Summary*

All pharmaceutical products have inherent risks, and their use involves trade-offs between their therapeutic benefits and their risks. However, the public has a limited understanding of the benefits and risks of drugs, and many individuals believe that drugs approved by the U.S. Food and Drug Administration (FDA) carry no risks. The FDA is responsible for evaluating and balancing the potential risks of drugs with their potential benefits. Assessing, managing, and communicating the benefit–risk profile of a pharmaceutical product is a complex and nuanced scientific, political, and sociological challenge. Once the assessment is made, the FDA is then responsible for managing how to communicate these risks and make healthcare decisions based on them.

To explore these issues, the Forum on Drug Discovery, Development, and Translation conducted a public workshop entitled Understanding the Benefits and Risks of Pharmaceuticals, with the broad goals of gaining a better understanding of the current system used to evaluate benefit and risk, and to identify opportunities for improvement. This workshop was held in Washington, D.C., on May 30–31, 2006.

The benefit–risk profiles of pharmaceuticals are constantly evolving as new data are collected throughout the life cycle of a drug. Discussions

*

The Forum’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteur as a factual summary of what occurred at the workshop.



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Understanding the Benefits and Risks of Pharmaceuticals: Workshop Summary Summary* All pharmaceutical products have inherent risks, and their use involves trade-offs between their therapeutic benefits and their risks. However, the public has a limited understanding of the benefits and risks of drugs, and many individuals believe that drugs approved by the U.S. Food and Drug Administration (FDA) carry no risks. The FDA is responsible for evaluating and balancing the potential risks of drugs with their potential benefits. Assessing, managing, and communicating the benefit–risk profile of a pharmaceutical product is a complex and nuanced scientific, political, and sociological challenge. Once the assessment is made, the FDA is then responsible for managing how to communicate these risks and make healthcare decisions based on them. To explore these issues, the Forum on Drug Discovery, Development, and Translation conducted a public workshop entitled Understanding the Benefits and Risks of Pharmaceuticals, with the broad goals of gaining a better understanding of the current system used to evaluate benefit and risk, and to identify opportunities for improvement. This workshop was held in Washington, D.C., on May 30–31, 2006. The benefit–risk profiles of pharmaceuticals are constantly evolving as new data are collected throughout the life cycle of a drug. Discussions * The Forum’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteur as a factual summary of what occurred at the workshop.

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Understanding the Benefits and Risks of Pharmaceuticals: Workshop Summary during the workshop focused on the following: (1) premarket assessment, during which clinical trial data are used to assess benefit and risk; (2) communication of that information to prescribing physicians and their patients; (3) healthcare decisions made by prescribing physicians and their patients; and (4) the accumulation of benefit–risk information from postmarketing experience, which feeds back into the other phases. PREMARKET ASSESSMENT Workshop participants identified several challenges that industry and the FDA must overcome as they make their premarket assessment of pharmaceutical benefit and risk: Lack of a systematic, consistent, and transparent approach to benefit–risk analysis; Uncertainty regarding how to balance risk and benefits; Insufficient knowledge about the risks of drugs at the time of their launch; Conflict of interest (for example, experts consult with industry and government on the same products) and involvement of stakeholders (for example, scientists, industry) in evaluating benefit and risk; Lack of involvement of prescribing physicians and the public in the FDA regulatory process; and Confusing and inconsistent terminology in benefit–risk assessment. As panelists considered how to construct a systematic, consistent, and transparent approach to benefit–risk analysis, discussion focused on whether and how such a framework should be quantitatively based. Creating a quantitative system has many challenges, including the following: Quantitatively capturing a complex drug benefit–risk profile; Quantitatively characterizing drug benefit–risk for individuals because of variation among patients in terms of both physiology and preferences; Updating benefit–risk assessments with new information through the drug life cycle; Addressing the inherent uncertainty in benefit–risk measurement; Resolving disagreement about the role that cost should play in benefit–risk calculations; Addressing the cost of adopting a quantitative framework and its potential adverse effect on innovation; and Effectively presenting and communicating quantitative information (see more below).

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Understanding the Benefits and Risks of Pharmaceuticals: Workshop Summary Participants discussed the pros and cons of using quality-adjusted life years (QALYs) as a systematic framework for integrating and evaluating the tremendous amount of complex information that must be sifted through in the process of evaluating safety. A proposal was also discussed to adopt a flexible regulatory approach for novel drugs for diseases with large unmet needs. Because safety issues for these drugs are less well-defined and liability risks are higher then usual, the requirements for clinical trials would be modified to include provisional approval for a limited launch to carefully defined physician and patient populations, along with explicit labeling with clear explanations of the known benefits and risks at the time of approval. For the FDA to use such an approach, legislative changes would be required. COMMUNICATION The difficulties associated with the communication of benefit and risk information to physicians and patients were discussed extensively. Most of this discussion focused on the challenges involved in physician-to-patient communication, with major challenges including the following: Widespread inability, even among well-educated patients, to interpret quantitative information provided about drug benefits and risks; Differences in how physicians and patients understand and respond to risk; Barriers that make it difficult for physicians to communicate with their patients; and Lack of confidence among physicians in their ability to effectively convey quantitative information, compounded by the reality that many physicians themselves are not as well informed as they should be about the benefits and risks of drugs. Discussion of how to improve communication included a review of recent research on labeling and several calls for the need to better understand the potential usefulness of new ways to visually represent benefit–risk data. The discussion focused on the use of the drug information by patients and clinicians in both product labels and advertising. A proposal for a Prescription Drug Facts Box, modeled after the Nutrition Facts Box for food products, was discussed. The transformation of drug labels currently under way at the FDA was also described.

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Understanding the Benefits and Risks of Pharmaceuticals: Workshop Summary HEALTHCARE DECISION MAKING An overarching theme of the workshop discussion was that the ultimate goal of improving benefit–risk assessment and communication is to enable “better” healthcare decision making. Rarely do ordinary individuals explicitly calculate benefit–risk trade-offs when making a decision. Most patients make on-the-spot, experiential decisions that are influenced by a complicated set of interacting factors that were described by the presenters, including the following: Patients’ inability to understand quantitative information (innumeracy); Patient assumptions about benefit and risk (for example, automatically associating high benefit with low risk); Whether or not the prescribing physician has voiced his or her opinion; How information on drug benefits and risks is presented to the patient; Nature of the patient’s condition; and Patients’ tolerance of uncertainty. Many contextual factors influence healthcare decision making; therefore improving the process is difficult. Many participants suggested that patient education regarding understanding pharmaceutical benefit and risk concepts was paramount, thus they should be more involved with the decision-making process. There was substantial debate on the FDA’s responsibility for guiding decision making. While some participants favored a more active FDA role in guiding decisions, others argued for an approach in which physicians and patients are given information with which to make their own, informed judgments. ACCUMULATION OF BENEFIT–RISK INFORMATION FROM POSTMARKETING EXPERIENCE At the time of approval, the benefit–risk profile of a typical drug is not fully understood. It is only after approval and widespread use that the profile will become fully understood. Ideally, this information would be used to update extant benefit–risk profiles. However, the limited capacity of the postmarketing surveillance system to acquire this information and use it to update the benefit–risk profiles of drugs on the market was documented and discussed extensively. Some workshop participants described the postmarketing safety data system as a “failure.” Major weaknesses in the current system, as identified during the meeting, included inadequate

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Understanding the Benefits and Risks of Pharmaceuticals: Workshop Summary data collection, methodological difficulties associated with detecting adverse drug events, and the lack of standardized approaches to coding and collecting data from multiple sources. While mining postmarketing information may generate better hypotheses about benefit and risk, some participants argued that this cannot replace controlled studies refining our understanding of drug benefits and risks over time. NEXT STEPS Several themes emerged from discussions at the workshop: It is important in pharmaceutical benefit–risk analysis to provide patients and physicians with the best possible information for making informed decisions about the use of pharmaceuticals. It is important to employ quantitative and standardized approaches when trying to evaluate pharmaceutical benefit–risk. These approaches should augment rather than replace current regulatory approaches to pharmaceutical approval and labeling. More work needs to be done to develop and validate such tools. It is important to educate patients and physicians about the concepts of pharmaceutical benefit–risk and how these are assessed throughout the life cycle of a drug. It is important to develop and validate improved tools for communicating pharmaceutical benefit–risk information to patients and physicians. It is important to involve patients and physicians in the development of new tools for evaluating and communicating data concerning pharmaceutical benefit–risk. It is important to improve the current system for collecting post-marketing safety and efficacy data on marketed pharmaceuticals. The workshop concluded with a discussion of possible next steps. There was general agreement that one or more pilot studies should be designed, in conjunction with the FDA, to address some of the suggestions discussed during the workshop, such as quantifying benefit–risk assessment through the use of QALYs and using a Prescription Drug Facts Box to better communicate drug information to patients and clinicians. Additional suggestions included developing a fact sheet to help educate the public about the benefits and risks of drugs, planning follow-up meetings to focus on specific issues, encouraging patient and community physician involvement in future discussions, incorporating costs in the discussion of benefit–risk analysis, and instituting citizen councils to involve the public in decisions made by the FDA regarding drug benefits

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Understanding the Benefits and Risks of Pharmaceuticals: Workshop Summary and risks. Individually, participants suggested the following initiatives for moving forward: Develop an eight- to ten-page bulleted summary of facts and assumptions about pharmaceutical risk and benefit that the IOM or the Forum could use to educate legislators and others. This could also be posted on the web for physicians and patients. Design one or more pilot studies with the FDA to address some of the suggestions and considerations voiced at this meeting—for example, a study on utility-based analysis of benefit–risk for either an existing drug or a drug that is under FDA consideration. A second pilot could test the utility of one or more new patient–physician communication tools such as the Prescription Drug Facts Box. Adopting an experimental attitude would be a way to move forward several of the specific initiatives suggested by meeting participants. Plan follow-up meetings that focus on specific problems. For example, one meeting could address novel approaches to postmarketing surveillance and the limits of the FDA’s Adverse Event Reporting System, another might compare different quantitative tools for evaluating drug benefit–risk, and a third might address risk management plans and whether and how they should be submitted at the time of a new drug application. Encourage patient and physician involvement in future discussions. Incorporate pharmaceutical pricing in the discussion of benefit– risk analysis because, at least for legislators, cost is a critical element of the discussion. Avoid assigning blame among the various stakeholders involved in benefit–risk assessment because it damages the public trust. Consider instituting citizen councils, as the United Kingdom’s National Institute for Clinical Excellence did when faced with a similar crisis in public trust. Decisions to be made by the FDA regarding benefit–risk assessment could be laid out for the councils, who would then be asked how they value the options. Not only would this tactic add legitimacy to the decisions being made, council members could become champions for those decisions—and “the state of the science”—in the larger community. Several participants suggested that there is a need for urgency in addressing these steps because of the imminent reauthorization of the Prescription Drug User Fee Act (PDUFA) and the possible enactment of other drug safety bills.