E

Benefit and Risk Assessment and Management Plan Document Template





This appendix serves as a template for the committee’s proposed Benefit and Risk Assessment and Management Plan (BRAMP) document. For some drugs, much of the information that the committee recommends be recorded in a BRAMP is available in various summary reviews and other documents. However, these documents can be difficult to locate, are often highly technical in language and level of detail, and are not necessarily easily linked or connected. By contrast, a key aspect of the recommendation for a BRAMP document is that it will be a single, easy to read, living document that is updated at periodic intervals, including whenever the benefit–risk profile of a drug is questioned or evaluated in the postmarketing setting, and therefore that will serve as a comprehensive source of information about a drug.

This BRAMP template is for a fictitious Drug X, approved by Food and Drug Administration (FDA) in 2005. Later regulatory decisions, documented in the BRAMP for this drug, are: a labeling change in 2006, the addition of a risk evaluation and mitigation strategy (REMS) requirement in 2009, and removal of the REMS requirement in 2011.

BRAMP DOCUMENT TEMPLATE

Contents Page

Section 1—Approval, 11/10/2005

Section 2—Labeling Change, 11/29/2006

Section 3—Requirement of a REMS, 05/21/2009

Section 4—Removal of a REMS Requirement, 09/05/2011



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E Benefit and Risk Assessment and Management Plan Document Template This appendix serves as a template for the committee’s proposed Benefit and Risk Assessment and Management Plan (BRAMP) document. For some drugs, much of the information that the committee recommends be recorded in a BRAMP is available in various summary reviews and other documents. However, these documents can be difficult to locate, are often highly technical in language and level of detail, and are not necessarily easily linked or connected. By contrast, a key aspect of the recommendation for a BRAMP document is that it will be a single, easy to read, living document that is updated at periodic intervals, includ - ing whenever the benefit–risk profile of a drug is questioned or evaluated in the postmarketing setting, and therefore that will serve as a comprehensive source of information about a drug. This BRAMP template is for a fictitious Drug X, approved by Food and Drug Administration (FDA) in 2005. Later regulatory decisions, documented in the BRAMP for this drug, are: a labeling change in 2006, the addition of a risk evaluation and mitigation strategy (REMS) requirement in 2009, and removal of the REMS requirement in 2011. BRAMP DOCUMENT TEMPLATE Contents Page Section 1—Approval, 11/10/2005 Section 2—Labeling Change, 11/29/2006 Section 3—Requirement of a REMS, 05/21/2009 Section 4—Removal of a REMS Requirement, 09/05/2011 261

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262 STUDYING THE SAFETY OF APPROVED DRUGS SECTION 1 DRUG X—APPROVAL 11/10/2005 1. Public Health Question This section of the BRAMP document specifies the public health problem or question that prompted a review of the benefits and risks associated with a drug. At the time of approval for marketing, the public health question is whether the benefits of Drug X outweigh its risks and, therefore, whether the drug should be approved for marketing. This section also should include a discussion of the context in which the public health question is asked. That is, it includes characteristics of the condition that the drug is approved to treat for, patients’ perceptions and concerns, practical considerations, availability of other treatments, and any other issues that should be considered in addressing the public health question. 2. Summary of the Benefit and Risk Assessment This section should include a description of the process used to assess the benefits and risks, including how stakeholder input was sought and incorporated. It should also include, in the sections below for benefit and for risk assessments, a summary of the available evidence used, the quality and uncertainty of the differ- ent studies, and the judgments made about the different studies, including how the studies were factored into decisions. The description of the evidence should include a characterization of the overall consistency and uncertainty of that evidence. All assumptions used in estimating benefits and risks should also be described. a. Benefit Assessment This section should include a description of the evidence used in the assess - ment of the benefits of the drug, including the quality, consistency, and relevance of the data. b. Risk Assessment This section should include a description of the evidence used in the assess - ment of the risks posed by the drug, including the quality, consistency, and relevance of the data. c. Overall Benefit–Risk Profile This section should include a description of the evidence used in the assess - ment of the benefit–risk profile of the drug, including the quality, consistency, and

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263 APPENDIX E relevance of the data. It should also include a characterization of the uncertainty around the estimates of the benefits and risks. 3. Regulatory Actions and Rationale This section should have a clear statement of the regulatory decision, and the rationale for that decision, including not only the final output of the benefit–risk assessment process but a description of any other factors that affected the deci - sion, such as ethical issues, timeframe issues, the lack of an available treatment for a disease, or the risk posed by a drug in a specific population. It should also include a description of any VOI analysis, decision conferencing, or multiple- criteria decision analysis that was conducted If there are any regulatory requirements that are meant to highlight or miti- gate a drug’s risks, such as labeling changes, boxed warnings, or a REMS, those requirements should be described in this section. This section should also include a description of any postmarketing surveillance, studies, or trial requirements or commitments. a. Regulatory Decision This section should include a statement of the regulatory decision, such as approval of the drug or the requirement for a postmarketing requirement. b. Rationale This section should discuss the rationale for the regulatory decision, includ - ing a description of any factors other than the benefit and risk assessment that might have affected the decision, such as ethical issues, patient perspectives, timeframe issues, the lack of an available treatment for a disease, and the risk posed by the drug in a specific population. c. Concomitant Actions This section should discuss any actions needed to highlight or mitigate a drug’s risks, including labeling, boxed warning, REMS, and postmarketing study requirements. It includes a discussion of the rationale for requiring these changes, and any remaining public health questions that need to be answered by postmarketing requirements. 4. Schedule of Future Reviews This section should include a schedule of future evaluations of the benefit– risk profile, taking into account when additional information on the benefits or

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264 STUDYING THE SAFETY OF APPROVED DRUGS risks associated with the drug might be expected. This section should also outline any plans to review the decision, and the decision-making process used for the drug. For example, if the approval of Drug X was controversial or difficult, this section should include a schedule for reviewing the affect of the decision on the public’s health, and reviewing the process used for the decision to identify ways to improve the decision-making process in the future. SECTION 2 DRUG X—LABELING CHANGE 11/29/2006 This section of the BRAMP document should contain a discussion of the labeling change that was made for Drug X on 11/29/2006. It should outline the public health question that prompted the label change, summarize the benefit and risk assessment that supported the change, and outline the regulatory change. 1. Public Health Question This section should detail the problem, or public health question, that led FDA and the sponsor of Drug X to consider changing the drug’s label. For example, if problems with administration of Drug X were reported, FDA should include a discussion of the problems in this section. 2. Summary of the Benefit and Risk Assessment This section of the document should include a description of the evidence used in the assessment of the risks posed by the drug and the benefits of the drug, including the increased risks or decreased benefits associated with improper use. 3. Regulatory Actions and Rationale a. Regulatory Decision This section should include a statement of the regulatory decisions consid - ered to respond to the public health question. b. Rationale This section should discuss the rationale for the regulatory decision, including a description of any factors other than the benefit and risk assessment that might have affected the decision, such as ethical issues, patient perspectives, timeframe issues, the lack of an available treatment for a disease, and the risk posed by the drug in a specific population. It should include a discussion of how the label changes are expected to increase the drug’s benefits, decrease the drug’s risks, or both.

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265 APPENDIX E c. Concomitant Actions If the label change is the only regulatory action considered and taken at this time, this section should indicate that no other regulatory actions were considered and taken at this time. 4. Schedule of Future Reviews This section should include a schedule of future evaluations of the benefit– risk profile, taking into account when additional information on the benefits or risks associated with the drug is expected. This section should also outline any plans to review the decision, and the decision-making process used for the drug. For example, if the approval of Drug X was controversial or difficult, this sec- tion should include a schedule for reviewing the affect of the decision on the public’s health, and reviewing the process used for the decision to identify ways to improve the decision-making process in the future. SECTION 3 REQUIREMENT OF A REMS 05/21/2009 This section of the document should contain a discussion of the decision to require a REMS for Drug X. It should outline the public health question that prompted consideration of the REMS requirement, summarize the benefit and risk assessment that supported the requirement, and outline the regulatory requirement. 1. Public Health Question This section should detail the problem, or public health question, that led FDA to consider requiring a REMS for Drug X. For example, if there is new evi - dence from postmarketing surveillance that the risks posed by Drug X outweigh its benefits, the evidence should be briefly introduced in this section. 2. Summary of the Benefit and Risk Assessment This section should include a description of the evidence used in the assess - ment of risks and benefits associated with Drug X, and an assessment of the effects of a REMS on the benefits and risks. 3. Regulatory Actions and Rationale a. Regulatory Decision This section should include a statement of the regulatory decisions consid - ered to respond to the public health question.

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266 STUDYING THE SAFETY OF APPROVED DRUGS b. Rationale This section should discuss the rationale for the decision to require a REMS, including a description of any factors other than the benefit and risk assessment that might have affected the decision, such as ethical issues, patient perspectives, timeframe issues, the lack of an available treatment for a disease, and the risk posed by a drug in a specific population. c. Concomitant Actions If the REMS requirement is the only regulatory action considered and taken at this time, this section should indicate that no other regulatory actions were considered and taken at this time. 4. Schedule of Future Reviews This section should include a schedule of future evaluations of the benefit– risk profile, taking into account when additional information on the benefits or risks associated with the drug is expected. It should include a discussion of FDA’s plans to assess the effectiveness of the REMS. This section should also outline any plans to review the decision, and the decision-making process used for the drug. For example, if the approval of Drug X was controversial or difficult, this section should include a schedule for reviewing the affect of the decision on the public’s health, and reviewing the process used for the decision to identify ways to improve the decision-making process in the future. SECTION 4 REMOVAL OF REMS REQUIREMENT 09/05/2011 This section of the BRAMP document should contain a discussion of the decision to remove a REMS requirement for Drug X. It should outline the public health question that prompted consideration of removal of the REMS require - ment, summarize the benefit and risk assessment that supported the change, and outline the regulatory change. 1. Public Health Question This section should detail the problem, or public health question, that led FDA to consider removing the REMS requirement for Drug X, for example, if there is evidence that the potential risks that prompted the previous requirement for a REMS were not as high as estimated or there is evidence that the REMS is not effective in mitigating those risks.

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267 APPENDIX E 2. Summary of the Benefit and Risk Assessment This section of the document should include a description of the evidence used in the assessment of the effects of the REMS on the risks and benefits asso - ciated with the drug. 3. Regulatory Actions and Rationale a. Regulatory Decision This section should include a statement of the regulatory decisions consid - ered to respond to the public health question. b. Rationale This section should discuss the rationale for the regulatory decision, includ - ing a description of any factors other than the benefit and risk assessment that might have affected the decision, such as ethical issues, patient perspectives, timeframe issues, the lack of an available treatment for a disease, and the risk posed by the drug in a specific population. c. Concomitant Actions If the removal of a REMS requirement is the only regulatory action consid - ered and taken at this time, this section should indicate that no other regulatory actions were considered and taken at this time. 4. Schedule of Future Reviews This section should include a schedule of future evaluations of the benefit– risk profile, taking into account when additional information on the benefits or risks associated with the drug is expected. This section should also outline any plans to review the decision, and the decision-making process used for the drug. For example, if the approval of Drug X was controversial or difficult, this sec- tion should include a schedule for reviewing the affect of the decision on the public’s health, and reviewing the process used for the decision to identify ways to improve the decision-making process in the future.

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