Comments on FDA Concept Paper

1. Comments on FDA Concept Paper Premarketing Risk Assessment Sidney N. Kahn, MD, PhD President Pharmacovigilance & Risk Management, Inc. www.pvrm.com

2. General comments on risk management • Benefit-risk optimization helps and requires all stakeholders • FDA commendation for forward thinking and stakeholder involvement • Caveats • danger of disproportionate reaction to very small but visible risk • adoption of untried and untested methods based on theoretical considerations of effectiveness and misperceptions of risk • “The ultimate goal …is to ensure that efforts and costs …are expended on effective processes that achieve a positive benefit/risk balance”

3. Premarketing Risk Assessment - omission • Increase emphasis on data quality • cf. case follow-up in proposed rule on Safety Reporting Requirements (FR, March 14, 2003) • refer to “quality case” components defined by CIOMS-V

4. Trial size – acute use / serious conditions • Impossible to generalize for unspecified safety analyses • quantitative analysis of prespecified safety endpoints with known study population background rate • dependent on patient population, trial design, type of comparator • Recommendation • continue current ad hoc safety data collection for most trials • better qualitative data on individual important adverse events as or more important than quantitative information

5. Trial size – chronic use • Most AEs of concern idiosyncratic, rare • If common, will be detected during development and usually lead to program termination • Low-frequency AEs, even if anticipated, unlikely to be detected in any reasonably sized dataset, including large simple safety studies (“rule of 3”)

6. Subgroup analysis • Meaningful subgroup differences often difficult to demonstrate even for efficacy (single prespecified endpoint) • Proposed analyses unlikely to have power to find meaningful differences • Subgroup effects markedly different from overall study population likely to be detected using current methods • Continue to conduct exploratory studies in relatively homogenous patient subgroups, e.g. elderly, renally impaired

7. Detection of unanticipated interactions • Catch-22; anticipating the unanticipated! • Suggestions: • identify existing drug usage patterns in target population • compare PK/PD of investigational agent with common / known interacting products • formal interaction studies of most likely/hazardous combinations • concomitant treatment with less obviously interacting products for some subjects in later phase III studies • compare incidences of AEs with “clean” study population • identify trends for subsequent study and monitoring

8. Biomarkers - caveats • False positive / false negative results • Many mild “abnormalities” reflect only biological and/or analytical variability • Mechanisms of common mild abnormalities not necessarily the same as those that lead to rare, severe outcomes

9. Biomarkers - suggestions • Consider both absolute and relative (vs. individual baseline) values • Using data from NDAs/BLAs, FDA could • develop criteria for optimal biomarker sensitivity and specificity • establish rates of different degrees of abnormality in treated and control populations • correlate results with documented clinical outcomes in clinical trials and marketed use • Pharmaceutical companies should allow use of proprietary submission data for this purpose.

10. Optimizing AE descriptions for signal detection - I • Great potential merit, requires refinement • Current rigid adherence to verbatim term for codification • investigator misclassification; e.g. “abnormal LFTs” for jaundice, “acute liver failure” without encephalopathy, coagulopathy, or jaundice • inconsistent clinical classification, e.g. similar findings reported variously as hepatitis, abnormal liver function, elevated aminotransferases and jaundice, etc.

11. Optimizing AE descriptions for signal detection - II • PvRM strongly supports FDA collaboration with sponsors to develop harmonized term definitions • Ensuring consistency / minimizing subjectivity requires uniform approach across all sponsors and FDA offices and divisions – cannot be done piecemeal / ad hoc • Ideally, should be internationally agreed / acceptable to regulatory authorities in other jurisdictions • Limited number of definitions developed (“Reporting Adverse Drug Reactions: Definitions of Terms and Criteria for Their Use” CIOMS, Geneva, 1999).

12. Additional viewpoint – CIOMS-VI (working draft) • Events of critical importance consistently defined using standard criteria (e.g. acute liver failure), or in consultation with appropriate experts • Describe definitions and requirements for use of particular terms in protocol and product safety plan • Rarely, overrule investigator’s diagnosis for analysis if clearly erroneous; document reason, maintain original verbatim for audit, show both terms in study AE tables • If not reported, assign probable diagnosis when signs, symptoms, and/or treatment strongly suggest a defined syndrome (e.g. chest pain, elevated CK, acute thrombolytic treatment = myocardial infarction)

13. Thank you