9
Looking to the Future

The final session of the symposium looked to the future. Panelists began by outlining three prerequisites for revitalizing the U.S. drug safety system: reauthorization of the Prescription Drug User Fee Act (PDUFA), thoughtful utilization of the FDA’s existing resources, and an emphasis on preserving patients’ trust in the drug safety regulatory system. This was followed by a summary of the symposium discussions on the future of drug safety regulation.

PREREQUISITES FOR REVITALIZING THE U.S. DRUG SAFETY SYSTEM

Reauthorization of PDUFA

PDUFA III is set to expire on September 30, 2007. As of this writing, Congress is deliberating the act’s reauthorization (PDUFA IV), and a vote is planned for sometime during the summer. If Congress does not pass this legislation before August, the FDA will have to initiate reductions in its workforce, many FDA staff will lose their jobs, and new drug reviews will likely come to a halt. Throughout the symposium, multiple panelists called for timely reauthorization of PDUFA. In her presentation, for example, Myrl Weinberg, President, National Health Council, stressed the urgent need for Congress to reauthorize PDUFA and increase appropriations to ensure that the FDA is adequately resourced to monitor drug safety. It is also important for Congress to support the FDA’s Critical Path



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Challenges for the FDA: The Future of Drug Safety - Workshop Summary 9 Looking to the Future The final session of the symposium looked to the future. Panelists began by outlining three prerequisites for revitalizing the U.S. drug safety system: reauthorization of the Prescription Drug User Fee Act (PDUFA), thoughtful utilization of the FDA’s existing resources, and an emphasis on preserving patients’ trust in the drug safety regulatory system. This was followed by a summary of the symposium discussions on the future of drug safety regulation. PREREQUISITES FOR REVITALIZING THE U.S. DRUG SAFETY SYSTEM Reauthorization of PDUFA PDUFA III is set to expire on September 30, 2007. As of this writing, Congress is deliberating the act’s reauthorization (PDUFA IV), and a vote is planned for sometime during the summer. If Congress does not pass this legislation before August, the FDA will have to initiate reductions in its workforce, many FDA staff will lose their jobs, and new drug reviews will likely come to a halt. Throughout the symposium, multiple panelists called for timely reauthorization of PDUFA. In her presentation, for example, Myrl Weinberg, President, National Health Council, stressed the urgent need for Congress to reauthorize PDUFA and increase appropriations to ensure that the FDA is adequately resourced to monitor drug safety. It is also important for Congress to support the FDA’s Critical Path

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Initiative so the agency can modernize the way in which the agency deals with new channels of scientific discovery. Dr. Franson likewise stated that reauthorization of PDUFA is absolutely vital. The FDA’s proposal for PDUFA IV includes programs and funding dedicated to measures aimed at increasing the regulation of postmarket drug safety. Ms. Pendergast stressed that if PDUFA IV is authorized, the resources dedicated to the FDA for drug safety must stay focused on drug safety. She explained how 5 years ago, during authorization of PDUFA III, the FDA received $71 million from industry to pay for large database studies and new drug safety reviewers. However, Congress rescinded much of that money and reprogrammed the small remainder elsewhere in the FDA. As a result, the Office of Drug Safety is no better off than it was 5 years ago. Thoughtful Utilization of Existing Resources Most of the panelists attributed some portion of the current drug safety problems and the FDA’s inability to initiate programs to improve the U.S. drug safety system to chronic underfunding and a lack of adequately trained personnel. However, some panelists suggested that the FDA needs to use its existing resources more wisely. Ms. Pendergast stated that the FDA has an obligation to be a steward of the money it receives and to spend that money wisely. Referring to the FDA-commissioned Breckenridge report (Breckenridge Institute, 2006), she remarked that, while the agency received a large sum of money ($25 million) to improve its information technology, it did not spent the money wisely, as the Adverse Event Reporting System (AERS) is no better today than it was many years ago. Dr. Franson suggested that, given the thousands of people throughout the pharmaceutical industry who are working on the same issues as the FDA, improving the U.S. drug safety system should be a process based on collaboration. The challenge is to coordinate these efforts in a way that will enable shared learning—particularly in precompetitive areas—and enable those involved to utilize resources more effectively by capitalizing on each other’s capabilities. If the current resources of the FDA, industry, and other stakeholders were inventoried, many complementary disciplines (e.g., epidemiology) and best practices would likely be identified. For example, with respect to using potential biomarkers to define risks and benefits in databases, it should be possible to collaborate with large health care organizations that routinely capture at least some of this information. According to Dr. Franson, the need for such coordination is a larger issue than the FDA’s inadequate resources.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Preserving Patients’ Trust in the Drug Safety Regulatory System Ellen Sigal, Chairperson, Friends of Cancer Research, and Ms. Weinberg both urged that the voice and views of patients be heard during the current reassessment of the U.S. drug safety system. Dr. Sigal emphasized that there is declining public trust in the FDA-led drug safety system and posited that the lack of public participation in the debate on how to improve the system may reinforce this lack of trust. She also expressed concern that a one-size-fits-all regulatory approach and excessive regulatory requirements would slow approval, increase drug prices, and discourage innovative product development, thereby making it more difficult for patients to gain access to much-needed drugs. Ms. Weinberg asserted that no drug is 100 percent safe, and that drug safety must be viewed within the context of a benefit–risk balance and consumer choice. She cited the case of a boy with epilepsy who benefits from a medication that carries a black box warning, illustrating how patients (or their parents) are willing to take risks “for just a shot at a normal life.” The National Health Council has formulated several key research-based findings that shed light on drug safety issues from the patient’s point of view: A patient’s assessment of risks and benefits is highly complex, involving both analytical and emotional factors (e.g., prior experience with a drug, severity of symptoms or condition, trust in doctors, credibility of outside information sources). Patients’ trust in the benefit–risk information they receive is critical to their willingness to take medications. People have incorrect assumptions about the benefit–risk correlation, usually believing that as benefit increases, risk decreases. In reality, the opposite may be true. It is unlikely that providing more detailed statistical information about risks in packaging or advertising is the best way to proceed. In fact, it is more likely that patients will pay less attention to the actual correlation. While patients are willing to take risks to improve their quality of life, they expect full disclosure about both risks and benefits so they can make informed decisions. Moreover, even patients who understand that no drug is completely safe are not always aware that the full risks cannot be known at the time of approval. Patients and the public need to understand that generally, detection of safety problems in premarket studies is limited to common adverse events occurring after a relatively short-term exposure and brief period of follow-up. These studies are not adequately powered to detect rare adverse events; therefore, postmarket surveillance is necessary to identify additional safety issues. Many patients fear restricted access to medications that carry risks but may nonetheless improve and/or prolong their lives, and they view

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary any limitations on their access to such drugs as a violation of their right to make personal health decisions with their physicians. Health care providers play a central role in patients’ understanding of the risks and benefits of medications, so it is critical that this bond between patient and provider be strengthened. In summary, Ms. Weinberg emphasized that, 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’ right to make informed decisions about drug use with their physicians. She asserted that the system needs to do a better job of putting the patient’s needs first. There must be a balance between access to drugs that help individuals lead independent, productive lives and attention to safety concerns, with the risks and benefits of prescription drugs being carefully weighed “in full public view.” THE FUTURE OF DRUG SAFETY REGULATION Dr. McClellan reflected on the many challenges to and opportunities for enhancing drug safety that had been discussed throughout the symposium. He also shared his thoughts on necessary next steps if the FDA is to be able to meet these challenges and exploit these opportunities. Significant progress has already been made since the IOM report was released in September 2006: The issue of drug safety is in the forefront of the American public’s awareness. The FDA made a formal point-by-point response to the IOM report (see Box 1-1 in Chapter 1 for highlights of the FDA’s response). That response included many new initiatives, some of which were discussed during the symposium. The strong attendance of FDA staff at the symposium illustrates the staff’s commitment to doing the best job possible with the available resources. All stakeholders (e.g., industry, consumer groups, patient advocates, medical and statistical experts) are engaged in and contributing to the debate. Some have even issued secondary reports on drug safety. Dr. McClellan emphasized the importance of taking immediate steps to build on this progress because of the forthcoming congressional action on the issue of drug safety in conjunction with the reauthorization of PDUFA. Because of its potential impact on the FDA’s activities related to drug safety, this upcoming action is the most significant legislative opportunity for the FDA in at least a decade.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Dr. McClellan identified five key issues around which much of the symposium discussion had revolved: The FDA’s limited resources and technical capabilities. The agency is regulating products representing 25 percent of the U.S. economy with a budget of under $2 billion, which amounts to a few cents per member of the population—far lower than the funding level of any other public health agency. This inadequate funding is compounded by the additional responsibilities the agency continues to accrue even as its budget remains the same. Operations and management, particularly with regard to changing the culture of the FDA and the way the agency is structured. The importance of improving information and communication about benefits and risks. Public–private collaboration—opportunities for stakeholders to work together to accomplish shared goals. The FDA’s regulatory authority. Dr. McClellan then summarized the discussions of pre- and postmarket components of the drug safety system that touched on these key issues. Premarket Enhancements Most of the discussion on enhancing premarket components of the drug safety system focused on two key concepts. First is the need to develop a better safety science that involves identifying biomarkers and other predictors of individual responses to drugs and characterizing individual differences in risk and benefit. Second is the idea that profiling and managing the risks and benefits of a drug should be a continuous learning process, one that employs a systematic life-cycle approach in which potential areas of concern requiring postmarket evaluation are identified during the premarket process. The view was widely expressed that there are at least two necessary next steps for achieving these goals: Provide the FDA with additional resources to support its Critical Path Initiative and related efforts aimed at improving drug safety. Currently, the agency has virtually no financial support in these areas. Change the culture of the FDA so it supports a continuous learning process and a life-cycle approach, and integrates perspectives from throughout the agency.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Postmarket Enhancements Most of the symposium discussions focused on the postmarket setting, including the need for better evidence on risks and benefits, for communication of information in a way that impacts clinical practice, and for greater clarity about postmarket regulation. Need for Better Evidence on Risks and Benefits Discussion of the gathering and analysis of benefit–risk information in the postmarket setting focused on the need for and advantages of adopting a broad population-based approach. Multiple speakers stated that the time has come to adopt a more population-based approach to determining safety signals. Such an approach could also provide more insight into how drugs are being used, both on and off label. A better infrastructure for understanding risks and safety signals and other aspects of drug utilization would enable more effective targeting of costly follow-up clinical studies. Several steps must be taken to develop a population-based approach, some of which the FDA has announced and others of which will require additional resources: FDA initiatives that have already been announced include enhanced tracking and follow-up of postmarket issues, planned improvements in AERS, and pilots of new postmarket drug-monitoring strategies. All of these steps are possible with existing funding and authority. There were repeated calls throughout the symposium for development of a federated public–private partnership to detect signals and support follow-up studies. It was asserted that with the proper funding and governance, such a partnership would provide better evidence at lower overall cost relative to multiple separate efforts. This partnership would also serve as a step toward a more complete electronic clinical database with greater interoperability, which would reduce the costs of follow-up clinical studies. Need for Better Communication of Information Discussion of the need to communicate information in a way that impacts clinical practice revolved around three major sets of needs. First is the need for increased transparency and clarity about FDA benefit– risk evaluation processes and regulatory conclusions. Second is the need for more comprehensive and useful information on clinical trials, made publicly available through the registration of trials and the reporting of results. Finally, information about risks and benefits needs to be communicated more effectively to both patients and physicians so they can make

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary more informed treatment choices. Several steps will be required to meet these needs, some of which the FDA has announced and others of which will require additional resources: The FDA has announced efforts to provide transparency in the review and advisory committee processes. While there have been some legislative proposals for reporting of clinical trials on ClinicalTrials.gov and elsewhere, more resources are required to meet this need. The FDA has outlined a number of steps toward providing time-lier and clearer updates on the latest safety-related evidence. However, patients do not always get their information from product labels or mainstream medical literature. Thus it is necessary to take a new look at how people access information on the risks and benefits of drugs, for example, by sharing information on blogs. Need for Clarity About Postmarket Regulation Discussion of postmarket regulation focused on two key concepts. First, the IOM report urged more clarity and the development of “graded” tools for evaluating benefit–risk profiles, including new enforcement steps that would lie somewhere between the exercise of the agency’s leverage and the removal of drugs from the market. Special attention was directed at the way new drugs are marketed and distinguished in the minds of clinicians and the public. At the same time, however, serious concern was expressed about this recommendation and whether the proposed regulatory authority would really respond appropriately and efficiently to the types of issues (e.g., the case of Vioxx) that have led the system to its present state. Two major steps currently being taken address this need: The FDA is taking the administrative actions necessary to evaluate the Risk Minimization Action Plan (RiskMAP) strategy on a pilot basis and does not anticipate that implementing this strategy would require additional authority beyond the usual monitoring performed by the agency. Congress is in the midst of a legislative debate on this topic, and further legislative action is likely that will provide the FDA with more powerful tools encompassing additional enforcement responses. Dr. McClellan emphasized the importance of bringing the best ideas to light to help guide that legislative process.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Conclusion In concluding, Dr. McClellan emphasized the following points: The FDA needs additional resources and technical capabilities to achieve the goals of the IOM recommendations. While additional regulatory authority, organizational change, and better information are necessary, they are not sufficient and will in fact require yet more resources, including personnel and expertise. A great deal is already being spent on safety in the health care system, and still more will be spent with the reauthorization of PDUFA and the passage of pending drug safety legislation. Additionally, health plans are investing considerably in systems for identifying how drugs are being used and with what consequences. Taking a more collaborative approach to addressing safety issues through public–private partnerships particularly in the conduct of postmarket surveillance would be much more cost-effective than the current piecemeal approach. There are a number of other opportunities for such public–private collaboration to achieve consensus on how to move forward. These include improving safety science; developing better postmarket evidence on the risks and the actual use of drugs; developing more individualized and effective benefit–risk communications; assessing the development and use of new regulatory tools; and ultimately, continuing to improve the regulatory system while avoiding unnecessary costs and delays in access, creating a health care system that delivers the best possible treatment to each patient.