Summary1

As the principal agency regulating food, drugs, medical devices, and biological products used by Americans, the U.S. Food and Drug Administration (FDA) serves one of the most critical consumer protection functions of the federal government. The FDA’s reach is enormous, regulating products that represent roughly 25 percent of all consumer spending in the United States (Coalition for a Stronger FDA, 2007).

Since 1992, however, federal funding for the agency has diminished, and the FDA’s Center for Drug Evaluation and Research (CDER) currently relies on the fees it receives from the industry it regulates to fund the majority of its drug regulation functions. Prescription drug safety is receiving heightened press coverage and congressional scrutiny as a result of recent, highly publicized events, such as the recall of Vioxx because of its link to heart attacks, and the link between certain antidepressants (selective serotonin reuptake inhibitors, or SSRIs) and an increased risk of suicidal ideation in children. There is growing public concern about the ability of the current drug safety system to prevent future Vioxx-like events.

To address these concerns, the FDA in 2005 commissioned the Institute of Medicine (IOM) to conduct an independent assessment of the current U.S. drug safety system. In September 2006, the IOM committee

1

The Forum’s role was limited to planning the workshop. This report was prepared by the workshop rapporteurs as a factual summary of the presentations and discussions.



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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Summary1 As the principal agency regulating food, drugs, medical devices, and biological products used by Americans, the U.S. Food and Drug Administration (FDA) serves one of the most critical consumer protection functions of the federal government. The FDA’s reach is enormous, regulating products that represent roughly 25 percent of all consumer spending in the United States (Coalition for a Stronger FDA, 2007). Since 1992, however, federal funding for the agency has diminished, and the FDA’s Center for Drug Evaluation and Research (CDER) currently relies on the fees it receives from the industry it regulates to fund the majority of its drug regulation functions. Prescription drug safety is receiving heightened press coverage and congressional scrutiny as a result of recent, highly publicized events, such as the recall of Vioxx because of its link to heart attacks, and the link between certain antidepressants (selective serotonin reuptake inhibitors, or SSRIs) and an increased risk of suicidal ideation in children. There is growing public concern about the ability of the current drug safety system to prevent future Vioxx-like events. To address these concerns, the FDA in 2005 commissioned the Institute of Medicine (IOM) to conduct an independent assessment of the current U.S. drug safety system. In September 2006, the IOM committee 1 The Forum’s role was limited to planning the workshop. This report was prepared by the workshop rapporteurs as a factual summary of the presentations and discussions.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary released its report—The Future of Drug Safety: Promoting and Protecting the Health of the Public—which included 25 recommendations for improving the system for drug safety review. The committee identified four major vulnerabilities in the U.S. drug safety system: (1) chronic underfunding; (2) organization problems, particularly inadequate integration of pre-and postmarket data review; (3) a range of technical problems related to the insufficient quantity and quality of postmarket data and inadequate capability to systematically monitor the risks and benefits of drugs after marketing; and (4) unclear regulatory authority and insufficiently flexible regulatory tools (IOM, 2007a). Since the IOM report was issued, the FDA has taken a number of steps toward implementing the recommended improvements. Like many government agencies, however, the FDA is financially strained by its existing responsibilities, and fully implementing the recommended improvements to the drug safety system would require significant financial commitments. The IOM report addressed some of the costs associated with its recommendations, but left many unanswered questions about the resources required to fully achieve the envisioned improvements. Without substantial increases in agency funding, making the recommended improvements in the agency’s ability to identify safety problems in new drugs, monitor routinely submitted safety data, and relay that information to the public would require the diversion of funds from other mission-critical areas. To better understand the types and magnitude of resources required to achieve the goals of the IOM report, the IOM’s Forum on Drug Discovery, Development, and Translation convened a 1-day symposium in March 2007. The symposium’s presentations and discussions were in most cases framed by selected recommendations from the report, and are summarized here in seven key areas: addressing the FDA’s resource challenges; strengthening the scientific base of the agency; integrating pre- and postmarket review; enhancing postmarket safety monitoring; conducting confirmatory drug safety and efficacy studies; enhancing the value of clinical trial registration; and enhancing the FDA’s postmarket regulation and enforcement. The presentations and discussions included the types and magnitude of resources required in these areas. A session at the close of the symposium looked to the future, exploring prerequisites for revitalizing the U.S. drug safety system and the future of drug safety regulation. It should be noted that, while the IOM report suggested some organizational and cultural changes at the FDA, those recommendations were not a focus of the dis-

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary cussions during the symposium. Additionally, participants did not deliberate upon whether the FDA in its current form is properly configured to lead the efforts that were discussed. ADDRESSING THE FDA’S RESOURCE CHALLENGES A central theme of the symposium was that many of the weaknesses of the national system for drug safety stem from a lack of resources. Since the passage of the Prescription Drug User Fee Act (PDUFA) in 1992, funding for the FDA has increasingly shifted from appropriations to user fees, which, until PDUFA III was authorized in 2002, could not be used for postmarket safety activities. Despite the dedication of monies for postmarket safety activities in PDUFA III, Congress rescinded much of that funding and reprogrammed the remainder elsewhere in the agency. Since 1992, the FDA has doubled the number of staff performing new drug reviews from approximately 1,300 to 2,600. Yet congressional appropriations paid for only 11 of those 1,300 additional staff; the remainder were funded by PDUFA. Further, over the last 10 years the FDA has lost some 1,000 staffers from the food, drug, and medical device safety programs not supported by PDUFA fees. User fees now represent more than 50 percent of the drug regulation budget, and some expect that PDUFA IV legislation may increase that figure to 80 percent or more. Alta Charo, University of Wisconsin–Madison, and member of the IOM Drug Safety Committee, stressed that, although the FDA regulates an extraordinary proportion of the products on the American market, it operates with a budget that is not commensurate with this broad regulatory authority. She noted that the committee responsible for the IOM report highlighted its consensus conclusion that more public funding is needed for the FDA, specifically more general appropriations. The Coalition for a Stronger FDA, a group of consumer, patient, industry, and nonprofit groups, has recommended a total increase of $175 million in appropriations for 2008 (over the fiscal year 2007 budget and over PDUFA IV increases).2 STRENGTHENING THE SCIENTIFIC BASE OF THE AGENCY The committee that authored the IOM report was charged with reviewing the U.S. drug safety system and providing recommendations for how to improve it. While the majority of the report’s recommendations focus on postmarket safety, there are opportunities to improve safety 2 In light of recent events regarding food safety, the Coalition for a Stronger FDA has begun advocating for a $310 million increase in appropriations for 2008 rather than the $175 million previously called for.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary throughout the drug development pathway. Gaining a better understanding of the safety profile of a drug and being able to discriminate more precisely among drugs within the same class before clinical testing begins would strengthen the drug safety system before a drug ever reaches the market. A primary goal of the FDA’s Critical Path Initiative is to increase the efficiency of the drug development process by building safety into products throughout their development life cycle. Panelists at the symposium described a broad spectrum of urgent safety science research needs and indicated that because the FDA is limited in its ability to conduct such research, one of its primary goals must be to collaborate with industry and academia to form public–private partnerships. Formation of these partnerships is important because by nature, this type of research requires access to people and resources outside the FDA. Given the agency’s unique role, panelists encouraged the FDA to promote collaboration among stakeholders in the research and development of publicly available scientific methodologies and technical tools that all stakeholders could use to design safer and more effective products more efficiently. Garret FitzGerald, University of Pennsylvania, characterized FDA–industry partnerships as a necessary component of an improved drug safety system. He argued that an enhanced training ground is needed to develop a workforce of scientists with an integrative understanding of drug safety evaluation, and he proposed a Jet Propulsion Laboratory–style public–private partnership to fund this critical training. INTEGRATING PRE- AND POSTMARKET SAFETY REVIEW A major focus of the symposium was the integration of pre- and postmarket review. There are fundamental differences in the way data are collected and analyzed in the pre- and postmarket environments. Premarket data are generally collected from focused, randomized controlled pre-clinical studies and clinical trials, whereas postmarket data are collected from a broader array of sources, including controlled and uncontrolled observational studies. Integration of the two datasets is difficult, and there have been reported tensions between reviewers in the FDA’s Office of New Drugs (OND) and Office of Surveillance and Epidemiology (OSE). Discussion of the integration of pre- and postmarket review was framed by IOM recommendations calling for joint authority of OND and OSE for postapproval regulatory decisions; timely review of Risk Minimization Action Plans (RiskMAPs); establishment of a systematic approach to benefit–risk analysis;

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary systematic review and publicizing of all postmarket study results; and evaluation of all data on new molecular entities within 5 years following approval. Panelists asserted that providing increased training opportunities for epidemiologists and clinical reviewers would help create a workforce capable of overcoming some of the scientific challenges to implementing the IOM recommendations. Additionally, panelists considered ways of developing better methods for data capture through sharing of best practices, one of many potential collaborative efforts discussed throughout the day. ENHANCING POSTMARKET SAFETY MONITORING A conclusion of the IOM report was that the FDA’s current postmarket surveillance system is neither as comprehensive nor as systematic as it needs to be to detect, interpret, and analyze safety signals effectively and efficiently. The current system for monitoring adverse events—the Adverse Event Reporting System (AERS)—is passive, with reports being submitted voluntarily by patients and physicians. While this passive surveillance system may be capable of detecting rare serious adverse events, it has several limitations, including underreporting, biased reporting, and difficulties in attributing an adverse event to a specific drug. Additionally, when analyzing postmarket epidemiological data collected through passive surveillance, it is difficult to know accurately how many people have taken a drug (i.e., to determine a denominator) and therefore to conclude the rate at which an event would take place. Multiple panelists discussed how rejuvenating the passive surveillance system and augmenting it with an active system would be a feasible next step toward a stronger and more effective drug safety system. Several panelists suggested establishing a public–private partnership comprising various federal agencies, pharmaceutical and biotechnology companies, and health care organizations to create an integrated health care claims database. This database would be enhanced and linked with other databases, including full-text medical records, pharmacy claims data, physician and facility claims data, laboratory test results data, and demographic and other consumer information. It was speculated that such a system, including data from 100 million persons and capable of being accessed in real time and in a web-based, interactive manner, would help detect future drug safety signals much more rapidly (within months rather than years) than is possible with the current system.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary CONDUCTING CONFIRMATORY DRUG SAFETY AND EFFICACY STUDIES The IOM report noted that the FDA is limited in its ability to conduct the larger studies sometimes necessary to follow up on signals and reduce uncertainty associated with the benefit–risk balance of approved drugs. Accordingly, the report recommended the development of public–private partnerships to prioritize, plan, and fund confirmatory drug safety and efficacy studies. The ideas expressed during this session dovetailed with those put forth in the previous session, as summarized above, supporting the necessity of and readiness for a public–private collaborative effort to improve postmarket safety and efficacy monitoring. Whereas the focus of the previous session was on the capacity of a linked public–private surveillance system to improve the detection of safety signals, panelists went a step further during this session by considering the potential of such a system to be used not just for detection, but also as a tool for addressing the broad spectrum of safety science research questions that arise over the course of a drug’s lifetime. A collaborative effort to this end would be more cost-effective than multiple isolated efforts, as presenters in the previous session emphasized with regard to detection. It would give researchers access to a larger volume of information resources, and it would generate information of value to multiple stakeholders. ENHANCING THE VALUE OF CLINICAL TRIAL REGISTRATION Since the International Committee of Medical Journal Editors began requiring registration of trials in a public trials registry as a condition of consideration for publication, the number of trials registered in Clinical-Trials.gov has increased. Nevertheless, the value and the transparency of the system are not optimal. To address the weaknesses of the current system, the IOM report recommended enhancing clinical trial registration. Four components of the IOM recommendation can be identified. The first is an expanded scope of mandatory trial registration. It was suggested that the system could readily handle an increase in the number of trials registered without requiring a significant budget increase. Second is the addition of a results database—a complex task that would cost an estimated $10–20 million annually. The third component of the recommendation—scientific review—would involve reviewing 40–200 trials weekly, with each review consisting of complex analyses and the gathering of other information. It is unclear who would be able to carry out these reviews or what the cost would be. The same can be said of the final component—monitoring and enforcement.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary ENHANCING POSTMARKET REGULATION AND ENFORCEMENT Once a drug has been approved by the FDA for marketing, the agency’s authority over the drug and the manufacturer changes markedly. Prior to approval, the FDA has complete control over when and by whom the drug can be used, how it can be discussed, and how it is manufactured. After approval, if the FDA finds problems in the way a product is manufactured or marketed or if it becomes aware of safety concerns, it has two options: withdraw approval of the drug, or try to persuade the manufacturer to comply with the agency’s requests. The IOM report called for clarifying and enhancing existing authority to regulate marketed drugs and for developing sufficient enforcement tools to ensure that regulatory requirements imposed at or after approval will be fulfilled. Some symposium panelists argued that additional resources, not new legal authorities, are the principal need, while others argued that enhanced FDA authority and enforcement are critical to success. LOOKING TO THE FUTURE In looking to the future, panelists began by outlining three prerequisites for revitalizing the U.S. drug safety system: reauthorization of PDUFA, thoughtful utilization of the FDA’s existing resources, and an emphasis on preserving patients’ trust in the drug safety regulatory system. Multiple panelists called for timely reauthorization of PDUFA; should this not occur, the FDA will be forced to cut staff, and new drug reviews will largely come to a halt. Thoughtful use of existing resources—for example, through enhanced coordination and increased collaboration—was suggested as a complement to the emphasis throughout the symposium on the FDA’s need for additional resources. Finally, panelists stressed that the voice and views of patients must be heard during the current reassessment of the U.S. drug safety system. Whatever steps are taken to improve drug safety, it is critical that those actions not restrict access to appropriate medications or otherwise interfere with patients’ rights to make informed decisions about drug use with their doctors, and that the risks and benefits of drugs be carefully weighed “in full public view.” With regard to the future of drug safety regulation, it is essential to take immediate steps to capitalize on the significant progress made since the release of the IOM report, especially in light of the opportunity represented by the anticipated reauthorization of PDUFA. The session closed with a summary of five key issues around which much of the symposium discussion revolved, and which can inform the next steps to be taken: (1) the FDA’s limited resources and technical capabilities; (2) operations and management, particularly with regard to changing the FDA’s culture and

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary the way the agency is structured; (3) the importance of improving information and communication about benefits and risks; (4) public–private collaboration so stakeholders can work together to accomplish shared goals; and (5) the agency’s regulatory authority.