1Presentation Name

Pre-Marketing Safety Assessment: The Safety Review Guidance

Armando Oliva, M.D.

Associate Director for Policy

Office of New Drugs

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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 guidancehttp://www.fda.gov/cder/guidance/3580fnl.pdf

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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

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Safety Review Guidance andthe 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

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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

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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

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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 AEs3. 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)

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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

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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

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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

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The Safety Review: Organization

7.1Methods and Findings

7.2Adequacy of PatientExposure and Safety

Assessment

7.3Summary of SelectedAdverse Reactions,

Important Limitations of DataAnd Conclusions

7.4General Methodology

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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

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7.1 Methods and Findings

7.1.1 Deaths

7.1.2 SAEs

7.1.3 ADOs, other sign. AEs

7.1.4 Other Search Strategies

7.1.5 Common AEs

7.1.6 Less Common AEs

7.1.7 Laboratory Findings

7.1.8 Vital Signs

7.1.9 ECGs

7.1.10 Immunogenicity

7.1.11 Human Carcinogenicity

7.1.12 Special Safety Studies

7.1.13 Withdrawal / Abuse

7.1.14 Repro / Pregnancy

7.1.15 Effect on Growth

7.1.16 Overdose

7.1.17 Postmarketing Exper.

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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?

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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

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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?

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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