id. See Transcript of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science Joint Meeting, April 23, 2002, hereinafter Transcript of Joint Meeting, available at http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3848T1.pd 232 Background Package, Goals of Risk Management. 231 72 The document also evaluates GSK’s proposed RMP in the context of Subpart H and the goals that the program should seek to achieve. The document referred to the definitions of serious under regulations that relate to pre and postmarketing safety reporting.233 According to the definition, serious includes “significant disability/incapacity”, which is further defined as “a substantial disruption of a person’s ability to conduct normal life functions.” Given the effect of IBS on the lives of at least some IBS patients, this definition justifies application of Subpart H to Lotrnex. The goals of a Lotronex RMP were defined as follows. To assure access to Lotronex (1) to informed, severely affected IBS patients, (2) by informed, qualified prescribers, (3) with appropriate medical supervision, (4) by informed pharmacists under a restricted distribution system, (5) with auditing of plan effectiveness.234 The document concluded that GSK’s proposed RMP failed to achieve or did not address the first and third goals and also fell short with respect to the other three. In addition to presentations by GSK and FDA, the panel heard testimony from members of patient advocacy groups including the International Foundation for Functional Gastrointestinal Disorders and the Lotronex Action Group, advocating the return of Lotronex to the market.235 Based on a total of 17-18 total reports of ischemic colitis in the clinical trials, FDA and GSK agreed that the rate for subjects treated with Lotronex was approximately 1 in 660.236 It was not possible, based on the limited number of cases, to identify a population at substantially higher or lower risk than others. FDA and GSK had also concluded that the development of severe constipation was largely avoidable with proper patient selection and monitoring and appropriate therapy (e.g., laxatives) if constipation developed. Patients must be able to understand the risks and the need to stop taking the drug immediately if they became constipated. Patients with a history of constipation or of various GI disorders or anatomical abnormalities should not receive the drug. Most members of the panel agreed that it was possible to define a population of patients in whom the benefits of Lotronex outweighed the risks, but they were unable to define the 233 Id. The referenced regulations are 21 C.F.R. 312.32 and 314.80. Id. 235 Transcript of Joint Meeting 236 Background Package, Executive Summary. 234 73 population and felt that more study was needed.237 Nevertheless, they voted overwhelmingly that Lotronex should be available to IBS patients with appropriate marketing restrictions. The restrictions favored by the panel included limitations on the type of physician who could prescribe Lotronex, but there was no consensus on what such restrictions should entail.238 Among the proposals were to limit initial prescriptions to gastroenterologists or to physicians who had completed a credentialing program to document expertise. The panel favored a physician registry over GSK’s proposal that physicians authorized to prescribe Lotronex affix a sticker to the prescription. The sticker concept was felt to be inadequate as a mechanism to allow pharmacists to determine whether a prescription was written by an authorized physician. The impermanent nature of the sticker was also a cause for concern. The panel also favored patient registration, feeling that GSK’s proposal that physicians and patients sign a Physician-Patient Agreement to be filed in the patient’s medical record was not adequate to ensure that only patients with the most favorable benefit-risk balance were receiving prescriptions.239 The panel also rejected the studies GSK proposed to audit whether appropriate patients were being prescribed Lotronex and to audit patients’ knowledge and awareness of the risks and benefits of Lotronex. Both proposals would have assessed only a small fraction of the patients receiving Lotronex. The panel felt that a mandatory program to gather data that could be used to evaluate the program, more clearly establish the risks and benefits of Lotronex, and further define appropriate patients populations should be required. Six weeks after the meeting, FDA approved the Lotronex supplemental NDA with a RMP that is essentially identical to that proposed to the panel by GSK.240 The sNDA provides for use of Lotronex only in women with severe diarrhea-predominant IBS who have chronic IBS symptoms, have had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and have failed to respond to conventional therapy.241 The recommended dose was reduced from 1 milligram twice a day to 0.5 milligrams twice a day. The Lotronex approval letter outlines the Risk Management Program to which GSK agreed as a condition for approval 237 See Transcript of Joint Meeting, supra. See also Summary Minutes of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science, available at http://www.fda.gov/ohrms/dockets/ac/02/minutes/3848M1.htm. When not otherwise noted, descriptions of the panel’s views were obtained by reviewing these documents. 238 Id. 239 Id. 240 See Lotronex Approval Letter, available at http://www.fda.gov/cder/foi/appletter/2002/21107s5ltr.pdf. 241 Id. 74 of the sNDA.242 The RMP fails to incorporate most of the recommendations of the panel and of FDA’s Office of Drug Safety. The Lotronex RMP includes four major components: a prescribing program, an educational program, adverse event reporting, and risk management evaluation.243 Under the Prescribing Program for Lotronex, physicians contact GSK to indicate their interest in prescribing Lotronex, following which the company sends them educational materials and a physician attestation form. GSK will enroll any physician who meets certain qualifications and agrees to accept certain responsibilities. Physicians must have the ability to diagnose and treat IBS, ischemic colitis, constipation, and the complications of constipation and possess an understanding of the risks and benefits of Lotronex,.244 Physicians do not need to undergo formal training or otherwise demonstrate their competence in these areas but may simply affirm that they have reviewed the educational materials and package insert, that they understand the information therein, and that they possess the required qualifications by submitting the selfattestation form to GSK.245 By submitting the form the physician also attests to acceptance of certain responsibilities including the duty to educate any patient who is considering treatment with Lotronex on the risks and benefits of treatment, to obtain the patient’s signature on the Patient-Physician Agreement form, sign it, place it in the patient’s medical record, and give a copy to the patient. Physicians promise to provide any patient considering Lotronex a copy of the Lotronex Medication Guide and instruct the patient to read it and ask any questions the patient may have, as a preliminary step to completing the Patient-Physician Agreement. Physicians also agree to affix prescription stickers to each Lotronex prescription and not to prescribe the drug by telephone, fax, or computer. In addition, physicians attest that they will report serious adverse events either to GSK or the FDA. Physicians may read the educational materials and register online by completing the attestation form, which requires entry of the physician’s DEA number, and submitting it via the Web.246 Once GSK receives the form it proceeds to distribute Lotronex prescribing materials, 242 Id. Id. 244 See Prescribing Program for Lotronex, available at http://www.lotronex.com/physicianinfo.htm. 245 See Physician Attestation of Qualifications and Acceptance of Responsibilities, available at https://www.lotronex.com/physicianattesttext.htm. 246 See Physician Enrollment Form, available at https://www.lotronex.com/physicianenroll.jsp. 243 75 which include the Medication Guide, Physician-Patient Agreement Form, and prescription stickers to the physician. The educational component includes materials for physicians, patients, and pharmacists. The physician educational materials describe the features of the Risk Management Program itself, explain the revised indication for Lotronex and the reasons why Lotronex is restricted to a particular subset of patients with IBS, and explain how to determine whether a patient satisfies the criteria247. Because there was no consensus in the literature about the different diagnostic categories for IBS, FDA and GSK developed their own definition for severe diarrheapredominant IBS. As described in the attestation form, physicians are supposed to educate patients regarding the risks and benefits of Lotronex prior to initiating therapy. Patients are supposed to receive a Medication Guide with each prescription refill. The Medication Guide stresses that the drug is only suitable for women with severe IBS whose main problem is diarrhea, warns of the risks of severe constipation and ischemic colitis associated with the drug, and stresses the importance of stopping the drug and seeking medical advice if any of the warning signs develop. Some members of the Advisory Committee expressed skepticism about whether it is really possible to predict the development of severe constipation or ischemic colitis early enough to prevent their development by stopping the drug, particularly since constipation is a subjective symptom. Once a decision to initiate Lotronex therapy has been made, physicians and patients complete and sign a Physician-Patient Agreement form, which is placed in the patient’s medical record. The form reiterates the information in the MedGuide, stressing that Lotronex should only be used by patients with severe IBS who have diarrhea as their main symptom. Patients sign to attest that they meet these criteria, will follow the guidelines for stopping the drug and seeking medical advice, and have read the MedGuide. Physicians sign to attest that they have enrolled in the Prescriber Program and have counseled the patient and provided a MedGuide. Under the program pharmacists are supposed to receive education about the risks and benefits of Lotronex, instructions that they should not fill prescriptions for Lotronex unless the prescription bears a sticker verifying that the prescribing physician is enrolled in the Prescribing 247 See Understanding the Risks and Benefits of Lotronex, available at https://www.lotronex.com/download/understanding.pdf. 76 Program for Lotronex and that they should not accept prescriptions by phone, fax, or computer. They are also instructed to dispense a Medication Guide with each prescription. GSK agreed to conduct a study to evaluate whether physicians not enrolled in the Prescribing Program for Lotronex are writing prescriptions for the drug and, if so, whether such prescriptions are being filled. The company also agreed to conduct a study to evaluate the effect of the Lotronex RMP on use of Lotronex by patients with severe, diarrhea-predominant IBS, patient knowledge of the risks of Lotronex, and the frequency of serious GI events and death associated with Lotronex. The Lotronex RMP seems to add relatively little to the plan GSK proposed at the June 2000 Advisory Committee Meeting, which was found unacceptable. Indeed it is difficult to see why the Lotronex sNDA was even considered under Subpart H since the RMP does not restrict distribution and any restriction on use is essentially voluntary. The Prescribing Program and Physician –Patient Agreement lack many of the elements that characterize an effective RMP such as those for clozapine or thalidomide. Although the RMP does provide a way to identify which physicians might be prescribing Lotronex, there is no mechanism to actually track prescribing behavior or to associate particular patients with physicians through a centralized database. There is no way to determine whether pharmacies are refusing to fill prescriptions that lack the sticker or even to assess whether pharmacists are aware of this requirement. It does not appear that it will be possible to meaningfully evaluate the effectiveness of the RMP. This is especially troubling, because to truly optimize the risk-benefit profile of the drug it is clearly necessary to perform further studies to identify a population of patients that obtains such significant benefit from Lotronex that the benefits exceed the risks. The Advisory Committee agreed that such a population exists but could not agree on criteria to identify it. It would also be very useful to identify a population in which the benefits clearly do not exceed the risks. Identifying such populations should be a priority for GSK. A program that required patients to complete follow-up surveys (such as in the S.T.E.P.S. program) would have greatly facilitated the identification of such populations. Physicians remain unaccountable for their prescribing decisions under the Lotronex RMP, and there is no way to determine whether they are providing appropriate patient education or selecting appropriate patients for Lotronex therapy. Reporting of adverse events by physicians and patients remains voluntary. 77 It is likely that the Lotronex RMP (and possibly the adverse publicity associated with Lotronex’s withdrawal) will reduce the number of patients for whom the drug is prescribed, at least in the short term. Whether it will actually improve the risk-benefit profile in those patients who do receive the drug remains to be seen. Unfortunately the unpredictability of the serious adverse events associated with Lotronex makes it difficult to design a truly effective RMP for this drug. Unlike clozapine or dofetilide, there is no test that can identify patients who should not receive the drug and no specific preventive measures that can be taken. In similar situations in the past, e.g., in the case of drugs that cause sporadic liver toxicity, such as cisapride, Rezulin™ , or Trovan, FDA has required withdrawal or extremely curtailed distribution. In the case of Lotronex, FDA has chosen to allow the drug to be marketed with a RMP approved under Subpart H, albeit one that imposes minimal requirements. FDA’s decision to allow Lotronex back on the market under the terms of the RMP described above has been sharply criticized.248 Several members of the joint panel have publicly expressed their concerns that the RMP is inadequate with one member referring to it as a “facade”.249 In addition, Paul Stolley, a senior consultant to FDA who was in charge of reviewing postmarketing safety of Lotronex and left the agency in June 2001, charges that the agency is unduly influenced by industry and points to the approval of the Lotronex sNDA as a prime example. Stolley and others, including Public Citizen, allege that FDA’s reliance on user fees from industry, coupled with pharmaceutical companies’ large contributions to political campaigns, make the agency “afraid to offend these companies”.250 Pointing to the failure of GSK’s enhanced educational efforts and relabeling following the June 2000 Advisory Committee meeting to prevent the increasing number of serious adverse events associated with Lotronex, critics suggest that the RMP will likely be ineffective. They draw attention to Committee findings and an internal FDA memo that suggest the impossibility of identifying patients at risk of ischemic colitis and the overlap between disease symptoms and symptoms associated with the adverse events.251 They also emphasize the serious nature of the adverse events relative to the disease. Although IBS can significantly affect patient’s quality of See Michel Lievre, Alosetron for irritable bowel syndrome: Some patients may pay a high price for the FDA’s decision to put the drug back on the market, British Medical Journal, 325, 14 September 2002, pp. 555-556; Roy Mohnihan, Alosetron: a case study in regulatory capture, or a victory for patient’s rights, British Medical Journal, 324, 14 September 2002, pp. 592-595. 249 Mohnihan, supra. 250 Id. 251 Id. 248 78 life, it does not affect life expectancy and has never been associated with ischemic colitis or severe constipation requiring surgery. If the critics are right, Lotronex may be withdrawn from the market for a second time. It remains to be seen whether the Lotronex RMP and future efforts to identify risk factors and more precisely define appropriate criteria for prescription of the drug will succeed in reducing the risk to an acceptable level. IV. THE GROWING IMPORTANCE OF RISK MANAGEMENT PROGRAMS INVOLVING RESTRICTIONS ON DISTRIBUTION OR USE: LEGAL AND POLICY CONSIDERATIONS A. Does the Food, Drug, and Cosmetics Act Give FDA Authority to Impose Restrictions on Distribution or Use of New Prescription Drugs? As is evident from the descriptions above of the various RMPs that include restrictions on distribution or use, FDA does not impose the restrictions by fiat but rather through a process of negotiation with the sponsor. In the case of restrictions under Subpart H, the sponsor has the option to seek approval through the regular NDA provisions. However, due to the extensive consultations that typically occur between FDA and the sponsor prior to submission of the NDA, sponsors are doubtless well aware that they will have difficulty obtaining approval without restrictions. In the case of restrictions that are placed on drugs postmarketing, the sponsor has the option of refusing to implement restrictions and face the possibility that FDA will seek withdrawal of the drug. Sponsors know they are very unlikely to prevail against FDA’s decision to withdraw the drug and generally desire to avoid outright confrontations with an agency on whom they depend for permission to market their products. The propensity of agencies to use informal mechanisms to exert authority over highly regulated industries has been criticized as “arm-twisting”.252 Informal mechanisms such as issuance of guidance documents or threatening denial of a license (e.g, approval of an NDA) unless certain conditions are met may give agencies power to exceed their statutory mandate. 252 See Lars Noah, Administrative Arm-Twisting in the Shadow of Congressional Delegations of Authority, 1997 Wis. L. Rev. 873. 79 Such techniques are not subject to traditional judicial review and lack procedural safeguards. On the other hand, they allow agencies to avoid the delay and inflexibility of notice and comment rulemaking and may represent a more efficient approach to achieving the ends desired by Congress. As discussed below, in the case of RMPs with restrictions on distribution or use it appears that FDA is striving to achieve an appropriate balance between the two goals that Congress has set forth in FDA’s recently codified mission statement.253 Since restrictions on distribution or use are imposed voluntarily by the sponsor, the issue of whether FDA has authority to impose restrictions when the sponsor is unwilling to do so may never arise. The most likely source of a challenge to FDA’s current approach may come from patient advocacy groups who find the restrictions burdensome or public interest groups who would prefer withdrawal to an RMP with restrictions. Another source of a potential challenge might be third party payers who believe that the restrictions add substantially to the cost of the drugs. Unlike the substitute endpoint component of Subpart H, Congress has not codified the restrictions component. Nor is there evidence that Congress considered doing so in either the Senate or House Reports for the bills that eventually became the FDAMA. Both bills originally contained Fast Track provisions codifying those sections of Subpart H that authorize use of surrogate endpoints and permit FDA to require post-marketing studies as well as the section providing for streamlined withdrawal. These features evidently met with broad support and were not the subject of debate. Whether Congressional silence indicates that Congress approves or disapproves of FDA’s assertion of authority to restrict distribution or use of drugs thus remains as unclear as it did when Weinberger was decided. In contrast to the dearth of information from which to discern congressional intent with respect to drugs, the FDCA gives FDA clear authority to place restrictions on the sale, distribution, or use of devices.254 See note 52, supra, setting forth FDA’s mission statement as codified in the Food and Drug Modernization Act of 1997. 254 See 21 U.S.C. 360j (e)(1), providing in part that the Secretary may by regulation require that a device be restricted to sale, distribution, or use -(A) only upon the written or oral authorization of a practitioner licensed by law to administer or use such device, or (B) upon such other conditions as the Secretary may prescribe in such regulation, if, because of its potentiality for harmful effect or the collateral measures necessary to its use, the Secretary determines that there cannot otherwise be reasonable assurance of its safety and effectiveness. 253 80 As discussed above, Judge McGowan’s concurrence in American Pharmaceutical Association rested on his holding that FDA had not adopted the best interpretation of “safe” when it argued that methadone could only be considered safe if its distribution was restricted to prevent misuse made possible by drug diversion. In rejecting this argument, the Judge McGowan and the lower court held that the term “safe” in the FDCA was “intended to include only the inherent safety or lack thereof of the drug when used in the manner intended. American Pharmaceutical Association was decided prior to the Supreme Court’s decision in Chevron, USA, Inc. v. Natural Resources Defense Council, Inc.255, the case that established the standard under which agency regulations are currently reviewed. Under the Chevron standard, a court must defer to an agency’s interpretation of statutory language within the agency’s area of concern if (1) Congress is silent on the matter or statutory language is ambiguous; and (2) the agency’s interpretation is reasonable. It is not clear whether a court would find that Congress had spoken directly to the issue of whether FDA has authority to establish a regulatory scheme such as that attempted in the methadone regulations. Judge McGowan rested his concurrence on his interpretation of the word “safe” in 355(d), an interpretation he referred to as “best” and “the most reasonable interpretation of the statutory language and the common understanding of the FDA’s mission.”256 However, after Chevron a reviewing court is not to base its decision on the interpretation it feels is best or most reasonable but rather is to defer to the agency’s interpretation unless it finds that Congress has spoken directly to the issue. Chevron “establishes that a reviewing court must often accept any reasonable agency construction, even if the court does not regard that construction as the best one.”257 There is certainly room to argue that Congress had not spoken directly to the issue of the meaning of safe and that FDA’s interpretation was reasonable. Although the extent to which Chevron actually increased judicial deference to agency decisions has been debated,258 it seems clear that a mere finding that FDA had not adopted the best interpretation would not suffice to overturn FDA’s interpretation. More significantly, with the exception of Actiq and Xyrem, 255 467 U.S. 837 (1984). American Pharmaceutical Association v. Mathews, at 1055. 257 Richard H. Fallon, Daniel J. Meltzer, and David L. Shapiro, Hart and Wechsler’s The Federal Courts and the Federal System, 5th ed., 2003, p. 373. 258 See Jeffrey E. Shuren, Modern Regulatory Administrative State: A Response to Changing Circumstances, 38 Harv. J. on Legis. 291 for an extensive discussion of Chevron, its effect on judicial review of agency decisionmaking, and the proper role of courts in reviewing agency statutory interpretations. 256 81 restrictions under Subpart H or as part of a postmarketing RMP have been imposed not because of the risk of drug diversion but rather to optimize the risk-benefit profile for patients who take a drug for a legitimate medical purpose. In such a situation FDA would be on stronger ground arguing that certain drugs can only be considered safe if steps are taken to ensure appropriate patient education, patient selection, and performance of certain tests. Furthermore, much may depend on the definition of “intended use” for a particular drug. Rather than defining “intended use” as “treatment of condition X in patients having characteristic Y”, the “intended use” could be defined more narrowly, for example, “treatment of condition X in patients having characteristic Y when administered in a hospital by physicians trained in diagnosis and treatment of side effect Z”. By incorporating the restrictions directly into the indication, it would appear that FDA could avoid any running afoul of American Pharmaceutical Association. In responding to comments following the publication of the proposed rule that became Subpart H, FDA distinguished American Pharmaceutical Association in exactly this way.259 FDA argued that the Court of Appeals determination that the kind of misuse by persons who have no intent to try the drug for medical purposes differed from safety issues to be addressed by restrictions contemplated under Subpart H. FDA argued that the latter are precisely the sort necessary to ensure that the FDCA’s safety requirements have been met. FDA also argued that the outcome in American Pharmaceutical Association rested in part on a holding that regulation of methadone’s distribution fell within the jurisdiction of the Department of Justice and not FDA, a suggestion that may call into question FDA’s authority to approve Actiq and Xyrem under Subpart H. As mentioned above, although Congress did not codify the restrictions component of Subpart H when it codified the surrogate endpoint component, Congress was surely aware of the existence of the former and did not voice any objection. While Congressional silence in the face of an agency’s promulgation of a regulation is generally not a very persuasive argument that Congress approves of the regulation, in this case the argument does carry some weight given that Congress has codified the closely related surrogate endpoint rules. In addition, Congress has amended the FDCA multiple times since the approval of thalidomide, the first drug approved with restrictions under Subpart H, and has left Subpart H intact. 259 57 Fed. Reg. 58942. 82 As discussed above, in the Accutane hearings held in December 2002, the issue of imposing similar restrictions on Accutane to those imposed on thalidomide was explicitly discussed. There was no suggestion that FDA had overstepped its authority in approving thalidomide with restrictions. On the contrary, FDA was criticized for the relative laxity of its approach to regulating Accutane. While it is impossible to predict future legislative developments, at present there appears to be no reason to anticipate any curtailment of FDA’s authority to approve drugs with restrictions under Subpart H or to allow drugs to be marketed subject to restrictions imposed after approval. B. Restrictions on Distribution or Use: Areas of Concern and Uncertainty 1. Characteristics of Drugs Subject to Restrictions As an increasing number of drugs are approved with restrictions or remain on the market subject to such restrictions, one may well wonder whether there are any substantive limits to the types of drugs that will be subject to restrictions. As discussed above, Subpart H applies only to drugs that provide a meaningful therapeutic benefit in a serious or life-threatening condition. It is likely that many drugs will meet this standard since FDA has thus far interpreted these terms broadly. Congress appears to approve of a broad interpretation. With respect to provisions to afford expanded access to investigational therapies and diagnostics under the FDAMA, the conference committee report stated The conference report provides statutory direction to expand access programs and emphasizes that opportunities to participate in expanded access programs are available to every individual with a life-threatening or seriously debilitating illness for which there is not an effective, approved therapy. The conferees note that they purposely used broad language in this section relating to "serious" conditions, without attempting to define them, in order to permit wide flexibility in implementation. Illnesses that do not cause death, or imminent death, can nonetheless destroy the lives of both patients and their families. The conferees therefore intend that the seriousness of an illness be given broad consideration, to take into account all of the circumstances involved. 260 It appears likely that a similar interpretative 260 See H. Rpt. 105-399, conference report on S. 830, "Food and Drug Administration Modernization Act of 1997," Nov. 9, 1997, discussing expanded access to investigational therapies and diagnostics (Sec. 402) 83 approach should be applied to Subpart H. Similarly, even a seemingly minor change such as a dosage form that can be given once rather than multiple times a day can confer a meaningful therapeutic benefit as it can greatly enhance patient compliance. Although the regulatory language may not pose a major limitation on the type of drugs that will be marketed with restrictions on distribution or use, in practice all the drugs currently subject to such restrictions are uniquely effective for the conditions they treat. It appears unlikely that a drug that did not possess uniquely desirable characteristics would successfully compete in the marketplace if it is subject to significant restrictions on distribution or use. Restrictions will inevitably add to the price of a drug and make it more difficult and timeconsuming for physicians to prescribe and pharmacies to dispense. Pharmacies may be reluctant to participate in RMPs that place additional responsibilities on pharmacists while offering them no direct compensation. Even a program with minimal requirements such as the Lotronex RMP requires the prescriber to enroll and creates additional paperwork with each patient for whom the drug is prescribed. Physicians may be reluctant to sign the required forms, particularly since the legal significance of doing so remains unclear (see below). Physicians may be reluctant to prescribe a drug that is perceived as having significant risks if there is any alternative, even one that may be somewhat less efficacious. Patients may be reluctant to take a drug once they are made aware of significant risks. Indeed a goal of many RMPs is to limit use of the drug to situations in which it is clearly the therapy of choice for the patient. Given the burdens associated with marketing under restrictions, there will be significant incentives for companies to develop safer alternatives. These considerations suggest that the number of drugs subject to restrictions on distribution or use will remain small relative to the total number of drugs available. The considerations discussed above suggest that the number of drugs that would successfully compete in the marketplace under RMPs that restrict distribution or use may be small. However, there is a danger that restrictions on distribution or use may be employed in a variety of inappropriate ways that might increase the number of drugs subject to such restrictions. It has been suggested that the stringency of the Mifeprex RMP was motivated at least in part by political considerations. This would suggest that FDA might take such factors 84 into account for other drugs whose use may be politically controversial such as drugs whose use implicates reproductive rights, cloning, physician-assisted suicide, etc. The number of drugs of this type is likely to remain small. A more significant possibility is that restrictions on distribution or use will be employed to allow the marketing of drugs that FDA should not approve at all. For example, a good case can be made for the proposition that Lotronex simply should not be marketed. It poses a significant risk of side effects that are of much greater severity than the disease it treats. There is no convincing data that development of such side effects can be prevented by appropriate patient selection or monitoring. In many similar situations in the past, FDA has insisted on withdrawal. With Lotronex, however, FDA has permitted the drug to remain on the market with a RMP that may well prove ineffective and has not insisted on rigorous studies to assess its effectiveness. There appears to be a danger that FDA will too readily accede to pressure from industry and/or patient advocacy groups if it can justify its decision by requiring an RMP, even one that is not appropriately designed to achieve its goals. The extent to which this danger will materialize remains to be seen. 2. Liability It is beyond the scope of this paper to consider the impact of RMPs with restrictions on distribution or use on possible tort liability. This section briefly highlights some of the issues that may emerge in the areas of products liability and malpractice liability. Companies that market drugs with restrictions on distribution or use may be subject to product liability suits under a number of different theories.261 Patients who experience an adverse event while taking the drug may allege that the need for an RMP demonstrates that the drug is unreasonably unsafe and should not have been marketed at all. They may also allege that the provisions of the RMP are not sufficiently strict, i.e., that there is a “design defect” in the RMP rather than in the drug itself. Conversely, in the case of a drug that does not have an RMP, patients might argue that one should have been adopted and that the company was negligent for 261 See Gilhooley, supra, discussing the design defect standard for prescription drugs under the new Restatement (Third) of Torts. See also W. Kip Viscusi, Steven R. Rowland, Howard L. Dorfman, and Charles J. Walsh, Deterring Inefficient Pharmaceutical Litigation: An Economic Rationale for the FDA Regulatory Compliance Defense, 24 Seton Hall L. Rev., 1437, discussing, inter alia, tort liability for pharmaceutical products under the Restatement (Second) of Torts and arguing that compliance with FDA regulations should provide a defense against product liability suits. 85 failing to do so. Patients might also sue on the grounds that an RMP is not adequately enforced. For example, if a company knows or should have known that many physicians are prescribing the drug though not certified to do so, or that the drug is widely dispensed by pharmacies without a required sticker on the prescription, it might be argued that the company has a duty to take reasonable steps to end these practices or remove the drug from the market. Just as approval of a drug by the FDA does not insulate a company from products liability, it seems unlikely that FDA’s approval of an RMP would offer much protection. Physicians who prescribe a drug that is subject to restrictions on distribution or use may be at increased risk of malpractice liability if they prescribe a drug in a manner that is not in accordance with the RMP. Normally physician malpractice suits are decided under a negligence standard, where the determination of what constitutes negligence is based on the standard of care adhered to by competent physicians.262 Thus prescribing for an off-label use is not grounds for liability provided that the patient is informed and that the prescription for the off-label use does not violate the standard of care. However, if a physician prescribes a drug for an indication other than that suggested in the RMP it may be very difficult for the physician to argue that this was not a violation of the standard of care. If a physician has signed an agreement certifying his understanding and acceptance of the restrictions, violation of this agreement may be held to constitute negligence per se or grounds for strict liability. Pharmacies and pharmacists are traditionally immune from liability for adverse events associated with drugs they dispense, provided that they dispense the drugs in accordance with the prescription. However, the increasing involvement of pharmacies and pharmacists in RMPs, particularly those with restrictions on distribution, may subject them to significant risk of liability. Under existing RMPs, pharmacists and pharmacies have a range of responsibilities. They may be responsible for checking that prescribers and/or patients are registered or certified, for making sure that patients have documentation of relevant test results, that patients receive Medication Guides, for ensuring that prescriptions by phone or fax are not accepted, for submitting prescription information to a central database, for contacting the prescriber under certain circumstances, etc. It is unclear what sort of liability pharmacies and pharmacists may incur if they do fail to fulfill these responsibilities. As an increasing number of drugs are 262 See Clark H. Havighurst, James F. Blumstein, and Troyen A. Brennan, Health Care Law and Policy: Readings, Notes, and Questions, 2d ed., 1998, Ch. 7, for discussion of malpractice liability of physicians and other health care personnel. 86 marketed subject to RMPs, pharmacies are already voicing their concerns regarding this question.263 C. Acceptance By and Burdens on the Health Care System As described above, FDA’s early efforts to impose restrictions on distribution or use of approved drugs met with considerable resistance. The methadone regulations were challenged in court and overturned in a decision that may have discouraged FDA from seeking to impose restrictions for well over a decade. The professional community greeted the Clozaril Patient Management System with dismay, deeming it an unwarranted intrusion by FDA into the practice of medicine and an attack on physicians’ traditional authority to manage their patients in the way they believe best. It seems likely that with the rise of managed care physicians became accustomed to accepting significant limits on their autonomy and even their professional judgment although they may be reluctant to admit that this is the case. Perhaps most physicians view the restrictions as appropriate to ensure that drugs are used safely. Although the requirements of some of the programs exceed the precautions physicians would probably take in their absence, it is difficult to argue that any of them are unreasonable, given the risks they are intended to address. In any event, it does not appear that physicians are expressing widespread opposition to the restrictions imposed by existing RMPs. This may change if, for example, the need to comply with a plethora of different requirements becomes extremely burdensome or if FDA begins to overtly discriminate, such as by restricting prescribing authority to certain specialties. Perhaps a more significant issue is the overall burden that RMPs with restrictions on distribution or use place on the health care system as a whole, including patients. Issues of cost and liability have already been mentioned. In addition to whatever increases in drug price result from the costs to companies of administering the RMP (plus whatever they seek to recoup to compensate for reduced sales of the drug), there are costs in terms of physician and pharmacist time. While less easy to quantify, these costs should not be ignored. They will become more and more important if the number and diversity of RMPs expands significantly. Physicians and See “Risk Management” May Be Too Risky for Pharmacy, NACDS Tells FDA, The Pink Sheet, Vol. 65, No. 016, p. 35, April 21, 2003. At a risk management workshop held by FDA on April 10, 2003, a representative of the National Association of Chain Drug Stores stated, “A fundamental question that has to be answered as pharmacists consider participation in these programs is the nature of risk and liability a pharmacist will be asked to assume and how the pharmacist will be compensated for taking on this additional liability.” 263 87 pharmacists will need to keep track of numerous differing requirements. They may be forced to deviate from customary and convenient practices such as phoning in prescriptions. FDA has recognized the burden that existing RMPs place on pharmacists and has announced plans to conduct a survey to assess the impact of such programs on the practice of pharmacy.264 Patients may experience undesirable disruptions in obtaining their medications if there is any error in the required procedures (e.g., if a physician forgets to attach a sticker to a prescription or the sticker detaches). Patients may be forced to seek a physician certified to prescribe a particular drug, thus disrupting established relationships and risking fragmentation of care. Without proper protections, patients risk a loss of privacy if required to participate in registries or surveys. D. Restrictions on Distribution or Use in the Context of FDA’s Evolving Risk Management Framework FDA’s regulations setting forth the requirements for a new drug application state that the application shall contain “a concluding discussion that presents the benefit and risk considerations related to the drug, including a discussion of any proposed additional studies or surveillance the applicant intends to conduct postmarketing”265 However, manufacturers are under no obligation to address possible mechanisms to identify and/or mitigate postmarketing risks, and, accordingly, there is no formal requirement for a risk management program. Nevertheless, FDA appears to be moving towards integrating the concept of the risk management plan into the NDA approval process. FDA’s increasing emphasis on RMPs may be seen as a response to increasing criticism that the agency’s standards for reviewing NDAs have declined following the implementation of the Prescription Drugs User Fees Act (PDUFA).266 This act established a mechanism under which FDA would rely on fees paid by sponsors seeking review of NDAs for a large portion of its budget. The fees could be used to hire additional personnel. In exchange, the agency agreed to a series of performance measures that would greatly decrease the time required for review of 264 See 68 Fed. Reg. 7124, February 12, 2003. See Applications For FDA Approval to Market A New Drug, 21 C.F.R. § 314.50, Content and Format of an Application. 266 Pub. L. No. 102-571, 106 Stat. 4491, codified as amended at 21 U.S.C. §§ 379g-h (1994 and Supp. III 1997). 265 88 NDAs. In addition to renewing PDUFA, the Food and Drug Administration Modernization Act of 1997 (FDAMA) included a provision that permits relaxation of the “substantial evidence” standard previously used by FDA.267 As a result of PDUFA and FDAMA, the average time from submission to approval of NDAs dropped from approximately 30 months to 12 months, and the number of approvals per year increased.268 During 1998 and 1999 five prescription drugs were withdrawn from the market, an unprecedented number for such a short period of time.269 In addition, a number of FDA employees charged that the increased time pressure had resulted in a decline in the standard of review.270 In order to evaluate and respond to these concerns, FDA Commissioner Dr. Jane Henney created a Task Force to examine FDA’s approach to risk management for medical products and to identify strengths and weaknesses in the system.271 The resulting report suggests that FDA develop a new, more integrated framework for risk management, outlines what such a framework would look like, and makes a number of specific recommendations for FDA actions. While it is beyond the scope of this paper to review the details of this report and its recommendations, it appears that the report has had significant impact on subsequent agency policies. The report listed restrictions on distribution or use, including mandatory education programs for prescribers and patients, restriction to certain use or prescriber category as among the risk intervention options FDA could employ while acknowledging the possibility that additional legislation or rule making might be required.272 Since issuance of the report, FDA appears to have embarked on a policy of systematically considering risk management issues both prior to approval of a new drug and following approval. Congress appears to have recognized and approved of FDA’s increasing emphasis on risk management. In the 2002 reauthorization of the Prescription Drug User Fee Act, Congress 267 Pub. L. No. 105-115, 1997, codified throughout 21 U.S.C. See FDA U.S. Department of Health and Human Services, Managing the Risks from Medical Product Use: Creating a Risk Management Framework, available at http:www.fda.gov/oc/tfrm/1999report.html, hereinafter Risk Management Report. The trend toward increasing numbers of approvals may have ended. The number of approvals in 2002 dropped substantially. 269 See Barbara Noah, supra, discussing effects of PDUFA and FDAMA on the new drug approval process. 270 Id. See also Risk Management Report, supra. A recently issued report from the U.S. Department of Health and Human Services’ Inspector General confirms some of these findings. See Department of Health and Human Services Office of Inspector General, FDA’s Review Process for New Drug Applications, A Management Review, March 2003, OEI-01-00590. 271 Risk Management Report, pp. 18-19. 272 Risk Management Report, pp. 92-93. 268 89 provided for the use of funds from user fees,” for a period of up to three years after approval, to cover risk management activities for products approved after October 1, 2002.”273 In conjunction with the reauthorization of PDUFA, FDA developed a set of performance goals and procedures that represent a projection of what FDA intends to accomplish with the fees it will collect from industry.274 The document contains a section entitled “Pre- and periNDA/BLA Risk Management Plan Activities” that suggests that FDA plans to incorporate risk management planning throughout the NDA review process. Without formally defining the contents of a risk management plan, the document states that “a pre-NDA/BLA meeting package may include industry questions/discussion points regarding proposed risk management plans and discussion of the need for any post-approval risk management studies”.275 It goes on to suggest that the proposed plan may include assessment of clinical trial limitations, assessment of risk management tools to be used to address known and potential risks, suggestions for Phase IV epidemiology studies, and suggestions for targeted post-approval surveillance.276 These elements are to be discussed during the pre-NDA/BLA meeting and may be included in the NDA/BLA. Significantly, “items to be included in the risk management plan to assure FDA of the safety and efficiency (sic) of the drug or biologic are to be addressed prior to approval of an application.”277 The document further indicates that FDA may employ user fees to review implementation of risk management plans during a “peri-approval” period, which is defined as two years post-approval for most products and three years for products that are deemed to require risk management that goes beyond standard labeling. Thus not only will FDA aim to integrate the development of risk management plans into the NDA process, it will also begin to formally evaluate the success of such programs. FDA also stated that it will issue guidance for industry on good practices in risk assessment, risk management, and pharmacovigilance by September 2004.278 FDA has published Concept Papers addressing these three areas in preparation for public meetings on the 273 See H.R. 107-481, Section 503. (2002). See “PDUFA Reauthorization Performance Goals and Procedures”, accompanying letter from Secretary of Health and Human Services Tommy S. Thompson to Senator Edward Kennedy, Vol. 148, No. 73 Cong. Rec. S5195, hereinafter PDUFA Goals Letter. 275 Id. at S5198. 276 Id. 277 Id. 278 Id. 274 90 content of these guidances.279 The Concept Paper on Risk Management Programs describes interventions and tools being used by current RMPs. It describes the purpose of such tools as, “to facilitate or constrain prescribing, dispensing, and/or use of a product to the most appropriate situations or patients populations.”280 The concept paper divides the tools used in current RMPs into the three broad categories of: (a) Generalized education and outreach to health professionals and consumers/patients (beyond the package insert), including health care professional letters, voluntary training programs, continuing medical education, public notices, patient package inserts, and Medication Guides; (2) Systems that guide the circumstances of individual prescribing, dispensing, and/or use; (3) Restricted access systems designed to enforce individual compliance with program elements; and (4) Marketing suspension with or without application withdrawal.281 The second and third groups include tools that fall within the broader category of restrictions on distribution or use. Combining the lists in the Concept Paper with a review of the components in the existing RMPs described above (and other proposals considered during development of the RMPs), leads to the following inventory of specific tools that may be employed in RMPs that incorporate restrictions on distribution or use: Systems that guide the circumstances of individual prescribing, dispensing, and/or use: (1) Patient agreements/informed consent (2) Certification programs for practitioners and/or hospitals and other health care institutions (3) Enrollment of physicians, pharmacies, and/or patients in a safety program (4) Limited supply or refills of product (5) Specialized product packaging (6) Specialized systems or records that attest to safety measures having been satisfied (e.g., stickers, physician attestation of capabilities, patient or prescriber quiz) (7) Limits on phone or fax transmission of prescriptions 279 See Concept Paper: Premarketing Risk Assessment March 3, 2003, available at http://www.fda.gov/cder/meeting/groupIfinal.pdf; Concept Paper: Risk Management Programs, available at http://www.fda.gov/cder/meeting/groupIIfinal.pdf, hereinafter Risk Management Programs; Concept Paper: Risk Assessment of Observational Data: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, available at http://www.fda.gov/cder/meeting/groupIIIfinal.pdf. 280 Risk Management Programs, supra, at p. 6. 281 Id. at p. 6. 91 Restricted access systems designed to enforce individual compliance with program elements: (1) Prescribing only by registered physicians (possibly including limitation to particular specialty) (2) Dispensing only by registered pharmacies or practitioners (3) Dispensing only by centralized pharmacy (e.g., mail order pharmacy) (4) Dispensing limited to hospitals or other health care institutions (5) Dispensing only if prescription states certain indication(s) (6) Dispensing only to patients with evidence or other documentation of safe use conditions (e.g., lab test results) The development of such lists allows the systematic comparison of different RMPs and provides a menu from which to select appropriate choices for implementation of future RMPs. There is also a need for auditing mechanisms, evaluations of the effectiveness of the various tools available, and a means of correlating the appropriate selection of tools with the specific risks posed by the drug. Ideally, an effective RMP should reduce the incidence of adverse events among the population of patients that receives the drug, not simply reduce overall use of the drug, although reducing the number of patients who receive the drug when alternatives are available is often an important goal. The Concept Paper suggests a further way of conceptualizing RMPs, namely a classification scheme that assigns them a level between 1 and 4 depending on how much their conditions diverge form conventional prescribing, dispensing, and use.282 While it remains to be seen how much of the approach articulated in the Concept Paper is eventually incorporated into the guidance, this document seems to confirm that an increasing number of drug approvals are likely to occur under Subpart H. E. Suggestions for Improving the Effectiveness of Restrictions on Distribution or Use 1. The Need for Evaluation 282 Id. at pp. 7-8. 92 Given the relative lack of experience with most of the RMPs with restrictions implemented to date, it may be too soon for a comparative evaluation of their effectiveness. In addition, the relatively small number and the diversity of drugs subject to restrictions makes it difficult to draw conclusions about what works and what doesn’t. However, efforts to develop approaches to evaluation should receive a high priority since it appears that FDA may make restrictions on distribution or use a more widely applied form of regulation. An understanding of which types of restrictions are most effective in achieving risk reduction goals would be very useful as FDA and sponsors seek to develop effective RMPs in the future. A number of studies have indicated that educational efforts have a minimal impact on prescriber and patient behavior. For example, FDA’s 1998 regulatory action involving cisapride (Propulsid) resulted in a black-boxed warning on the labeling and a "Dear Health Care Professional" letter from the manufacturer. However, a study to assess the impact of these actions on contraindicated uses of cisapride indicated that the percentage of patients inappropriately exposed to cisapride was virtually unchanged after the warnings.283 The drug was eventually withdrawn. One possible lesson from this study is that efforts to constrain prescribing behavior may be much more difficult to achieve after a drug is marketed than if the drug is introduced with restrictions. An evaluation of the effectiveness of the Trovan and Tikosyn RMPs, both of which were adopted after marketing of the drug (albeit after only a very short period of marketing) may shed light on whether this is the case. Both the Clozaril RMP and S.T.E.P.S. for thalidomide appear to have been highly effective in achieving their respective goals. These plans rely on mandatory, centralized patient and physician registries, coordinated with distribution only by certified pharmacies. S.T.E.P.S. includes the innovative feature of a patient quiz. The Tikosyn RMP goes furthest in establishing requirements that health care providers must meet to be certified to prescribe the drug. Not only must physicians complete an educational program, but all staff who will be involved in caring for the patient must also be certified. Accutane’s S.M.A.R.T. program and the Lotronex RMP represent risk management programs that are significantly less strict in terms of their requirements. It is too soon to predict whether these programs will be successful in achieving 283 Smalley, W., et al., Contraindicated use of cisapride: impact of food and drug administration regulatory action., JAMA 2000 Dec 20;284(23):3036-9, 2000. 93 acceptable risk reduction. A careful evaluation of the effectiveness of these programs may help guide FDA deciding what sort of restrictions should be implemented in future RMPs. The need to gather comprehensive data in order to perform meaningful evaluation of the effectiveness of RMPs argues in favor of requiring mandatory participation of patients (and possibly also pharmacists and physicians) in surveys, recognizing that the mere existence of a mandatory survey may modify behavior. Comparative studies to determine the effect of specific requirements such as patient quizzes or educational programs for physicians could be very valuable. 2. Dealing With a Sponsor’s Threat to Withdraw When FDA seeks to impose restrictions on distribution or use it must always take into account the possibility that the sponsor will prefer withdrawal of the drug to an option that would impose the burdens of a RMP with a restricted distribution scheme and limit the market for the product. Companies may decline to make the drug available to patients who might truly benefit from it, as did GSK in the case of Lotronex. If FDA believes strongly that the drug should be available to such patients, it may be compelled to compromise on the stringency of the RMP or simply allow the drug to be marketed under normal conditions, relying on labeling to attempt to reduce the risk. FDA and patients should not be held hostage to the business decisions of pharmaceutical corporations. If a company decides that it would prefer withdrawal to continued manufacture of the drug, FDA should have options available to ensure patient access. It is perhaps significant that many of the drugs available with restrictions on distribution or use are marketed by small pharmaceutical companies. These companies may be more willing to provide drugs for a small market than the larger pharmaceutical companies, which frequently aim for “blockbusters”. To many small companies, simply having a drug on the market, even subject to restrictions, is highly valuable. FDA should be able to require a pharmaceutical company that declines to make a drug available with restrictions on distribution or use to license rights to manufacture and sell the drug to a company that would be willing to market it under the conditions FDA believes are appropriate. Congress has recognized that the public interest may require limitations on patent rights in the area of pharmaceutical products. For example, under the patent laws, making and 94 testing a patented compound does not constitute patent infringement if the purpose is to develop data to be submitted to a federal agency such as FDA.284 This provision is intended to allow manufacturers of generic drugs to do the required studies for submission of an NDA so that they can begin marketing the generic version as soon as the patent on the brand name drug expires. Congress should similarly modify patent rights in situations where a company refuses to continue marketing a drug under a RMP that FDA believes is necessary for the safety of the public. Companies that would be willing to market the drug should be allowed to do so without fear of being sued for patent infringement. Compulsory licensing is but one possible approach to addressing this issue. 3. Enforcing Restrictions on Distribution or Use As has often been pointed out, FDA lacks the authority to assess civil penalties. In practice, its regulatory options are often limited to seeking criminal sanctions or injunctions, or recalling or seizing products that are deemed misbranded or unsafe.285 In addition, FDA has no authority to enforce postmarketing commitments that sponsors enter into “voluntarily” even though such commitments are set forth in the letters issued by FDA when it approves a drug. In the case of drugs approved under the surrogate endpoint provisions of Subpart H, if a sponsor fails to perform the studies needed to establish the correlation between the surrogate endpoint and a clinically meaningful benefit, FDA is faced with the choice of leaving a possibly ineffective drug on the market and withdrawing the drug. Similar dilemmas arise frequently in other areas of the laws and regulations that FDA enforces. This situation raises the question of what steps FDA could take if a sponsor fails to fully implement and enforce the restrictions to which it has agreed. For example, FDA might find that the company continued to certify physicians or pharmacies despite evidence that the physicians or pharmacies were not complying with the requirements. FDA could determine, based on adverse event reports, that the drug was unsafe and threaten withdrawal. However, it would be preferable if FDA had the authority to audit company compliance with the requirements of the RMP prospectively, and to assess monetary penalties for deficiencies in compliance. FDA should be able to require companies to enforce contracts with distributors, wholesalers, or 284 285 See 35 U.S.C. 271(e)(1). See Hutt & Merrill, supra, Ch. 11, for discussion of FDA’s enforcement powers. 95 pharmacies who have agreed to distribute or dispense the drug subject to conditions. Preferably FDA should also have authority to impose sanctions directly on such entities In the course of considering the bill that became the FDAMA, Senators Kennedy, Bingaman, and Reed argued unsuccessfully that FDA should be given similar authority to enforce commitments to perform Phase IV studies.286 4. Improving Efficiency The confusion and inefficiency that may result from proliferation of a variety of programs with differing requirements is a real source of concern. Physicians and pharmacists may be forced to spend an increasing amount of time learning and conforming with the intricacies of such programs – time that would be better spent with the patient. It would be desirable to develop a means of integrating the various restricted distribution schemes, or at least minimizing their diversity. For example, rather than having multiple different registries and differing mechanisms by which pharmacists confirm physician and/or patient registration, a single centralized system should be employed for all the drugs. There should be minimal reliance on devices such as stickers and maximum reliance on information technology. It seems likely that electronic transmission of prescriptions will increasingly become dominant. Appropriate use of information technology can provide a streamlined mechanism to perform many of the administrative functions of current restricted distribution or use schemes. A recently proposed FDA rule mandates the use of bar code technology for prescription drugs.287 Information about a drug’s restricted status could be incorporated into the bar code, and dispensing or administration of the drug could thereby be controlled. FDA should explore, and encourage companies to explore, ways to employ 286 See H. Rpt. 105-399, conference report on S. 830, "Food and Drug Administration Modernization Act of 1997," Nov. 9, 1997. Minority Views of Senators Kennedy, Bingaman, and Reed: The FDA should have the authority to enforce a request for post-market or confirmatory clinical trials especially when this data is pursuant to an accelerated approval of a new drug. If a company fails to complete a requested trial, currently the only remedy available to the Secretary is to remove the drug from the market. Even if the process of withdrawal is expedited, this remains a cumbersome process which punishes patients who depend upon the drug in question. The Patient Coalition regards enforcement procedures for phase IV studies as a high priority. If we are truly trying to enhance patient access to important medicines by providing accelerated approvals, we should be prepared to assure that these drugs are truly safe and effective. The FDA should be given the authority to impose intermediate sanctions of civil money penalties for failure to perform post-approval research. 287 See 68 Fed. Reg. 12499, March 14, 2003. 96 information technology to improve the efficiency and quality of RMPs with restrictions on distribution or use. F. Conclusion FDA and its employees face a very challenging task in fulfilling their dual role of protecting the public from unsafe and ineffective drugs and assuring patient access to beneficial medications. The 1962 Drug Amendments ushered in an era during which the complexity and length of the NDA process increased substantially, leading to calls for a less stringent regulatory approach. FDA responded with a number of initiatives aimed at expanding and expediting access. Congressional action with the PDUFA and FDAMA led to a major reduction in the length of time between submission and action on NDAs. The reduction in review time, coupled with the reliance of FDA on user fees, resulted in an ongoing backlash of criticism accusing FDA of neglecting its mandate to protect the public from risk. FDA has responded with initiatives aimed at integrating risk management into all stages of regulation, both pre and post approval. Approving drugs subject to risk management programs that impose restrictions on distribution or use, or conditioning the continued marketing of such drugs on adoption of such restrictions, is a way FDA can balance its dual mandates. The ten RMPs described above each contain a variety of different elements aimed at reducing risk. Each was developed in response to specific concerns. FDA is using the experience gained from these plans to develop a broad framework for risk management. It seems increasingly likely that the tools they employ will feature more and more prominently in the regulatory scheme. Thus the importance of the RMPs described herein goes well beyond their effects on the safety of the particular drugs concerned. As mentioned briefly above, a number of potentially problematic issues remain to be resolved, but with their successful resolution it seems likely that RMPs with restrictions on distribution or use are here to stay and will contribute to enhancing the safety of prescription drugs. 97