The Future of Drug Safety Promoting and Protecting the Health of the Public (2007) / Chapter Skim
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3 A Culture of Safety
3 A Culture of Safety
Pages 65-104
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From page 65... ...
. 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.
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From page 66... ...
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)
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From page 67... ...
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 discus sions with over 30 current FDA staff, including personnel from the Office of New Drugs (OND)
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From page 68... ...
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.
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From page 69... ...
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.
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From page 70... ...
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.
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From page 71... ...
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)
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From page 72... ...
THE FUTURE OF DRUG SAFETY 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)
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From page 73... ...
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)
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From page 74... ...
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.
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From page 75... ...
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.
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From page 76... ...
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.
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From page 77... ...
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.
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From page 78... ...
It has been suggested that use of the phrase "clinical review" indicates that a primary reviewer need not necessarily be a physician, although most of them are. In this report we will use the more inclusive term "clinical review" or "clinical reviewer." SOURCE: FDA (2005d)
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From page 79... ...
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.
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From page 80... ...
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.
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From page 81... ...
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)
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From page 82... ...
, 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)
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From page 83... ...
. 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)
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From page 84... ...
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
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From page 85... ...
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.
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From page 86... ...
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.
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From page 87... ...
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.
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From page 88... ...
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)
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From page 89... ...
. In 2002, FDA staff were questioned in a congressional hearing without the support of a Senate-confirmed commissioner (Kaufman, 2004a)
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From page 90... ...
Proposed Solutions to CDER's Organizational Dysfunction Management 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.
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From page 91... ...
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, Senateconfirmed leader, it is harder for the agency to define and achieve its strategic vision.
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From page 92... ...
. Finally, the committee believes that a fixed-term appointment for the FDA commissioner may help to lessen turnover.
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From page 93... ...
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 9Two examples of independent advice in identifying members of Federal Advisory Com mittees: DHHS consults with the NAS on the composition of the National Vaccine Advisory Committee, and the Consumer Product Safety Commission appoints a Chronic Hazard Advisory Panel of independent scientific experts from nominations submitted by the president of the NAS.
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From page 94... ...
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.
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From page 95... ...
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.
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From page 96... ...
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.
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From page 97... ...
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.
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From page 98... ...
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.
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From page 99... ...
. 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)
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From page 100... ...
2003. Approval times for new drugs: does the source of funding for FDA staff matter?
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From page 101... ...
2005b. White Paper, Prescription Drug User Fee Act (PDUFA)
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From page 102... ...
2005. Kaiser HealthPoll Report Views on Prescription Drugs and the Pharmaceutical Industry.
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From page 103... ...
2006. Comments Before the Food and Drug Administration's Public Meeting on the Prescription Drug User Fee Act (PDUFA)
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From page 104... ...
2005. The Prescription Drug User Fee Act: is a faster Food and Drug Administra tion always a better Food and Drug Administration?
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