Ethical and Scientific Issues in Studying the Safety of Approved Drugs (2012) / Chapter Skim
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1 Introduction
1 Introduction
Pages 29-60
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From page 29... ...
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.
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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.
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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?
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; 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.
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From page 33... ...
. 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)
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From page 34... ...
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)
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. second authority to require postmarketing studies for approved drugs through the deferred-submission policy under the Pediatric Research Equity Act (PREA)
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. Under this act, for the first time some user fees were allocated to postmarketing safety– related activities, for example, to support postmarketing surveillance of alreadyapproved drugs and to allow risk-management oversight of newly approved drugs (2–3 years after approval)
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From page 37... ...
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)
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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 discussion of the committee's terminology for postmarketing studies) , provided FDA with the authority to require a risk evaluation and mitigation strategy (REMS)
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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)
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. • Clinical trials with a safety endpoint evaluated with prespecified " assessments and adequately powered to analyze the serious risk.
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. • Studies and clinical trials conducted with vaccines, such as sur " veillance and observational pharmacoepidemiologic studies when data do not suggest a serious risk or signals of serious risk related to the use of the vaccine and when available data do not indicate the potential for serious risk", including studies to "evaluate long term effectiveness or duration of response.
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. Risk Evaluation and Mitigation Strategies As discussed above, PDUFA III in 2002 allowed drug sponsors to provide a RiskMAP for products that posed serious risks that outweighed their benefits when specific precautions could be implemented that would result in a favorable benefit–risk profile.
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A medication guideb and, if helpful to mitigate a serious risk posed by the drug, a patient package insert.
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Sentinel will be an active surveillance system and will complement the existing mandatory and voluntary reporting systems that FDA already has in place to track reports of adverse events linked to use of its regulated products. Sentinel will enable FDA to actively query diverse automated health care data holders -- such as electronic health-record systems, administrative and insurance-claims data bases, and registries -- and to obtain the results of specific queries rapidly and securely (FDA, 2008)
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Consequently, an internal Manual of Policies and Procedures was developed 44 "A significant safety issue for purposes of this memorandum of agreement is a safety issue that has the potential to lead to, for example: withdrawal of an approved drug from the market; withdrawal of an approved indication; limitations on a use in a specific population or subpopulation in the postmarketing setting; changes to the warnings, precautions, or contraindication sections of the labeling (including the addition of a boxed warning to the label) ; the establishment of, or changes to, the proprietary name/container label/labeling/packaging to reduce the likelihood of medication errors; the establishment or modification of a risk evaluation and mitigation strategy (REMS)
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From page 46... ...
. FDAAA gave FDA expanded authorities and additional regulatory tools, such as the ability to require changes in a product label or to require the conduct of clinical trials or other studies in the postmarketing setting, all of which enable FDA to protect the health of the public better.
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In the case of rosiglitazone, FDA had to evaluate results from numerous studies, including clinical trials that used a variety of regimens, comparators, outcomes and dosing, and meta-analyses of data from these trials, and observational studies using administrative and outcomes data. • How should FDA's response to concerns about the safety of an approved drug be affected by the existence of a similar drug that is approved for the same indication?
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. Major questions about the safety of rosiglitazone arose after a meta-analysis of the results of clinical trials showed an increased risk of cardiovascular events in people who took rosiglitazone (odds ratio [OR]
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id=bcf5aef6-9bc5-45ca-9cab-aadf5df135fa. c FDA required the drug sponsor to issue a risk evaluation and mitigation strategy according to which "the drug will be available to patients not already taking it only if they are unable to achieve glycemic control using other medications and, in consultation with their health care professional, decide not to take pioglitazone [a diabetes medication in the same class of drugs]
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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 present report.
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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)
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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.
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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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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.
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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 analytic 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.
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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.
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2006. National surveillance of emergency department visits for outpatient adverse drug events.
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2011c. Guidance for industry postmarketing studies and clinical trials -- implementation of section 505(o)
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2007a. The future of drug safety: Promoting and protecting the health of the public.
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1998. Making medicines safer -- the need for an indepen dent drug safety board.
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