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2
Incorporating Benefit and Risk Assessment
and Benefit–Risk Management into Food
and Drug Administration Decision-Making
As part of its charge the committee was asked how the US Food and Drug
Administration (FDA) should “factor in different kinds of safety evidence in
considering different kinds of regulatory action”. To respond to that question, the
committee considered the relevance of different evidence to decisions about differ-
ent potential regulatory actions, and how FDA should apply that evidence across
the lifecycle of a drug. The committee concluded that there is no one answer to
that question, because the evidence and circumstances surrounding each regula-
tory decision are different. Although decisions as to how to weigh evidence will
always have to be made case by case, the committee provides a broad overall
approach to guide the assessment of safety evidence and FDA decision-making.
In this chapter, the committee highlights the importance of a lifecycle approach to
FDA’s regulatory decisions and proposes two mechanisms to facilitate adopting
such an approach: a framework for decision-making and a document, referred to as
a Benefit and Risk Assessment and Management Plan (BRAMP), to formalize the
implementation of the lifecycle approach discussed in Chapter 1, and make FDA’s
decisions about each drug transparent. The framework is not intended as a one-
time activity, but rather an activity that recurs when questions about the benefits
or risks associated with a drug arise. The document is a record that tracks the
experience of a drug across its lifecycle, to be updated whenever the framework
is used to evaluate the benefits and risks associated with a drug.
EVALUATING BENEFIT AND RISK OVER A DRUG’S LIFECYCLE
FDA’s decision to approve a drug for sale in the United States is based on
a judgment that in view of the evidence from premarketing studies and clinical
61
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62 STUDYING THE SAFETY OF APPROVED DRUGS
needs, it is, all things considered, in the interest of the public’s health for the
drug to enter the marketplace. In other words, the benefits of the drug outweigh
its risks for the intended use and population. Although at the time of approval
knowledge about efficacy from small, short-term clinical-trial populations is
limited, far less is known about the drug’s risks. Some adverse effects may be
too rare to be identified in the small numbers of people who participate in pre -
marketing studies. For example, although the premarketing clinical trials for a
second-generation rotavirus vaccine involved relatively large numbers of research
participants, the small, increased risk of intussusceptions with rotavirus vaccines
was only identified in post-licensure safety monitoring (approximately 1 of every
51,000 to 68,000 vaccinated infants) (Greenberg, 2011; Patel et al., 2011). Other
adverse events may have a latent period longer than the duration of premarketing
trials or may occur in people who are unlike those who participated in the pre -
marketing trials in relevant respects. For example, they may be less healthy, take
other medications, or have comorbidities. Such patients are often excluded from
or enrolled in small numbers in premarketing trials (Fung, 2001).
For several reasons, questions about the effectiveness of a drug in actual
clinical practice may also remain at the time of approval (Borer et al., 2007;
Hiatt, 2006; IOM, 2007a; Ray and Stein, 2006). Long drug exposure during the
postmarketing period could lead to a loss of effectiveness as tolerance or resis-
tance to the drug develops. The population taking an approved drug is likely to
be more heterogeneous than the people who participated in premarketing clinical
trials. The drug may not be as effective in the postmarketing general population
as it was in the premarketing test population. Many factors can account for those
differences, including differences in environmental factors, genetics, age, race,
ethnicity, or sex; interactions with other drugs; comorbidities; and problems with
drug adherence. For example, a person who has liver disease might not fully
metabolize and activate a drug, leading to decreased clinical effectiveness. A drug
approved on the basis of a surrogate endpoint might not be as effective in improv -
ing a clinical endpoint, for example tumor shrinkage may not correlate strongly
with survival. Once a drug is allowed to enter the market, physicians are free to
use it, on-label or off-label, for any indication, including those of which there
may be little or no scientific evidence of effectiveness from premarketing trials.
In the remainder of this chapter, the committee outlines a three-stage frame-
work for making regulatory decisions and how FDA could apply the framework
as part of the lifecycle approach to drug safety discussed in Chapter 1. (See
Box 2-1 for definitions of key terms used in this chapter.) The committee then
proposes a BRAMP document as a mechanism for implementing a lifecycle
approach to drug regulation and for making FDA’s decisions transparent. Figure
2-1 shows how FDA can incorporate the framework and the BRAMP into a
lifecycle approach to drug oversight. The chapter concludes by addressing the
circumstance under which regulatory decisions should include requiring manu -
facturers to conduct postmarketing studies, a focus of the committee’s charge (see
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BENEFIT–RISK AND FDA DECISIONS
BOX 2-1
Key Definitions
Benefit assessment and risk assessment: The gathering and
analyzing of information on the nature and magnitude of potential benefits
and potential harms (risks) associated with a drug and the determination
of the likelihood that those benefits and harms will occur.
Benefit–risk profile: An overall evaluation of the benefits and risks
associated with a drug.
Benefit–risk management: The process of identifying, evaluating,
selecting, and implementing actions to increase benefits and reduce risk
to human health. The goal of benefit–risk management is scientifically
sound, integrated actions that increase or maintain benefits and reduce
or prevent risks while taking into account social, cultural, ethical, political,
and legal considerations. “A good risk management decision emerges
from a decision-making process that elicits the views of those affected
by the decision, so that differing technical assessments, public values,
knowledge, and perceptions are considered” (Presidential/Congressional
Commission on Risk Assessment and Risk Management, 1997). The
process of benefit–risk management should include not only information
about current regulatory actions but plans for future evaluations and
regulatory actions as part of the lifecycle process.
Uncertainty: Lack or incompleteness of information. Quantitative
uncertainty analysis attempts to analyze and describe the degree to
which a calculated value may differ from the true value; it sometimes
uses probability distributions. Uncertainty depends on the quality, quan-
tity, and relevance of data and on the reliability and relevance of models
and assumptions.
Box 1-1; the question of which study designs FDA should require is addressed
in Chapter 4).
THREE-STAGE FRAMEWORK FOR
REGULATORY DECISION-MAKING
Overview and Rationale
Responding in a timely and appropriate way to safety signals from already-
approved drugs is among the most important and challenging public health jobs
that FDA must accomplish. Permitting a drug to stay on the market that is on
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64 STUDYING THE SAFETY OF APPROVED DRUGS
Premarketing Setting
Postmarketing Safety
Monitoring
Postmarketing Setting
Product Discovery
Product
Pre-Clinical Studies
Remains on
and NDA
Market
Clinical Trials Review
BRAMP
Developed Drug Approved Drug’s Benefit–Risk
FDA Oversight
Product
Update
and Enters the Profile is Questioned or
Begins
Removed from
BRAMP
Market There is a Periodic
Market
Evaluation of the Drug
Make and
Define Public Assess
Implement
Health Drug Benefits
Regulatory
Question and Risks
Decision
Framework for Decision-Making
FIGURE 2-1 The lifecycle of a drug for a new molecular entity. After a product is discov-
ered and the sponsor approaches FDA with the product as an investigational new drug, FDA
oversight begins. During approval, the company submits information about the benefits,
risks, and benefit–risk profile of the drug, and FDA develops a BRAMP. After approved,
FDA and the drug sponsor conduct postmarketing safety monitoring of the drug, which
could include passive surveillance, active surveillance, observational studies, and random -
ized controlled studies. If evidence arises that calls into question the benefit–risk profile
of the drug, FDA uses the decision-making framework to review the new evidence in the
context of existing evidence and the public health context of the drug, to make a regulatory
decision about the drug. Depending on the decision, the drug will remain on the market,
either with the same or different restrictions and conditions, or will be removed from the
market. FDA updates the BRAMP document when it considers a regulatory decision for
the drug, and when periodic evaluations occur over the drug’s lifecycle. FDA oversight of
the drug continues for as long as the drug is on the market.
balance harmful threatens public well-being,1 but so too does limiting access to a
drug whose benefits outweigh its harms. As discussed in Chapter 1, the Food and
Drug Administration Amendments Act (FDAAA) of 20072 provides FDA with
new tools and authorities to adopt a lifecycle approach to regulatory decision-
making—an approach that FDA has endorsed (FDA, 2004). However, FDA has
not yet taken full advantage of its new tools and authorities to implement a life -
cycle approach in a systematic or comprehensive manner.
1 There are instances where a drug is, on balance, harmful to the overall population but nevertheless
provides a net benefit to a specific subgroup within the population. In those instances, the drug could
remain on the market with restrictions to limit its use to those subgroups for whom the drug has a
favorable benefit–risk profile.
2 Food and Drug Administration Amendments Act of 2007, PL No. 110-85, 121 Stat. 823 (2007).
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BENEFIT–RISK AND FDA DECISIONS
The assessment of benefits and risks and making management decisions
in response to the assessment are not new challenges for FDA. The agency has
a process in place for reviewing premarketing data on efficacy and risks, and
making regulatory decisions about approving a drug on the basis of those data
and other considerations. Similarly mature processes do not exist for evaluating
a drug’s benefits and risks in the postmarketing setting using FDA’s authority in
FDAAA, although in April, 2011 FDA issued guidance providing information
for industry on how it would implement the section of FDAAA3 that authorizes
FDA to require postmarketing research. The link between benefit assessment, risk
assessment, and FDA’s regulatory decision-making has been criticized for failing
to be explicit and transparent to external stakeholders (Asamoah and Sharfstein,
2010; Transparency Task Force et al., 2010).
Other US government agencies and organizations have a history of making
decisions on the basis of formal assessments of risks. The US Environmental
Protection Agency (EPA), for example, conducts formal chemical risk assess -
ments to guide its decisions on allowable concentrations of chemicals in the
environment (see for example EPA, 2005, 2009). The process used by EPA has
evolved after publication of a number of reports outlining best practices for risk
assessment and regulatory decision-making (NRC, 1983, 1989, 1996, 2009;
Presidential/Congressional Commission on Risk Assessment and Risk Manage -
ment, 1997). Characteristics of those best practices include the use of the best
available scientific evidence, the involvement of parties that would be affected
by the decision in the decision-making process, especially to incorporate the per-
spectives of patients and consumers in the process, and transparency in the pro-
cess (NRC, 1989, 1996, 2009; Presidential/Congressional Commission on Risk
Assessment and Risk Management, 1997). The 2009 National Research Council
report Science and Decisions: Advancing Risk Assessment proposed that EPA use
a formal three-phase framework when making its regulatory decisions (NRC,
2009, 2011). The framework includes a problem-formulation phase, a phase for
the planning and conduct of the risk assessment, and a risk-management phase.
A recent National Research Council report, A Risk-Characterization Framework
for Decision-Making at the Food and Drug Administration, highlighted the 2009
framework and its general usefulness for FDA in its regulatory purview (NRC,
2011). It proposed a similar, three-step process for decision-making that involved
identifying and defining the decision context, estimating or characterizing the
public health consequences of each decision option, and using the completed
characterization to compare decision options and to communicate their public
health consequences within the agency, to decision-makers, and to the public.
The report highlighted factors that are considered in FDA’s decision-making,
including scientific, social, and political factors, as well as the importance of the
context of the decision to all steps of the decision-making process.
3 21 USC § 355(o) (2010).
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66 STUDYING THE SAFETY OF APPROVED DRUGS
The need for a systematic process for drug-regulatory decisions has been
discussed previously. The Pharmaceutical Research and Manufacturers of Amer-
ica’s Benefit–Risk Action Team (BRAT)4 discussed the need for a consistent
framework for “transparent, rational and defensible decision-making that benefits
patients, drug developers, and decision makers” (Coplan et al., 2011). The BRAT
proposed a six-step framework for decision-making (Coplan et al., 2011). Health
Canada and the European Medicines Agency have also discussed the need for a
benefit–risk framework (CHMP, 2008; Health Canada, 2000).
In the present report, the committee adapts the framework from Science
and Decisions: Advancing Risk Assessment specifically to FDA’s postmarketing
drug-regulatory setting to facilitate managing the benefits and risks associated
with a drug throughout its lifecycle (see Figure 2-2). The framework should be
used whenever FDA needs to make a regulatory decision about a drug; given its
charge, the committee focuses on the use of the framework in the postmarketing
setting where it could be used, for example, in choosing regulatory actions when
the presence of a serious safety signal may precipitate or require consideration
of a regulatory action. The adapted framework has three stages: define the public
health question, assess the drug’s benefits and risks, and make and implement the
regulatory decision. Central to the framework is the need to elicit and incorporate
the perspective of the patient.5
The three-stage framework is designed to be broadly applicable and assist
the decision-maker in the exercise of sound judgment. It is intended to place rea-
sonable demands on the limited resources of FDA given the volume of approved
drugs, but to ensure that comprehensive evaluations of benefit and risk can be
conducted when disagreements arise or when the public health effects may be
substantial. FDA’s decisions vary in their complexity (see Box 2-2). A recent
NRC report noted that FDA’s decision-making framework should be flexible
enough to be applicable to the broad array of decisions FDA faces for its different
regulatory purviews (NRC, 2011). That need for flexibility is equally true within
the drug-regulatory setting. Although all three stages are necessary regardless
of the complexity of the regulatory decision under consideration, the scope of
each stage required to support sound policy decision-making will depend on
the circumstances and available evidence. Many regulatory decisions will not
require comprehensive evaluations at every stage, and efforts should be scaled
accordingly.
A number of methods have been proposed for assessing benefits and risks,
and for making regulatory decisions in response to these assessments. Some
4 The Pharmaceutical Research and Manufacturers of America has transferred its Benefit–Risk
Action Team (BRAT) framework to the Centre for Innovation in Regulatory Science “to further the
program’s technical development and broaden input from the scientific community” (PhRMA, 2012).
5 FDA also recognizes the importance of the participation of patients, patient advocates, and health
professional organizations in its regulatory decisions, and has established an office to facilitate such
interactions (FDA, 2011a).
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(from Stage 2)
Do the benefits of a drug continue
to outweigh its risks? If not, are
there actions (such as labeling
changes, box warnings, or
REMS) that FDA could require
that would adequately mitigate
the risks?
67
FIGURE 2-2 Three-stage framework for regulatory decision-making.
SOURCE: Modified from Science and Decisions: Advancing Risk Assessment (NRC, 2009).
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68 STUDYING THE SAFETY OF APPROVED DRUGS
BOX 2-2
Two Examples of the Diversity and Complexity of
Food and Drug Administration (FDA) Decisions
FDA’s decisions on drugs range from relatively easy decisions for
which the science and the appropriate regulatory action are clear to ones
for which the scientific evidence can be complex or contradictory and
determining the appropriate regulatory action would benefit from input
from many experts.
1. As an example of the former, the scientific evidence on the risk of liver
problems associated with trovafloxacin (Trovan®), an antibiotic used for
treatment for various infections, was clear soon after it was approved.
Trovafloxacin was approved by FDA in December 1997 and became
available to patients two months later (FDA, 1999). None of the 7,000
patients in the premarketing clinical trials experienced serious liver
problems (hepatic failure, sometimes requiring liver transplantation,
or death), but soon after entered the market, FDA began to receive
reports of adverse events as early as two days after treatment; more
serious adverse events (acute liver failure) occurred in patients after
more than two weeks of treatment. Within seven months of approval,
FDA had received more than 100 reports of patients’ experiencing
symptomatic and asymptomatic hepatic toxicity; some who sustained
hepatic damage had to have transplants or died (FDA, 1999). In July of
1998, FDA worked with the drug sponsor to add further toxicity informa-
tion on the medication label and package insert, informing physicians of
the potential for hepatic toxicity. In addition, distribution of trovafloxacin
was limited to inpatient facilities, patients receiving trovafloxacin had
to have life-threatening or limb-threatening disease, and a physician
must believe that the drug’s benefits outweighed the risks it posed for
a patient (FDA, 1999). In this example, once the drug was marketed,
there was evidence of an association between trovafloxacin and se-
vere, sometimes fatal adverse events. Other drugs that could be used
effectively to treat for most infections were on the market. Given that
evidence, FDA placed severe restrictions on the use of Trovan.
2. In contrast, when deciding about postmarketing regulatory decisions
about aprotinin (Trasylol®), FDA was faced with conflicting scien-
tific evidence about the risks associated with the drug. Aprotinin is a
bovine-derived natural protease inhibitor that was approved by FDA in
1993 for use during coronary arterial bypass surgery to reduce blood
loss and diminish the need for blood transfusions in surgical patients.
From the time of its FDA approval through 2005, several studies and
meta-analysis of results of randomized controlled trials supported
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BENEFIT–RISK AND FDA DECISIONS
the efficacy of aprotinin for reducing the inflammatory response, the
need for transfusions, and the risk of stroke, and it showed either
no effect or a reduction in mortality, myocardial infarction, or renal
failure risk (Henry et al., 2001; Levi et al., 1999; Sedrakyan et al.,
2004). In early 2006, however, two observational studies further raised
concerns about aprotinin’s safety. Mangano et al. (2006) compared
health outcomes related to the use of aprotinin (1,295 patients) with
outcomes related to the use of two other hemostatic agents—amino-
caproic acid (883 patients) and tranexamic acid (822 patients)—and
results in 1,374 patients who did not receive a hemostatic agent. The
study found that use of aprotinin doubled the risk of renal failure and
was associated with higher rates of heart attacks and stroke than the
use of other medications or no treatment. The study by Karkouti et
al. (2006) used propensity scores and compared 449 of 586 patients
who had received aprotinin during high–transfusion-risk surgery with
449 patents who received tranexamic acid; it determined that aprotinin
may be associated with renal dysfunction. On the basis of the results
of those two studies, FDA released a public health advisory for apro-
tinin in February 2006, detailing the results of the two observational
studies and cautioning physicians to “consider limiting [aprotinin] use
to those situations in which the clinical benefit of reduced blood loss
is essential to medical management of the patient and outweighs the
potential risks”.
In late September 2006, after FDA held a public meeting of the
Cardiovascular and Renal Drugs Advisory Committee, the drug spon-
sor disclosed preliminary findings from a new observational study that
confirmed the findings of the previous observational studies. The new
study, which was commissioned by the drug sponsor, reviewed hospital
records of 67,000 patients who had undergone coronary bypass graft
surgery. Preliminary study results found that the 30,000 patients who
received aprotinin during surgery had an increased risk of death, renal
failure, congestive heart failure, and stroke. Final study results, pub -
lished in 2008, concluded that patients who received aprotinin had an
estimated mortality 64% higher than patients who received aminocaproic
acid (relative risk [RR], 1.64; 95% confidence interval [CI], 1.56–2.02)
(Schneeweiss et al., 2008). Another advisory committee meeting was
held, but the committee did not find the evidence compelling enough
to recommend withdrawal of the product from the market, but did find it
compelling enough to recommend a label change and that an RCT be
Continued
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70 STUDYING THE SAFETY OF APPROVED DRUGS
BOX 2-2 Continued
conducted (FDA, 2007a). Taking the preliminary data into account, FDA
issued a new statement in September 2006, reiterating the cautions from
the earlier health advisory and asking physicians to monitor patients for
the occurrence of toxicity. In December 2006, FDA strengthened the
safety warnings regarding aprotinin and added a warning that the drug
increases the possible risk of renal damage. The advisory also included
guidance for minimizing the risk.
In the meantime, the Blood Conservation Using Antifibrinolytics in
a Randomized Trial (BART)—a multicenter, blinded, randomized, con-
trolled study comparing aprotinin with two other antifibrinolytic agents
(aminocaproic acid and tranexamic acid)—had begun to enroll patients
in 2002. In October 2007, the study was halted early when preliminary
results indicated a higher death rate seen in aprotinin-treated patients
(RR, 1.53; 95% CI, 1.06–2.22) (Fergusson et al., 2008). In November,
2007, FDA announced that the sponsor agreed to an FDA-requested
marketing suspension of aprotinin in February 2007, after preliminary
results from the BART were released.
In May 2008, FDA announced that the drug sponsor would remove
remaining stock of aprotinin from the market and limit access to aprotinin
to investigational use. The special protocol allows the use of aprotinin for
“certain patients who are at increased risk of blood loss or transfusions
during coronary artery bypass surgery and who have no acceptable
alternative therapy” (FDA, 2008a).
The differences in the complexity of these two examples illustrate
FDA’s need for a scalable framework for decision-making. Where the
evidence is somewhat more clear-cut, such as the case of trovafloxacin,
FDA could use the three stages of the framework, but the decision might
not require as extensive weighing of the evidence, or engagement of
stakeholders and external experts. Where the evidence is not as clear,
where scientists might disagree about the value of different sources
of evidence, or where requiring a randomized controlled trial is likely
to be ethically controversial, such as in the case of aprotinin, each of
the three stages might be more involved, with FDA eliciting external
scientific advice, the perspectives of patients, and the concerns of other
stakeholders.
a Thecommittee uses these drugs as examples of the variability in FDA’s decisions and its ap-
proach to safety signals, evidence, and regulatory decision-making. The committee is not com-
menting on, or drawing any conclusions about, the timing or nature of the regulatory decisions.
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BENEFIT–RISK AND FDA DECISIONS
researchers and decision scientists have proposed the use of either decision-
conferencing or multicriteria decision analysis for benefit-and-risk–based
regulatory decision-making (see Appendix D for discussion) (NRC, 2011). The
process of decision-conferencing or multicriteria decision analysis can increase
transparency in regulatory decision-making, provide formal opportunities for
input from stakeholders, and delineate the sources of disagreements among par-
ticipants. Some of the methods, however, rely heavily on using a common met -
ric, such as dollars saved, lives saved or quality-adjusted life-years, to quantify
benefits and risks related to different endpoints and assigning numerical values
to a number of subjective considerations, such as the importance of a given
adverse event or a specific improvement in quality of life. Appendix C discusses
the use of those processes as tools to elicit input into the decision-making pro -
cess. They can be useful, and, in some cases, can provide informative results,
but the committee emphasizes, as have others, that reducing benefits and risks
to a common metric as the only output considered in a decision can sometimes
lead to oversimplifying complex decisions, misunderstanding, and a lack of
trust (NRC, 1989, 2011).
Consistent use by FDA of the proposed framework for decision-making
would be valuable for several reasons. First, it would allow stakeholders to
understand and anticipate key components of the process by which decisions
are made. Second, it would emphasize the dynamic nature of benefit and risk
assessments, particularly in the postmarketing setting, and the need for continual
re-evaluation of decisions by an organization dedicated to protecting and pro-
moting the public health. Third, it would provide an opportunity to consider the
value of additional postmarketing studies (for example, through postmarketing
requirements), to explore scientific and ethical issues with regard to the type of
postmarketing studies under consideration, and to evaluate the potential effects of
future regulatory decision-making. Fourth, use of a systematic approach for the
routine re-evaluation of benefits, risks, and regulatory decisions could minimize
long delays in decision-making or lack of transparency in the rationale for regu -
latory decisions may be minimized. It is important to note that while the need to
change or modify a regulatory decision about a drug in the postmarketing context
can sometimes be traced to errors in premarketing regulatory decision-making,
often that is not the case. Rather, the ability to respond to the changing knowledge
base regarding the benefit–risk balance is a valued characteristic of the agency
that seeks to secure population benefits while mitigating harms, and modifications
of regulatory decisions should be expected in the postmarketing phase and not
regarded as reflecting a failure.
The following sections describe the three stages and the key elements for
consideration in each stage. The three stages should not be interpreted as iso -
lated activities, but as interconnected activities that inform each other and help
to ensure that the characterization of risks or, in this case benefits and risks, is
decision-driven, recognizes all significant concerns, includes both analysis and
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110 STUDYING THE SAFETY OF APPROVED DRUGS
required, by integrating the evaluation of the evidence of benefits and risks
from Stage II with legal and ethical considerations and input from stakehold-
ers; communicate to the public the reasoning behind the decision; imple -
ment the regulatory response; and, particularly for difficult or controversial
decisions (see Recommendation 2.5), evaluate the impact of the regulatory
response.
Finding 2.2
No single, clear, comprehensive, and public document currently captures FDA’s
assessments of a drug’s benefits and risks over the course of its lifecycle, nor
does any documentation help to standardize FDA’s decision-making processes or
describe FDA’s rationale for its regulatory actions. Capturing such information
in a living document would formalize the lifecycle approach to drug regulation,
improve regulatory oversight, and improve the transparency of FDA’s decisions.
Recommendation 2.2
FDA should require and maintain, for each new drug and for already
approved drugs for which questions about the benefit–risk profile are raised,
a publicly available and understandable Benefit and Risk Assessment and
Management Plan (BRAMP). For new drugs, the BRAMP document should
be initiated during the drug-approval phase and updated over the lifecycle
of the drug at pre-specified times in the postmarketing setting and when -
ever questions about the drug’s benefit–risk profile arise. The document
should include a description of: any public health questions raised during
the drug’s lifecycle; the benefit and risk assessment specific to each public
health question; key stakeholder input specific to each question; any regu -
latory decisions or actions and the rationale for each decision, including
requirements for postmarketing research or a risk evaluation and mitigation
strategy (REMS); a schedule for future assessments of benefits and risks;
and plans for and results of evaluating the effectiveness of any regulatory
decisions or actions.
• n the premarketing phase, the drug sponsor should provide a summary of
I
the drug’s benefits and risks, any uncertainties in the evidence, and plans
for decreasing those uncertainties. FDA should use that information as a
starting point to develop the BRAMP document. FDA staff involved with
the drug’s premarketing application and staff with expertise and knowl -
edge in postmarketing safety assessment should finalize the initial entry
to the BRAMP document.
• n composing teams to monitor the safety of a drug and maintain its
I
BRAMP in the postmarketing phase of the drug’s lifecycle, FDA should
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BENEFIT–RISK AND FDA DECISIONS
consider the real or perceived confirmation bias of staff that played a sig -
nificant role in approving the drug. This should be managed by ensuring
that the leader of the postmarketing safety monitoring team is without
the potential for such bias. The monitoring team should have expertise
in surveillance, epidemiology, and the evaluation of safety data collected
from different observational and clinical trial designs. The team should
review and modify the BRAMP document at specified intervals through-
out the lifecycle of the drug, including when new information warrants
re-evaluation of the drug’s benefit–risk profile.
Finding 2.3
In the premarketing setting, evidence is derived primarily from randomized con -
trolled trials. In the postmarketing setting, however, evidence may be derived
from surveillance, observational studies, patient registries, published and unpub -
lished clinical trials, meta-analyses, and relevant case reports or series. Data
sources, study designs, and analytic approaches for the postmarketing context
are evolving rapidly. Given those differences, the expertise needed to evaluate
and characterize the quality of evidence in the postmarketing setting is different
from and broader than that needed in the premarketing setting.
Recommendation 2.3
In making determinations about appropriate regulatory decisions to be imple-
mented in the postmarketing context, FDA should ensure that the full range
of methodologic expertise is used to evaluate the strength of evidence of a
drug’s benefits and risks from a wide range of designs. For complex regula-
tory decisions, including decisions about requiring additional postmarketing
research, such expertise should include, but not be limited to
• Clinical medicine and clinical practice, such as pharmacy.
• Biostatistics: Bayesian, frequentist, and causal inference methods.
• Epidemiology and pharmacoepidemiology.
• Clinical trials.
• Benefit–risk analysis.
• Research and public health ethics.
• Risk communication.
Finding 2.4
Section 901 of FDAAA14 stipulates the purposes for which FDA has the authority
to require postmarketing observational studies and RCTs, and 2011 FDA guid -
14 21 USC § 355(o) (2010).
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112 STUDYING THE SAFETY OF APPROVED DRUGS
ance for industry provides information on FDA’s implementation of that section
of FDAAA. Although FDA’s decisions to require postmarketing research need to
be made case by case, there are some identifiable conditions that are concordant
with but more specific and detailed than those outlined in FDAAA and FDA guid-
ance, which make information from additional postmarketing research important.
Recommendation 2.4
FDA should prospectively determine and publicly identify specific condi -
tions, including drug characteristics and other features, that are associated
with greater uncertainty about a drug’s benefit–risk profile in the postmar-
keting setting. Under those identified conditions, FDA should require post-
marketing research in a timely fashion unless there is a compelling reason
not to, and should make public the rationale for requiring or not requiring
postmarketing research in each case. Those premarketing and postmarketing
conditions should include the following
• drug is approved when several surrogate endpoints provide conflicting
A
evidence about the likely health outcomes associated with the drug.
• first-in-class drug is approved on the basis of surrogate endpoints used
A
in drugs of a different class.
• drug is associated with safety signals from premarketing data or post-
A
marketing surveillance when
there is a substantial public health concern,
a severe adverse event is seen, or
there is a strong biologic rationale for a particular adverse effect.
• drug is expected to have a different benefit–risk profile in a subgroup
A
or under real-world conditions.
• drug is in a class for which a substantial safety signal has previously
A
been identified.
• vidence of a lack of benefit of a drug in the whole population or in
E
identifiable subgroups emerges in the postmarketing setting.
Finding 2.5
Some FDA decisions in response to postmarketing public health questions are
controversial or difficult. Complex instances tend to occur when FDA must make
a decision despite scientific disagreement about the relevant evidence or when
the likely effects of a given regulatory action are uncertain. These cases serve
as important opportunities for FDA, external scientists, and the public to learn
about the complexities of the decision-making process and the consequences of
a regulatory decision, and for FDA to improve its processes and practices.
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113
BENEFIT–RISK AND FDA DECISIONS
Recommendation 2.5
FDA should conduct after-action reviews of postmarketing drug-related deci-
sions that are particularly controversial or difficult or when a major regulatory
decision is made after marketing. Such a review should include an assessment
of the decision-making process itself and the effects of the final decision on
the public’s health.
Finding 2.6
Surrogate endpoints are often relied on in the drug-approval process, and their use
has been related to a number of high-profile drug-safety problems. The findings
of postmarketing studies can be used to revise the approval process and improve
the endpoints and methods used in it.
Recommendation 2.6
As part of a continuing effort to improve regulatory science, FDA should
maintain and annually update a list of surrogate endpoints allowed for use
in the approval of drugs, the rationale for their use, the postmarketing expe -
rience regarding their correlation with health outcomes of interest, and any
revisions of approval requirements that may have been suggested by the
results of the postmarketing studies. The list should accumulate the post -
marketing experience of the successes and failures of various surrogates so
that for each major drug class, the regulatory science related to approval
methods can be modified and improved. FDA should also revise or develop
guidance documents for the use of selected surrogate endpoints that, on the
basis of postmarketing studies, appear to be inconsistently predictive of
clinical outcomes.
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