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1
Introduction
We are in the beginning of a new era for drug safety where protecting public
health means that [the Food and Drug Administration’s] responsibility doesn’t
end when we grant a product market approval; that is merely the first check
point in ensuring safety.
—Dr. Margaret Hamburg, Commissioner, US Food and Drug Administration
(FDA, 2011a).
An estimated 48 percent of the US population take at least one prescription
drug1 in a given month (Gu et al., 2010). Drugs provide great benefit to society by
saving or improving lives. Antibiotics can cure infections, heart medications can
decrease the risk of heart attacks, and drugs for multiple sclerosis can decrease
the symptoms of the disease and improve patients’ quality of life. At the same
time, virtually all drugs have some unintended side effects, some of which are
serious and can harm the people who take them. Budnitz et al. (2006) estimate
that about 700,000 people are treated in US emergency rooms each year for
severe adverse drug reactions, and about 120,000 require hospital admission. In a
more recent study using data from 2007 through 2009, Budnitz et al. (2011) esti -
mate that there are about “265,802 emergency department visits (95% confidence
interval [CI], 184,040 to 347,563) for adverse drug events annually . . . among
adults 65 years of age or older”, of which 99,628 (95% CI, 55,531 to 143,724)
required hospitalization.
The US Food and Drug Administration (FDA) is the agency responsible
for ensuring that prescription drugs are safe and effective. FDA’s approval of a
drug for use in the United States is the result of a considered judgment based on
available data and the agency’s experience with such decisions that overall the
potential benefits of the drug outweigh the risks to patients for whom the drug
1 For simplicity, the committee uses the term drugs throughout this report, but similar considerations
would apply to biologics. The committee’s charge is related to the US Food and Drug Administration
(FDA) regulation of the drug and biologics supply. When discussing FDA’s regulatory authority and
mission, therefore, the committee does not address FDA’s roles related to other products, such as
tobacco, medical devices, veterinary medicines, food, or animal feed.
29
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30 STUDYING THE SAFETY OF APPROVED DRUGS
is indicated. However, premarketing data used in approval applications are col-
lected from studies that involve small numbers of participants2—often only a few
hundred or a few thousand—over a relatively short period of time (IOM, 2007a),
so not all risks associated with a drug are known at the time of approval. Warn-
ings or restrictions may be added to the product label, or a drug may be removed
from the market because unexpected or greater than expected morbidity or mor-
tality is identified only after a drug enters widespread use. The discovery of new
adverse events in the postmarketing setting is part of the normal, natural history
of approved drugs. The timely identification of and response to drug-related risks
are central to the mission of FDA.
Recent advances in information technology, including electronic health
records, and changes in FDA laws, such as the Food and Drug Administra-
tion Amendments Act (FDAAA) of 2007,3 provide the opportunity to improve
the system for ensuring that drugs are safe and effective. Previous Institute of
Medicine (IOM) reports have made recommendations about improving aspects of
drug-related patient-safety issues to FDA, other federal agencies, and Congress
(IOM, 2002, 2004, 2007a,b). However, no report has focused specifically on the
ethical and scientific issues that arise in the postmarketing environment, including
how these issues intersect with the authority of FDA to require manufacturers to
conduct postmarketing research and how FDA should integrate that authority and
evidence, into its regulatory decision-making. The present report addresses those
issues in response to the committee’s charge (see Box 1-1) and offers specific
recommendations about the ethics and science of FDA required postmarketing
research and about the decision-making process about approved drugs when
safety issues arise.
THE EVOLUTION OF THE FOOD AND DRUG ADMINISTRATION’S
RESPONSIBILITIES IN THE POSTMARKETING SETTING
Food and Drug Administration Authority Before 2007
FDA’s regulatory authority has evolved over the last 100 years, often as a
result of serious drug-related adverse events or deaths. Table 1-1 presents some
milestones in FDA’s regulatory history. The initial grant of authority to FDA’s
predecessor agency began in 1906 with the passage of the Pure Food and Drug
Act,4 which, for drugs, focused on misbranding and adulteration. Thirty years
2 Throughout this report, the committee uses the term participants or research participants rather
than human subjects. The committee recognizes that both terms have been used in policy discussions
on this topic for decades and that neither term perfectly captures the nature of the relationship between
the persons who are studied in research (who are both subjects of research and participants in research)
and those who are conducting the research.
3 Food and Drug Administration Amendments Act of 2007, PL No. 110-85, 121 Stat. 823 (2007).
4 Pure Food and Drug Act of 1906, PL 59-384, 34 Stat. 768 (1906).
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31
INTRODUCTION
BOX 1-1
Charge to the Committee
The US Food and Drug Administration (FDA) has requested that the
Institute of Medicine convene a committee to evaluate the scientific and
ethical issues involved in conducting studies of the safety of approved
drugs. Questions to be explored by a committee include
1. What are the ethical and informed consent issues that must be
considered when designing randomized clinical trials to evaluate
potential safety risks?
2. What are the strengths and weaknesses of various approaches,
including observational studies, including patient registries,
meta-analyses, including patient-level data meta-analyses, and
randomized controlled trials, to generate evidence about safety
questions?
3. Considering the speed, cost, and value of studies, what types
of follow-up studies are appropriate to investigate different kinds
of signals (detected pre-approval or postapproval) and in what
temporal order?
4. Under what circumstances should head-to-head randomized clini-
cal trials for safety be required?
5. How should FDA factor in different kinds of safety evidence in
considering different kinds of regulatory actions?
later, after more than 100 deaths, many in children, caused by diethylene glycol
in an elixir of sulfanilamide, the Food, Drug, and Cosmetic Act (FDCA) 5 was
enacted (FDA, 2009a). Under the FDCA, a new drug could not enter into inter-
state commerce unless its sponsor filed a new-drug application (NDA) with FDA
that contained convincing evidence from preclinical toxicity testing that the drug
was safe for its intended uses (Daemmrich, 2004a; Marks, 1997a). A drug was
to be evaluated only with regard to its toxicity; its sponsor was not required to
provide FDA with evidence of effectiveness or benefits. FDA could, however,
deem a drug misbranded “if its labeling is false or misleading”.6 Under those
conditions, FDA had the authority to withdraw its approval of the drug and to
prosecute the drug sponsor (Carpenter, 2010a; Daemmrich, 2004a; Grossman et
al., 2007; Marks, 1997a).7
5 Food,Drug, and Cosmetic Act, PL No. 75-717, 52 Stat. 1040 (1938).
6 21 USC §§ 331(a), (b), (c), (k) (2010).
7 21 USC § 331 (2010).
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32 STUDYING THE SAFETY OF APPROVED DRUGS
TABLE 1-1 Key Milestones in Food and Drug Administration History Related
to Drug Safety and Drug Studies
Year Milestone
1906 Pure Food and Drug Act passed
1938 Federal Food, Drug, and Cosmetic Act passed
1962 Kefauver–Harris Drug Amendments of 1962 passed
1981 Food and Drug Administration (FDA) and Department of Health and Human Services
revise and promulgate separate regulations for protection of research participants
1987 Investigational-drug regulations revised to expand access to experimental drugs for
patients who have serious diseases for which there are no alternative therapies
1991 Regulations published to accelerate the review of drugs for life-threatening diseases
1992 First Prescription Drug User Fee Act (PDUFA) passed
1992 FDA given the authority to require postmarketing trials for accelerated approvals
1993 Consolidation of several adverse-reaction reporting systems launched as MedWatch
1997 Food and Drug Administration Modernization Act reauthorizes PDUFA (PDUFA II)
2002 Public Health Security and Bioterrorism Preparedness and Response Act reauthorizes
PDUFA (PDUFA III); some funds allocated for drug-safety activities
2003 Pediatric Research Equity Act allows FDA to require clinical research into possible
pediatric applications for new drugs and biologic products
Drug Safety Board formeda
2005
2007 Food and Drug Administration Amendments Act passed; act reauthorizes PDUFA
(PDUFA IV) and dedicates a greater portion of funds to drug safetyb
aConsisting of FDA staff and representatives of the National Institutes of Health and the Department
of Veterans Affairs. The board advises the FDA Center for Drug Evaluation and Research (CDER) on
drug-safety issues and works with CDER in communicating safety information to health professionals
and patients. The administrative action creating this body occurred after prominent drug-safety con-
troversies (such as controversies about Cox-2 selective agents, such as Bextra and Vioxx). The board
was later codified in FDAAA (121 Stat 938).
bPDUFA IV expires in September 2012. PDUFA V is under discussion. Abbreviations: FDA, Food and
Drug Administration; FDAAA, Food and Drug Administration Amendments Act; PDUFA, Prescrip-
tion Drug User Fee Act.
SOURCE: FDA (2009a).
The next major change in FDA’s statutory authority occurred in the early
1960s. Thousands of children in a number of countries other than the United
States were born with limb defects to mothers who had been administered thalid -
omide for morning sickness; FDA had prevented marketing of thalidomide in the
United States (Carpenter, 2010b; Hilts, 2003a). Concerns about the implications
of this tragedy prompted Congress to pass the Drug Amendments of 1962 (PL
87-781), often referred to as the Kefauver–Harris amendments. That legislation
shifted the burden of proof for a drug from FDA proving harm to manufactur-
ers proving safety and efficacy, and represented a major shift in FDA’s role and
authority. For the first time, a drug sponsor was required by statute to provide
evidence of the effectiveness of a drug, codifying some of FDA’s practices during
the 1950s (Carpenter, 2010b). After enactment of the 1962 amendments, the ran -
domized controlled trial (RCT) emerged as the gold standard for the adequate and
well-controlled studies required to demonstrate efficacy (Marks, 1997b) and led
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33
INTRODUCTION
to the current drug-approval process summarized in Box 1-2. The 1962 amend -
ments emphasized FDA’s role as the marketplace gatekeeper for new drugs. The
Kefauver–Harris amendments also required pharmaceutical companies to keep
records of “clinical experience”,8 which were later interpreted as a requirement to
report adverse reactions and events. That requirement evolved into today’s Med -
Watch program, a consolidation of several adverse-reaction reporting systems
(available at http://www.fda.gov/Safety/MedWatch/default.htm).
Concerns emerged in the 1980s that the length and complexity of the drug-
approval process were delaying the availability of new life-saving drugs, such as
those to treat AIDS and cancer (Anderson, 1989; Carpenter, 2010c; Daemmrich,
2004a,b; Hilts, 2003b). Patient groups, regulators, pharmaceutical companies,
and others argued that a lack of resources at FDA was slowing the drug-approval
process and preventing important drugs from coming to market in a timely mat -
ter (FDA, 2011b). In response, Congress passed the Prescription Drug User Fee
Act (PDUFA) of 1992,9 whose aim was to increase the pace of drug review by
increasing FDA’s resources to expand its drug-review staff and capabilities. In
exchange for sponsors paying user fees, FDA agreed to use the funds to meet
scheduled review goals, and Congress guaranteed not to reduce FDA’s appropria-
tions to compensate for the user fees (Carpenter, 2010c). FDA also agreed that
the increased funds from the PDUFA would “be dedicated towards expediting
the drug development process and the process for the review of human drug
applications”.10
In an effort to decrease the approval time for selected life-saving drugs, FDA
promulgated its accelerated approval regulations in 1992 (21 CFR pt. 314, subpt.
H, often referred to simply as “Subpart H”). Under these regulations, FDA may
approve new drugs that treat “serious or life threatening illnesses” 11 based on
clinical trials that used surrogate endpoints12 in assessing the drug’s efficacy.13 In
1997, Congress confirmed FDA’s statutory authority to approve drugs under
8 21 USC § 355(k) (2010).
9 Prescription Drug User Fee Act of 1992, PL No. 102-571, 106 Stat. 4491 (1992).
The PDUFA was written to expire in 5 years, but later laws (PDUFA II through PDUFA IV) have
ensured that the user fees continued. The current Congress is expected to approve another extension
before October 1, 2012, when PDUFA IV user-fee authority expires.
10 21 USC § 379g note (2010).
11 21 CFR § 314.500 (2011).
12 FDA defines a surrogate endpoint as a “biomarker intended to substitute for a clinical efficacy
endpoint. Surrogate endpoints are expected to predict clinical benefit (or harm, or lack of benefit
or harm)” (Atkinson et al., 2001; IOM, 2010a). In contrast, a “clinical endpoint is defined as a
characteristic or variable that reflects how a patient feels, functions, or survives” (Atkinson et al.,
2001; IOM, 2010a). For example, blood pressure might be used as a surrogate endpoint in tests of
a drug that decreases the risk of a heart attack or stroke associated with hypertension. As another
example, delay in progression to blast crisis—a phase in which immature granulocytes (white blood
cells) rapidly proliferate in the chronic phase of chronic myelogenous leukemia—is used as a surrogate
endpoint in studies used for evaluation and approval of drugs, but the true clinical benefit of the drug
is long-term survival.
13 21 CFR § 314.510 (2011).
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34 STUDYING THE SAFETY OF APPROVED DRUGS
BOX 1-2
Drug-Approval Process
The development of a candidate drug can begin with preclinical
research and short-term animal testing by a drug sponsor. If a candidate
drug shows therapeutic potential and low toxicity, the sponsor can submit
an investigational new drug (IND) application to the US Food and Drug
Administration (FDA), and agency oversight begins.a The IND should
contain
• Manufacturing and chemical information about the drug.
• he results of any completed animal tests, toxicology studies, and
T
any other preclinical tests that have been conducted.
• The protocols for Phase 1 human studies.
• he results of any human studies that the sponsor has con-
T
ducted outside the United States; local institutional review boards
must review Phase 1 protocols to ensure protection of reserach
participants.
FDA then has 30 days to place a hold on the proposed human tri-
als because of safety concerns. Without a hold, the sponsor can begin
to test the compound in humans at 31 days. Long-term animal studies,
including carcinogenicity and reproductive-toxicity studies, might occur
simultaneously with human studies.
Phase 1 clinical trials test several increasing doses of a drug to
assess toxicity and, to some degree, efficacy. In the absence of unac-
ceptable toxicity, Phase 2 clinical investigations (which are conducted
on a few dozen to several hundred patients who have the condition for
which the drug is being developed) examine both efficacy and safety.
Typically, two Phase 3 clinical trials, which can involve fewer than 100
patients or many thousands, are then conducted to evaluate the efficacy
of the new product, usually in comparison with a placebo and sometimes
in comparison with an already approved drug for the condition. Spon-
these conditions.14 As a condition of the accelerated approval process, Subpart
H also requires postmarketing clinical studies15 to confirm the health benefits of
the drug that were predicted on the basis of the surrogate endpoints; those tri -
als are typically already underway at the time of approval. FDA also obtained a
14 2 1
USC § 356(b)(2) (2010).
15 Studies
conducted after a drug has been approved for marketing are referred to as postmarketing,
postapproval, or Phase 4 studies. For consistency the committee refers to such studies as postmarketing
studies.
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35
INTRODUCTION
sors develop the study protocols, and trials are conducted under their
auspices. FDA provides guidance documents for clinical trials, and the
Office of New Drugs review team consults with the sponsor as trial pro-
tocols are developed, studies are conducted, and results are obtained.
Sponsors are required to notify FDA of serious or unexpected adverse
effects that are experienced by trial participants and are potentially at-
tributable to the drug and any findings from animal tests that suggest an
important risk for humans, including reports of mutagenicity, teratogenic-
ity, or carcinogenicity.
After the completion of Phase 3 trials, the sponsor can submit a new
drug application (NDA) for a chemical drug or a biologic license applica-
tion for a biologic, which should include
• The chemical composition of the drug.
• The results of pharmacokinetic studies.
• The results of animal tests and clinical trials.
• D
etails of the manufacturing, processing, labeling, and packaging
of the drug.
FDA will either approve the drug and send an “approval” letter to the
sponsor with specified labeling and any postmarketing requirements or
not approve the drug and send a “complete response” letter to the spon-
sor explaining why an application is not approved. FDA has a goal, in ac-
cordance with the Prescription Drug User Fee Act, of reviewing NDAs for
standard approved drugs and for expedited approved drugs determined
to be potentially breakthroughs or life-saving within a particular timeframe
in accordance with the law.
aAn investigational new drug application can be opened at any phase of drug testing. Given
the global nature of drug development, it is not unusual for the first trial to be submitted to
FDA to be a Phase 2 or 3 trial (FDA, 2003).
SOURCE: Modified from FDA (1998).
second authority to require postmarketing studies for approved drugs through the
deferred-submission policy under the Pediatric Research Equity Act (PREA) of
2003,16 which allows a drug to be approved for sale if sponsors agree to conduct
the required trials in children after a drug enters the market.
16 Pediatric Research Equity Act (PREA) of 2003, PL 108-155, 117 Stat. 1936 (2003). FDA initially
published the pediatric rule in the Federal Register in 1998. After that rule was overturned in court
because it went beyond FDA’s regulatory authority, Congress passed PREA in 2003, giving FDA the
necessary authority.
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36 STUDYING THE SAFETY OF APPROVED DRUGS
FDA began receiving more resources for postmarketing activities through
the Public Health Security and Bioterrorism Preparedness and Response Act of
2002,17 which included the PDUFA Amendments of 2002 (PDUFA III). Under
this act, for the first time some user fees were allocated to postmarketing safety–
related activities, for example, to support postmarketing surveillance of already-
approved drugs and to allow risk-management oversight of newly approved
drugs (2–3 years after approval). Furthermore, pharmaceutical companies could
develop and submit a risk-minimization action plan (RiskMAP) with an NDA
(FDA, 2005). RiskMAPs were plans intended for a small number of drugs that
posed serious risks that warranted additional precautions beyond labeling to man-
age or limit the risks and ensure that the benefits18 of the drugs outweighed their
risks. For example, thalidomide was approved for use in the treatment of mul-
tiple myeloma and forms of leprosy and was accompanied by a RiskMAP19 that
outlined measures to prevent the risk of fetal exposure. As of February 2007, 30
drugs had been approved with RiskMAPs20; most plans contained only targeted
education and outreach requirements (Office of Surveillance and Epidemiology,
2007; Shane, 2009).
The Institute of Medicine’s 2007 Report
Despite those changes, the focus of FDA’s authority and resources remained
on the drug-approval process, with little oversight responsibility or authority
related to drugs that had entered the market. High-profile withdrawals of some
drugs within 5 years of their approval—such as troglitazone (Rezulin®, Resulin®,
or Romozin®), cerivastatin (Baycol® or Lipobay®), rofecoxib (Vioxx®), and
valdecoxib (Bextra®)—underscored concerns not only about FDA’s ability to
recognize and respond to safety signals in the postmarketing setting in a timely
fashion but its ability to conduct appropriate oversight of approved drugs and
to undertake appropriately targeted regulatory actions short of withdrawal. In
2006, FDA, the Centers for Medicare and Medicaid Services (CMS), the Agency
for Healthcare Research and Quality (AHRQ), the National Institutes of Health
(NIH), and the Department of Veterans Affairs asked the IOM to examine the US
17 Public Health Security and Bioterrorism Preparedness and Response Act of 2002, PL 107-188,
1165 Stat. 594.
18 When discussing the benefits and risks of a drug, like the term risk, the committee uses the term
benefits in a probabilistic manner, that is, the potential or probability of benefits. To emphasize the
importance of the benefit side of a drug’s benefits and risks, the committee purposefully uses the
phrase benefit–risk rather than the more traditional risk–benefit.
19 FDA approved thalidomide in 1998 with a System for Thalidomide Education and Prescribing
Safety (STEPS) oversight program that contained restrictions on use (see approval letter at http://www.
accessdata.fda.gov/drugsatfda_docs/appletter/1998/20785ltr.pdf). The STEPS oversight program
predates the establishment of RiskMAPs, but it was considered a RiskMAP after they were established.
20 RiskMAPs were replaced with Risk Evaluation and Mitigation Strategies (REMS) following
implementation of the FDAAA.
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37
INTRODUCTION
drug-safety system and to make recommendations to improve risk assessment,
surveillance, and safe use of drugs (IOM, 2007a).
The 2007 IOM committee’s report, The Future of Drug Safety, focused on
how FDA’s structure, organization, and scientific and regulatory activities should
change to improve the monitoring and evaluation of drugs. The report concluded
that “a transformed drug safety system has at its core a lifecycle approach to
drug risk and benefit—not a new concept, but one that has been implemented,
at best, in a limited and fragmented manner” (IOM, 2007a). The 2007 IOM
committee recognized that changes were needed to implement such a safety
system and made a number of recommendations, including (1) changes in the
organization and culture of FDA to provide long-term stability and consistent
direction for the agency and to increase the role of the Office of Surveillance and
Epidemiology (OSE) in drug regulation; (2) an increase in funding for postmar-
keting activities in FDA; (3) improvements in FDA’s information-technology
infrastructure for monitoring drugs once they are approved, including develop -
ment of public–private partnerships to gain access to and analyze data related to
drug safety; (4) development by FDA of “a systematic approach to risk-benefit
analysis for use throughout the FDA in the preapproval and postapproval set -
tings”; (5) provision to FDA of new authority to require “postmarketing risk
assessment and risk management programs as are needed to monitor and ensure
safe use of drug products”21; (6) development and implementation by FDA of a
high-quality, flexible system for the evaluation of postmarketing safety issues;
and (7) the requirement for industry to register at NIH’s ClinicalTrials.gov all
Phase 2 through Phase 4 clinical trials (postmarketing trials) that are intended
to be submitted to FDA.22
The Food and Drug Administration Amendments Act: The Food and Drug
Administration’s Increased Postmarketing Authority and Responsibility
In 2007, less than a year after that IOM report was published (IOM, 2007a),
Congress passed FDAAA, which amended the FDCA to include many of the
recommendations presented in the report. In addition to reauthorizing a higher
level of prescription-drug user fees (PDUFA IV), Congress earmarked increased
resources for postmarketing drug activities and included a number of substantial
changes in FDA’s regulatory authority. Described as “the most momentous shift
21 The committee recommended that the risk-assessment and risk-management program could
include the authority to require label changes, specific warnings or moratoriums on direct-to-consumer
advertising for specific drugs, and restrictions on distribution of a specific drug, such as limiting
distribution to particular facilities, pharmacists, or physicians with specific training or only after the
performance of specific medical procedures (IOM, 2007a).
22 FDA’s responses to IOM’s 2007 report can be found at http://www.fda.gov/Safety/Safety
ofSpecificProducts/ucm184598.htm (accessed June 9, 2011).
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38 STUDYING THE SAFETY OF APPROVED DRUGS
in drug regulation in half a century” (Evans, 2010), FDAAA gave FDA expanded
authority and responsibility in the postmarketing setting.
FDAAA increased requirements for registering clinical trials,23 increased
FDA’s authority over the contents of direct-to-consumer advertising,24 increased
resources for FDA’s premarketing and postmarketing activities related to drug
risks,25 gave FDA the authority to implement safety-labeling changes including
class labeling,26 and required that FDA increase the transparency of its informa -
tion about drugs and improve its risk communication.27 In addition—and most
relevant to the present report—FDAAA provided FDA with the authority to
require postmarketing studies in some circumstances28 (see Box 1-3 for a discus-
sion of the committee’s terminology for postmarketing studies), provided FDA
with the authority to require a risk evaluation and mitigation strategy (REMS), 29
and required that FDA develop an active surveillance system.30 Those three
elements are described in the subsections below; more details of other parts of
FDAAA are presented in Appendix A.
Authority to Require Postmarketing Studies
Before FDAAA, most postmarketing studies were performed under vol-
untary written agreements between the sponsor and FDA called postmarketing
commitments (PMCs), established at the time of drug approval (FDA, 2011c).
FDA could require postmarketing studies or clinical trials in only two situations:
in 21 CFR 314.510 and 21 CFR 601.4, for products that enter the marketplace
as a consequence of accelerated approvals to demonstrate clinical benefit; and in
PREA, for products that are approved based only on research with adult partici-
pants where postmarketing research is needed to assess their safety and efficacy
of the drug in children.31 A number of people have criticized the low completion
rate of the postmarketing studies required by FDA through these mechanisms
(Avorn, 2005; Carpenter, 2010d; GAO, 2008; Strom, 2006; Wood, 2006). 32
FDAAA expanded FDA’s authority to require sponsors of marketed drug and
biologic products to conduct and report on postmarketing research studies. 33 A
23 4 2 USC § 282(j) (2010).
24 21 USC § 353b (2010).
25 21 USC § 379g note (2010).
26 21 USC § 355(o)(4) (2010).
27 21 USC § 360bbb–6.
28 21 USC § 355(o) (2010).
29 21 USC § 355(p) (2010).
30 21 USC § 355(k)(3) (2010).
31 In the remainder of this report, when the committee discusses FDA-required studies, it is referring
to studies FDA requires using its authorities in FDAAA, not those it requires using its authorities in
21 CFR 601 Subpart E or in PREA.
32 As discussed below, however, at least part of the low completion rate has since been attributed
to the tracking system.
33 21 USC § 355(o) (2010).
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39
INTRODUCTION
BOX 1-3
Nomenclature for Postmarketing Studies
The Food and Drug Administration Amendments Act of 2007 differ-
entiates between clinical trials and studies.a In response to that differen-
tiation, FDA defines clinical trials and studies as follows (FDA, 2011d):
“Clinical trials are any prospective investigations in which the applicant
or investigator determines the method of assigning the drug product(s) or
other interventions to one or more human subjects.”
“Studies are all other investigations, such as investigations with humans
that are not clinical trials as defined above (e.g., observational epidemiologi-
cal studies), animal studies, and laboratory experiments.”
In this report, however, the committee uses the term studies in accor-
dance with ordinary usage in the scientific literature as a parent or generic
term that encompasses research projects of all types and regardless of
design. Thus, as the committee uses the term, studies applies to both
clinical trials and non-clinical trial investigations such as observational
investigations. When referring specifically to either observational designs
or randomized controlled trial (RCT) designs, the committee uses those
specific terms.
a21 USC § 355(o)(3) (2010).
postmarketing requirement (PMR) is an FDA-required research study that a spon-
sor must conduct after a drug has been approved and is released to the market.
Under FDAAA, a PMR can be required to
• Assess a known serious risk related to use of the drug.
• Assess signals of serious risk related to use of the drug.
• dentify an unexpected serious risk when available data indicate the
I
potential of a serious risk.34
Within its definition of a serious risk of an adverse drug experience, FDAAA
includes “any failure of expected pharmacological action of the drug” that results
in serious medical consequences for the patient.35 On the basis of that definition,
Evans (2010) considers FDAAA to provide FDA with the authority to require
a postmarketing study when emerging data or results suggest that patients are
suffering serious harm because a drug is not performing as effectively as was
expected at the time it was approved, either overall or in identifiable patient
34 2 1 USC § 355(o)(3)(B) (2010).
35 21 USC §§ 355-1(b)(1)(E), (b)(4), (b)(5) (2010).
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50 STUDYING THE SAFETY OF APPROVED DRUGS
drugs”. The five specific questions posed by FDA appear in Box 1-1. In response
to FDA’s request, IOM convened a committee of 12 members who have expertise
in bioethics, biostatistics, clinical trials, epidemiology, health policy, law, patient
safety, pharmacoepidemiology, and regulatory science.
FDA requested two reports: a letter report due in July 201045 and the pres-
ent report. In its letter report, Ethical Issues in Studying the Safety of Approved
Drugs: A Letter Report (see Appendix A), released on July 9, 2010, the commit-
tee addressed the first question of the committee’s charge—related to the ethical
and informed consent issues that must be considered in designing RCTs—by
presenting a conceptual framework for analyzing the ethics of postmarketing
RCTs required by FDA (Box 1-7) (IOM, 2010b). In this final report the commit -
tee addresses all five specific questions posed to the committee by FDA.
THE COMMITTEE’S APPROACH TO ITS CHARGE
The committee met in person six times, including two open information-
gathering sessions at which representatives of FDA, AHRQ, NIH, other stake -
holders, and researchers appeared (see Appendix B) to address the committee’s
broader charge.
The committee used the conceptual framework in its letter report (Box
1-7) (IOM, 2010b) as a starting point for this final report but conducted further
research and deliberations related to its full charge. Several underpinnings of
the conceptual framework and additional themes that emerged as the committee
deliberated on its full charge shaped this report. These include an understanding
of FDA’s public health mission; the importance of adopting a lifecycle approach
to drug safety and benefit–risk assessment (see Figure 1-1 for a schematic of
a drug’s lifecycle); FDA’s ethical obligations in making regulatory decisions,
including the centrality of transparency and communication of the decisions; and
a commitment to using best practices in regulatory science46 and high-quality
evidence in regulatory decision-making.
Considerations of the Agency’s Mission
FDA is a public health agency; its mission is to protect “public health by
assuring the safety, effectiveness, and security of human and veterinary drugs,
vaccines and other biological products” (FDA, 2011h). In making decisions about
potential regulatory actions, therefore, FDA should consider their potential public
45 FDA requested that the letter report be completed before a July 13–14, 2010, joint meeting
of FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk
Management Advisory Committee on rosiglitazone.
46 FDA has defined regulatory science as “the development and use of new tools, standards and
approaches to more efficiently develop products and to more effectively evaluate product safety,
efficacy and quality” (FDA, 2010b).
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INTRODUCTION
BOX 1-7
Conceptual Framework from Ethical Issues in Studying the
Safety of Approved Drugs: A Letter Report (IOM, 2010a) for
Analyzing the Ethics of Postmarketing Randomized Clinical
Trials Required by the Food and Drug Administration:
Four Central Classes of Considerations and Recommendations
I. The Public Health Context. The Food and Drug Administration
(FDA) should determine that there is a substantial public health
question about the nature or acceptability of the risks, or the
risk–benefit profile, of a marketed drug—a question that requires
a policy decision from FDA.
II. Regulatory Science and Public Accountability. FDA should
use regulatory-science principles and practices that include pro-
cesses of public accountability and transparency to determine
the need for a policy decision, the need for new knowledge to
support a policy decision, and the policy decision based on the
new knowledge.
III. Design Considerations. It is appropriate for FDA to require
that a randomized controlled trial be conducted to provide ad-
ditional evidence about an approved drug’s efficacy and safety
only when (i) uncertainty about the risk-benefit balance is such
that a responsible policy decision cannot be made based either
on the existing evidence or on evidence from new observational
studies, and (ii) the trial is properly designed and implemented
to reduce uncertainty about the benefit–risk balance sufficiently
for a responsible policy decision to be made.
IV. Additional Ethical Obligations to Trial Participants. FDA
should ensure that the trial will answer the public health ques-
tion with a design that minimizes risks to trial participants
and involves ongoing monitoring of risks. The risks should be
judged to be acceptable by appropriate oversight bodies before
and during the trial and by trial participants at enrollment and
as appropriate during the trial. Specifically, FDA and appro-
priate oversight bodies should ensure that the trial includes
a comprehensive and meaningful informed consent process
that continues during the trial and that takes into account any
substantial changes in clinical practice and professional stan-
dards and any new research findings relevant to a participant’s
willingness to accept the risks associated with the trial. The
FDA and appropriate oversight bodies should ensure that those
conducting the trial convey such changes to participants in a
timely and understandable fashion.
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52 STUDYING THE SAFETY OF APPROVED DRUGS
Premarketing Setting
Postmarketing Safety
Postmarketing Setting
Monitoring
Product Discovery
Pre-Clinical Studies Product
and NDA Remains on
Clinical Trials Review Market
FDA Oversight Drug Approved Product
Begins and Enters the Removed from
Market Market
FIGURE 1-1 The lifecycle of a drug for a new molecular entity. After a product is dis -
covered and the sponsor approaches FDA with the product as an investigational new drug,
FDA oversight begins. After approved, FDA and the drug sponsor conduct postmarketing
safety monitoring of the drug, which could include passive surveillance, active surveil -
lance, observational studies, and randomized controlled studies. A product remains on the
market until it is removed from the market either at FDA’s request, FDA’s withdrawal of
marketing approval, or the company decides to no longer market it. FDA oversight of the
drug continues for as long as the drug is on the market.
health consequences.47 The committee emphasizes FDA’s public health role, and
the consequences of not protecting the public’s health, throughout this report
(Hamburg and Sharfstein, 2009).
FDA has a complex mission with obligations that sometimes conflict with
one another. The committee recognizes that the effort to resolve those conflicts
can complicate the agency’s decisions but could only provide general guidance on
how FDA may do it. In the premarketing context, FDA has to balance the effort to
approve new drugs that could be beneficial to people with the effort to character-
ize potential harms, as well as benefits, and to make measured judgments about a
new drug’s benefit–risk profile with incomplete information. In the postmarketing
context, new information requires that FDA continually re-examine its judgment
about the benefit–risk profile and make regulatory decisions about the drug while
being responsive to advocacy groups that are working from both sides of the
issue. From an ethical standpoint, throughout the lifecycle of a drug, FDA has to
balance its obligation to protect the public’s health by having strong science on
which to base regulatory decisions with its obligation to protect participants in
research that it requires.
Such factors as the severity and prevalence of a disease or an adverse event,
and the availability of effective alternative treatments necessarily affect FDA’s
regulatory decisions, including decisions about what postmarketing studies to
require and how to use the information from different studies. Such decisions
47 The committee views FDA’s decisions as having public health consequences regardless of whether
they affect a large population or a small group.
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53
INTRODUCTION
need to be made case by case, so the committee cannot provide a prescriptive
formula for making them. Instead, the committee discusses principles that should
be taken into account in decision-making, provides guidance on how to account
for the factors, and offers a general framework for decision-making.
The FDA mission is to allow a drug to enter and remain on the market if, on
the basis of its considered judgment, the benefits of the drug outweigh the risks that
it poses; it is not charged with establishing, either for initial approval or for contin-
ued presence on the market, that a drug has the most favorable benefit–risk profile
compared with other drugs for the same indication. FDA is one of many entities that
influence the availability and safe use of drugs in the United States. Physicians and
other health care providers, professional societies, pharmacies, and hospitals play
crucial roles in ensuring that the expected benefits of a prescribed drug outweigh
the risks in an individual patient. In addition, payers, such as medical insurance
companies, take cost and the availability of alternative treatments into account and
decide which drugs they will cover and at what level of reimbursement.
Government agencies are involved in sponsoring drug research, including an
increasing focus on translational research in NIH and comparative-effectiveness
research in AHRQ, CMS, and the Patient-Centered Outcomes Research Insti-
tute. Research sponsored or conducted by those agencies may inform FDA’s
evaluations of the benefits and risks associated with drugs. Moreover, the studies
required by FDA may inform health care providers, payers, and other agencies
and organizations in their drug-related decisions. The intersections of those
roles require increased interactions among agencies; a number of initiatives
indicate that the agencies recognize the need to coordinate their activities better.
For example, FDA and NIH have established a collaborative initiative to move
innovations to the public quickly (FDA, 2010b). The fact that the present report
was financially supported by NIH and AHRQ, as well as FDA, illustrates the
cooperation among the agencies. However, the committee’s charge is related to
FDA’s role in regulating drugs, so it does not discuss the roles of other agencies
and entities related to drugs.
A Lifecycle Approach to Safety and the Assessment
of a Drug’s Benefits and Risks
The committee starts with the assumption that ensuring the acceptability
of the benefit–risk profile of a drug after it is approved for the US market is as
important to FDA’s public health mission as ensuring the acceptability of the
benefit–risk profile before it is permitted to enter the market. A lifecycle approach
to the regulatory oversight of drugs is therefore critical. The new authorities in
FDAAA provide FDA with the tools to adopt a more comprehensive lifecycle
approach than prior to FDAAA.
FDA assesses drug safety in relation to the drug benefits. For example, can -
cer chemotherapy drugs can cause serious adverse effects, including death, but
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54 STUDYING THE SAFETY OF APPROVED DRUGS
are deemed adequately safe for their intended use because of the greater benefit of
reducing cancer mortality risk. This report will use the word “safe” in this same
sense, that is, that the magnitude and distribution of benefits and risks is accept -
able for the intended use. The word “safety endpoint” will be used to describe
the harms associated with a drug. “Risk” is the probability that those harms will
be incurred. The committee will use an “efficacy” or “effectiveness” endpoint as
the clinical outcome that a drug is intended to improve.
Major regulatory changes in a drug once it is on the market—such as changes
in a drug’s label, the addition of a boxed warning, or withdrawal of the drug—
may appear to represent failures of the drug regulatory system (IOM, 2007a). It
is important to recognize that the discovery of new information about a drug’s
adverse events or clinical effectiveness, if ascertained in a timely manner, is a
normal and desirable part of the natural history or lifecycle of the drug. It is
impossible to know everything about a drug at the point of approval. A respon-
sible public health agency is structured to learn continually about the drugs that
it approves with the expectation that what is known about a drug’s benefits and
risks will change over time. The timeliness of the identification of and response
to new serious adverse events is an indication of a high-quality postmarketing
system. The focus of this report thus responds to an expanded understanding
of FDA as a public health agency whose approach to its mission is and should
be shifting from a premarketing focus on efficacy and short-term harms, and a
postmarketing focus on harms, to a continuous and integrated assessment of the
benefit–risk profile of a drug throughout its market life.
Ethics and Decision-Making in the Food and Drug Administration
The committee’s letter report focused heavily on FDA’s ethical obligations
to research participants. The present report continues that focus but broadens the
discussion to include the ethical aspects of study design, how ethical consider-
ations should be taken into account and integrated in FDA’s decision-making
framework, and how FDA can incorporate two key components of the ethics of
public processes—stakeholder engagement and transparency—into its decision-
making practices. The committee views ethical issues as inextricably intertwined
with scientific and regulatory issues. Ethical issues are therefore discussed
throughout this report.
Public engagement and transparency increase the likelihood that the per-
spectives of patients and consumers, who have knowledge different from those of
technical experts, are included in the making of policy decisions. When including
such perspectives, however, FDA should ensure that patient advocacy groups
represent the views of patients rather than the views of commercial entities that
provide funding to the organizations. The concerns and practical considerations
voiced by other stakeholders, such as health care providers, payers, industry, and
academe, are also important to include. Transparency and other public account -
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55
INTRODUCTION
ability processes may also increase the likelihood that the public will view regu -
latory and policy decisions, including a decision by FDA to require a sponsor
to conduct postmarketing research or a decision to continue or discontinue a
required postmarketing clinical trial, as fair and acceptable. 48
Modern tools for risk communication and public engagement ensure that
all stakeholders—including physicians, other health professionals, interested
patients and their families, and members of the general public—understand the
decision the agency is facing, including what is known about the benefits and
risks associated with the therapy in question and the pertinent uncertainties.
Uncertainties might pertain to the quantity and quality of evidence, the benefit–
risk profile, or the effect of policy decisions on the health of the public. Engage -
ment with stakeholders helps to explain the types of uncertainties at issue and
how the agency is dealing with uncertainties in making its policy decisions and
helps the agency to understand how those affected by its actions weigh benefits
and risks.49 Communication to stakeholders will be more important, and in some
ways more complex, as FDA moves more toward a lifecycle approach to drug
regulation. Education and outreach will help to ensure that the public understands
the change in the regulation of a drug as part of the normal natural history of its
lifecycle.
Regulatory Science and High-Quality Evidence
The committee was guided by the view that regulatory decision-making,
including decisions that require the integration of postmarketing safety infor-
mation, should be based on the best principles and practices for making policy
decisions under conditions of uncertainty, such as appropriate processes for
transparency in decision-making and public accountability. Those principles
and practices, sometimes referred to as the emerging field of regulatory science,
require that policy decisions reflect the best available scientific evidence and ana-
lytic techniques drawn from a wide array of disciplines and technical expertise,
including decision science, behavioral economics, and cognitive psychology.
Accurately assessing the potential benefits of and risks posed by a drug
requires the use of a wide variety of scientific data, including findings from clini -
cal trials; epidemiologic and outcomes research, such as observational studies
and meta-analyses; and postmarketing surveillance systems that detect and help
to characterize adverse events. All sources of data—not only or primarily those
48 FDA and those advising it should have access to all information relevant to a given public health
question, whether or not the information is deemed proprietary or to constitute a trade secret. One
source of tension in meeting acceptable standards of transparency with stakeholders is the management
of public access to such information.
49 The committee acknowledges that there are important challenges to implementing policy making
and regulatory processes that balance scientific evidence and stakeholder input appropriately (Lomas,
2005).
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56 STUDYING THE SAFETY OF APPROVED DRUGS
obtained from clinical trials—have the potential to contribute to sound regulatory
decision-making. The critical factors in determining how much weight to give to
various data resources are the quality of the studies that generated them and their
relevance to the public health questions at issue, not simply whether the studies
were experimental or observational. The committee further recognizes the impor-
tance of toxicology studies—including molecular toxicology and animal stud -
ies—in both the premarketing and postmarketing setting, especially as genomic
sciences progress. The committee, however, considered a review of pharmaco-
logic, metabolic, or toxicologic studies as beyond the scope of its charge.
OVERVIEW OF THE REPORT
The transformation in FDA’s authorities and responsibilities over the last five
years provides FDA with valuable tools to help ensure that the benefits of a drug
outweigh its risks throughout its lifecycle. Despite the challenges that this new
era in postmarketing oversight brings, FDA should embrace the opportunities
presented by FDAAA to protect the public’s health. FDA has made policy and
organizational changes, and has implemented new initiatives that are aimed at
improving its oversight in the postmarketing setting. There are also indications in
FDA’s strategic plan and in negotiations for PDUFA V that FDA is moving further
in the direction of strengthening its assessment of benefits and risks throughout
a drug’s lifecycle. The effects of these policies and initiatives, and even the full
effect of the sweeping changes precipitated by FDAAA, will take several years
to be completely realized. Those changes are promising, and they posed a chal -
lenge for the committee, which was dealing with a rapidly evolving FDA role in
the postmarketing setting as this report was being written. The committee tried
to make general, flexible recommendations that would be relevant in this chang -
ing landscape, and that could affect the course of these changes. The committee
sees the present report and its recommendations as providing guidance to FDA as
part of its evolving approach to drug oversight in which drug safety monitoring
and regulatory action after drug approval is seen as increasingly important for
protecting the health of the public.
Chapter 2 presents a broad framework for FDA’s regulatory decision-
making. The framework addresses the need for a clear explanation of the agency’s
decisions and organizational considerations that facilitate decision-making, and
the committee recommends a process and formal documentation intended to
help FDA assess the benefits and risks associated with a drug throughout its
lifecycle. A major challenge for FDA is making decisions in the face of scientific
disagreement about available evidence, and the implications of that evidence.
Chapter 3 looks more closely at that particular challenge and discusses the nature
of evidence and why scientists sometimes disagree about how to interpret and
respond to evidence in a regulatory decision. Chapter 4 focuses on one of FDA’s
regulatory actions that were highlighted in the committee’s charge (Box 1-1): the
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INTRODUCTION
ability to require different types of postmarketing studies. That chapter discusses
and makes recommendations about the circumstances under which different types
of studies are ethically and scientifically justified. Chapter 5 summarizes the com-
mittee’s findings by answering the specific questions in the committee’s charge,
and it reiterates the committee’s recommendations.
A summary of key aspects of FDAAA, the agendas of the committee’s public
meetings, the committee’s letter report, information on decision conferencing and
multicriteria decision analysis, and biographies of the committee members are
presented in Appendixes A, B, C, D, and E, respectively.
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