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Integrating Pre- and Postmarket Review

Recommendations on Integrating Pre- and Postmarket Review from the IOM Report

The Future of Drug Safety: Promoting and Protecting the Health of the Public


Recommendation 3.4 The committee recommends that CDER [Center for Drug Evaluation and Research] appoint an OSE [Office of Surveillance and Epidemiology] staff member to each New Drug Application review team and assign joint authority to OND [Office of New Drugs] and OSE for postapproval regulatory actions related to safety.

Recommendation 4.4 The committee recommends that CDER assure the performance of timely and scientifically-valid evaluations (whether done internally or by industry sponsors) of Risk Minimization Action Plans (RiskMAPs).

Recommendation 4.5 The committee recommends that CDER develop and continually improve a systematic approach to risk-benefit analysis for use throughout the FDA in the preapproval and postapproval settings.

Recommendation 4.13 The committee recommends that the CDER review teams regularly and systematically analyze all postmarket study results and make public their assessment of the significance of the results with regard to the integration of risk and benefit information.

Recommendation 5.4 The committee recommends that the FDA evaluate all new data on new molecular entities no longer than 5 years after approval. Sponsors will submit a report of accumulated data relevant to drug safety and efficacy, including any additional data published in a peer-reviewed journal, and will report on the status of any applicable conditions imposed on the distribution of the drug called for at or after the time of approval.

A major focus of the symposium was the integration of pre- and postmarket review. There are fundamental differences in the way data are collected and analyzed in the pre- and postmarket environments. Premarket data generally come from focused, randomized con-



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Challenges for the FDA: The Future of Drug Safety - Workshop Summary 4 Integrating Pre- and Postmarket Review Recommendations on Integrating Pre- and Postmarket Review from the IOM Report The Future of Drug Safety: Promoting and Protecting the Health of the Public Recommendation 3.4 The committee recommends that CDER [Center for Drug Evaluation and Research] appoint an OSE [Office of Surveillance and Epidemiology] staff member to each New Drug Application review team and assign joint authority to OND [Office of New Drugs] and OSE for postapproval regulatory actions related to safety. Recommendation 4.4 The committee recommends that CDER assure the performance of timely and scientifically-valid evaluations (whether done internally or by industry sponsors) of Risk Minimization Action Plans (RiskMAPs). Recommendation 4.5 The committee recommends that CDER develop and continually improve a systematic approach to risk-benefit analysis for use throughout the FDA in the preapproval and postapproval settings. Recommendation 4.13 The committee recommends that the CDER review teams regularly and systematically analyze all postmarket study results and make public their assessment of the significance of the results with regard to the integration of risk and benefit information. Recommendation 5.4 The committee recommends that the FDA evaluate all new data on new molecular entities no longer than 5 years after approval. Sponsors will submit a report of accumulated data relevant to drug safety and efficacy, including any additional data published in a peer-reviewed journal, and will report on the status of any applicable conditions imposed on the distribution of the drug called for at or after the time of approval. A major focus of the symposium was the integration of pre- and postmarket review. There are fundamental differences in the way data are collected and analyzed in the pre- and postmarket environments. Premarket data generally come from focused, randomized con-

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary trolled clinical trials; the scientists who review those data are well trained in evaluating them. Postmarket data are collected from a broader array of sources, including controlled clinical studies, as well as from single-arm observational studies that lack comparator data. Further, because it is difficult to determine how many people received a drug, benefit–risk calculations are complex, and therefore postmarket data are more likely to reflect safety problems than beneficial results. Like the scientists who review premarket data, those who review postmarket data are well trained in evaluating them. However, integration of the two datasets is difficult, and there have been reported tensions between reviewers in the FDA’s Office of New Drugs (OND) and Office of Surveillance and Epidemiology (OSE). As Dr. FitzGerald said, “We are all conscious of the limitations that apply to other people’s work. We are a little less conscious of those that apply to our own.” Discussion of the integration of pre- and postmarket review was framed by the recommendations of the IOM report listed above. OPERATIONAL CHALLENGES TO INITIATING A LIFE-CYCLE APPROACH TO DRUG REVIEW1 Dr. Tilson identified and discussed four major sets of operational challenges to the implementation of a life-cycle approach to drug review: Methodological challenges—Knowledge of product safety does not readily build over time and in a linear fashion; rather, gaining such knowledge is a complex and nuanced process. The methodological challenges include understanding how to determine a calculus for benefit-to-risk balance, how to recalculate benefit–risk balance on an ongoing basis (see IOM Recommendation 4.5), how to monitor effectiveness (Recommendation 5.4), and how to manage risk and evaluate Risk Minimization Action Plans (RiskMAPs) (Recommendation 4.4). Human resource challenges—Dr. Tilson echoed earlier comments stressing the need for more experts trained in epidemiology while also pointing out that improving the U.S. drug safety system will require an expanded workforce in all areas, not just epidemiology. He urged that a companion study be undertaken to consider not only who should do the work, but also where they should work (e.g., see Recommendation 3.4), what their competencies should be, what the mix of staffing should be, and what it will take to educate and train these new personnel, including the required academic infrastructure. The need for evidence—Benefit–risk data from preclinical, clinical, and postmarket spontaneous reports are all limited with respect to their 1 This section is based on the presentation of Dr. Tilson.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary predictive value and generalizability. The drug safety system needs better resources for capturing and analyzing population-based data and a way to harness the power of large, automated, multipurpose population-based databases (see Recommendation 4.13). Organization challenges—While many of the recommendations of the IOM report focused on the FDA and what that agency must do to improve the U.S. drug safety system, other stakeholders—including industry; health care organizations; and other government organizations, such as the Centers for Medicare and Medicaid Services (CMS) and the Agency for Healthcare Research and Quality (AHRQ)—have responsibilities as well. A culture of safety within the FDA will not be created simply by contracting with an outside organization, but will require the involvement of many outside partners, each with its own need to create a culture of safety. Moreover, the roles of industry, academia, and other organizations in the drug safety system need to be clarified and the best locus for work in each organization identified, and cross-organizational collaboration and public– private partnerships need to be developed, strengthened, governed, and funded. The Centers for Education and Research on Therapeutics (CERTs), created as the FDA’s academic partner as part of the FDA Modernization Act of 1997, is an example of the type of public–private partnership (led by the FDA) needed to fulfill the agency’s public health mission. CURRENT INITIATIVES FOR INTEGRATING PRE- AND POSTMARKET REVIEW2 In response to the IOM report, the FDA provided a formal written statement detailing the programs and initiatives the agency will be employing to improve the U.S. drug safety system (see Box 1-1 in Chapter 1 for highlights of the FDA’s response) (FDA, 2007b). The FDA’s initiatives are geared toward effectively integrating the pre- and postmarket review programs, as well as strategically monitoring drugs throughout their life cycle so as to be able to determine their benefit–risk balance more accurately and relay that information to the public. These initiatives were discussed at the symposium within the context of Recommendations 3.4, 4.4, 4.5, 4.13, and 5.4 of the IOM report. In response to Recommendation 3.4 (joint authority of OND and OSE for postapproval regulatory decisions), the FDA plans to (1) evaluate the feasibility of involving OSE staff earlier in the review process, a policy change that would be both labor- and resource-intensive; (2) evaluate 2 This section is based on the presentations of Bob Temple and Ellis Unger, CDER, FDA, and Tim Franson, Vice President, Global Regulatory Affairs, Lilly Research Laboratories, Eli Lilly and Company.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary models for more significant OSE involvement in postapproval decision making, including joint signatory authority (being considered for a pilot on a small scale); and (3) implement a process improvement initiative that will introduce a safety focus into OND’s review divisions. Dr. Temple expressed enthusiasm for the safety focus initiative in particular, partly because there is already a model for how it might work: the Division of Neuropharmacology, now the Division of Neurologic and Psychiatric Drug Products, has a safety group comprising about half a dozen clinical reviewers, most with epidemiological training, playing a role in both pre- and postapproval drug evaluation. In his view, it was the clear safety focus of the group and its regular meetings with OSE that led to fully cooperative interactions with OSE without the type of culture clash cited by the IOM report as part of the rationale for Recommendation 3.4. While some review divisions might not need a safety group this large, others would. Minimum personnel requirements under the current plan would be an associate director of safety and a safety regulatory project manager within each division. Dr. Franson cautioned that if designated OSE personnel are going to work with OND staff at the time of and after approval, OSE–OND processes and interactions must ensure timely review. Other relevant industry concerns from the perspective of Eli Lilly and Company include the need for common standards for benefit–risk criteria and review, and a way to ensure that all divisions across the FDA and all companies across the industry aspire to these standards. Additionally, Dr. Franson encouraged establishment of a process for reconciling disagreements. One symposium panelist asked why the FDA response did not embrace the IOM recommendation regarding a formal and authoritative role for OSE staff in postapproval reviews and evaluations. Dr. Temple responded that while no one doubts the need for significant input from both OSE and OND, it is premature to reach a conclusion about what arrangement to this end would be best. Once pilot programs have been assessed, the agency will be better equipped to make that decision. Further, he emphasized that whoever has responsibility for sign-off, the postmarket review and assessment, as well as any revisions to labeling, must involve clinical judgment and understanding of both the risks and benefits of the therapy. Dr. Unger expressed his impression that there is not a great deal of clinical experience within OSE, and that OSE would need to expand its resources to include clinicians who understand both risk and benefit. In response to Recommendation 4.4 (timely review of RiskMAPs), the FDA is planning to (1) identify risk management tools and programs and conduct assessments of the effectiveness of particular RiskMAPs and risk management and communication tools, using input from academia

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary and industry; (2) conduct annual systematic reviews and generate public discussion of the effectiveness of perhaps one or two RiskMAPs and one major risk management tool; and (3) post reports of these discussions on the Internet and hold a public workshop to obtain input on the prioritization of the plans and tools to be evaluated. Dr. Franson commented that this recommendation raises questions about how RiskMAPs will capture postapproval benefit information and incorporate benefit–risk over time. He stated that although virtually no health care entities currently capture postapproval benefit data, the system needs a plan for doing so. If risk data are the only information available, “all we are going to be talking about is problems.” Additionally, Dr. Franson suggested that RiskMAPs might be renamed benefit–risk maps (“B/R maps”). In response to Recommendation 4.5 (establishment of a systematic approach to benefit–risk analysis), Dr. Temple remarked that the FDA already has a systematic approach to benefit–risk assessment, but added that it could be improved and better communicated. Benefit–risk analyses are complex and inevitably involve considerable judgment, and whether they can be compared on the same scale is unclear. That said, Dr. Temple noted that the FDA’s assessment methodology and communication of that methodology could be improved. Dr. Franson supported this recommendation and proposed using the integrated summary of risk and benefit information that is submitted as part of every New Drug Application (NDA) as a springboard for subsequent benefit–risk assessments throughout the life cycle of the product. Dr. Unger explained that the FDA’s formal written response to the IOM report described several initiatives aimed at improving quantitative benefit–risk assessment. He chose to highlight an initiative that began in March 2005—a postmarketing “Process Improvement Team.” The goal was to identify best practices for improving safety processes that span the postmarket activities of OND and OSE so the two offices can better carry out their respective missions and enhance CDER’s responsiveness to postmarket safety issues. The team formulated three key policy concepts: (1) create a postmarket safety entity within each OND review division (i.e., the safety focus initiative discussed above under Recommendation 3.4); (2) create an electronic postmarket safety tracking system3 (this has been done, and each division is tracking its safety issues); and (3) initiate periodic, perhaps annual, assessments of recently approved new molecular entities (NMEs) (see the discussion of Recommendation 5.4 below). 3 The electronic postmarket safety tracking system will replace individual systems that were office- and division-specific. This single system will ensure that all units within CDER have access to the same information and should help reviewers prioritize their work and monitor safety issues more effectively (FDA, 2007b).

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary In response to Recommendation 4.13 (systematic review and publicizing of all postmarket study results), Dr. Franson agreed that regular CDER review and dissemination of postapproval benefit–risk assessments would enable a more thoughtful approach to communicating benefit–risk information. Not only can a one-time adverse event frighten as much as warn the public, but the burden of proof for safety is usually only a single adverse event, in contrast to the randomized controlled study that is required to establish benefit. Drs. Galson and Unger reported that the FDA plans to publish a newsletter on the agency’s website that will include summaries of the methods and results of postmarket drug reviews; given the proprietary nature of most predecisional information, however, this will be done on a case-by-case basis. In response to Recommendation 5.4 (evaluation of all data on NMEs within 5 years following approval), the FDA initiated a pilot program to examine whether a periodic review of all data at 18 months postapproval can adequately identify potential safety issues and whether more frequent reviews are needed. Dr. Temple reported that this will be a resource-intensive effort, as it will involve reviewing all data sources (e.g., the Adverse Event Reporting System, further trials, literature reports) and will require using informed human judgment in addition to the data. The pilot program involves four NMEs, whose names the FDA has not yet made public. The reviews will be conducted consecutively using currently available staff and budgeted resources (i.e., review divisions and OSE). Dr. Franson stressed that it is important to look at the information accrued throughout a product’s life cycle, not just through 18 months or 5 years. The above reviews raise questions about how standards will be set and what actions will be taken based on these reviews.