1
Introduction

“… [A]lmost every morning’s newspaper and each evening’s television news-casts include a new and more disturbing episode of pharmacological crisis and medical mayhem in the United States” (Markel, 2005).


“… FDA has become synonymous with drug safety. In a sense, ‘FDA approved’ is the brand that the entire $216 billion US drug market is founded upon. Dilute the confidence of the public in the agency, and many billions of dollars in current and potential sales vanish overnight. That’s exactly what’s happening right now in the wake of the biggest drug withdrawal ever” (Herper, 2005).


The recent highly publicized controversies surrounding the safety of some drugs have contributed to a public perception that the drug safety system is in crisis. It seems fair to say that this perception has created an opportunity for a thorough evaluation of the US drug safety system. News media coverage and congressional examination of the Center for Drug Evaluation and Research’s (CDER’s) handling of safety concerns have raised questions about the review and approval process and whether it has become so accelerated that adequate attention may not be given to safety, and about the completeness and timeliness of risk communication to the public. Questions also surfaced about the independence of the scientific expertise relied on by the Food and Drug Administration (FDA) (conflict of interest in its advisory committees) and about the possibility of undue industry influence related to CDER’s increasing dependence on Prescription Drug User Fee Act (PDUFA) funding. It would be easy to conclude that FDA’s most recent troubles are just a reflection of the swinging of the pendulum from tighter to looser regulation and back again (Applebaum, 2005; Geraghty, 2006). The committee believes that the reality is more complicated than that. The committee did not attempt to document whether or not a drug safety crisis exists, and this report should not be interpreted as commenting on that claim one way or the other. The committee also did not set out to—nor was it asked to—conduct in-depth reviews of the industry and the agency’s handling of safety information and data for drugs with potential safety problems. Instead, the committee examined the existing drug safety system



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The Future of Drug Safety: Promoting and Protecting the Health of the Public 1 Introduction “… [A]lmost every morning’s newspaper and each evening’s television news-casts include a new and more disturbing episode of pharmacological crisis and medical mayhem in the United States” (Markel, 2005). “… FDA has become synonymous with drug safety. In a sense, ‘FDA approved’ is the brand that the entire $216 billion US drug market is founded upon. Dilute the confidence of the public in the agency, and many billions of dollars in current and potential sales vanish overnight. That’s exactly what’s happening right now in the wake of the biggest drug withdrawal ever” (Herper, 2005). The recent highly publicized controversies surrounding the safety of some drugs have contributed to a public perception that the drug safety system is in crisis. It seems fair to say that this perception has created an opportunity for a thorough evaluation of the US drug safety system. News media coverage and congressional examination of the Center for Drug Evaluation and Research’s (CDER’s) handling of safety concerns have raised questions about the review and approval process and whether it has become so accelerated that adequate attention may not be given to safety, and about the completeness and timeliness of risk communication to the public. Questions also surfaced about the independence of the scientific expertise relied on by the Food and Drug Administration (FDA) (conflict of interest in its advisory committees) and about the possibility of undue industry influence related to CDER’s increasing dependence on Prescription Drug User Fee Act (PDUFA) funding. It would be easy to conclude that FDA’s most recent troubles are just a reflection of the swinging of the pendulum from tighter to looser regulation and back again (Applebaum, 2005; Geraghty, 2006). The committee believes that the reality is more complicated than that. The committee did not attempt to document whether or not a drug safety crisis exists, and this report should not be interpreted as commenting on that claim one way or the other. The committee also did not set out to—nor was it asked to—conduct in-depth reviews of the industry and the agency’s handling of safety information and data for drugs with potential safety problems. Instead, the committee examined the existing drug safety system

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The Future of Drug Safety: Promoting and Protecting the Health of the Public with a view to identify areas of vulnerability and facets of the system that could be strengthened in order to improve its overall functioning in meeting the needs of the American public. Complaints about delayed patient access to drugs already approved in other countries and the AIDS advocacy movement of the 1980s are considered among the major factors that motivated legislative action to speed up FDA’s drug approval process. However, criticism of the pace of drug approval may be traced to the early 1970s. At that time, pharmaceutical companies, scientists, and consumer organizations argued that the 1962 Drug Amendments to the Food, Drug, and Cosmetic Act, intended to strengthen the drug approval process by requiring that sponsors demonstrate efficacy, also stifled drug development and delayed drug approval (DHEW, 1977). In the 1990s, FDA attributed the delays to shortages of staff and computers (FDA, 2005b). Concern about the slow pace of drug review finally led to PDUFA. The enactment of PDUFA in 1992 resulted from a potent combination of interests. Patient advocacy groups called for faster access to promising therapies, the industry desired a more efficient regulatory process to enable faster marketing of new drugs and a longer patent life, FDA needed more resources to expand its review staff to meet demand for greater regulatory expediency, and some members of Congress were concerned that new drug approvals in the United States lagged behind those of comparable European nations. With congressional oversight and input, PDUFA was enacted with the goal of meeting the needs of FDA, industry, and patients. Although the 1992 PDUFA succeeded greatly in decreasing review times (FDA, 2005b), its first two iterations (PDUFA I in 1992 and PDUFA II in 1997, see below) specifically prohibited the use of fees for any postmarketing drug safety activities. Also, the speeding up of the review process highlighted potential weaknesses and limited capability in the area of postmarketing safety. By the latter part of the 1990s, various observers, including consumer groups and researchers, became concerned that the increased pace of drug approvals had unintentionally led to a neglect of—or at least insufficient attention to—safety considerations, resulting in what was seen as a greater rate of drug withdrawals (Lurie and Wolfe, 1988; Hart, 1999; Tone, 1999). Numerous journal editorials and articles by scientists, consumer advocates, and agency leadership continued the dialogue (Kleinke and Gottlieb, 1998; Wood et al., 1998; Friedman et al., 1999; Landow, 1999; Lurie and Sasich, 1999). In response to mounting unease, FDA Commissioner Jane Henney convened “a Task Force to evaluate the system for managing the risks of FDA-approved medical products” (DHHS/FDA, May 1999). Although the task force found that rates of withdrawals were low (the limitations of treating withdrawals as a safety metric are discussed below), the group identified process, resource, and statutory constraints on FDA’s ability to

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The Future of Drug Safety: Promoting and Protecting the Health of the Public identify adverse events and made a series of substantive recommendations to strengthen risk management. Some of the recommendations of the task force have been implemented, including the convening of public meetings to solicit input on drug safety and risk management from various constituencies. Drug safety concerns have continued to emerge, as have the proposals to address them. Alosetron was withdrawn and then returned to market with restrictions and a label warning. Troglitazone, propulsid, cerivastatin, rofecoxib, and valdecoxib have been withdrawn. Celecoxib and other non-selective non-steroidal anti-inflammatory drugs had boxed warnings added to their labels. Warnings have been added to all antidepressant labels. FDA’s performance in approving drugs or monitoring their safety after approval has been questioned and criticized. Several major factors converged to create at the least the appearance of a crisis in drug safety, among them, CDER’s limited resources, organizational and management challenges, seemingly long reaction times, poor external communication, questions about external influences on CDER’s decision making, an ever more diverse information environment (news media, the Internet and the blogosphere, and advertising) coupled with increasing consumer awareness and engagement, and growing congressional concern. The Committee on the Assessment of the US Drug Safety System believes that as more drugs are being approved faster with less time to intensively investigate premarketing safety data, FDA does not have adequate resources or procedures for translating preapproval safety signals into effective postmarketing studies, for monitoring and ascertaining the safety of new marketed drugs, for responding promptly to the safety problems that are discovered after marketing approval, and for quickly and effectively communicating appropriate risk information to the public. The committee is aware of promising components of the current drug safety efforts at CDER and of agency improvement initiatives (see Appendix A), but it believes that neither the agency’s newly enhanced postmarketing safety initiatives nor the necessary contributions of other actors in the US drug safety system are equal to the task. Major obstacles remain. They include inadequate resources, the complexity of the science and technology involved in drug development and regulation (e.g., assessing risk and benefit), a dysfunctional organizational culture, problems with credibility and public trust, and the lack of adequate communication about and limited public awareness of drug risks and benefits. The credibility of FDA, the industry, the academic research enterprise, and health care providers has become seriously diminished in recent years (Kaiser Family Foundation, 2005; Wall Street Journal and Harris Interactive, 2005). FDA’s reputation has been hurt by a perceived lack of transparency and accountability to the public, a legacy of organizational changes that have not been completed or sustained, and an apparent slowness in

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The Future of Drug Safety: Promoting and Protecting the Health of the Public addressing lack of sponsor compliance (US House of Representatives Committee on Government Reform Minority Staff, 2006). The industry’s once sterling reputation has been blemished by reported compliance problems, delays in responding to safety concerns and complying with postmarketing commitments, highly publicized concerns about the effects of direct-to-consumer advertising, and the preponderance of “me-too” products, rather than truly pioneering therapies (PricewaterhouseCoopers Health Research Institute, 2005; Wall Street Journal and Harris Interactive, 2005). The integrity of the academic research enterprise has also been questioned, as universities and scientists are increasingly dependent on industry funding for their work. The behavior of prescribers, the gatekeepers for patient access to prescription drugs, are also under public and congressional scrutiny, as health care providers receive intense and targeted promotional (“detailing”) efforts of pharmaceutical companies. Of particular concern are the common but inaccurate perceptions that FDA approval represents a guarantee of safety, that approval is based on a high degree of clarity and certainty about a drug’s risks and benefits, and that such safety actions as boxed warnings on drug labels and withdrawals reflect sponsor or agency failures. Addressing weaknesses and missed opportunities in the drug safety system requires some fundamental changes in the organizational culture of CDER to support effective action on drug safety (Chapter 3), in the scientific approaches to drug safety (Chapter 4), in the regulations pertinent to drug safety (Chapter 5), in communication about drug safety (Chapter 6), and in the agency’s funding structure (which currently leaves critical regulatory and public health functions inadequately resourced) (Chapter 7). Some of the recommendations offered in this report echo proposals made over the last two decades by various groups convened by the agency or by the Department of Health and Human Services (DHHS) (DHEW Review Panel on New Drug Regulation, 1977; Joint Commission on Prescription Drug Use, 1980; DHHS/FDA, 1999). It is puzzling and troubling that despite this series of reviews and recommendations, some have not been fully implemented and some issues have resurfaced repeatedly. A primary obstacle, the committee suspects, may be the chronic underfunding of core FDA activities owing to inadequate attention to resource needs by Congress and by the Office of Management and Budget. The committee asserts that the piecemeal organizational modifications and short-lived programmatic initiatives of the past and the current, seemingly fragmented and reactive initiatives to improve CDER are not sufficient to meet the need to improve postmarket drug safety activities and protect the public health better. The present report endeavors to provide an integrative approach to transforming drug safety in FDA and in the agency’s interactions with other stakeholders

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The Future of Drug Safety: Promoting and Protecting the Health of the Public in five major areas: organizational culture and leadership, science, regulatory authority, communication, and the funding without which improvements in these areas would not be possible. No one in FDA, industry, or academic research enterprise would disagree with the importance of implementing a lifecycle approach to the assessment of drug risks and benefits. Nevertheless, a great deal of separation persists between premarket and postmarket activities and functions. The separation, both structural and cultural, is reinforced by user-fee funding that is predominantly devoted to premarket activities and funding from appropriations that has not kept up with need in vital areas of the agency’s work, by regulatory authority that is stronger and clearer preapproval, and by data requirements that are more structured and intensive for approval than for the postmarketing period (see Chapter 3) (DHEW Review Panel on New Drug Regulation, 1977; FDA, 2005b). The year 2006 is a good time for thoughtful attention to transforming the drug safety system to address existing areas of vulnerability, and to prepare for the challenges and opportunities of the future. In this year of FDA’s centennial,1 public attention to drug safety matters has reached a high point, negotiations in advance of the September 2007 sunset of PDUFA have begun, Medicare Part D has enrolled tens of millions of senior citizens in a system that is expected to yield a wealth of population data about experience with drugs, new research promises further progress against illness (including more targeted therapies), and congressional interest in drug safety is intense. Those are but some of the factors that make this a moment of opportunity to renew and transform CDER, to enable it to function more effectively and to position itself for a far more complex future. Changes in the Broad Context of Drug Regulation Prescription drug development, regulation, and use have changed greatly since the 1962 drug amendments and continue to evolve. The scientific and demographic changes of the future will present challenges and opportunities for drug development and regulation. The promise of personalized medicine shimmers on the horizon, but considerable work remains to identify candidate measures, validate them, and show that their use in a clinical setting improves health outcomes, reduces costs, or both. The population of the United States is aging and requires more therapeutics for prevention and treatment for the chronic diseases associated with older people. Increasing ethnic and cultural diversity will require better under- 1 The year 2006 is technically the centennial of the 1906 Pure Food and Drug Act, but the FDA asserts that “the modern era of the FDA dates to 1906 with the passage of the Federal Food and Drugs Act” (CDER, 1998).

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The Future of Drug Safety: Promoting and Protecting the Health of the Public standing of disparities in health status and the development of appropriate means of communicating useful therapeutic and health care information to heterogeneous populations. The science and technology that underpin drug discovery are in a process of dramatic transformation. Advances in the basic sciences have increased the number of targeted drugs, and technological advances promise to transform and expand the array of drugs available for the prevention and treatment of human disease (Gwynne and Heebner, 2001; Cockburn, 2004). Technologic and scientific developments also promise to enhance the prediction of safety problems and opportunities earlier in the development process, but much more work is needed to actualize these promises (FDA, 2004). The practice of drug discovery and drug development research has also changed substantially in response to scientific and technological advances. Drug discovery research is funded by both industry and government, and takes place in academe, government—especially the National Institutes of Health (NIH)—and industry. Almost all drug development occurs in industry, but an increasing proportion of industry-funded studies is being conducted outside academic health centers by contract research organizations, and more clinical trials are being conducted abroad (Cockburn, 2004). Biomedical research accounts for 5.6 percent of health expenditures in the US, with 57 percent of the research is funded by industry, and 28 percent by NIH (Moses et al., 2005). Despite advances, the development of new pharmaceutical problems is facing challenges—in its Critical Path report (FDA, 2004), FDA asserted that the translation from the basic sciences of drug discovery to the applied sciences of drug development has become sluggish because “the development path is becoming increasingly challenging, inefficient, and costly.” The practice of medicine and the provider-patient interaction—the point where the pharmaceutical product traditionally “meets” the patient—also have undergone great transformation in the last two or three decades. First, use of prescription drugs has been increasing steadily (Ganslaw, 2005). Physicians and other health care providers have more therapeutic options at their disposal, and both polypharmacy2 and the chronic use of drugs have become extremely common, especially in the rapidly growing segment of the population in late middle age and older. Use of drugs to treat chronic disease risk factors such as high blood pressure and high cholesterol has expanded immensely. Second, the role of the patient has changed as part of the larger shift toward consumer empowerment in the private sector. The health care system (like other sectors) places increased emphasis on consumer choice. 2 The administration of multiple drugs concurrently, with the concomitant increased risk of drug interactions.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Quality of care also has become a major issue for consumers. Pharmaceutical and health plan offerings are promoted to consumers now empowered to be decision-makers. Patients have unprecedented access to information about drugs, their benefits, and side effects. This is due in part to changes in the information environment. Promotion of drugs to patients has increased, including broadcast direct-to-consumer advertising. Access to the Internet has become widespread; this powerful tool provides access to information that varies greatly in accuracy, quality, and completeness (Tatsioni et al., 2003). The relationship between patients and their physicians has changed as patients have become more engaged and knowledgeable. Third, a category of “lifestyle” drugs has arrived in the marketplace. Two decades ago, patients used drugs chronically for treatment for and control of serious diseases. Today, many fundamentally healthy people take drugs long-term for purposes ranging from cosmetic improvement (such as botox) to symptomatic management (such as antihistamines) to performance enhancement (such as erectile dysfunction). For people who need to take drugs for control or treatment of serious diseases, the potential of adverse drug effects may be of less concern than it is for people who take drugs for very minor issues (see Box 1-1 for some FDA milestones). Defining and Meeting the Charge The Charge Given the changes outlined above and in response to growing public concern with health risks posed by prescription drugs, FDA requested that the Institute of Medicine (IOM) convene an ad hoc committee of experts to conduct an independent assessment of the current system for evaluating and ensuring drug safety and to make recommendations to improve risk assessment, surveillance, and the safe use of drugs (see Box 1-2). In recognition of their roles in the drug safety system, the Centers for Medicare and Medicaid Services (CMS), the Agency for Healthcare Research and Quality (AHRQ), NIH, and the Department of Veterans Affairs are also sponsors of the report. In responding to the charge, the committee focused much of its attention on FDA’s CDER. Although the report is addressed to the FDA as a whole, a considerable proportion of the committee’s discussion and recommendations pertain to CDER’s structure, organization, and scientific and regulatory activities. Given the study timeframe, the committee found it difficult to accord the same level of attention (in terms of a detailed assessment and recommendations) to all other important stakeholders in the drug safety system. The roles of industry, the health care delivery system, and health care

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The Future of Drug Safety: Promoting and Protecting the Health of the Public BOX 1-1 Some Key Milestones in FDA History The Pure Food and Drug Act of 1906 gave FDA’s predecessor, the Bureau of Chemistry in the Department of Agriculture, its first regulatory powers. At inception, the agency’s pharmaceutical regulatory work focused largely on misbranding and adulteration of drugs. In 1937, elixir sulfanilamide caused more than 100 deaths and led to the passing of the 1938 Federal Food, Drug, and Cosmetic (FD&C) Act. The act prohibited false therapeutic claims for drugs and for the first time required premarket notification of FDA by the sponsor for all new drugs. This meant that a company submitted its New Drug Application (NDA) and, if FDA did not explicitly prohibit marketing, the company was free to market the product without any type of approval after 60 days (unless FDA extended that period to 180 days), when the NDA became “effective.” Although the FD&C Act required a manufacturer to prove a drug’s safety by conducting preclinical toxicity testing and gathering and submitting drug safety data, it did not require proof of efficacy (Swann, 1998; Stergachis and Hazlet, 2002). Some two decades later, thousands of children with birth defects were born to European mothers who had taken the popular sedative thalidomide for morning sickness. Marketing of thalidomide in the United States had been held up in the approval process and this so-called near miss led to the Drug Amendments of 1962. The drug amendments required companies to provide proof of efficacy of a drug for it to be considered for marketing approval, and the randomized controlled trial became established as the gold standard for demonstrating efficacy (Stergachis and Hazlet, 2002). In the 1980s, the public health crisis of HIV/AIDS motivated a powerful advocacy movement whose aims included faster approval of drugs for patients with incurable disorders. Other consumer and patient advocacy groups began to call for changing the drug approval process to speed up the availability of potentially life-saving or life-sustaining drugs to patients in need of them. Consumer groups, regulators, the regulated industry, and others contributed to and Congress passed the PDUFA legislation that aimed to ensure that FDA had adequate resources to expand its drug review staff and capabilities, and so to increase the pace of drug reviews. Agreements among FDA, industry, and Congress are crystallized in a series of performance goals for FDA. These are not part of the PDUFA statute, so they lack the force of law (Tauzin, 2002) but they reflect activities the agency considers its obligations—“The letter outlines goals that the agency must meet, which help frame the basis to judge the

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The Future of Drug Safety: Promoting and Protecting the Health of the Public user fee programs success” (Tauzin, 2002). These goals are contained in the “PDUFA Reauthorization Performance Goals and Procedures,” or the PDUFA “goals letter” (a letter with enclosures), which is transmitted by the Secretary of HHS to Congress annually. PDUFA required that FDA and specifically CDER review staff meet certain performance goals and report annually to Congress on their progress in meeting those goals. PDUFA also required that companies pay three types of fees to FDA, including a one-time fee submitted with each NDA, an establishment fee, and a product fee (FDA, 2005a,b).* Congress reauthorized PDUFA in 1997 (as part of the FDA Modernization Act) and in 2002 as part of the Bioterrorism and Preparedness and Response Act. In PDUFA I and II, funds were limited to use to the review of sponsor applications for new drugs and indications. No PDUFA funds were allocated to postmarketing drug safety activities until 2002, when limited funds were allocated for limited safety activities. The 1992 PDUFA Amendments to the FD&C Act stipulated that PDUFA user fees must not be used in lieu of but to supplement appropriations. FDA was authorized to assess user fees only if appropriations for drug review were equal to or greater than appropriations for salaries and other FDA expenses in 1992 (Zelenay, 2005). PDUFA II set the trigger at 1997 levels: “Fees under subsection (a) of this section shall be refunded for a fiscal year beginning after fiscal year 1997 unless appropriations for salaries and expenses of the Food and Drug Administration for such fiscal year (excluding the amount of fees appropriated for such fiscal year) are equal to or greater than the amount of appropriations for the salaries and expenses of the Food and Drug Administration for the fiscal year 1997 (excluding the amount of fees appropriated for such fiscal year) multiplied by the adjustment factor applicable to the fiscal year involved” (21 US Code 379h(f)). The adjustment factor is based on the Consumer Price Index (Zelenay, 2005), and that may help explain why, although the agency has always met the trigger that allowed the collection of user funds, appropriations have grown at a much lower rate than user fees (FDA, 2005b). Appropriations have not only not kept pace, but they have declined since 2003, as FDA’s payroll costs have increased (FDA, 2005b).    *For FY 2006, the application fee is $767,400, the establishment fee is $264,000, and the product fee is $42,130 (FDA, 2005a).

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The Future of Drug Safety: Promoting and Protecting the Health of the Public BOX 1-2 The Statement of Task In response to growing public concern with health risks posed by approved drugs, the FDA has requested that the IOM convene an ad hoc committee of experts to conduct an independent assessment of the current system for evaluating and ensuring drug safety postmarketing and make recommendations to improve risk assessment, surveillance, and the safe use of drugs. As part of its work, the IOM committee will: examine the FDA’s current role and the role of other actors (e.g., health professionals, hospitals, patients, other public agencies) in ensuring drug safety as part of the US health care delivery system; examine the current efforts for the ongoing safety evaluation of marketed drug products at the FDA and by the pharmaceutical industry, the medical community, and public health authorities; evaluate the analytical and methodological tools employed by FDA to identify and manage drug safety problems and make recommendations for enhancement; evaluate FDA’s internal organizational structure and operations around drug safety (including continuing postmarket assessment of risk vs. benefit); consider FDA’s legal authorities for identifying and responding to drug safety issues and current resources (financial and human) dedicated to postmarketing safety activities; identify strengths, weaknesses, and limitations of the current system; and make recommendations in the areas of organization, legislation, regulation, and resources to improve risk assessment, surveillance, and the safe use of drugs. providers, patients, the public, Congress, the academic research enterprise, and other government agencies are discussed in much less detail. However, the committee’s recommendations have implications for those stakeholders, and are discussed in the report where appropriate. What This Study Is Not This report does not address the related area of medication errors. That was the purview of the IOM Committee on Identifying and Preventing Medication Errors, whose report was released July 2006 (see Appendix E

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The Future of Drug Safety: Promoting and Protecting the Health of the Public for that report summary). The present report does not treat several very important issues that were not in the charge given to the committee, including the regulation or safety of medical devices or biological products other than those regulated by CDER; pharmaceutical product abuse, overuse, or misuse; over-the-counter (OTC) drugs or the switch from prescription to OTC status; generic drugs; drug pricing; or the causes and consequences of the current challenges in pharmaceutical innovation. Finally, although the postapproval stage of a drug’s life cannot be discussed in isolation from the preapproval stages, this report does not consider in any detail the complex ethical, practical, economic, and scientific issues related to the Investigational New Drug process or the clinical trial conduct in the testing of drugs. Study Process The committee gathered information to address its charge through a variety of means. It held three information-gathering meetings and one workshop that were open to the public. The first meeting focused on obtaining background on the committee charge from a number of perspectives, including FDA’s. This and all other meeting agendas can be found in Appendix D. The second meeting focused on hearing from the public on day 1, and learning about the role of FDA, AHRQ, and CMS in US drug safety activities on day 2. The committee also held a workshop on Advancing the Methods and Application of Risk-Benefit Assessment of Medicines and held a final information-gathering meeting to hear opinions on proposals to improve drug safety in the United States. The committee met in executive sessions for deliberative discussions throughout the study process. All the open meetings were Webcast in real time so that members of the public could listen to the proceedings and send questions to the committee by e-mail. The committee also received public submissions of material for its consideration at the meetings and by mail, e-mail, and fax throughout the course of the study. A Web site (http://www.iom.edu/drugsafety) and a list-serv were created to provide information to the public about the committee’s work and to facilitate communication with the committee. Many of the speakers’ presentation slides from the three information-gathering meetings and workshop are available in electronic format on the project’s Web site. A few committee members and staff visited FDA to gain a better understanding of the background and daily operations of CDER. The committee and staff also conducted over 30 discussions with present and past FDA staff, managers, and leadership. Those discussions were confidential, but a summary of the main themes and points of discussion is provided in the public access file for this project (see IOM Staff Notes, 2005–2006). The committee also commissioned two papers to inform it about industry’s views of drug safety in the United States (written by Hugh Tilson)

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The Future of Drug Safety: Promoting and Protecting the Health of the Public and those of academe (written by Brian Strom); these papers were based in part on small meetings convened by the authors and can be found in the public access file.3 Moving Target—The Shifting Landscape of Drug Safety in the United States The committee has worked in the context of continuing change and proposals for change: modifications in the organizational structure of CDER and in the evaluation and monitoring of drug safety undertaken by FDA and to a lesser extent other stakeholders; multiple legislative proposals for changing the structure, resources, and authorities of CDER in FDA; and consumer and patient organizations’ calls for changes in CDER. Those efforts have, in some cases, informed the work of the committee during its deliberations. Some of these changes have closed gaps, others have raised new questions and concerns, and still others have helped to increase the knowledge base of the committee. The efforts are described in greater detail in Appendix A. Toward a New Vision of Drug Safety The increasingly complex interface between innovation and regulation has been characterized by binary opposites: speed vs. safety, tight preapproval regulation vs. loose postapproval regulation, active collection of data before approval vs. passive surveillance after approval, and an abundance of clinical efficacy data before approval compared to much fewer safety data after approval. The polarity of approach and emphasis is inconsistent with the widely accepted notions that risk must be considered in the context of benefits, that understanding of the risks and benefits associated with a drug changes over a drug’s lifecycle (FDA, 2004), and that the attention paid to safety and efficacy before approval must therefore be sustained as a drug enters and diffuses through the market and is used by a growing number and diversity of patients. Timely approval and attention to safety can become complementary rather than antithetical goals as postapproval surveillance becomes more effective, and regulatory authority and its exercise is commensurate with how a drug performs in real-life conditions over its lifecycle. 3 A list of materials reviewed by the committee (in the form in which they were reviewed), including all submissions of information from the public and many items not cited in this report, can be found in the study’s public access file, obtained from the National Academies Public Access Records Office at (202) 334-3543 or http://www8.nationalacademies.org/cp/ManageRequest.aspx?key=162.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public The approval decision does not represent a singular moment of clarity about the risks and benefits associated with a drug—preapproval clinical trials do not obviate continuing formal evaluations after approval. However, the approval decision is a critical juncture in a product’s lifecycle because it releases a drug to the market, where the public will gain broad exposure to it. In a strengthened drug safety system, that juncture should mark the beginning of another important stage in the lifecycle, when regulators, sponsors, health insurers, health care providers, and independent researchers actively pursue and manage emerging knowledge about risk-benefit relationships and uncertainty and they communicate that knowledge to patients, and health care organizations in a timely manner. Regulatory, health insurance coverage, and treatment decisions over a drug’s lifecycle depend on the quality and timeliness of data collected, evaluated, and transmitted by trustworthy stakeholders in the health care system. In short, a drug safety system oriented around the new paradigm requires: A culture of safety in CDER supported by strong leadership, effective management, science-based decision making that is, insofar as possible, insulated from outside influences, and a healthy organization that encourages debate, teamwork, and independent scientific inquiry. Science that is rigorous and that through the individual and joint efforts of sponsors, academic researchers, and health care organizations describes a drug’s risk-benefit profile, patterns of drug use, comparative effectiveness of drugs, behaviors of prescribers and users, and behaviors of institutions that affect prescribers and users. A regulatory process that is flexible, dynamic (e.g., proactive, responsive), and attentive to safety throughout the lifecycle of a drug, and a regulatory agency that is sufficiently empowered to take actions necessary to protect the public health. Communication about safety that is timely and effective and that facilitates transparency and enhances credibility. The committee’s vision of a transformed drug safety system has at its core a lifecycle approach to drug risk and benefit—not a new concept, but one that has been implemented, at best, in a narrow and fragmented manner. For FDA, attention to risk and benefit over the life of a drug requires continuous availability of new data and ongoing, active reassessment of risk and benefit to drive regulatory action (in response to the accumulating information on a given drug), and regulatory authority that is strong both before and after approval. For the industry, attention to risk and benefit over the lifecycle will require more careful assessments of emerging information about possible new risks and timely communication of this information to

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The Future of Drug Safety: Promoting and Protecting the Health of the Public FDA, and acceptance of changes intended to strengthen drug safety. FDA’s credibility is intertwined with that of the industry, and a more credible drug safety system is in everyone’s best interest. For the health care delivery system, a lifecycle approach to risk and benefit implies the need to heed and follow FDA communication about drug safety matters and to exercise appropriate caution in drug-related decision making (from formularies to prescribing) in recognition of the limited information available at the time of drug approval. The health care delivery system will benefit by consistently basing prescribing decisions on the science, and by exercising caution in regard to the industry’s influence on the practice of medicine. Health care organizations and professional societies can contribute to prescribers’ understanding of the evolving science behind the assessment of drug risk and benefit. The academic research enterprise can enhance its contributions of data to the assessment of risk and benefit at all points in a drug’s lifecycle, continue its crucial advisory relationship with FDA, and uphold the value of complete transparency in recognition of real and perceived conflicts associated with financial involvement with the industry. Other government agencies can contribute to the lifecycle approach to drug risk and benefit by collaborating with FDA and the private sector to ensure that data streams from publicly funded health care settings contribute to an improved drug safety system. The public and patients can do their part by communicating with their health care providers about the pharmaceutical products they are using, learning about and discussing with their providers a drug’s risks and benefits in the context of their health needs and characteristics, informing their providers about side effects they experience, and calling for more useful and timelier information about drug benefits and risks associated with new drugs. REFERENCES Applebaum A (The Washington Post). 2005. The Drug Approval Pendulum. [Online]. Available: http://www.washingtonpost.com/wp-dyn/articles/A48135-2005Apr12.html [accessed April 21, 2005]. CDER (Center for Drug Evaluation and Research). 1998. Guideline for the Format and Content of the Clinical and Statistical Sections of an Application. Rockville, MD: CDER. Cockburn IM. 2004. The changing structure of the pharmaceutical industry. Health Aff (Mill-wood) 23(1):10-22. DHEW (Department of Health Review Panel on New Drug Regulation), Dorsen N, Weiner N, Astin AV, Cohen MN, Cornelius CE, Hamilton RW, Rall DP. 1977. Final Report. Washington, DC: DHEW. DHHS (Department of Health and Human Services), FDA, Task Force on Risk Management. 1999. Managing the Risks from Medical Product Use: Creating a Risk Management Framework. [Online]. Available: http://www.fda.gov/oc/tfrm/riskmanagement.pdf [accessed October 10, 2005].

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