# Presentation: 210469

## Update on SEND(Standard for Exchange of Nonclinical Data)Thomas Papoian, Ph.D., D.A.B.T.Senior PharmacologistDivision of Cardio-Renal Drug Products March 4, 2004

## Overview

- Current CFR requirements for data submission
- Current approaches to data submission in CDER
- Advantages of developing data standards
- SEND model and Consortium
- Ongoing pilot project with industry participants
- Software development (i.e., ToxVision)
- Next steps
- Potential issues
- Conclusions

## CFR Requirementsfor Animal Toxicity Data

- INDs: 21 CFR 312.23(a)(8)(ii)(b)
- A full tabulation of _data_ suitable for detailed review...
- NDAs: 21 CFR 314.50 (d)
- Required to contain _data_ and information in sufficient detail to permit the agency to make a knowledgeable judgment ...

## Current Approachesto Data Submission

- Paper Submissions
- Electronic Submissions (eNDA Guidance 1999)
- PDF files (includes *scanned* study reports)
- Datasets (optional):
- SAS Transport files
- Guidance gives examples of meta-data options
- Ex: Animal ID, dose, duration, test name (e.g., glucose), results, units, etc.
- Sponsors decide which variables and terminology to use as needed (i.e., flexibility to capture data generated), but only as long as terms used are consistent within each study

## Current Approachesto Data Submission (cont)

- Currently, viewing and analysis of nonclinical datasets requires use of JMP/SAS software
- Advantage: powerful program for data analysis
- Disadvantage: difficult to use for most reviewers
- Therefore, nonclinical datasets not preferred or requested by most review divisions
- Goal should be to encourage use of datasets to enhance review process

## Advantages of Developing Data Standards

- Improves communication with sponsors
- Results in more consistent data submission and storage
- Increases efficiency and reduces review time
- Allows development of *customized* software to:
- Enable reviewers to _easily_ replicate sponsor’s tables and graphs (as both line listing and summary tables)
- Enables reviewers to _easily_ view and subset any data (i.e., by dose, time, test, gender, etc.)
- Having customized software is_ key_ to reviewer acceptance and use of datasets
- Does not change sponsor’s study design, conduct, or data capture methods (i.e., remains flexible)

## Standard for Exchange of Nonclinical Data (SEND)

- Discussions began in July 2002
- Modeled after CDISC’s SDS model (v.3)
- Defines domains and variables for submitting _all_ data generated from animal toxicity studies
- SEND Consortium consists of ~100 representatives from pharma/biotech industry, several FDA Centers, CROs, and software vendors
- Teleconferences are held every month
- SEND model v.1 released Aug 2003
- Current version is 1.4 (March 2004)
- CRADA (May 1999) with PharmQuest, Inc. to develop and evaluate software tools for viewing and analyzing nonclinical data based on SEND data model

## SEND Consortium

- Industry:
- Amgen		AstraZeneca		Aventis
- Bayer 		Boehringer-Ingelheim	Eli Lilly & Co.
- GSK		J&J			Merck
- Novartis		P&G			Pfizer
- Sanofi-Synthelabo	Schering			BMS
- CROs:
- Covance		PPDI			Quintiles
- Vendors:
- Dataceutics 	Image Solutions		LifetreeTechnol.
- Lincoln Tech. 	Metamatrix		Mindspring
- PharmQuest 	Phonescreen		Webclin
- Xybion
- FDA Centers:
- CDER		CFSAN			CVM
- NCTR		CBER			CDRH(?)

## SEND Model (v1.4)

- Variable categories:
-  **Interventions** (dose, frequency, route, lot number, etc.)
-  **Findings** (test name, result, units, etc.)
-  No ***Events*** (considered as “Findings” in SEND)
- A list of variables are used to define specific domains:
- Body Weights, Clinical Pathology, Microscopic Findings, etc.
- “Relates” table will be in next version:
- For linking related observations in a particular animal
- Ex: palpable mass observed during in-life phase > gross observation of tumor at necropsy > diagnosis of tumor-type at microscopic observation

## SEND Model (cont)

- All datasets (one per domain) pre-screened by a validator tool being developed by PharmQuest, Inc.
- All study data then deposited into database repository
- Selected data accessed via a web-browser through use of specially-designed software tools
- XML format will replace SAS Transport files in future

## SEND Domains (v1.4)

- Animal Characteristics
- Animal Disposition
- Body Weights
- Clinical Pathology
- Clinical Signs
- Drug/Metabolite Levels
- Exposure
- Food Consumption
- Fetal Data
- Female Fertility
- Group Characteristics
- Group Observations

- Macroscopic Findings
- Male Fertility
- Microscopic Findings
- Ophthalmoscopic Findings
- Organ Weights
- Rodent Micronucleus
- Study Summary
- Study Timing
- Tumor Analysis
- Water Consumption

## Body Weights Domain (SEND)

**Body Weights Domain (SEND)**

## Body Weights (from Dataset)(One observation per row)

## Body Weights (from Database)(Multiple observations per row)

## Pilot Project (Fed. Reg., Jan 27, 2003)

- Volunteers from industry providing sample nonclinical (i.e., animal toxicity) datasets using SEND format
- Experience from this ongoing pilot will be used to modify SEND model and associated software tools

## Pilot Project (cont)

- 3-Phases (to be completed by end of 2004):
- 1. Single and repeat-dose toxicity studies:
- 	- Datasets from 6- studies (rat and dog) received so far
- 2. Carcinogenicity studies
- 	- Required data for _statistical_ analysis of tumor incidences to be exported from database
- 3. Reproductive toxicity studies
- 	- Complex issues of multi-generational design (F0, F1, F2)

## Pilot Participants

- Amgen
- AstraZeneca
- Bristol-Myers Squibb
- Eli Lilly & Co.
- Merck
- Novartis
- Pfizer
- Proctor & Gamble
- Sanofi-Synthelabo

## ToxVision

- Software tool for viewing and analyzing nonclinical data received by the FDA in the SEND format
- Being developed through CRADA with PharmQuest, Inc.
- Enable reviewers to easily view and subset the data for further analysis or graphing
- Data converted from single observation per row to more traditional view of multiple observations per row
- Allow reviewers to replicate most analyses, tables, graphs, and line listings from a submission with minimal or no transformation

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## Next Steps

- Complete pilot project (end of 2004)
- Revise SEND model accordingly
- Develop data viewing and analysis tool (ToxVision)
- Merge (harmonize) SEND with CDISC’s SDS model
- To be called Data Tabulation Model (DTM)
- Single model for both clinical and nonclinical data with additional variables added as needed
- Each with own _Implementation Guides_ (to include detailed description of variables and domains with examples)
- DTM and Implementation Guides to be posted on CDISC (and FDA?) web sites (to be used as data submission guidance for sponsors)

## Potential Issues

- Ensure that DTM model for clinical and nonclinical data is truly adequate to capture and display all data generated from an animal toxicity study
- Requires completion of the ongoing pilot and further technical and scientific discussions between CDISC, SEND, (and FDA?) representatives
- Ensure that customized software tools being developed are _intuitive_ (i.e., manual-free) and meet the needs of *non*clinical reviewers
- Otherwise, no better off than before with JMP
- Some additional training _may_ be required to familiarize reviewers with software tools
- But this should not be a major issue if the tool works the way we expect

## Conclusions

- From a nonclinical perspective, development and acceptance of data standards promises to significantly improve our capability to display and analyze animal toxicity data.
- This should result in a more efficient and effective review process.
- However, importance of capturing animal toxicity data in a single Data Tabulation Model (DTM), designed primarily for clinical data, should not be underestimated, so that significant toxicities not monitorable in humans can still be detected (e.g., cancer, birth defects, and irreversible tissue damage, etc.).