Ethical and Scientific Issues in Studying the Safety of Approved Drugs (2012) / Chapter Skim
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4 Selection and Oversight of Required Postmarketing Studies
4 Selection and Oversight of Required Postmarketing Studies
Pages 169-212
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From page 169... ...
3 It is important to note that FDA could require multiple investigations or a staged approach, in which it could start by requiring an observational study and then require a randomized controlled trial if the observational one does not produce sufficient evidence for decision-making. Because FDA could require multiple postmarketing studies in response to concerns about a particular drug, the committee refers to the "types" of research design that FDA might require.
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From page 170... ...
Over the years, the agency has amassed considerable expertise in the design and interpretation of RCTs and in the ethics of randomizing research participants to receive unapproved, investigational drugs. For example, FDA has provided guidance documents on good clinical practice, institutional review boards, and informed consent (FDA, 2011a)
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From page 171... ...
Although the remit of FDA is not to ensure that the drug supply contains only the comparatively "best" drugs for an indication, it has a duty to the public's health to remove or restrict from the supply drugs that pose unacceptable risks in relation to benefit. In this respect, FDA's responsibility to ensure that drugs continue to have a favorable benefit–risk profile may on occasion move the focus of required postmarketing research more toward comparative-effectiveness
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From page 172... ...
In both the premarketing and postmarketing contexts, FDA must balance those potentially competing obligations. Difficult choices must be confronted when a study design that seems to offer the greatest potential for obtaining knowledge relevant to the public health question also involves the greatest burden on and risks to research participants.
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From page 173... ...
REQUIRING OBSERVATIONAL STUDIES AND RANDOMIZED CONTROLLED TRIALS General Criteria in Selection of Required Postmarketing Studies In theory, and assuming that there is no public health need to obtain relevant evidence quickly, an ideal RCT would almost always provide the evidence that regulators need to identify the best regulatory response to the public health ques tion of interest. The design of such an ideal hypothetical trial would be structured to be responsive to the scientific uncertainties that underlie the public health question that is the focus of the regulatory decision.
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From page 174... ...
The first consideration is whether resolution of the public health question requires new evidence primarily on a drug's benefits, its risks, or on both. In some cases, the benefit–risk profile is close enough to an unacceptable threshold that obtaining high-quality evidence on both in the same population, in the same study is critical for resolving the public health question.
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From page 175... ...
As previously noted, the best approach may be a combination strategy in which a range of different observational study types are initiated, with a postmarketing trial required only if the required observational research does not adequately clarify the concern. Third and fourth are the issues of the magnitude of effect that is being sought, either with respect to benefit or harm, and how this magnitude compares to the expected or plausible degree of confounding.
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From page 176... ...
The target population at risk must be defined, and the achievable design measured against its relevance for that population. For example, the public health question may be whether the drug has an acceptable benefit–risk profile in high-risk patients, but the RCT that is deemed feasible may need to exclude some people at high risk for either ethical or practical reasons (for example, patients who have severe disease that may be difficult to enroll and keep under observation)
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From page 177... ...
The Presumption in Favor of Observational Designs FDAAA provides FDA with a starting point for decisions about which type of postmarketing studies to require. FDAAA specifies that in the postmarket ing setting FDA may require an RCT only when sufficient information cannot be obtained from an observational study.
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From page 178... ...
That is so not because they necessarily impose more risks on research participants or because they necessarily offer participants less in the way of offsetting clinical benefits, but because research that alters the clinical experi ence of patients in such ways also is likely to alter the norms and expectations of the clinical encounter. Most notably, in the traditional clinical context, treat ment choices are made with the intent of bringing about the best outcome for the patient that is commensurate with the patient's values and priorities.
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From page 179... ...
The relative merits of RCTs and observational studies in the postmarketing context are thus more nuanced than the statutory conditions prioritizing observational designs stipulated in FDAAA, which, for example, does not distinguish between observational studies that impose burdens or additional risks on patients and observational studies that do not. Nonetheless, because RCTs alter a particu larly salient feature of a patient's clinical experience in the postmarketing context, the committee believes that the general requirement established by FDAAA in favor of observational research is ethically justifiable and consonant with FDA's ethical obligations to research participants in the postmarketing context.
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From page 180... ...
• the RCT can be carried out in a manner that provides sufficient protection of and respect for research participants. Whether this last, independent condition is satisfied hinges on such issues as the ability to obtain meaningful informed consent, whether the risks to research 8 Basic design variations of RCTs are described in Strom (2005)
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From page 181... ...
• Would an appropriately designed RCT entail serious practicability issues? DESIGN, ANALYTIC, AND ETHICAL CONSIDERATIONS IN SELECTING SPECIFIC OBSERVATIONAL AND RCT DESIGNS TO REQUIRE Observational Studies The determination by FDA that the additional evidence it needs to resolve a public health question can be obtained with observational studies presupposes that FDA has already identified a specific type of observational design that is both capable of generating the needed data and can be feasibly and ethically implemented.
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From page 182... ...
Case–control and case–cohort designs may also be used to generate data on the endpoint of interest to the regulatory decision but use only a sample of persons in the cohort. Rather than selecting patients on the basis of the exposure of interest and observing whether they develop the outcome of interest, case–control designs select persons on the basis of whether they have experienced the outcome of interest and then select controls -- persons who have not experienced the out come of interest -- to compare their past exposures (such as use of a particular drug)
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From page 183... ...
Selecting the appropriate comparison group is key in the design of observa tional studies. In an RCT, randomization is used to ensure an equal distribution of measured and unmeasured risk factors in large samples, and this reduces the BOX 4-1 Rofecoxib and Coronary Heart Disease: An Observational Study A nested case–control study was conducted with computer records from the database of an integrated managed-care organization to evalu ate the risk of acute myocardial infarction (MI)
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From page 184... ...
High-quality observational research can provide sufficient evidence to ground a well-reasoned regulatory decision; in some cases, such research can provide more relevant and timely evidence than any feasible RCT. Observational studies of harm outcomes have some advantages over RCTs.
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From page 185... ...
Selecting an observational design that involves an increased burden on research participants over designs that involve a smaller burden requires a determination that the additional benefit outweighs the increased burden. While often methodologically superior to studies that use existing data, an FDA-required postmarketing observational study that requires the collection of new data -- such as a study for which followup begins at the same time as the start of the clinical intervention -- can raise ethical issues that are parallel in some respects to the issues raised by an RCT, assuming both are initiated at the same time in the drug's lifecycle.
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From page 186... ...
Randomized Controlled Trials If FDA determines that the evidence that it needs to resolve a public health question includes data obtainable only with an RCT, it must then determine which type of RCT to require. Just as in the selection of observational studies, FDA should consider which RCT would best approximate the ideal hypothetical trial, subject to ethical, legal, and practical constraints.
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From page 187... ...
THE FOOD AND DRUG ADMINISTRATION'S ETHICAL OBLIGATIONS REGARDING THE CONDUCT AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES As noted by the National Bioethics Advisory Commission, two principal mechanisms of protecting research participants are independent peer review, such as that provided by IRBs, and voluntary informed consent (National Bioethics Advisory Commission, 2001 #3514; National Bioethics Advisory Commission,
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From page 188... ...
This section addresses FDA's duties to ensure that the postmarketing research it requires is conducted ethically; it explores FDA's responsibilities with respect to each of the mechanisms of protection, including FDA's role in the ethical oversight of such research. Informed Consent Issues in the Postmarketing Setting One component of FDA's obligation to ensure that required postmarketing research is conducted ethically focuses on securing the voluntary informed con sent of research participants.
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From page 189... ...
Going forward, it is important that FDA clarify whether its human subjects regulations govern required postmarketing observational studies, and, if so, how FDA will address and will expect IRBs to address any differences in oversight and research participant protections, including consent requirements, for different observational designs between 21 CFR 50 and 45 CFR 46 so that its regula tions are not a bar to what would otherwise be ethically acceptable observational designs. FDA also will need to determine how best to ensure that required post marketing observational studies can be feasibly conducted, in view of HIPAA and other potential constraints, while still protecting the privacy of the people whose data are used.
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From page 190... ...
Randomized Controlled Trials Although there is commentary defending the conduct of some clinical trials without prior express consent (Faden et al., 2011; Largent et al., 2011; Truog et al., 1999) , the dominant view in research ethics is that clinical trials are paradigmatic of the sorts of study designs that must involve informed consent.
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From page 191... ...
To fulfill the ethical obligation to obtain informed consent, research participants should understand what is being asked of them, including the benefits (if any) and risks, and not merely be given information (Faden and Beauchamp, 1986)
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From page 192... ...
, in Box 4-2. Comprehensive informed consent processes can help to ensure that trial participants understand the potential consequences of study participation in addition to what they are contributing to the advancement of public health in the regulatory arena.
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From page 193... ...
For example, acute myocardial infarction is mentioned only 5 times, whereas cancer and Vitamin D are mentioned 4 and 18 times, respectively. • ultiple unrelated potential side effects are lumped together (for M example, it refers to heart attack, stroke, death, broken bone, and cancers as "diseases")
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From page 194... ...
3. Discussion of the Study Procedures • ligibility criteria should be clearly stated in a distinct section of E the informed consent form to avoid patients automatically think that they will be enrolled in the study if they sign the consent form.
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From page 195... ...
Its location after the discussion of additional risks from rosiglitazone make it less likely that potential research participants will take not of it. • he consent form's disclosure about "important new information" is T worded such that it is not clear if this information is about adverse events.
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From page 196... ...
. For all FDA-required postmarketing clinical trials, a properly qualified DMC should be appointed and given a written charter and pre-specified data-monitoring plan.
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From page 197... ...
Some of the countries in which the TIDE trial was conducted had research and oversight infrastructures equivalent or superior to those in the United States, but others did not have equivalent systems. Concerns about research quality and participant protections in some non-US sites pose challenges for FDA's obligations to ensure adequate protection of the rights and interests of research participants in premarketing and postmarketing research that it requires and to ensure that such research can provide the evidence needed to identify the appropriate regulatory response to a public health question.
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From page 198... ...
is aimed at modernizing and strengthening the agency's oversight and protec tion of subjects in clinical trials and the integrity of resulting data.
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From page 199... ...
The remit of IRBs is to protect research participants. Ensuring that the design of a proposed research study is scientifically acceptable
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From page 200... ...
That should include information about the public health question at issue; the specif ics of the study design intended to address that question, including any design features that it views as necessary to the ethical justification of the study; and any changes in clinical practice or professional standards that arise over the course of the study that might affect the benefit–risk profile of a drug and influence a person's decision to join or remain in the study, which the IRB should consider for dissemination to potential and current study participants. FDA should also communicate to IRBs what it is (and is not)
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From page 201... ...
Thus, there is already an architecture in place for the ethical oversight of postmarketing studies required by FDA, but stronger relationships between the parts of the system are needed, including specific duties for FDA, to enhance its capacity to attend properly to the particular features of postmarketing research. SUMMARY Requiring drug manufacturers to conduct research is at the core of FDA's regulatory responsibilities before drug approval.
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From page 202... ...
FDA has an obligation to ensure that the postmarketing studies that it requires are conducted ethically. The main mechanisms through which FDA can honor that obligation are requiring studies whose designs can provide the evidence needed to help to resolve a public health question, assessing the ethics of candidate designs as it makes its determination about what kinds of studies to require, and accepting specific responsibilities to work closely with IRBs and, when it is appropriate, DMCs to protect the rights and interests of research participants.
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From page 203... ...
In the postmarketing setting, both observational studies and RCTs have advantages and disadvantages. In some circumstances, the evidence provided by an observational study may be as good as or better for informing a public health question than the evidence provided by a feasible clinical trial; that is more likely to occur when the magnitude of the relative risk is large in contrast with the potential for confounding, which occurs with many drug harms.
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From page 204... ...
Recommendation 4.4 FDA should require a postmarketing RCT that might expose research par ticipants to more risk or less net clinical benefit than they would probably face if decisions about their drug treatment were being made in the context of clinical practice only if a question of pressing public health significance is at stake, if no other design with a better benefit–risk balance for participants could supply the evidence needed for a responsible regulatory response to the question, and if special safeguards are in place to protect the rights and interests of the research participants. Those safeguards should include the determination by an appropriately constituted review committee that the additional risk is small enough for it to be ethical to ask people whether they are willing to accept it solely to contribute to the public good; the minimiza tion of additional risk by careful study design and implementation of a robust monitoring plan throughout the study; the inclusion of special measures in the process of soliciting informed consent to confirm that patients understand and willingly accept that they are assuming an additional risk, beyond what they are likely to face in clinical practice, solely in the interest of the public good; and the implementation of processes to ensure that over the course of the trial participants are regularly informed of any changes in clinical practice or the medical literature relevant to assessments of the comparative benefits and risks associated with trial participation and (nonresearch)
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From page 205... ...
, should clarify whether its human subjects regulations (21 CFR 50) govern required postmarketing observational studies and, if so, how FDA will address and will expect IRBs to address any differences between 21 CFR 50 and other potentially applicable human subject regulations (45 CFR 46 Subpart A)
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From page 206... ...
and each DMC with the up-to-date BRAMP document for the study drug and sufficient information in writing for the IRB or DMC to provide appropriate oversight, including information about the public health question at issue, the specifics of the study design intended to address the question, design features that FDA views as necessary for the ethical justification of the study, and any changes in clinical practice or professional standards that arise over the course of the study that might affect the risk– benefit profile of a drug and influence a person's decision to participate or remain a participant in the study. Finding 4.7 There are heightened informed consent concerns in the conduct of FDA-required RCTs in the postmarketing setting.
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From page 207... ...
Finding 4.8 During the last two decades, the volume of clinical trials conducted outside the United States has increased dramatically, and this has led to concerns about the quality, reliability, and transportability of research results and about the adequacy of protections for research participants. Those concerns apply as well to FDArequired postmarketing research that uses research sites outside the United States.
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From page 208... ...
2004. Interventions to improve research participants' understanding in informed consent for research.
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From page 209... ...
2001. Quality of informed consent in cancer clinical trials: A cross-sectional survey.
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From page 210... ...
Clinical trials in developing countries. Vol 1: Report and recommendations of the National Bioethics Advisory Commission.
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From page 211... ...
2009. Must research participants understand randomization?
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