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.
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.
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
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).
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-
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”
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).
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-
A Short History of the Prescription Drug User Fee Act (PDUFA)
Use revenues from user fees to achieve certain “performance goals”
PDUFA I Commitments:
PDUFA II was reauthorized for 5 years (FY 1998–2002) as part of Title I of the Food and Drug Administration Modernization Act
New PDUFA II commitments:
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-
Changes in commitments
PDUFA III was reauthorized for 5 years (FY 2003–2007) as part of Public Health Security and Bioterrorism Preparedness and Response Act
New PDUFA III commitments:
Changes to commitments:
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
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].
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
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
and postmarketing activities are that authority over postmarketing safety is solely in the hands of people who did the work of reviewing and approving a drug and that postmarketing safety activities appear to be secondary or subservient to the premarket processes and the task of approving drugs for marketing (Wolfe SM, 2006).
CDER’s culture seems to have been influenced by how premarket and postmarketing functions have been divided historically. Randomized controlled trials are the gold standard for studies leading to drug approval. Epidemiologic, population-based studies are used after approval, when a drug is on the market and being used in real-life circumstances. Medical knowledge derives from both randomized clinical trials and epidemiologic studies (including observational studies that use automated health care databases), but the methods of the two approaches differ, as does the degree of confidence that can be accorded analytic results. Although the two approaches are complementary and can both be valuable depending on the nature of the medical problem addressed—for example, population-based studies provide different kinds of information that randomized controlled studies do not deliver before approval—recent depictions of the workings of CDER suggest that the disparate respect afforded to results of the different approaches adversely affects interactions when uncertainties about the data abound and the “call” regarding regulatory action is close. Most OND reviewers are physicians who are trained to analyze prospective, randomized controlled clinical trial data, whereas the ODS/OSE staff, including the safety evaluators and the epidemiologists, must typically work with uncontrolled or observational data. Most data bearing on safety issues generated and reviewed in the postmarketing period are from case reports and from epidemiologic studies. Recent controversies show that there is sometimes a marked difference of opinion between OND and ODS/OSE about the interpretation of such data. OND staff often view observational data as “soft” and unconvincing, whereas ODS/OSE staff see them as informative and carrying great weight in evaluating postmarketing safety questions.
The interdisciplinary tension is also an obstacle to full implementation of a lifecycle approach to drug regulation, in which the preapproval process actively and creatively involves anticipation of postapproval uncertainties and a plan for addressing them. That is a clear example of how structure and culture can connect. A structure that provides opportunities for crosscutting discussion and methods—an interdisciplinary “team approach”—would go a long way to encouraging a collaborative culture, in which differing viewpoints and types of expertise can make a contribution.
In the last decade, there have been four major restructuring efforts in the variously named office responsible for postmarketing safety and in CDER; most recently, steps have been taken to clarify and elevate the previously ad hoc role of ODS/OSE as part of a broader effort to “sustain a multi-
disciplinary, cross-center approach to drug safety” (Galson email to staff, May 15, 2006; see also Appendix A). Although those efforts may reflect CDER’s desire to improve the effectiveness of its safety surveillance programs, the frequency of repositioning organizational “boxes” and changing unit names raises concern that such changes are more cosmetic than functionally effective responses to public dissatisfaction with the CDER’s performance. Committee discussions with CDER staff and the history of reports documenting problems in CDER suggest that previous efforts at restructuring did not fundamentally alter the characteristics of or the relationship between OND and ODS/OSE or the morale and functioning of the center. Thus, the committee is not convinced that the recent changes will succeed without additional specific actions.
Policies and Procedures
The committee has reviewed the relevant CDER guidance documents and the numbered documents in the Manual of Administrative Policies and Procedures (individual documents are known as MAPPs)4 to understand the current structure defining the roles of OND and ODS/ODE, and it reviewed various congressional and public proposals for restructuring (CDER et al., 2005; FDA, 2005d; Grassley, 2005; Johnson and US PIRG, 2005).5 The committee has also discussed the technical or administrative details with the appropriate FDA staff and managers, and reviewed reports describing the many dimensions of drug regulation and its challenges (GAO, 2002, 2006; DHHS and OIG, 2003; Thaul, 2005).
CDER constitutes teams for New Drug Application (NDA) reviews (see Box 3-3). OND plays a formal lead role in most regulatory actions, and OND reviewers sign components of the approval package; OND managers (division directors, office directors, and the OND director) act in a final
A description of MAPPs is available at http://www.fda.gov/cder/mapp.htm.
CDER has issued several guidances and MAPPs related to the preparation of the review package; several of these are mandated by the PDUFA. FDA’s guidance documents include the following disclaimer: “This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance … FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, Guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word ‘should’ in Agency guidances means that something is suggested or recommended, but not required.” MAPPs, however, establish procedures to be used (with variations, as appropriate) by CDER staff.
Composition of the NDA Review Team
Review teams include a review project manager (RPM) and primary reviewers, who complete the discipline reviews, as needed, in the following disciplines:
SOURCE: FDA (2005d).
decision-making capacity in most cases. Some members of the review team, such as statisticians, work in offices other than OND. The committee has learned that there is little integration of and a limited role for ODS/OSE staff in the premarket review process; they work in a consultative and supportive capacity and, with one exception, have no regulatory authority (CDER, 2005; GAO, 2006). Although postapproval responsibilities for ODS/OSE have been growing, resources have improved only modestly (since 2004, a growth from 94 to 132 full time equivalents dedicated to postmarketing safety), and its formal role has not expanded.
FDA’s Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA Products (GRMP) outlines in great detail the roles and responsibilities of the team leaders and reviewers drawn from other disciplines in CDER. It also addresses so-called consults from non-team members, such as staff from ODS/OSE, the Office of New Drug Chemistry, and the Division of Drug Marketing and Communication. The guidance document describes ODS/OSE staff as consultants, not as members of the review team, and their formal responsibilities, other than
participating in consults, include participation in the preapproval safety conference and review of product labeling. The only formal authority given to ODS/OSE is to grant waivers to the industry sponsors of the postmarketing reporting requirements in 21 CFR 314.80.
The PDUFA deadlines, which affect mostly OND staff, may play a role in contributing to an organizational structure that limits ODS/OSE involvement. Review packages accompanying an NDA approval letter include what are called discipline reviews, often long documents written by CDER scientists reviewing material in a specific scientific discipline submitted by an applicant in support of the NDA. Discipline reviews and other documents related to the review of a drug, such as the approval letter, are made public on FDA’s Web site only if an application is approved for marketing (see Chapter 4 for additional discussion). Review packages for products that are not approved are not made public. The clinical review is usually written by one OND staff person and includes summaries by the clinical reviewer of other discipline reviews.
A policy and procedure (MAPP 6010.3, see Box 3-4) (CDER, 2004a), the Clinical Review Template introduced in 2004, provides an opportunity for formal involvement of ODS/OSE medical officers in the review process. The purpose of the MAPP was to standardize the safety review components of an NDA and in particular the approach to postmarketing safety of the product (Racoosin, 2006). The MAPP suggests options for involvement of more than one OND clinical reviewer. If there is more than one, a lead reviewer is identified and has the responsibility for writing the overview and section 4.3, which describes how the review was prepared. Two options exist for the final review; one allows for multiple reviews by multiple authors incorporated into a single overview, and the other limits the review package to one final clinical review with sections prepared by multiple reviewers.
Although there is no formal public documentation of changes instituted by the MAPP, the committee’s informal review of NDA packages approved before July 2004 suggests that the “Recommendation on Postmarketing Actions” introduced a substantial change in the clinical review template by creating a location in the review package for a review and recommendations on postmarketing actions pertaining to the drug to be approved. Based on a review of more recent NDA packages, it appears that the new template is being used by reviewers of new drugs, but the committee believes that that responsibility would be a reasonable and appropriate function for ODS/OSE medical officers.
There have been many opportunities for CDER and FDA leadership to acknowledge to the committee and to others that there is a culture problem
Clinical Review Template—Postmarketing Actions
In July 2004 CDER issued MAPP 6010.3, the Clinical Review Template (CDER, 2004a), which established procedures for documenting the primary clinical review of NDAs. The clinical review is one of the discipline reviews prepared in response to an original or supplemental NDA (or Biologic License Application reviewed by CDER), amendments in response to action letters, and efficacy supplements. The MAPP describes the format of the discipline review and the responsibilities of the reviewers, other team members, and those in the supervisory chain. The review template includes 11 sections:
Section 9.3 of the template (part of Overall Assessment) is entitled “Recommendation on Postmarketing Actions” and includes subsections on “Risk Management Activity,” “Required Phase 4 Commitments,” and “Other Phase 4 Requests,” and a review of and recommendations for the applicant’s postmarketing risk management plan.
in CDER. However, although agency and center leaders generally mentioned the flurry of drug safety activities being undertaken, they did not seem to recognize the tensions and other strains within the center as anything more than a minor distraction. On the basis of its discussions with current and past FDA employees (both staff and management), and its review of several government reports and other relevant literature, the committee believes that CDER’s organizational culture is characterized by problems in several important areas: a suboptimal work environment, a polarization between
two major functions, an underestimation and poor handling of scientific disagreement and differences of opinion, a lack of consistency across divisions, and instability and politicization at the top (in the Office of the Commissioner). The committee believes that these issues may directly or indirectly affect CDER’s handling of drug safety concerns.
A Suboptimal Work Environment
There is evidence of a persisting problem with retention, turnover, and morale in CDER. CDER’s organizational culture does not seem to readily embrace the values of staff participation, inclusion, and empowerment that are generally thought to be essential to a healthy organization (Coffee, 1993). Relevant staff members are sometimes excluded from planning of administrative and program improvements and their initiative in proposing improvements is not well received (or “received” at all). Staff members are sometimes left out of discussion and decision making about the future of the center, new initiatives, etc.
Two government reports provide some information suggestive of potential difficulties in the CDER work environment. A GAO report (GAO, 2002) on the rate of safety withdrawals after enactment of PDUFA found that attrition among medical officers and other relevant FDA staff from 1998 to 2000 was noticeably greater than attrition in similar disciplines at the National Institutes of Health and the Centers for Disease Control and Prevention (10.5 percent vs. 5.5 and 4.7, respectively). Although one explanation for the turnover is that FDA staff leave for promising opportunities in industry (that arguably leads to a propagation of competent individuals with regulatory agency experience throughout industry), it is possible that turnover is indicative of a less-than-ideal organizational culture that requires attention. The GAO report attributed the turnover to reasons that included workload and decreased training opportunities. FDA data in a 2003 report on the drug review process showed that medical officers and pharmacologists had the highest attrition rates in CDER (DHHS and OIG, 2003).
The committee learned from its conversations with OND staff that their considerable workloads and time pressures exacerbated by PDUFA make it difficult for them to be as thorough as they would like in their assessments of safety after marketing. The committee’s discussions with CDER staff resonated with the findings of previous assessments—reviewers of new drugs are often overwhelmed merely keeping up with the routine aspects of review, which leave little time to consider postmarketing safety plans thoughtfully, or to investigate (for example, with colleagues in other disciplines) safety signals that arise after approval (IOM Staff Notes, 2005–2006). In such circumstances, it is little wonder that professional development and
internal interaction to facilitate communication and understanding among divisions and offices become luxuries. In 2005, a group of OND medical officers organized itself to identify possible causes of attrition and to make recommendations to CDER management about ways to improve retention (Medical Officer Retention Subcommittee, 2006). The group’s recommendations included addressing OND reviewer workloads by hiring more staff, increasing division and office director awareness of reviewer needs, redefining the CDER vision, and in general transforming the CDER leadership philosophy. Members of that staff subcommittee expressed concern that the leadership philosophy in CDER did not encourage staff participation and input at all levels (Medical Officer Retention Subcommittee, 2006).
The failure of management to implement effective changes to address those important issues indicates that there is a problem. ODS/OSE and OND staff have reported being left out of regulatory meetings directly related to their work, and ODS/OSE staff have frequently been left out of relevant advisory committee meetings (GAO, 2006). There is evidence of a lack of consistent processes to facilitate and resolve safety issues identified by ODS/OSE and passed on to OND. The 2006 GAO report’s finding that ODS/OSE consults and questions often went into a “black hole” and that initiating staff never received feedback is consistent with what this committee learned.
Some staff-generated ideas for process or culture improvements appeared to receive little or no attention from management. In its 2006 report, GAO noted that in December 2004, ODS epidemiologists requested a broadening of their role to include “presenting all relevant ODS data at advisory committee meetings” but management did not respond (GAO, 2006:22). To the best of the present committee’s knowledge, CDER management also did not respond to the OND Medical Officer Retention Subcommittee’s May 2005 proposal until June 2006. The committee was surprised to find out that although the Drug Safety Oversight Board (DSB) had been introduced to a variety of audiences (Congress, the public, etc.), some CDER staff seemed uninformed about what the board was expected to accomplish and how it could affect their work.
Management scholars have identified a strong attachment to the status quo in many organizations and a tendency to commit “sunk cost” errors by pursuing a course of action because so much has already been invested in it (Edmonson et al., 2005). A panel convened by the National Aeronautics and Space Administration after the Columbia disaster identified similar organizational tendencies, noting, for example, that “once the Agency is on record as committed to a specific achievement, it becomes unpalatable to back off of that target for fear of appearing to fail” and that there was an attitude of “comfort with existing beliefs” that justified a resistance to
internal or external criticism and a stifling of dissenting views (Return to Flight Task Group, 2005; O’Leary, 2006). The perception that there are somewhat similar cultural attitudes in CDER is evident in the concerns of consumer advocates and academics and confirmed by the DHHS OIG and GAO reports that new drug reviewers feel pressured by the unstated expectations of the agency leadership (due to PDUFA goals and other reasons) to approve drugs and are unable to revise the regulatory approach to an already-approved drug.
The committee has seen evidence of a divide between the premarketing and postmarketing staff in CDER (generally represented by staff in OND and staff in ODS/OSE, respectively). ODS/OSE staff has been left out of regulatory discussions and advisory committee meetings (GAO, 2006; IOM Staff Notes, 2005–2006). The user-fee funding system may have also allowed (or at least exacerbated) the emergence of a major resource gap between OND and ODS/OSE (IOM, 2005; IOM Staff Notes, 2005–2006; Zelenay, 2005; GAO, 2006) (also see Chapter 7 for a more detailed discussion of the funding and staff imbalance). Although the committee did not explore the history of this divide, conversations with CDER leadership revealed disparities in how the two offices and their contributions to the agency’s work are regarded. The 2006 GAO report has also confirmed the difference in status between the two offices. Given the high-profile concerns about drug safety, the fact that an office bearing the title of “Drug Safety” had a lower status than an office of “New Drugs,” and agency spokespersons appeared dismissive of the work of staff in that office may have also exacerbated the perception of tension (Harris, 2006b). The committee is aware that there have been repeated attempts to reorganize or restructure CDER, both by moving boxes around a chart and by developing internal policies, procedures, and guidance documents (as described above), but culture problems have persisted.
The committee has seen little historical evidence of successful initiatives to strengthen ODS/OSE capabilities or to stabilize the office, which has experienced eight changes in leadership and four reorganizations in the past 10 years (GAO, 2006). Although the committee was encouraged by the appointment of a new permanent ODS/OSE director (after much turnover in that position [GAO, 2006]) and by evidence of planning to improve communication and collaboration between OND and ODS/OSE, it remains concerned that these attempts are “too little, too late.”
The committee believes that management in CDER has not done enough to cultivate an atmosphere of mutual respect and appreciation across some
of the disciplines. In interactions with CDER leadership, the committee formed the impression that ODS/OSE staff have been considered marginal players, compared with OND staff, in contributing to the work of ensuring drug safety. When the committee inquired about the apparent cultural divide in discussions with CDER leadership, it heard that ODS/OSE was not capable of a greater function in postmarketing safety because of a lack of qualified and trained staff, a lack of analytic sophistication, and inadequate understanding of the data and their weighing in the approval process. The committee also heard that problems between ODS/OSE and OND are simply a squabble, not warranting management attention. The GAO report (2006) appeared to touch a nerve when it interpreted ODS/OSE’s role of consultant to OND as secondary, not well defined, and lacking clear responsibilities. In its response to GAO, FDA argued that the consultative role is important and that the GAO report did not recognize that; but the agency did little to explain specific steps it would take to clarify the role of ODS/OSE and to pay more than lip service to its contributions. The committee acknowledges that some recent changes have occurred in CDER. Some have been on ODS/OSE’s own initiative—as the GAO report has acknowledged, the level of expertise and sophistication of analyses conducted by the office have evolved, and a promising new leader has been appointed to head the office (FDA News, 2005; GAO, 2006). As noted in Chapter 1 and in Appendix A, in the wake of highly publicized concern about the safety of some drugs approved by FDA, the agency and CDER announced the implementation of several strategies to improve attention to postmarketing safety and to strengthen the administrative processes that underlie drug safety work in FDA. Those strategies included two processes for dispute resolution at the staff level, and the establishment of the DSB for interdivisional difficulties (discussed below) (CDER, 2004b; CDER and FDA, 2005).
It does not appear that the various efforts to restructure CDER have improved interactions between review and postmarketing staff. The dispute resolution mechanism has yet to be used, and mass media reports about emerging drug safety concerns continue to give the appearance that the center is not managing those concerns adequately. On several occasions when the findings of safety staff have been cited in the mass media, agency spokespersons have downplayed or disparaged the information’s quality or completeness, instead of assuring the public that the agency takes the concerns of its staff seriously and that staff collaborate to bring such important questions to resolution. New documents to guide CDER staff have not necessarily translated into greater clarity and effectiveness at the level of interoffice relationships and procedures; in fact, there is a continuing lack of established mechanisms for communicating about and following safety signals between offices. That attitude was apparent on numerous occasions when members of this committee spoke with FDA and CDER management
who described ODS/OSE as lacking in needed expertise, sophistication, and depth of experience (IOM Staff Notes, 2005–2006). That disparity in management attitudes toward OND and ODS/OSE is also suggested by information provided in the 2006 GAO report, in the comments of FDA officials to the press, and in a recent response from the CDER director to an internal group’s proposal to address medical officer attrition. May and June 2006 newspaper articles about the agency’s handling of drug safety concerns about an antibiotic indicated that some postmarketing safety staff expressed concerns that were not addressed in a timely manner by CDER management. An FDA spokesperson described a safety reviewer’s report of her concerns “a preliminary, raw assessment” and stated that “the final decision will be made by experts who have the full benefit of a large section of opinion and scientific fact” (Harris, 2006a).
Underestimation and Poor Handling of Scientific Disagreement and Differences of Opinion
Management’s difficulties in addressing internal agency conflict and scientific disagreement transparently and competently, in communicating scientific uncertainty to diverse audiences effectively have played an important role in damaging the credibility of CDER and the FDA. As discussed in Chapter 4, the regulation of drugs rests on a foundation of incomplete but growing knowledge, and the risk-benefit assessment for every drug continues to evolve after approval, when use of the drug moves from the carefully controlled confines of clinical trials to the largely uncontrolled and much more complex circumstances of real-life prescribing and use. Legitimate scientific disagreement may occur at various points in the lifecycle of a drug. There may be disagreement about whether a reasonable threshold of certainty has been reached to justify approval (the absence of standard approaches to the risk-benefit assessment before approval is discussed in greater detail in Chapter 4). After approval, there may be scientific disagreement about the interpretation of adverse event signals (for example, there is no clear guidance on when a noise becomes a signal) and about what regulatory action is warranted.
The committee is concerned about information suggesting that scientific disagreement in the center is sometimes handled in ways that may create an inappropriate atmosphere of pressure or poor tolerance of disagreement. The 2003 DHHS OIG report of survey findings on 401 CDER reviewers (most in OND) stated that “18 percent of respondents indicated that they have felt pressure to approve or recommend approval for a drug, despite reservations about its safety, efficacy, or quality” (18 percent accounts for about 72 of 401 respondents to the survey). Although scientific disagreement is understandable and there are cases where a division or office director
disagrees with a reviewer’s recommendation on the basis of the science, having even one or two staff members who report pressure to approve or recommend approval is an entirely different and deeply troubling occurrence.6
In its visit and later discussions with FDA staff, the committee learned that differential valuation of disciplinary approaches affects the relationship between OND and ODS/OSE and contributes to a perception in each office that its counterpart does not have the full picture or does not give enough consideration to colleagues’ different disciplinary perspectives. Although OND staff includes physicians, some of whom have training in statistics or epidemiology, their efforts are oriented substantially toward review of data from randomized controlled trials, and their experience with and confidence in epidemiologic studies may be slight. ODS/OSE staff, in contrast, have a greater level of comfort with epidemiologic approaches but less familiarity with randomized controlled trials and their analysis. But as mentioned above, the imbalance in formal role and authority between the new drug review staff and surveillance and epidemiology staff denotes subservience of the safety function, and a management devaluation of the latter discipline and approach.
The DSB, which consists of staff members of several CDER offices and representatives of other FDA centers and other government agencies is established to “improve public knowledge of emerging important drug safety concerns; strengthen internal drug safety management; foster practical policy development to improve consistency and timely resolution of important drug safety concerns; and provide a standing venue for resolution of CDER organizational disputes” (Cummins, 2006). Including members drawn from CDER offices not primarily responsible for any given product or issue, and from other federal agencies, is intended to provide some independent oversight regarding emerging issues while maintaining the ability to convene quickly without conflict-of-interest considerations or concern about the discussion of proprietary matters. Items for discussion can be brought to the DSB by a CDER division or by OND or ODS/OSE leaders. It is not
clear whether DSB can on its own initiative address an issue of which it has become aware if it is not formally referred to them. The DSB emerged as part of the agency’s response to congressional and public concern over highly publicized drug safety problems. Because many critics called for independent external oversight of drug safety, the creation of the board was believed by some to be a solution to address that particular concern (FDA, 2005c). The composition of the board caused confusion and gave rise to criticism that the board as constituted was not independent. That confusion was furthered by FDA’s silence on the board’s actual (and potentially useful) function, and the underlying public and legislative concern about independence was left unaddressed. Because the DSB has been in operation for only a short time, it is too early to judge its effectiveness, but some of its drug safety problem resolution, management, and policy functions seem to constitute a sensible approach. DSB is analogous to industry practices of bringing together leaders of different groups in a company to consult with a group facing a difficult problem. However, the committee believes that the external communication function of the board seems to be a vastly different and equally important set of concerns that should be handled by a different entity in CDER (see Chapter 6). That would allow the DSB to focus its energies and resources on addressing the internal management of drug safety issues.
There has been additional confusion about the apparent overlap between the Drug Safety and Risk Management Advisory Committee (DSaRM) and DSB. CDER management has described the latter as a “venue for resolving CDER organizational drug safety disputes” and “discussing [the] need for AC [advisory committee] meetings about emerging safety information” whereas DSaRM has been described as a way to obtain public input and facilitate discussion to inform CDER decision making. The committee believes that DSaRM fulfills the function of the sought-after independent, external safety advisory and review body, in contrast with DSB, which is intended to bring serious and complex internal safety issues to resolution.
Many interactions in CDER appear to be idiosyncratic and personality-driven. The committee understands that there is great variation within and among drug classes and from one product to another and that flexibility is desired. However, there seem to be subjects on which consistency would be beneficial, for example, methods of risk-benefit analysis, preapproval decisions on postmarketing studies, handling of disagreements between offices, ODS/OSE participation in the review process, monitoring of drug safety signals after approval, responding to drug safety signals, communication of important risks to the public, and followup of postmarketing study commitments. Some best practices have not been disseminated throughout CDER.
For example, one division’s model for ensuring internal safety capacity by establishing its own safety team of epidemiologists has attracted interest in CDER and from drug safety advocates but has not yet been replicated in any other division (the committee has heard that this model may be expanded to other divisions).7
Instability and Politicization at the Top
The absence of stable leadership at the commissioner level and lack of consistent oversight of CDER by the commissioner may have contributed to overarching management problems in CDER. Although the day-to-day work of CDER is not immediately affected by what is happening in the commissioner’s office, the recurring absence of a confirmed commissioner has implications for the agency. First, the absence of stable leadership has meant much more than going without an agency figurehead. As discussed above, the external environment places great pressure on FDA and its centers, and the agency’s top leadership plays a crucial role in setting the course for the agency and in mediating the effects of external pressures by representing the agency in interactions with other government agencies, Congress, the industry, and the public. An acting commissioner does not carry the same weight symbolically, and lacks the authority to articulate agency positions. PDUFA reauthorization talks in 2002 were reportedly slowed down by the lack of a commissioner (Validation Times, 2002). An individual in an acting capacity also may be unable to act decisively; such a person would likely defer making any difficult decisions or setting a new course for the agency. Furthermore, staff may be unlikely to take such a leader seriously because an acting position is by its very definition temporary (Miller, 2006; Ross, 2006). In cases when an acting commissioner is also the president’s nominee facing the prospect of challenging Senate hearings, making decisions on high-profile issues could potentially complicate the road to confirmation. As appointing and confirming a permanent commissioner is delayed, FDA staff and the public may also conclude that their government does not consider a commissioner’s position important, and that may have demoralizing consequences on staff and affect the agency’s credibility (Kaufman, 2004b; Alonso-Zaldivar, 2006).
Industry leaders have asserted that the lack of a leader leads to an increase in agency caution and a decrease in predictability in the eyes of companies and investors (Young, 2005). In 2002, the Biotechnology Industry Organization (BIO) petitioned President George W. Bush to appoint
a commissioner, arguing that the industry and the nation needed “strong leadership from an FDA commissioner with vision and experience in science, medicine and administration” (BIO, 2002). In the same year, the PhRMA president and CEO reported that the industry was challenged by the absence of agency leadership and that PDUFA negotiations were slowed down by the absence of a commissioner (National Journal’s Congress Daily, 2002; Validation Times, 2002). Former commissioner Jane Henney stated that in the absence of leadership, “industry loses because it needs predictable and strong signals about the review process, the consumers need to make sure somebody is in charge and the FDA staff needs somebody who can take the heat if necessary” (Kaufman, 2004a). In 2002, FDA staff were questioned in a congressional hearing without the support of a Senate-confirmed commissioner (Kaufman, 2004a). In the 2005 Senate committee session on the nomination of the then Acting Commissioner, Senator Enzi cited a letter from the Senate committee to the president urging the nomination of a commissioner “to provide the agency with greater clarity and certainty in its mission,” and stated that a “fully confirmed Commissioner is essential to ensuring that these medical breakthroughs can be brought to the market safely and effectively. Consumers deserve to have a fully functional FDA that can oversee the industry with confidence and authority and harness the technical achievements that can improve and save lives” (Senate Executive Session, July 18, 2005).
Management literature has made it clear that organizations, including government agencies, cannot function well without effective leadership to set them and keep them on course to achieve their mission (GAO, 1996). In the last 30 years, FDA has had eight commissioners and seven acting commissioners (including the current acting commissioner) or, when the post was vacant, an acting principal deputy commissioner. The eight commissioners have served an average of 2.5 years with a range of 2 months to 6.3 years (FDA, 2006b). That instability is thought to have contributed to CDER’s problems. CDER is the largest center in the agency, the center director reports to the commissioner, and the center’s decisions and their repercussions are highly visible and sometimes controversial, as was the case with the Plan B over-the-counter switch application (GAO, 2005). The committee believes that turnover and instability in the commissioner’s office leave the agency without effective leadership or the potential to emphasize safety as having high priority in the work of the agency. Without stable leadership strongly and visibly committed to drug safety, all other efforts to improve the effectiveness of the agency or position it effectively for the future will be seriously, if not fatally, compromised. A priority for the agency should be to regain the trust of the public while positioning itself for the future.
The controversy over the emergency contraceptive Plan B has further highlighted the power of the commissioner. In this area, the political environ-
ment interfaces with issues of leadership. Plan B, a prescription emergency contraception drug, was approved in 1999. In 2002, FDA staff met twice to discuss and prepare for the sponsor’s expected application for a switch of Plan B from prescription to over-the-counter (OTC) status. In April 2003, the sponsor submitted its supplemental NDA for the OTC switch, and FDA set a PDUFA goal date of February 2004 (for a total of 10 months, a typical timeline for a standard review) to reach a decision on the application. A joint meeting of the two relevant advisory committees—those for non-prescription drugs and for reproductive health drugs—concluded with a vote that overwhelmingly favored an OTC switch (GAO, 2005). However, the agency denied the application, raising questions about the basis for that decision making. In the end, it became clear that the ultimate decision was made in the Office of the Commissioner for reasons that were not clearly linked with a scientific rationale. The perception of political considerations overruling scientific judgment, even just in a single case, inevitably raises concerns about the legitimacy of decision making in every case.
Proposed Solutions to CDER’s Organizational Dysfunction
On the basis of its review of relevant government reports, conversations with present and former FDA staff and managers, and its examination of CDER guidance and policies and procedures documents, the committee finds that CDER’s organizational culture is under great strain and that change is needed to ensure that the center can fulfill its components of the FDA mission. The last several years of newspaper articles about FDA and CDER specifically and relevant public opinion polls have shown a decline in FDA’s credibility with the public, some scientists and academics, and others. Over the years, there have been multiple initiatives, taskforces, and panels on CDER’s work and multiple government reports identifying problems and recommending solutions. The fact that many substantial changes have not been made may be a primary symptom of management failure, a lack of leadership, and of a lack of appropriate oversight by Congress.
According to management research, organizational cultures that are constructive or healthy are more effective in accomplishing their mission. But cultural change may take many years to implement and requires sustained and comprehensive effort (GAO, 1996; Khademian, 2002). Assessments of federal agency management have found that when federal executives reorganize agencies, organizational culture is rarely a focus of attention—it is often an afterthought or considered a nicety irrelevant to the complex and technically challenging work of many government agen-
cies (Khademian, 2002).8 In that regard, FDA is no different. The consistent neglect of cultural problems in the organization betrays a lack of recognition of the importance of healthy culture. Even if FDA and CDER leaders do not see themselves as managers who stifle dissent or exclude participation from staff, that perception clearly exists (affecting agency credibility), and problems with retention and morale confirm it.
Healthy organizations require effective and stable leadership. The committee believes that there is an urgent need for a full-time, confirmed FDA commissioner who will be visible and forceful in creating a culture of safety by facilitating a systematic, science-based approach to continually assessing and acting on risk-benefit during the lifecycle of every drug (pre- and post-approval). The commissioner’s role is also to provide effective oversight of CDER, particularly given the strong external pressures on the center’s work. Many observers from industry and from the scientific community have expressed concern in recent years that the commission position has remained unfilled or filled by deputy commissioners functioning as acting commissioner for long periods of time.
The committee recognizes that the daily work of FDA staff may not be strongly affected by what happens in the office of the commissioner, but there is fairly widespread agreement, described above, that the absence of a commissioner has been a problem because without a legitimate, Senate-confirmed leader, it is harder for the agency to define and achieve its strategic vision.
The committee wishes to emphasize that in making the following recommendations, it does not imply that politics can or should be removed from a top scientific position, such as the FDA commissioner. However, it is important to the credibility of a science-based regulatory agency that scientific evidence, not solely political considerations, prevail in cases where high-profile regulatory decisions must be made. The Plan B decision described above may have undermined the agency’s credibility, as evidence
emerged that the basis for decision making was not scientific, but other types of considerations (Bridges, 2006; Rockoff, 2006; Washington Drug Letter, 2006).
Finally, the committee believes that a fixed-term appointment for the FDA commissioner may help to lessen turnover. Reports from GAO and from the National Academy of Sciences (NAS) have found that turnover in government agency leadership is linked with a focus on short-term goals and uncertain accountability and that fixed terms for presidential appointments help to ensure stability and strengthen an agency’s leadership (GAO, 1996; GAO, 2003). Currently, presidential appointment with Senate confirmation positions for fixed terms include: surgeon general of the Public Health Service, 4 years; director of the National Science Foundation (NSF), 6 years; commissioner of the Bureau of Labor Statistics, 4 years; under secretary for health in the Department of Veterans Affairs (also the Chief Executive Officer of the Veterans Health Administration), 4 years; commissioner of the Social Security Administration, 6 years; and commissioners of the Federal Communications Commission, 5 years. Another NAS committee that recommended a 6-year term for the National Institutes of Health (NIH) director concluded that the NSF director’s 6-year term “has been a good model for creating a system of accountability and periodic review that has the possibility of transcending changes in administration” (NRC, 2003).
Fixed terms can vary in length, be renewable or not, and have more or less strict terms of removal, depending on the degree of insulation desired. In all cases, to be constitutional, the president must retain the power of removal—incumbents of term appointments should be accountable and subject to removal by the president. On the one hand, establishing a term appointment and specifying the reasons for which an appointee may be removed changes the terms of removal to some extent. It creates a presumption that individuals in these positions should stay rather than be automatically removed with every change in administration, and it requires an administration to give good reasons for such a removal. On the other hand, the use of terms also indicates that there should be periodic turnover—not for partisan reasons but to ensure new blood and fresh ideas.
3.1: The committee recommends that the FD&C Act be amended to require that the FDA Commissioner currently appointed by the President with the advice and consent of the Senate also be appointed for a 6-year term of office. The Commissioner should be an individual with appropriate expertise to head a science-based agency, demonstrated capacity to lead and inspire, and a proven commitment to public health, scientific integrity, transparency, and communication. The President may remove the Commissioner from
office only for reasons of inefficiency, neglect of duty, or malfeasance in office.
Given the influence of the social, policy, and economic environment on CDER’s work and its major structural and management challenges, the committee believes that a confirmed commissioner will need support to effect organizational change, particularly with respect to CDER. The committee believes that a mechanism to support the commissioner is necessary because transforming an organization’s culture requires relevant leadership and management expertise and sustained effort.
3.2: The committee recommends that an external Management Advisory Board be appointed by the Secretary of HHS to advise the FDA commissioner in shepherding CDER (and the agency as a whole) to implement and sustain the changes necessary to transform the center’s culture—by improving morale and retention of professional staff, strengthening transparency, restoring credibility, and creating a culture of safety based upon a lifecycle approach to risk-benefit.
Although the committee is not aware of entities analogous to what it is recommending, it is worth noting that NIH has an Advisory Committee to the Director, which advises the agency head on major plans and policies, including those related to resource allocation, program development, and “administrative regulation and policy” (NIH, 2006). The external Management Advisory Board to the FDA commissioner would operate under Federal Advisory Committee Act rules. The secretary of HHS should consult with an independent organization in identifying candidates to ensure that the board’s composition is appropriate for the task, including familiarity with the regulatory system for drug development and FDA’s role in it and proven experience in successfully managing culture or organizational change.9 (Ideally, conflict-of-interest concerns would be addressed by ensuring that a majority of board membership should have no substantial personal financial interest in the pharmaceutical industry, and board members should not be selected from current pharmaceutical industry representatives.) Board
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.
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.
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.
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.
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.
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
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.
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).
Including labeling changes, black boxes, and measures leading to drug withdrawal (see Chapter 5 for discussion and recommendations on strengthening FDA’s authority).
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.
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