1Presentation Name Pre-Marketing Safety Assessment: The Safety Review Guidance Armando Oliva, M.D. Associate Director for Policy Office of New Drugs

2Presentation Name Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review Issued February 2005 Collaborative effort across CDER: OND, ODS, OMP OMP was the lead office in finalizing and issuing the guidance

3Presentation Name What is the guidance’s purpose? Assist reviewers conducting the clinical NDA/BLA safety review Describe Good Review Practices (GRP) for a premarketing safety review Provide Standardization and Consistency of format and content Ensure critical presentations and analyses of safety data are not omitted

4Presentation Name Safety Review Guidance and the Clinical Review Template Clinical Review Template MAPP Issued in July 2004 Headings for the safety review in the template are harmonized with the guidance Guidance provides an expansion of the annotations to Section 7 of the template: the Integrated Review of Safety

5Presentation Name Collaboration Guidance geared toward the clinical reviewer Recognizes the need for additional skill sets: analysis of event rates, subgroup differences, identification of risk factors Guidance stresses the need for collaboration with biostatistical colleagues when necessary

6Presentation Name What’s in the Guidance? Advice on how to conduct and organize the safety review Annotated Outline of the safety component of the clinical review of an NDA/BLA

7Presentation Name Safety Review : Four Principal Tasks 1.Identify serious AEs that could: Prevent use altogether Limit use Require special risk management efforts 2.Estimate frequency of common AEs 3.Evaluate adequacy of the data and the analyses (eg, was exposure at relevant doses adequate?) 4.Identify unresolved safety concerns that need further attention (either pre-approval, or post- marketing)

8Presentation Name Safety Review: Additional Tasks Identify factors that predict the occurrence of AEs (both intrinsic and extrinsic) Identify ways to avoid AEs (dosing, monitoring) and ways to manage them when they occur Provide comprehensive evaluation of risk information to support labeling

9Presentation Name Key Sources of Safety Information Integrated Summary/Analysis of Safety (ISS) AE tables in the NDA/BLA submission CRFs for SAEs and adverse dropouts (ADOs) AE data listings, laboratory listings, including baseline listings (often electronic) Narratives of deaths, other SAEs, ADOs Patient profiles (individual displays of safety data over time) Safety section of proposed labeling CTD safety-related sections (2.5.5, 2.7.4) Other: eg, data on related drugs, AE coding dictionaries

10Presentation Name Causality Determination Heavily dependent on comparisons of event rates between treatment groups Coding of AEs very important in order to get the correct numerator Emphasis on individual case review of deaths, SAEs, and ADOs

11Presentation Name The Safety Review: Organization 7.1 Methods and Findings 7.2 Adequacy of Patient Exposure and Safety Assessment 7.3 Summary of Selected Adverse Reactions, Important Limitations of Data And Conclusions 7.4 General Methodology

12Presentation Name 7.1 Methods and Findings How did the applicant assess safety, and what were the findings? Discusses the relevant data sources Safety assessments that were conducted Major safety findings Use of a systematic approach

13Presentation Name 7.1 Methods and Findings Deaths SAEs ADOs, other sign. AEs Other Search Strategies Common AEs Less Common AEs Laboratory Findings Vital Signs ECGs Immunogenicity Human Carcinogenicity Special Safety Studies Withdrawal / Abuse Repro / Pregnancy Effect on Growth Overdose Postmarketing Exper.

14Presentation Name 7.2 Adequacy of Patient Exposure and Safety Assessments Was patient exposure adequate? (e.g., overall numbers, duration, dose levels, in specific subgroups Quality and Completeness of the safety evaluation (animal tests, in vitro tests, long-term safety testing, specific assessments) Are additional safety testing needed, either pre-approval or post-marketing?

15Presentation Name 7.3 Summary of Selected AEs, Important Limitations of Data, and Conclusions Brief summary of the critical findings of the safety review Contains AEs that the review considers important and drug-related Summary of important limitations of the safety database Safety conclusions

16Presentation Name 7.4 General Methodology Describes analytical methods used in the safety review General discussion of methodological issues not discussed elsewhere What studies were pooled and why? How was exploration for predictive factors conducted? How was causality determined?

17Presentation Name Summary Final guidance on how to conduct a clinical NDA/BLA safety review Promotes Good Review Practices (GRP) Provides Standardization and Consistency of format and content of the safety review Ensure critical presentations and analyses of safety data are not omitted Harmonized with the Clinical Review Template