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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was allowing a drug to go back on the market after it had previously been withdrawn for safety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
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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.
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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.
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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.
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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
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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.
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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.
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