The Food and Drug Administration (FDA) recently announced the availability of a draft 5-year plan describing the Agency’s approach to further developing and implementing a structured framework for benefit-risk assessment in the human drug and biologic review process and the opportunity for public comment on the draft plan. This plan is part of FDA’s commitments that were made as part of the fifth authorization of the Prescription Drug User Fee Act (PDUFA V), which was included in the Food and Drug Administration Safety and Innovation Act (FDASIA).
Section 905 of FDASIA amends section 505(d) of the Federal Food, Drug, and Cosmetic Act (FDCA) by requiring FDA to “implement a structured risk-benefit assessment framework in the new drug approval process to facilitate the balanced consideration of benefits and risks, a consistent and systematic approach to the discussion and regulatory decision making, and the communication of the benefits and risks of new drugs.” Title I of FDASIA reauthorizes PDUFA and provides FDA with the user fee resources necessary to maintain an efficient review process for human drug and biological products. The reauthorization of PDUFA includes performance goals and procedures for the Agency that represent FDA’s commitments during fiscal years 2013-2017.
Section X of the PDUFA Goals Document, titled “Enhancing Benefit-Risk Assessment in Regulatory Decisionmaking,” addresses the development of a 5-year plan that describes the Agency’s approach to further develop and implement a structured benefit-risk framework in its human drug and biologic review process. The publication and implementation of this plan are intended to fulfill the requirement in section 905 of FDASIA and the commitments described in Section X of the PDUFA Goals Document.
Ensuring the safety, effectiveness, and quality of human drugs is a complicated regulatory task, requiring FDA’s consideration of a multitude of complex factors. FDA’s regulatory decision making process takes into consideration not only the data submitted in a marketing application, but also a broad set of additional factors, including the clinical context for the proposed product (such as the nature and severity of the disease or condition that the proposed product is intended to treat or prevent and the benefits and risks of other available therapies for that disease or condition) and any risk management tools that might be necessary to ensure that the benefits of the proposed product outweigh its risks.
“FDA believes that implementing a standardized structure for the analysis of the various benefit and risk considerations that make up a regulatory decision will help to facilitate balanced and consistent consideration of the benefit and risk factors during the review process and to enhance the transparency of regulatory review.” FDA therefore developed the draft plan describing a “benefit-risk assessment framework that is designed to make explicit the consideration of the various benefit-risk factors and the role of those factors in the regulatory decision-making process for human drug and biological product marketing applications.” It is important to note that, as specified in section 905 of FDASIA, this framework does not change the criteria for approval of a drug or biological product. All new drug applications and biological license applications must meet the requirements for approval under the FD&C Act and the Public Health Service Act, respectively.
By clearly articulating FDA’s key considerations in a standard structure, this framework can serve as an important tool for the analysis and discussion of the relevant benefit and risk considerations during the review process.
A second and equally important purpose of the benefit-risk framework is that it can serve as a tool to communicate the reasoning of FDA's regulatory decisions to the public. When FDA approves a new drug or biological product, it generally posts decisional memos on the Agency’s Web site. These documents may be highly technical and may not be easily understandable to a broad audience with varying backgrounds. The benefit-risk framework aims to enhance FDA’s communication of its decisions by making clear the important considerations in the Agency's decision-making process, and how they affected the final regulatory decision, in a clear, succinct summary.
From an analysis of prior regulatory decisions, FDA developed a basic structure of a benefit-risk framework that includes the following categorization of key decision factors:
Analysis of Condition and Current Treatment Options provide a summary and assessment of the severity of the condition that the product is intended to treat and other therapies available to treat the condition. This represents the context of the decision that can provide useful information for weighing the benefits and risks of the drug under review
Benefit and Risk provide a summary and assessment of the submitted evidence concerning the drug under review. Key considerations of benefit include the results of the clinical trials and the clinical meaning of primary and secondary endpoints, as well as appropriate analyses of subpopulations.
Key considerations of risk include the adequacy of the safety database, the severity and reversibility of adverse events, and the potential for sub-optimal management in the post-market setting that may be of concern. In assessing benefit and risk, consideration is also given to other factors that may be relevant for a particular drug review, including nonclinical pharmacology and toxicology data; clinical pharmacology (e.g., mechanism of action, pharmacodynamics, and pharmacokinetics); chemistry, manufacturing, and controls (CMC); and clinical microbiology.
Risk Management provides a summary and assessment of any efforts that could help to mitigate the identified safety concerns, or ensure that the drug is directed to those patients for whom the risk is considered acceptable.
Within each of these factors, there are two considerations that inform the regulatory decision. The first consideration consists of identifying facts as well as uncertainties and any assumptions that need to be made to deal with what is not known. The second consideration consists of the conclusions that must be made about each decision factor. These conclusions are the subjective interpretation of the evidence for each aspect of the benefit-risk assessment. FDA terms these two categories as Evidence and Uncertainties and Conclusions and Reasons, where:
Evidence and Uncertainties presents the facts, uncertainties, and any assumptions made to address these uncertainties that contribute to the assessment of benefit and risk.
Conclusions and Reasons captures the implications of the facts, uncertainties, and assumptions with respect to regulatory decision-making, drawing conclusions from the evidence and uncertainties and explaining the bases for those conclusions.
The first two decision factors, Analysis of Condition and Current Treatment Options, represent the framework’s therapeutic area considerations and are distinct from the other drug-specific considerations in the framework. The therapeutic area information represents the current state of knowledge regarding the condition and the available therapies and can be completed for any disease area. As the available therapies for a disease area change or as knowledge and understanding of the disease improves, this information can be updated.
The additional factors of Benefit, Risk, and Risk Management represent the product-specific area of the framework. The information found here relates specifically to the drug under review. As our knowledge of a drug’s benefits and risks changes post-approval, this information can be updated in the framework, reflecting the dynamic nature of benefit-risk assessment during the drug lifecycle.
The final part of the framework is the Benefit-Risk Summary Assessment, a succinct well-reasoned summary that clearly explains FDA’s rationale for the regulatory action including important clinical judgments that contributed to the decision. The summary should integrate the analyses of benefit and risk and the applicable statutory and regulatory standards into a coherent explanation of the conclusions reached.
The assessment draws on the key supporting evidence and uncertainties, accounts for the understanding of the condition, and considers the available therapies that establish
the context in which benefits and risks are weighed. It also includes the rationale to support the labeling and other risk management as well as post-marketing requirements/commitments if more information is necessary to further characterize the benefits or risks of the drug. Where there are differences of opinion within a review team with respect to scientific or clinical judgment, they are noted in the assessment along with an explanation of how the differences were resolved or taken into account in the final decision.
Characterization of Uncertainties in Benefits and Risks
Although drug regulatory decisions are informed by an extensive body of evidence on the safety and efficacy of a proposed product, in many cases, FDA must draw conclusions from imperfect data. Therefore, identifying and evaluating sources of uncertainty (e.g., absence of information, conflicting findings, marginal results) is an important part of reviewers' work, and FDA acknowledged the role of uncertainty in the benefit-risk framework. However, drawing conclusions in the face of uncertainty can be a complex and challenging task.
Furthermore, being explicit about the impact of uncertainty on decision-making is an important part of communicating regulatory decisions. An approach that allows for more systematic accounting of the various sources of uncertainty and the role of uncertainty in decision-making can facilitate the characterization, integration, and communication of this information in drug review. There are two areas where FDA intends to focus efforts beginning in FY 2013.
The first is characterizing the uncertainty in how well the benefit-risk assessment based on pre-market clinical trial data translates to the post-market setting after the drug is approved and used in a much wider patient population. Clinical trials are designed to demonstrate a benefit of a drug compared to some comparator, such as placebo or another drug. During those trials, certain patients may be excluded to improve the ability to detect a benefit that can be attributed to the drug, or they may be excluded because of a potential safety concern.
However, a clinical trial population with these exclusions may not be representative of the broader patient population that will ultimately take the drug in the postmarket setting. Examples of potential differences include trial exclusions of patients on concomitant therapies, patients with other chronic conditions, or patients over a certain age. In other cases, the duration of the clinical trials may be different from the expected duration of use (e.g., antihypertensive drugs and antidiabetic drugs used chronically) or the quality and extent of patient monitoring may not be as rigorous in the post-approval setting as in the clinical trial (e.g., anticoagulants). Being clear about such differences, understanding their impact on decision-making, and adequately communicating these sources of uncertainty are very important.
The second area pertains to FDA’s level of uncertainty about a result or finding, particularly a new finding that becomes available in the post-market setting where the basis for the finding comes from sources of varying levels of rigor. In contrast to the prospective and highly planned studies of effectiveness, safety findings emerge from a wide range of sources, including spontaneous adverse event reports, epidemiology studies, meta-analyses of controlled trials, or in some cases from randomized, controlled trials. However, even controlled trials, where the evidence of an effect is generally most persuasive, can sometimes provide contradictory and inconsistent findings on safety as the analyses are in many cases not planned and often reflect multiple testing. A systematic approach that specifies the sources of evidence, the strength of each piece of evidence, and draws conclusions that explain how the uncertainty weighed on the decision, can lead to more explicit communication of regulatory decisions. FDA anticipates that this work will continue beyond FY 2013.
Implementation and Meetings
FDA plans to use a staged approach in implementing the benefit-risk framework in human drug review. This allows opportunity for continued refinement of the framework and its integration into the human drug review process before further expansion into additional types of applications.
During FY 2014 and 2015, FDA plans to implement the framework in the review of NME NDAs and original BLAs. As the benefit-risk assessment is revisited in the post-market setting based on new information for these applications, review teams analyzing the safety issue will be expected to update the benefit-risk framework with the analysis conducted, including any regulatory action resulting from that work, as appropriate. Following implementation in NME NDAs and original BLAs, FDA intends to implement the framework in efficacy supplements for new/expanded indications in FY 2016 and all original NDAs in FY 2017.
Following integration of the benefit-risk framework with the CDER and CBER clinical review templates and summary memoranda templates, training will be offered to reviewers and decision-makers in the use of these materials. Such training may entail face-to-face (just-in-time) training for the reviewers and decision-makers who will be expected to implement the framework, as well as an introduction to the benefit-risk framework as part of CDER and CBER’s New Reviewer Training.
Both Centers will also revise current procedural documents for staff and decision-makers that include revision of the Manual for Policies and Procedures that governs CDER’s clinical review template and associated appendices as well as the Standard Operating Practices and Procedures document that governs CBER’s clinical review template.
Current clinical reviews can be rather lengthy, highly detailed documents. Distilling such an extensive document down to a short and concise summary can be challenging and may also highlight the need for an additional type of training. Over time, CDER and CBER will build a database of worked examples of benefit-risk frameworks that can be used as a reference for reviewers. Such a database can serve a dual purpose of providing examples of high quality frameworks as well as establishing an easily accessible set of regulatory precedents that can be a future reference when similar regulatory decisions must be made.
Following implementation of the benefit-risk framework in the drug review process, FDA intends to publish the completed frameworks for newly approved products on its website, to the extent that FDA is permitted to release the information under applicable disclosure laws. By the end of FY 2014, FDA anticipates posting benefit-risk frameworks of approved products following the regulatory action. Over this same time period, FDA also anticipates integrating the benefit-risk framework as part of Advisory Committee background packages to quickly orient the committee to the important review issues in the application under discussion.
Change Control Board
Consistent with CDER and CBER’s approach to continuous improvement, inevitably there will be a need to periodically review and modify the benefit-risk framework as well as the review templates and decision memoranda in each Center. These revisions could result from increased reviewer experience with the framework, feedback from Center management related to increasing the utility of the framework, and feedback from public stakeholders related to the framework’s ability to communicate FDA’s rationale for regulatory decisions.
Because CDER and CBER are responsible for the regulation of different types of products, each Center plans to establish a Change Control Board (CCB) that will be responsible for analyzing feedback and input on the benefit-risk framework from their respective review staffs and making recommendations for enhancements to the framework and the clinical review templates for each Center. Although each Center will maintain some autonomy in terms of their respective clinical review templates, the CDER and CBER CCBs will ensure close coordination across the Centers on the harmonization of the benefit-risk framework structure as well as implementation of the framework in the review of human drugs and biological products.
A key source of feedback regarding recommended modifications to the benefit-risk framework will come from the review staff who use it during their review work. Accordingly, the CCBs in CDER and CBER will be composed of primary clinical review staff as well as review management from the Office of New Drugs in CDER or the review offices (Blood, Vaccines, and Cellular, Tissue, and Gene Therapies) in CBER, as appropriate. Because of the risk and risk management considerations in the framework, representation is also expected from CDER’s Office of Surveillance and Epidemiology on the CDER CCB and from CBER’s Office of Biostatistics and Epidemiology on the CBER CCB.
Each Center also intends to maintain an internal Benefit-Risk Advisory Group that will serve three purposes: (1) to provide overall direction in implementing structured benefit-risk assessment in the drug and biological product review process in each Center, (2) to evaluate finished benefit-risk frameworks and other work products to ensure consistent and high-quality representation of CDER and CBER decision-making before publication, and (3) to review and approve proposed modifications to the benefit-risk framework and the clinical review template that are recommended by the respective CCBs.
The CDER and CBER Advisory Groups will ensure close coordination across the Centers regarding the harmonization of the benefit-risk framework structure as well as implementation of the framework in the review of human drugs and biological products.
As part of enhancing benefit-risk assessment in PDUFA V, FDA has committed to holding two public workshops on benefit-risk considerations from the regulator’s perspective. The first workshop, slated to be held in early FY 2014, is expected to focus on the various frameworks and methods available and their appropriate application to drug regulatory decision-making. FDA anticipates that this workshop will include participation of other drug regulatory authorities who are also implementing benefit-risk frameworks in their drug decision processes. This discussion will examine the ability of frameworks to make explicit the benefit and risk considerations and associated uncertainties and assumptions that are part of drug regulatory decision-making.
The second workshop is expected to focus on the results of implementing frameworks at regulatory agencies both in pre-market application review as well as post-market safety review. This meeting will be an opportunity to share any challenges and lessons learned in applying a more structured approach to regulatory decision-making. As implementation progresses in PDUFA V, further detail regarding FDA’s plan for this workshop will be included in an update to this document.
Evaluation of the Benefit-Risk Framework
The PDUFA V Commitments also require that this draft five-year plan include a plan to evaluate the impact of the benefit-risk framework in the human drug review process. The specifics of FDA’s implementation approach are still evolving as review staff acquire experience and provide feedback on the framework and its implementation in drug review. In addition, comments received on this draft plan from the public may suggest alternatives to FDA’s approach.
Furthermore, as FDA integrates the framework concepts into it’s clinical review template during FY 2013, FDA expects that this experience will lead to best practices that will be applied to implementation of the framework in FY 2014. At that time, a more informed evaluation of the impact of the benefit-risk framework can be specified. FDA anticipates that this evaluation will consider the utility of the framework in communicating key benefit and risk considerations both internally and externally, facilitating decision-making including decisions about risk management, and training new review staff.
Some of the evaluation questions FDA expects to examine include (1) whether the framework provides a clearer explanation of FDA approval decisions to public stakeholders, including patients, consumers, healthcare professionals, and industry; (2) whether the framework provides value to internal reviewer communications and discussions related to premarket regulatory decisions; and (3) whether the framework provides value in supporting consideration of emerging safety and efficacy information in post-market drug decision contexts. Given the implementation timetable described in Section 4, FDA expects that the evaluation will begin in FY 2015-2016 after full implementation has occurred in a sufficient number of application reviews. More information regarding the evaluation will be included in an update to the draft plan.