# Presentation: 449462

## 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

## Defining the Issue

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

## FDA Committees for Pregnancy Labeling  Issues

- <date/time>

**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**

## Integration Working Group

*Paul Andrews*
*Joseph DeGeorge*
*Jim Farrelly*
*Ed Fisher*

*Abby Jacobs*
*David Morse*
*Mercedes Serabian*
*Joseph Sun*

## Task for Integration Working Group:

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

## Objectives Of Integration Working Group

- Standardize a method for judging relevancy of nonclinical reproductive toxicity study data to human risk
- Characterize findings in context of the total nonclinical and clinical data set
- Organize study findings for consistent, effective communication to others

## Approach Taken

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

## Product

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

## Integrated Analysis of Positive Signals

- 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)**

## Presentations

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

## General Feedback

- Several pharmaceutical company toxicologists have used it with their drugs and have found it a useful approach
- European regulatory comments have been favorable
- Two major comments
- Use of biomarkers in integration
- Views on factor weighting

## Current Status

- Finalizing Draft Guidance on Integration
- Publication of Availability Notice in Federal Register July 2000

## Reproductive Toxicology Committee 

*Amy Ellis*
*Jim Farrelly*
*Ed Fisher*
*Alex Jordan*
*Robin Huff*
*David Morse*

*Amy  Nostrandt*
*Krishan Raheja*
*Mercedes Serabian*
*Susan Wilson*
*Josie Yang*
*Ita Yuen*

## Serve as a resource to reviewers for reproductive toxicology studies
Generate a guidance for evaluation of reproductive toxicology study adequacy and evaluation

- Serve as a resource to reviewers for reproductive toxicology studies
- Generate a guidance for evaluation of reproductive toxicology study adequacy and evaluation

## Provide a reference resource for study evaluation 
Chapters based on organ system analysis with case studies

- Provide a reference resource for study evaluation
- Chapters based on organ system analysis with case studies

## Current Status

- Chapters in Final Phase of Preparation
- Will Seek External Peer Review
- Target Publication of Draft 1st Quarter 2001