1. UPDATE: Nonclinical Reproductive Toxicity Information in Assessing Human Risk Joseph J. DeGeorge Ph.D. Associate Director for Pharmacology and Toxicology Office of Review Management CDER, FDA

2. Defining the Issue n n Absent human data, animal data are relied on in assessing potential human risk n n Not all preclinical reproductive toxicity findings are relevant to humans n n A standardized approach is needed to better assess the relevancy of preclinical findings to actual human risk

3. FDA Committees for Pregnancy Labeling Issues FDA Pregnancy Labeling Task Force S. Kweder and B. Schwetz, Chairs CDER’s PTCC J. DeGeorge, Chair SubCom. on Reprotox. A. Jordan and D. Morse, Chairs Integration Work Group A. Jacobs, Chair Preclinical Guide for Repro Tox Study Evaluation Integrative Analysis of Reprotox. Findings for Humans Pregnancy Labeling Proposed Rule and Guidance Clinical Guidance for Evaluation of Human Reproductive Toxicity Studies Guidance for Industry for Establishing Pregnancy Registries Pregnancy Task Force Working Groups

4. Integration Working Group n Paul Andrews n Joseph DeGeorge n Jim Farrelly n Ed Fisher n Abby Jacobs n David Morse n Mercedes Serabian n Joseph Sun

5. Task for Integration Working Group: n Develop a reviewer’s “tool” for interpretation of findings from studies of reproductive and developmental toxicity in evaluation of potential risk for humans n Generate consistent assessments based on a common framework for review and discussion n NOT a guide to evaluate reproductive and developmental toxicity studies

6. Objectives Of Integration Working Group n n Standardize a method for judging relevancy of nonclinical reproductive toxicity study data to human risk n n Characterize findings in context of the total nonclinical and clinical data set n n Organize study findings for consistent, effective communication to others

7. Approach Taken n n Enumerate and codify the thought processes of experts in reproductive toxicity and regulatory sciences in assessing drug- induced reproductive risks n n Group information addressing similar questions n n Assign “weights” for weight of evidence based conclusion on risk n n Evaluate reproductive and developmental endpoints separately; acknowledge potential for interrelationship in the assessment

8. Product n Document describing overall assessment process for reviewer n 3 Flow charts summarizing process: Assess overall study utility and adequacyAssess overall study utility and adequacy Assess negative endpoint applicabilityAssess negative endpoint applicability Integrative assessment positive signals with conclusion of risk in relation to background experienceIntegrative assessment positive signals with conclusion of risk in relation to background experience

9. Integrated Analysis of Positive Signals n n 6 Types of Information Evaluated Signal Strength 1 (species concordance, multiplicity, time dependency) Signal Strength 2 (maternal tox., DR, rare events) Pharmacodynamics (Therapeutic index, PD based toxicity) Concordance with Human (Metabolism, Toxicity) Comparative Exposure (Exposure margin) Class Alert (Human based)

10. Presentations n n July 98’- Toxicology Forum Concept Outline n n June 3, 99’- PLS Reproductive Health Advisory Committee Overview of Proposed Approach n n June 24, 99’- FDA Industry Public Meeting Detailed Discussion Preclinical Assessment of Reproductive Toxicity Data n n June 29, 99’- Drug Information Association Detailed Discussion of Approach n n February, 00’-Toxicology Forum FDA and Industry Presentation Approach and Application n n Scientific Societies (SOT, Teratology Society, ACT, etc.) Approach and Application

11. General Feedback n Several pharmaceutical company toxicologists have used it with their drugs and have found it a useful approach n European regulatory comments have been favorable n Two major comments Use of biomarkers in integrationUse of biomarkers in integration Views on factor weightingViews on factor weighting

12. Current Status n Finalizing Draft Guidance on Integration n Publication of Availability Notice in Federal Register July 2000

13. Reproductive Toxicology Committee n Amy Ellis n Jim Farrelly n Ed Fisher n Alex Jordan n Robin Huff n David Morse n Amy Nostrandt n Krishan Raheja n Mercedes Serabian n Susan Wilson n Josie Yang n Ita Yuen

14. Tasks for Reproductive Toxicology Committee n n Serve as a resource to reviewers for reproductive toxicology studies n n Generate a guidance for evaluation of reproductive toxicology study adequacy and evaluation

15. Objectives and Approach for Reproductive Toxicology Committee n n Provide a reference resource for study evaluation n n Chapters based on organ system analysis with case studies

16. Current Status n Chapters in Final Phase of Preparation n Will Seek External Peer Review n Target Publication of Draft 1st Quarter 2001