3
A Culture of Safety

The Committee on the Assessment of the US Drug Safety System has examined three determinants of organizational culture in the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER): the external environment, structural factors, and management. The committee believes that cultural changes are urgently needed to support a stronger, more systematic and more credible approach to drug safety in CDER, and it recommends solutions to problems created or exacerbated by elements of CDER’s management, structure, and environment. However, implementing some of these recommendations may require additional resources, as discussed in greater detail in Chapter 7.

ORGANIZATIONAL CHALLENGES

A number of highly publicized events, including the Vioxx withdrawal and concern about other cox-2 inhibitors, and ongoing drug safety problems including those related to salmeterol, Ketek, and others have brought FDA’s, and specifically CDER’s, performance under the scrutiny of the American public (via the mass media) and Congress (Harris, 2006b; Hendrick, 2006; Washington Drug Letter, 2006). Critics have charged that there were failures or delays in informing patients about important drug risks, inadequate postmarketing assessment of drug safety, and failures to follow up and enforce sponsors’ postmarketing study commitments agreed on at the time of approval. Others have expressed concern that the recent focus on safety could reverse considerable gains in the pace of drug review and the speed of approving new therapies.



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The Future of Drug Safety: Promoting and Protecting the Health of the Public 3 A Culture of Safety The Committee on the Assessment of the US Drug Safety System has examined three determinants of organizational culture in the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER): the external environment, structural factors, and management. The committee believes that cultural changes are urgently needed to support a stronger, more systematic and more credible approach to drug safety in CDER, and it recommends solutions to problems created or exacerbated by elements of CDER’s management, structure, and environment. However, implementing some of these recommendations may require additional resources, as discussed in greater detail in Chapter 7. ORGANIZATIONAL CHALLENGES A number of highly publicized events, including the Vioxx withdrawal and concern about other cox-2 inhibitors, and ongoing drug safety problems including those related to salmeterol, Ketek, and others have brought FDA’s, and specifically CDER’s, performance under the scrutiny of the American public (via the mass media) and Congress (Harris, 2006b; Hendrick, 2006; Washington Drug Letter, 2006). Critics have charged that there were failures or delays in informing patients about important drug risks, inadequate postmarketing assessment of drug safety, and failures to follow up and enforce sponsors’ postmarketing study commitments agreed on at the time of approval. Others have expressed concern that the recent focus on safety could reverse considerable gains in the pace of drug review and the speed of approving new therapies.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Mass media coverage of perceived organizational problems in CDER has been frequent and detailed, for example, describing an apparent lack of mutual respect and tension between preapproval review staff and postmarketing safety staff, and a work environment thought to be marginalizing dissenting voices on drug safety (Mathews, November 10, 2004; Harris, February 20, 2005; Henderson, December 6, 2005). As questions about culpability mounted, a series of organizational and programmatic problems in the center highlighted in the mass media were also examined in government reports, including the reports of the DHHS Inspector General that surveyed CDER staff (DHHS/OIG, 2003) and reviewed the state of postmarketing commitments (DHHS/OIG, 2006), respectively, and the reports of the Government Accountability Office that assessed the impact of the Prescription Drug User Fee Act (PDUFA) on CDER staff’s morale and workload (GAO, 2002) and examined the structure and effectiveness of CDER postmarketing decision-making processes (GAO, 2006). Many observe signs of an organizational culture in crisis. It has also become apparent that drug safety events, whether indicative of or associated with organizational and cultural problems, have led to diminished agency credibility among the public. Drug safety experts, members of Congress (including Senators Michael Enzi, Edward Kennedy, and Charles Grassley, and Representatives Rosa DeLauro and Maurice Hinchey), consumer organizations (such as Consumers Union, Public Interest Research Group, the National Consumers League, Public Citizen), and others have called for organizational, statutory, and resource changes in the agency. Proposals have included restructuring the agency to segregate the drug review and postmarketing safety functions by creating an independent drug safety center (Fontanarosa et al., 2004; Consumers Union, 2005; Grassley, 2005; Ray and Stein, 2006; Wolfe S, 2006). FDA itself has undertaken a series of initiatives and changes, described in detail in Appendix A, including the commissioning of this Institute of Medicine report (see discussion in Chapter 1) (Crawford, 2004; Wall Street Journal and Harris Interactive, 2006). In its discussions with current and recent FDA staff and managers (see Box 3-1), and on the basis of its review of relevant government reports, the committee found that the organizational culture in CDER confirms some of the adverse perceptions conveyed in the mass media, and that the center is an organization in urgent need of great change. The committee found that CDER’s organizational culture has both strengths and weaknesses. The positives are that science-based decision making is a clear priority that shapes CDER’s culture, as does the staff’s obvious awareness of the potential consequences of their decisions on the health of the public and individual patients. The negative features of the culture include a work environment that is not sufficiently supportive of staff (as evident in problems with morale and attrition), polarization between

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The Future of Drug Safety: Promoting and Protecting the Health of the Public BOX 3-1 Committee Information Gathering About CDER Organizational Culture To inform its deliberations, the committee held information-gathering sessions to hear from FDA and other stakeholders (see Appendix D). A small group of committee members and Institute of Medicine (IOM) project staff visited CDER on October 11, 2005, and February 22, 2006. From November 7, 2005, to May 2006, IOM staff with rotating committee representation of one or two members also held confidential discussions with over 30 current FDA staff, including personnel from the Office of New Drugs (OND) and the Office of Drug Safety (recently renamed Office of Surveillance and Epidemiology and referred to hereafter as ODS/OSE), FDA and CDER management, and several former FDA staff and leaders.* The committee’s high regard for the professionals who perform CDER’s preapproval and postapproval functions under considerable time and resource constraints was reinforced by these conversations. As the committee gained greater understanding of CDER’s work and functioning, committee members were able to identify or confirm a number of structural and related cultural challenges, including a troubling relationship between OND and ODS/OSE, insufficient management and leadership to address emerging problems and implement needed reforms, a lack of clear and consistent processes (for example, for identifying and addressing drug safety concerns both in the review process and in the postmarketing period, for determining the need for and nature of postmarketing, or phase 4, studies), overextended human and financial resources, and pressures added by the requirements of the current user-fee funding mechanism that funds about 50% of CDER’s work (FDA, 2005b). The major themes that emerged from the committee’s conversations are consistent with those identified in government reports on FDA and CDER. The committee also found it helpful to refer to assessments of organizational problems in other government agencies that deal with risk and uncertainty, albeit in very different contexts, such as the National Aeronautics and Space Administration and the Federal Aviation Administration (GAO, 1996; Return to Flight Task Group, 2005).    *At the committee’s request, the CDER Director sent a letter to all center staff urging them to contact IOM study staff if they wished to discuss issues related to their work and recent concerns.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public the premarketing and postmarketing review staff, and evidence suggesting insufficient management attention to scientific disagreement and differences of opinion. Change is needed because CDER’s organizational problems may affect its ability to accomplish the mission of protecting and advancing the public’s health; they clearly affect public perception of the agency’s performance and credibility. Every organization has its share of dysfunctions, disgruntled staff members, and internal disputes, but the committee came away from various encounters with CDER staff and management with a deep concern about CDER’s organizational health. The committee approached this component of its work with special care, recognizing that structure and culture, as fundamental features of an organization, connect in complex and not easily discernible ways. Management literature shows that an organization’s ability to fulfill its mission is considerably influenced by the health of its culture, the “social architecture” that determines whether excellence is promoted; whether the organization is adaptable, robust, and learning; and whether broad staff participation (in shaping the vision, making decisions, and so on) is prized and encouraged (Coffee, 1993; Heifetz and Laurie, 1998; Khademian, 2002). The committee was explicitly charged with assessing the structure and function of CDER, but because organizational function is linked to organizational culture, the committee had to consider CDER’s culture and how it has been shaped by important changes in the policy, economic, and social environment; by structural factors, and the related policies and procedures that contribute to organizational dynamics; and by management. In the pages that follow, the committee describes the evidence and outlines the steps to be taken to align CDER’s culture better with its mission “to make certain that safe and effective drugs are available to the American people.”1 The External Environment Organizational culture is rooted in the external environment, and this is particularly true of government agencies, which experience the environment as “a set of constraints, expectations, and pressures” (Khademian, 2002: 136). Some environmental and organizational challenges are peculiar to government agencies (Claver et al., 1999; O’Leary, 2006; Ostroff, 2006). For example, their leaders are chosen for attributes that do not necessarily include a track record of organizational leadership, an ability to transform complex organizations, or an in-depth knowledge of the leadership issues routinely faced by an agency, and their time in office is usually brief. Government agency operations are less flexible than those of their private- 1 Source: http://www.fda.gov/cder/learn/CDERLearn/.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public sector counterparts because of a wide array of laws and regulations and the requirement that they be responsive to the often conflicting expectations of multiple constituencies (Ostroff, 2006). For FDA, and specifically CDER, the environment is shaped by many factors. First, the evolution of FDA’s regulatory role has been shaped by the expectations of American society, as expressed through its national legislature, in its courts, and in the influence of its patient and consumer advocacy movements. The American public desires timely access to effective and safe therapies. Legislative attention to the regulation of drugs (and other products in FDA’s purview, has resulted in the statute that dictates FDA’s role: the Food, Drug, and Cosmetic (FD&C) Act of 1938 and its many subsequent amendments. Another influence on FDA’s work is the economic and political agenda of a powerful and influential industry, whose concerns include the potential of regulation to dampen innovation. The health care delivery system (organizations, payors, pharmacies, etc.) and health care professionals who act as intermediaries between patients and the drug development and distribution system are another factor in FDA’s environment. Patients must secure a prescription from a qualified health care provider, and health care providers can only prescribe drugs that are approved by FDA. FDA actions, including findings from postmarketing surveillance, inform drug formulary and reimbursement decisions by payors. Although FDA does not regulate drug pricing, and cost-effectiveness is not a consideration, these are important issues to the health care delivery system, given financial constraints and the diverse therapeutic needs of its patients. A final crucial dimension of FDA’s external environment is the potential influence exercised by the top levels of the executive branch (the White House, the Office of Management and Budget) and the legislative branch. Congress plays an oversight function and provides a forum for the push and pull of legislative factions concerned with consumer safety and those inclined toward spurring economic competitiveness. Congressional concern about the public’s safety may be one contributing factor to what the industry and other critics have seen as the agency’s historically risk-averse stance in carrying out its regulatory duties. In their view, the agency has generally been more likely to err on the side of greater caution in approving drugs than to err on the side of faster approval, perhaps in response to the fact that congressional investigations generally focus on errors of commission (approving an unsafe drug) rather than omission (not approving a potentially good drug) (Cohn, 2003; Steenburg, 2006). The multiple and often conflicting pressures of the external environment add to the complex nature of the agency’s work (science-based decision making) and the enormous medical, social, and economic impact of its regulatory decisions. FDA has a dual mission: to protect public health “by assuring the safety, efficacy, and security of human … drugs”

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The Future of Drug Safety: Promoting and Protecting the Health of the Public and to advance public health “by helping to speed innovations that make medicines … more effective, safer, and more affordable.” Balancing speed and safety is not always easy. Many drugs are both life-saving, motivating timely approval and release to the marketplace, and life-threatening, requiring careful monitoring of safety and rapid action to address safety risks as appropriate. The challenge in regulating prescription drugs is to weigh the available evidence of efficacy and safety in the context of the prevalence and severity of specific disorders, and the availability, safety and efficacy of other approved therapies. Although FDA and the industry share an interest in the discovery and development of beneficial products that improve health,2 the decisions of regulators may affect the regulated industry’s success in the marketplace (House of Commons Health Committee, 2005a,b). Two dimensions of the external environment deserve more detailed discussion in the context of this report. These include the relationship between FDA and the industry, which has been complicated by PDUFA, and FDA’s relationships to Congress and to the White House. The FDA–Industry Interface It has become increasingly clear that the credibility of FDA is intertwined with that of the industry it regulates. If FDA is viewed as less trustworthy to make decisions that serve the public good, that may diminish the value and meaning of FDA approval, casting a shadow of doubt on FDA-approved products’ reliability, quality, and most importantly, their safety and effectiveness. The concerns over drug safety described above have affected not only FDA’s image, but that of the industry. In fact, the industry’s integrity and its commitment to finding effective therapies for patients in need has been questioned (PricewaterhouseCoopers, 2005). Industry’s credibility has been considerably affected by judicial action in response to non-compliance and by lawsuits related to how companies handled information about their products and in particular, whether they were adequately forthcoming about what they knew and when (Hensley et al., 2005; Kaiser Family Foundation, 2005; Wall Street Journal and Harris Interactive, 2005). The user-fee funding mechanism established in 1992 to supplement congressional appropriations helped to expand and strengthen preapproval functions and the capabilities of the responsible CDER offices. PDUFA was renewed and revised in 1997 and 2002 and will be considered for reauthorization in 2007. The user-fee program has increased considerably the resources available for drug review (see Chapter 7) and made the review process more predictable and expeditious (see Box 3-2 and Appendix C). 2 The Critical Path initiative is an example of FDA’s interest in supporting innovation in drug discovery; it maps the way forward for applying cutting-edge science to drug discovery.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public However, it has had some drawbacks, including increasing the agency’s dependence on industry funding for its drug review activities, severely skewing CDER’s focus to facilitating review and approval perhaps at the expense of other center activities, and creating an environment of intense pressure on its reviewers (Zelenay, 2005). A Department of Health and Human Services (DHHS) Office of the Inspector General (OIG) survey of CDER staff found that 40 percent of “respondents who had been at FDA at least 5 years indicated that the review process had worsened during their tenure in terms of allowing for in-depth, science-based reviews. Respondents cited lack of time as the main reason” (DHHS and OIG, 2003). In discussions with FDA staff, the committee learned that the emphasis on timely review that is at the core of PDUFA and is linked with specific performance goals has added to reviewer workloads despite the increase in review staff. FDA must report to Congress annually about its success in reaching the performance goals. Some observers have charged that increased speed of review has led to decreased safety, in part because the time demands of PDUFA limit the ability of reviewers to examine safety signals as thoroughly as they might like (Sasich, 2000; Wolfe SM, 2006). Performance goals with reporting requirements for actions relating to review speed, but not for other actions, such as postmarketing safety monitoring and risk communication, may lead to the assigning of higher priority to those actions that have associated performance goals. There has been some debate about PDUFA’s effect on drug safety as demonstrated by drug withdrawals. Abraham and Davis (2005) found that in the period before enactment of PDUFA the United States had 50 percent fewer drug withdrawals than the United Kingdom largely because of the longer periods that the FDA took to review drug applications. They suggested that US efforts to speed approval may be compromising drug safety in the PDUFA era. However, drug withdrawals are very rare occurrences in general, and the total number of withdrawals in the last two decades of the 20th century represents a modest figure that may not be useful for generalization. For example, in reviewing 20 drug withdrawals in 1980–2004 (nearly half of which occurred before PDUFA was enacted), the Tufts Center for the Study of Drug Development found that “no trend emerges between speed of approval and withdrawal” (Tufts Center for the Study of Drug Development, 2005). Drug withdrawals are just one indicator of drug safety; the timeliness of a withdrawal may be more important than the fact of the withdrawal. Furthermore, drug withdrawals say nothing about the safety of drugs that remain on the market and continue to affect public health. Olson (2002) makes the point that drug withdrawal data are of limited value in drawing inferences about drug safety more generally and instead focuses on adverse drug reactions among all new chemical entities approved between 1990 and 1995. The Government Accountability Of-

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The Future of Drug Safety: Promoting and Protecting the Health of the Public BOX 3-2 A Short History of the Prescription Drug User Fee Act (PDUFA) 1992 Use revenues from user fees to achieve certain “performance goals” Primary focus: decrease review times PDUFA I Commitments: Complete review of priority original new drug and biologic applications and efficacy supplements (90% in 6 months) Complete review of standard original new drug and biologic applications and efficacy supplements (90% in 12 months) Complete review of priority supplements (90% in 6 months) Complete review of standard supplements (90% in 12 months) Complete review of supplements that do not require review of clinical data (manufacturing supplements) (90% in 6 months) Complete review of resubmitted new drug and biologic applications (90% in 6 months) 1997 PDUFA II was reauthorized for 5 years (FY 1998–2002) as part of Title I of the Food and Drug Administration Modernization Act Primary focus: decrease review times and shorten development times New PDUFA II commitments: Complete review of resubmitted efficacy supplements (90% in 6 months) Respond to industry requests for meetings (90% within 14 days) Meet with industry within set times (90% within 30, 60, or 75 days depending on type of meeting) Provide industry with meeting minutes (90% within 30 days) Communicate results of review of complete industry responses to FDA clinical holds (90% within 30 days) Resolve major disputes appealed by industry (90% within 30 days) Complete review of special protocols (90% within 45 days) fice (GAO) analysis looked at withdrawals over 4-year intervals between 1985 and 2000, and found that the rate of withdrawals fluctuated from 4.39 percent in 1985–1988, to 1.96 percent in 1989–1992, to 1.56 percent in 1993–1996, to 5.34 percent in 1997–2000 (GAO, 2002). There were 15 drug withdrawals between 1985 and 2000, and in its response to GAO, FDA asserted that the variation in the withdrawal rate was probably related to the small number of withdrawals in any given year (GAO, 2002). The Berndt et al. (2005) analysis found that the proportion of approvals ulti-

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Electronic application receipt and review (in place by the end of FY 2002) Changes in commitments Complete review of standard original new drug and biologic applications and efficacy supplements (90% in 10 months instead of 12 months) Complete review of manufacturing supplements that do not require review of clinical data (90% in 4 months instead of 6 months if prior approval is needed, otherwise 6 months) Complete review of resubmitted new drug and biologic applications (90% of class 1 in 2 months, and 90% of class 2 in 6 months instead of all in 6 months) 2002 PDUFA III was reauthorized for 5 years (FY 2003–2007) as part of Public Health Security and Bioterrorism Preparedness and Response Act Focus: expand interaction and communication in IND phase and during first cycle review Includes some funding for postmarket safety for 2–3 years after drug approval for drugs approved after 2002 New PDUFA III commitments: Discipline review letters for presubmitted “reviewable units” of new drug and biologic applications (90% in 6 months) Report of substantive deficiencies (or lack thereof) (90% within 15 days of filling date) Changes to commitments: Complete review of resubmitted efficacy supplements (90% of class 1 in 2 months and 90% of class 2 in 6 months instead of all in 6 months) Electronic application receipt and review (enhanced by end of FY 2007) SOURCES: FDA (1995, 2002, 2005e, 2006a). mately leading to safety withdrawals prior to PDUFA and during PDUFA I and II were not statistically significantly different. The user-fee system has exacerbated concerns about the relationship between FDA and the regulated industry by creating the appearance of conflict of interest in the regulators—critics assert that PDUFA gives sponsors inappropriate leverage or influence over regulation because FDA is obliged to please sponsors, now its “clients,” in return for fees for service (Grassley et al., 2004; Harris, 2004; Wolfe S, 2006). Regulatory capture is a term used

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The Future of Drug Safety: Promoting and Protecting the Health of the Public by regulatory scholars (such as Stigler, 1971) to describe successful industry pressure on regulators, and some observers actually believe that PDUFA has facilitated the capture of FDA. The core problem in the relationship between industry and FDA (leading FDA to consider industry a client) may lie in the power of the industry to shape the scope and nature of PDUFA goals (Olson, 2002; Carpenter et al., 2003; DHHS and FDA, 2005; Okie, 2005). In the negotiations between FDA and the industry, Congress has given the industry a considerable role in influencing what activities the user fees will fund, thus limiting regulatory discretion and independence. In particular, fee revenues only could be used to support activities designed to increase the speed and efficiency of the initial review process. Fee revenues could not be used to support postmarketing safety surveillance from 1992 to 2002. In the 2002 PDUFA reauthorization, a small amount of fee revenues (about 5 percent) was permitted to be used for postmarketing drug safety activities; however, restrictions on when these funds could be spent (only for drugs approved after 2002, and for up to 2 years after approval, or up to 3 years for “potentially serious drugs”) limited their effectiveness (Zelenay, 2005). In Chapter 7, the committee discusses this troubling feature of PDUFA and suggests an alternative. Concerns about inappropriate influence on regulatory decision making are not new, although it can be argued that PDUFA has made the connection between CDER performance and industry expectations much more explicit. In 1977, a government panel examined whether there was pressure on reviewers of new drugs to make regulatory recommendations favorable to the industry (DHEW3 Review Panel on New Drug Regulation, 1977; DHEW, 1977). The panel concluded that the problem was largely linked to poor management rather than verifiable industry influence. The second basic issue explored by the Panel was whether industry exerts undue influence on FDA decisions. Many current and former FDA employees and consultants had testified to Congressional committees that industry pressure caused FDA officials to approve drugs that did not meet agency safety and effectiveness standards and that those who attempted to oppose industry demands were harshly and improperly treated by senior FDA officials. From detailed investigations of these allegations by its staff, the Panel concluded that there was no widespread use of improper influence by industry representatives. It did identify several instances in which FDA supervisors unfairly disciplined dissenting employees, but these lapses were found to result from poor management rather than improper efforts of industry to control agency decision-making [Dorsen and Miller, 1979:910]. 3 Department of Health, Education, and Welfare, predecessor of the DHHS.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public The concerns raised or exacerbated by PDUFA have an additional dimension. The interests of industry and the public are sometimes at odds, and some critics fear that PDUFA may have increased FDA’s responsiveness to one set of interests at the expense of the other set of interests, in some circumstances. It is important to note that FDA’s various constituencies have mixed expectations. The public, as reflected in the goals of multiple consumer and patient advocacy groups, has a simultaneous desire for speed and safety. Although the public wants to preserve the consumer protections afforded by drug regulation in America, it also may demand earlier patient access to potentially life-saving therapies, as was so effectively exemplified in the successes of the AIDS treatment advocacy movement. The industry, while developing a product that serves the public good by providing reliable and effective therapies, has a superseding fiduciary duty to its shareholders—a duty that requires that it be profit-seeking and asset-conserving—so its expectations are for smooth review and approval processes and the fewest regulatory impediments. FDA itself is accountable to Congress, whose members represent the American people. The committee believes that FDA’s most important constituency is the public and that commitment to the public good will ideally influence and check FDA’s interactions with the industry. Structural Factors, Policies, and Procedures Structural Factors External observers, from scientists to legislators, have noted that a key organizational challenge for CDER is the striking disparities between divisions responsible for premarket and postmarketing activities. There are disparities in the formal role, authority, resources, and relative institutional value conferred on the two groups of staff. Many of those issues have been confirmed by the 2006 GAO report on FDA’s postmarket decision-making and oversight process. The committee is not arguing that the responsibilities, resources, and other features of OND and ODS/OSE must necessarily be equal in every respect. The committee did not attempt to undertake a point-by-point comparison of OND and ODS/OSE (roles, capabilities, resources currently and in a perfect world), but it does assert that the formal function and resources of ODS/OSE have not been commensurate with the importance of safety or with the tasks of monitoring postmarketing drug safety. Inadequate management, discussed later in this chapter, also may contribute to the gap between ODS/OSE and OND and to the sense of interoffice tension or, at best, disharmony between the two offices. To some critics, the most concerning outcomes of the disparities between the premarketing

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The Future of Drug Safety: Promoting and Protecting the Health of the Public members would serve staggered 3-year terms that may be renewed once. The board would meet no less frequently than twice a year. The Management Advisory Board would assist FDA and CDER in their efforts to understand how organizational culture in the center is shaped by the environment, by a legacy of structural imbalance, and by management problems. The committee has learned that a variety of promising steps have been taken to improve interactions among offices, evaluate and improve internal processes, and even familiarize disciplines with one another. However, given CDER’s long history of reorganizations, external studies, and fitful change initiatives, the committee is not optimistic that current efforts will be sustained without the absolute commitment of managers and of center and agency leaders to act on many different levels, with broad staff participation and input and in an atmosphere of openness, and to be “relentless” in creating, seizing, and sustaining opportunities for change (Khademian, 2002:126). The committee believes that it is imperative that the director of CDER, with support from the commissioner and the assistance of the Management Advisory Board, take immediate steps to strengthen leadership, organization, and function to create and visibly champion a culture of drug safety in the center. 3.3: The committee recommends the Secretary of HHS direct the FDA commissioner and Director of CDER, with the assistance of the Management Advisory Board, to develop a comprehensive strategy for sustained cultural change that positions the agency to fulfill its mission, including protecting the health of the public. As part of the strategy for cultural change, the director of CDER should establish an effective organizational development capability in CDER by forming a staff working group consisting of people who represent diverse disciplines, roles, and viewpoints and including one or two staff members with organizational development expertise. The group would work with and support the center director in providing meaningful opportunities for two-way communication with staff, identifying and addressing culture problems, and nurturing a culture that values disagreement and thinking outside the box. Structural Factors The imbalance in authority, formal role, and resources between OND and ODS/OSE constitutes a major obstacle to a healthy organizational culture in CDER. On the basis of the rationale described above, the committee sets forth its recommendation to address the cultural challenges exacerbated by the existing structure.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public The aforementioned development of MAPPs as the primary strategy to manage how OND and ODS/OSE interact and to document differences of professional opinion may indicate that using procedural modifications to mollify critics is easier than engaging in the hard work of transforming a culture to embrace scientific disagreement and dissent and handle them in a constructive and transparent manner. Organizational literature shows that the bureaucratic cultures of public organizations are frequently rigid, authoritarian, and oriented toward obeying orders rather than toward innovation and independent thought (Kets de Vries and Miller, 1986; Claver et al., 1999; Khademian, 2002; O’Leary, 2006). That could explain why it is so easy to turn to policy and procedure development. However, it is important to note that the inflexibility and conformity that characterizes some government agencies are at least in part created by the requirements of Congress and the Office of Management and Budget. As described above, creating a healthy organizational culture in CDER depends on more than the efforts of management and staff—the external environment, including the top levels of the executive branch and relevant congressional committees. The tension between the approaches of CDER professionals who focus largely on the premarketing period of a drug’s lifecycle and those who deal with the postmarketing period is not unusual (consider, for example, areas of scholarship where the practitioners of quantitative and qualitative methods come in conflict). However, the friction has often been unconstructive, particularly when the goal is to achieve close integration of the two approaches, and to facilitate an atmosphere of mutual respect and appreciation between the two sets of disciplines involved. Facilitating such a shift, from an uneasy relationship to a collaborative and constructive one, requires skilled management and leadership. The committee believes that a public health orientation and a lifecycle approach to understanding and minimizing the risks posed by drugs is best served by better and formal integration of the OND and ODS/OSE perspectives. The committee understands that new drug review and approval are undertaken with a matrix team approach, however it notes with concern the lack of formal participation of ODS/OSE in the review team. That might reflect a sentiment in CDER that ODS/OSE has only incidental contributions to make to the intellectual basis of new drug review and to recommendations about postapproval regulatory actions. A strengthened ODS/OSE would have much to contribute. The committee believes that in keeping with the goal of an integrated lifecycle approach to considering drug safety, mechanisms for anticipating potential postmarketing safety issues at the time of approval can be formalized and strengthened. Although OND retains authority over approval decisions, the committee believes that ODS/OSE’s role in the approval process needs to be formalized, specifically in the area of postmarketing safety.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 3.4: The committee recommends that CDER appoint an OSE staff member to each New Drug Application review team and assign joint authority to OND and OSE for postapproval regulatory actions related to safety. To formalize the changes recommended above, CDER’s GRMP should be modified as appropriate. The ODS/OSE team member should be responsible for formal review of and comments on the clinical reviewer’s “Integrated Review of Safety” (Section 7 in the Clinical Review Template) and for authoring the “Recommendation for Postmarketing Actions” (Section 9.3 in the Clinical Review Template). Through their active and formal participation in the NDA review process, ODS/OSE staff members would develop a fuller appreciation of the risks as well as the benefits associated with a drug, which some have stated they do not now have because of their exclusive focus on postmarketing safety. That appreciation would strengthen their evaluation and advice on postmarketing safety actions, which have been described as too risk-averse and lacking in understanding of the efficacy data and clinical context, that is, the benefits of the drug to individual patients. In addition, active participation could lead to better communication and understanding between the clinical reviewers and the epidemiologists, who have been described as “speaking different languages.” The committee believes that following this recommendation would help to break down cultural barriers between OND and ODS/OSE as staff work together on integrated review teams with the common goal of evaluating and ensuring drug safety and efficacy over a product’s lifecycle. However, bringing the two types of staff together in teams is not sufficient to facilitate mutual understanding and appreciation. Additional efforts are needed to apply this ethos to all interactions between pre- and postmarketing, and OND and ODS/OSE staff. The committee was pleased to learn about plans in ODS/OSE to conduct a class to orient OND colleagues to the approaches and methodologies employed by ODS/OSE epidemiologists. The committee hopes that the leadership of the center will initiate other such efforts and sustain them. The goal of a more integrative, lifecycle approach to drug risk and benefit is to have a preapproval process in which there is more active discussion about using clinical trial data to move drugs out quickly for high-need populations while coupling the process with far greater attention to a comprehensive plan for addressing uncertainties or emerging risks when used after marketing in lower-need populations. Incorporating a lifecycle approach to risk and benefit into various aspects of CDER organizational culture and communicating that fact to all stakeholders could help bring speed and safety into optimal balance.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public The committee is aware that consumer advocates, legislators, and others have asserted that the only solution to what, in their view, appear to be intractable problems in CDER with regard to ensuring drug safety and efficacy would be to create a separate center in FDA (or even a separate agency) to work on postmarketing safety. The committee acknowledges the legitimacy of the concerns that underlie such proposals, and it recognizes that if the full complement of recommendations made in this report fails to restore public trust in CDER’s (and FDA’s) credibility, competence, and appearance of independence, the secretary of DHHS and Congress may have no alternative but to mandate substantial structural changes in the agency. The committee believes, however, that if the recommendations made in this report are implemented fully and change is sustained, other, more drastic measures would be unnecessary. Safety and efficacy must always be in balance, and the ideal organizational solution is a team approach to assessing both. Achieving a balanced approach to the assessment of risks and benefits would be greatly complicated, or even compromised, if two separate organizations were working in isolation from one another. Premarket reviewers develop extensive knowledge based on years of experience of monitoring and reviewing the results of the premarket studies, and the system would stand to lose a great deal if that knowledge were excluded from postmarketing safety considerations. External Environment As described above, the environment that shapes the culture of CDER and FDA is the product of societal expectations, legislative imperatives, and economic forces. PDUFA represents a convergence of these factors. Although PDUFA has led to increases in the speed of review and has facilitated patient access to innovative drugs, it has also altered the environment in CDER, increased the pressure on reviewers to meet review deadlines, and perhaps even affected the agency’s relationship with sponsors. The presence of PDUFA performance goals for review timeliness has increased agency accountability to Congress and sponsors and has contributed to the success of this reform in increasing review speed over time. However, the existing PDUFA goals relate only to the speed of approval or non-approval decisions and do not also reflect goals related to safety. If PDUFA is reauthorized in 2007, the committee believes that the goals on which FDA reports to Congress need to include actionable performance goals for drug safety activities in the premarket and postmarketing periods to ensure that important agency functions receive sufficient resources. That would also help to demonstrate that timeliness and safety are valued equally, just as risks and benefits must be assessed together. There are now no explicit safety-related

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The Future of Drug Safety: Promoting and Protecting the Health of the Public goals that drive CDER’s work, whether or not associated with PDUFA funding. Introducing new safety goals would be consistent with the lifecycle approach to regulation. The committee offers a series of suggested goals to assist CDER in thinking about ways to couple accountability for timeliness and safety. Such goals will ideally be quantifiable. Whether or not PDUFA is reauthorized the committee believes it is important to measure and report on achieving safety goals. 3.5: To restore appropriate balance between the FDA’s dual goals of speeding access to innovative drugs and ensuring drug safety over the product’s lifecycle, the committee recommends that Congress should introduce specific safety-related performance goals in the Prescription Drug User Fee Act IV in 2007. Those goals, independent of funding source, could include the following (organized topically): Expertise in preapproval evaluation: Target participation rate for ODS/OSE staff involvement in drug review teams: for priority original NDA and biologic license application submissions 60 percent year 1, 70 percent year 2, 80 percent year 3, 90 percent year 4, and 100 percent year 5; for standard original NDA and BLA submissions 40 percent year 1, 50 percent year 2, 60 percent year 3, 70 percent year 4, and 80 percent year 5. Report annually to Congress on the number of new molecular entities (NMEs) for which data were evaluated by external advisory committees, and the proportion of all NME NDAs that that number represents. Monitoring of adverse drug reactions and Adverse Event Reporting System (AERS): Prepare a summary analysis of the adverse drug reaction reports received for a newly approved drug, which identifies any new risks not previously identified, potential new risks, or known risks reported in unusual number not previously identified within 18 months of drug launch or after exposure of 10,000 persons, whichever is later. Reports should be publicly available and posted on the agency’s Web site. Conduct regular (biweekly) screening of the AERS database, especially 15-day reports, to identify new safety signals. Ensure that public access to AERS reports is updated every 6 months.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Postmarketing study commitments: Review the entire backlog of postmarketing commitments to determine which commitments require revision or should be eliminated and report to Congress on these determinations. Of commitments that remain, those without start dates should have start dates associated with them to prevent perpetual “pending” status (12 months from PDUFA IV initiation) (also see Chapter 5 for a discussion of postmarketing, or Phase IV, commitments). Report completion rates (by company) for (i) postmarketing studies requested prior to approval and (ii) postmarketing studies requested when a drug is already on the market and the number of delinquent studies (past the original projected completion date) in each category. Report on enforcement actions taken to ensure timely completion of postmarketing study commitments (for commitments that are currently required, such as those associated with accelerated approval, and for other commitments FDA will be able to require and enforce after implementation of recommendations made in Chapter 5). Review and propose action, if warranted, on completed postmarketing studies (within 60 days from submission of the study for actions deemed urgent, 120 days for less urgent actions). Postmarketing risk communication activities and risk management: In the annual PDUFA performance report to Congress, include the timeliness of implementing regulatory actions10 (from the date of the agency’s initial proposed action to the date of the actual labeling change) and the number of such changes. In the annual PDUFA performance report to Congress, include the number of patient information sheets developed for new drugs and the proportion of new drugs approved in that year for which patient information sheets are developed. (The committee recognizes that DrugWatch and other activities of the Drug Safety Oversight Board are still under development. The final outcome could affect the relevance and usefulness of this suggestion.) Review an applicant’s implementation of risk management plans and make the report available on the agency’s Web site. Review and act on drug advertisements and promotional materials submitted to the agency (within 90 days in year 1, 60 days in year 2, 30 days in year 3 and beyond). 10 Including labeling changes, black boxes, and measures leading to drug withdrawal (see Chapter 5 for discussion and recommendations on strengthening FDA’s authority).

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Performance management: Convene an open forum 12–18 months before renewals of the PDUFA to solicit public and industry comments on proposed and existing safety goals for FDA. In the annual PDUFA performance report to Congress, include the status of meeting of all agency safety goals. Discussion among all stakeholders is needed to consider what goals would be the most valuable from a public health perspective. REFERENCES Abraham J, Davis C. 2005. A comparative analysis of drug safety withdrawals in the UK and the US (1971-1992): implications for current regulatory thinking and policy. Soc Sci Med 61(5):881-892. Alonso-Zaldivar R. 2006. Without Clear Leadership, the FDA Is Falling Short. [Online]. Available: http://seattletimes.nwsource.com/html/health/2002968229_fda03.html [accessed June 5, 2006]. Berndt ER, Gottschalk AHB, Strobeck MW. 2005 (June). Opportunities for Improving the Drug Development Process: Results From a Survey of Industry and the FDA. National Bureau of Economic Research (NBER), Working Paper 11425. BIO (Biotechnology Industry Organization). 2002 (May 21). FDA Commissioner. Letter to the Honorable George W. Bush. Bridges A. 2006. Plan B Pill Snarls FDA Nominee Hearings. [Online]. Available: http://www.nexis.com [accessed August 1, 2006]. Carpenter D, Chernew M, Smith DG, Fendrick AM. 2003. Approval times for new drugs: does the source of funding for FDA staff matter? Health Aff (Millwood) Suppl Web Exclusives W3-618-624. CDER (Center for Drug Evaluation and Research). 2004a. Clinical Review Template, MAPP 6010.3. [Online]. Available: http://www.fda.gov/cder/mapp/6010.3.pdf [accessed May 19, 2006]. CDER. 2004b. Documenting Differing Professional Opinions and Dispute Resolution—Pilot Program, MAPP 4151.2. [Online]. Available: http://www.fda.gov/cder/mapp/4151.2.pdf [accessed June 20, 2005]. CDER. 2005. Review Management: Risk Management Plan Activities in OND and ODS, MAPP 6700.1. [Online]. Available: http://www.fda.gov/cder/mapp/6700.1.pdf [accessed November 14, 2005]. CDER and FDA. 2005. Drug Safety Oversight Board Membership Center for Drug Evaluation and Research. [Online]. Available: http://www.pharmtech.com/pharmtech/article/article-Detail.jsp?id=163473 [accessed June 29, 2005]. CDER, FDA, DHHS. 2005. Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review. [Online]. Available: http://www.fda.gov/cder/guidance/3580fnl.pdf [accessed December 30, 2005]. Claver E, Llopis J, Gasco JL, Molina H, Conca FJ. 1999. Public administration: from bureaucratic culture to citizen-oriented culture. Int J Pub Sector Man 12(5):455-464. Coffee JN. 1993. A Comparative Study of Organization Culture Change in Federal Agencies’ Success Patterns of Long-Term Efforts. Los Angeles: University of Southern California. Cohn J. 2003. Politics, Profits & Pharma. [Online]. Available: http://www.pbs.org/wgbh/pages/frontline/shows/prescription/politics/ [accessed September 14, 2006].

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