The
tumult arising from revelations of serious safety risks associated with
widely prescribed drugs, including rosiglitazone (Avandia,
GlaxoSmithKline), rofecoxib (Vioxx, Merck), and celecoxib (Celebrex,
Pfizer), has led to widespread recognition that improvement is needed in
our national system of ensuring drug safety. Notwithstanding federal
legislation in 2007 that strengthened the authority of the Food and Drug
Administration (FDA) in the postmarketing period,
1 critical weaknesses in the national system persist.
Central to these weaknesses are dilemmas surrounding not only the science but also the ethics of drug-safety research,
2
many of which came to the fore in the heated public debate about the
Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial,
which compared the cardiovascular outcomes of long-term treatment with
rosiglitazone with those of pioglitazone (Actos, Takeda) in patients
with type 2 diabetes.
3
At the request of the FDA, an Institute of Medicine (IOM) committee, on
which we served, was convened to examine the ethics and science of
FDA-required postmarketing safety research. In this article, we review
the key ethics findings from the committee's May 1, 2012, report
4 and offer some reflections on the challenges ahead.
Lessons from the TIDE Trial
In
May 2008, the FDA ordered the manufacturer of rosiglitazone,
GlaxoSmithKline, to conduct a trial in response to evidence from
meta-analyses that rosiglitazone was associated with a higher risk of
myocardial infarction and death from cardiovascular causes than placebo
or medications that were not based on nonthiazolidinedione comparators.
5,6 Other studies suggested that pioglitazone, an alternative thiazolidinedione, was not associated with such risks.
7,8
Before enrollment began, some argued that the evidence of the inferior
safety of rosiglitazone was strong enough to make the trial ethically
unjustifiable. Two FDA epidemiologists wrote in a 2008 memorandum that a
head-to-head trial “would be unethical and exploitative” and that even a
robust informed-consent process could not overcome the problem.
9
This was not the consensus FDA view, which was that the uncertainty
regarding the cardiovascular risks associated with rosiglitazone, as
well as those associated with pioglitazone, was sufficient to justify a
trial.
10
These
concerns triggered a February 2010 letter from members of Congress to
the FDA demanding a justification for the trial and alleging that the
consent form did not provide adequate risk information.
11
In response, FDA Commissioner Margaret Hamburg expanded the FDA
investigation of the safety of rosiglitazone, obtained advice from an
FDA advisory committee, and asked the IOM to convene our committee.
6
Although the FDA advisory committee recommended that the TIDE trial be
continued if rosiglitazone was permitted to remain on the market, in
September 2010, the FDA halted the trial and placed stringent new
restrictions on the availability of rosiglitazone.
12,13
The
TIDE experience made the FDA appreciate the need for greater attention
to the ethics of postmarketing research. First, it posed questions about
what standard of evidence about drug risk justifies a decision by the
FDA to require postmarketing research, particularly randomized trials,
as well as what evidence could render such trials unacceptable. Second,
it raised questions about what ethical obligations the FDA has to
patients who participate in these studies. Finally, it highlighted a
potential FDA role in ensuring that institutional review boards (IRBs)
are completely informed in their efforts to protect study participants.
Although major deficiencies with the TIDE consent form were identified
by some FDA scientists and, later, by the IOM committee (
Table 1Table 1
Major Deficiencies in the Informed-Consent Form for the TIDE Trial.),
4,9 the TIDE investigators countered that it had been approved by “480 ethics committees and IRBs.”
14
However, the language of the consent form, the trial design, and the
materials supporting the justification of the trial raised a question
for the IOM committee about whether these bodies adequately understood
the nature of the evidence that gave rise to the trial. The IOM
committee proposed a framework for evaluating the ethics of FDA-required
postmarketing research
15 and made a number of ethics findings and recommendations.
4
Ethical Responsibilities of the FDA
The
IOM committee began by noting that the public health mission of the FDA
gives rise to potentially competing ethical obligations “to protect the
public's health by having strong science on which to base regulatory
decisions” and “to protect participants in research that it requires.”
4 Requiring a postmarketing study is an ethical decision, reflecting a weighing of these values.
The
committee described the conditions that must be present to justify a
decision to require a postmarketing study. The FDA should require
postmarketing research only when, first, the uncertainty about the
benefit–risk balance of a drug is so great that a responsible decision
about its regulatory status cannot be made on the basis of existing
evidence; second, the research will reduce this uncertainty; third, the
FDA will use the research results expeditiously to make a regulatory
decision; and fourth, sufficient protections for research participants
can be ensured.
The committee argued that when the FDA requires a
postmarketing study, it assumes a measure of ethical responsibility for
the welfare of the study participants; exercise of that responsibility
cannot be handed off to contractors or the industry sponsor. The
responsibility is particularly strong when the patients' treatment is
determined by the study, such as in a randomized trial, linking any
adverse outcomes directly to a regulatory decision to require a study of
that type. This determination led to one of the most important
recommendations from the IOM committee: the responsibilities of the FDA
to research participants mean that it should mandate a randomized design
only if the FDA “has concluded that an observational study could not
provide the necessary information [to help answer the important public
health question at issue], that an RCT [randomized, controlled trial] is
likely to generate the information within the necessary timeframe, and
that the necessary RCT is ethically acceptable.” This recommendation
comports with but adds some further conditions to the current legal
authority of the FDA under the FDA Amendments Act of 2007, which
empowers the agency to require a randomized trial if it cannot obtain
the data it needs from an observational study.
1
In
light of the critiques of the TIDE trial as inherently unethical, the
committee addressed the justifiability of trials in which participants
may encounter a net increase in risk, as compared with ordinary clinical
care, but no realistic prospect of personal benefit. It argued that
such trials can be justified only if they are necessary to answer a
critically important public health question, if the potential risk is
acceptable and minimized, and if special safeguards are in place,
including a highly explicit informed-consent process to ensure that
patients understand that they are potentially shouldering additional
risk solely to contribute to the public good.
Specific actions
that the FDA should take to meet its ethical obligations include
specifying the study design, title, end points, and primary analyses;
identifying design features that it views as ethically and
scientifically indispensable; and, for clinical trials, specifying a
safety-monitoring scheme. The committee recommended that the FDA
routinely communicate with IRBs about required postmarketing studies —
for example, by issuing a letter to accompany IRB applications that
conveys information that is material to the IRB's determination of the
ethics of the research, as well as providing additional communications
over the life of the study as warranted by new information about the
drug or by changes in professional practice. The committee also believed
that the FDA was ethically obligated to actually use the findings from
required studies to make timely regulatory decisions.
Informed-Consent Process for Required Postmarketing Trials
The
IOM committee emphasized that the adequacy of the informed-consent
process is only one element in the ethics of FDA-required postmarketing
research. Other central, and indeed prior, features include ensuring
that the selection of participants is equitable and that the level of
risk to which they are exposed is acceptable. The committee also
recognized, however, that there are challenges to achieving meaningful
informed consent in postmarketing trials of drugs for which there is a
signal indicating the possibility of drug-related harm. In such cases,
there is a suspicion that the benefits of the drug may not justify its
risks and often that it may have a worse benefit–risk profile than
alternative drugs available to treat the same condition. The committee
concluded that for postmarketing trials of such drugs, there are
“heightened obligations to ensure that potential research participants
understand the risks posed by study enrollment.”
4
This was of particular importance for rosiglitazone, because the
cardiovascular problem it appeared to cause was the same outcome that
good diabetic control was supposed to improve — in other words, if this
elevation in risk were real, there could be little offsetting benefit.
The
committee recommended several measures to strengthen the consent
process in order to maximize patients' understanding of the context in
which the trial is being conducted, including what is already known
about the risks associated with the drug. The report discussed both
specific disclosures in the informed-consent form and special efforts
that could be made to ensure adequate comprehension of complex
information regarding risks (
Table 2Table 2
Mechanisms for Strengthening the Informed-Consent Process for Postmarketing Drug-Safety Studies.).
To assist IRBs, the committee recommended that the FDA issue guidance
interpreting current informed-consent regulatory requirements in the
context of required postmarketing studies.
Strengthening Postmarketing Research and Its Governance
Because
a true picture of the benefit–risk profile of a drug only emerges over
time, two different IOM committees have stressed the need for the FDA to
fully embrace a “life-cycle approach” to drug regulation, in which its
obligations to protect public health are taken as seriously once a drug
is on the market as they are before approval is granted.
4,16
Postmarketing regulatory oversight is assuming heightened importance as
the FDA accrues additional authority to fast-track drugs for approval
on the basis of more limited evidence than was previously required in
order to address unmet medical needs and accelerate innovation.
17-19
This changing landscape raises several challenges for ensuring the
ethical conduct of research with approved drugs and balancing societal
interests in drug innovation and drug safety. We highlight two of these
challenges here.
First, not all postmarketing research is
ethically equivalent. The TIDE trial represented an iconic kind of
postmarketing study: an FDA-required randomized trial to study a drug
whose benefit–risk profile was under a cloud of suspicion and at a time
when alternative treatments were available, albeit not all well studied.
The risks to patients of participating in the trial probably outweighed
the prospect of direct benefit. By contrast, when the FDA requires an
observational study that uses previously collected data, the clinical
experience of the participants is unaffected, the risks incurred are not
at the behest of the FDA, and ethical concerns are largely confined to
confidentiality and the right to control one's medical information.
Both
of these scenarios can be distinguished from the context in which a
phase 4 trial is required as a condition of an accelerated drug approval
and is initiated soon thereafter. Here, the trial requirement is not
imposed because of a newly emerging concern about a drug already in
clinical use but because additional evidence is needed to confirm the
initial judgment that the benefits of a new drug are likely to outweigh
its risks. Often, this initial judgment is based on the use of a
surrogate end point for drug benefit, not on the clinical outcomes that
matter most. Especially when the new drug targets an unmet medical need,
it may be in the patients' best interest to take it, pending further
timely research. The ensuing trial is undertaken to confirm the
improvement in clinical outcomes predicted by the surrogate — a
different epistemic and ethical situation than that in which substantial
evidence suggests that the surrogate is misleading or that other harms
might offset a known clinical benefit.
The volume of phase 4 and
other research with FDA-approved drugs is increasing, not only because
of the expanded authority of the FDA to require such research but also
because of the growing volume of comparative-effectiveness research. In
some cases, there may be no or little ethical difference between
FDA-required postmarketing research and comparative-effectiveness
research initiated by academic investigators. By contrast, a
comparative-effectiveness study of two widely used drugs that is not
occasioned by heightened concern about the risks of one drug relative to
the other is markedly different, ethically, from a study required by
the FDA to pursue a safety signal that is already of such concern that
practice patterns are shifting, even if both studies use randomized
designs.
These differences highlight the need for IRBs to be
sensitive to the place where a study falls within the life cycle of a
drug and to the reason for the research. Depending on who is initiating
the research, for what reasons, and when, the same study design may have
very different ramifications for the benefit–risk balance of the study
and what patients need to know in order to provide meaningful informed
consent. Trials that may be regarded as unethical late in the life cycle
because of accumulated evidence can be much easier to initiate earlier
if the need for additional research is anticipated and planned at the
time of initial approval. In the case of rosiglitazone, this need could
have been anticipated from preapproval data showing an adverse effect on
serum lipids as well as the use of a surrogate end point (glycemic
control) for a first-in-class drug.
5,20
Second,
the experience with rosiglitazone underscored the fragility of our
current system of discovering risks associated with drugs. This system
relies heavily on drug sponsors and FDA scientists to conduct safety
analyses on the basis of data from clinical trials, some or all of which
are not publicly available, and to release findings to the public. It
has been shown repeatedly that the published record can misrepresent
evidence known to the FDA.
21,22
In the case of rosiglitazone, scientists from GlaxoSmithKline and the
FDA had information from 42 clinical trials, of which only 7 were
published and the others were inaccessible. Triggered by concerns
expressed by the World Health Organization in 2006, GlaxoSmithKline
conducted and shared with the FDA a meta-analysis of the safety of
rosiglitazone that used these data, confirming a possibly elevated risk
of ischemic events, but neither these results nor the primary trial
results were shared with the public until an unrelated court settlement
forced GlaxoSmithKline to release its complete clinical-trial data.
23 This access led to the published meta-analysis by independent researchers that made these data and concerns public in 2007.
5
It is often the work of independent scientists that has highlighted critical safety problems with approved drugs.
5,24-29
Yet currently, data from premarketing studies that are submitted as
part of a new drug application or a supplemental new drug application
are largely shielded from release to external scientists and the public
owing to concerns about a competitive disadvantage to drug sponsors.
30,31
The IOM committee stopped short of calling on the FDA to increase
public access to such data but recommended that the agency initiate a
process to determine ways to “appropriately balance public health,
privacy, and proprietary interests to facilitate disclosure” of relevant
data.
4 Greater transparency would better equip independent scientists to investigate early safety signals.
31
Consideration should be given to making drug-safety data from clinical
trials available to the public on request once the FDA has reached a
decision regarding a new drug application or a supplemental new drug
application or once the manufacturer has abandoned the application,
unless the manufacturer can articulate a persuasive reason why it would
result in competitive harm and the FDA determines that this harm
outweighs the public health benefits of releasing the information.
Conclusions
The
experience with rosiglitazone and the TIDE trial offers a lesson in how
our current approach to the oversight of drug-safety and postmarketing
research can fail both the public and the research participants.
Although terminating the TIDE trial was justifiable, it left regulators
with highly suggestive but nondefinitive data on the relative safety of
rosiglitazone and the closest clinical alternative, pioglitazone.
32
Reactive
policymaking is tempting but problematic. The history of regulation of
human subjects research suggests that rules that are “born in scandal
and reared in protectionism”
33
often fall short of providing meaningful protections to research
participants and that, once adopted, regulations can ossify and become
difficult to dislodge. Nevertheless, the IOM committee's report makes a
number of actionable recommendations that the FDA can implement under
its existing authority.
34
In addition, appointment of an independent ethics advisory board would
strengthen the decision making of the FDA as it confronts emerging
ethical challenges — both those arising from required postmarketing
trials and those stemming from powerful new drug surveillance systems,
such as the FDA's Sentinel Initiative. As the pace of the translation of
discoveries from bench to bedside continues to intensify, so too does
the imperative for thoughtful ethical governance throughout the life
cycle of a drug.
The
views expressed in this article are those of the authors and, except
where noted, do not represent the official position of the Institute of
Medicine or of the committee that produced the report discussed in this
article.
Drs. Faden and Goodman chaired, and Dr. Mello was a
member of, the Institute of Medicine committee that produced the report
discussed in this article.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on August 22, 2012, at NEJM.org.
We thank the other IOM committee members for contributing to some of the ideas discussed.
Source Information
From
the Department of Health Policy and Management, Harvard School of
Public Health, Boston (M.M.M.); the Departments of Medicine and Health
Research and Policy, Stanford University School of Medicine, Stanford,
CA (S.N.G.); and the Berman Institute of Bioethics, Johns Hopkins
University, Baltimore (R.R.F.).
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