# Presentation: 765701

## Standard for Exchangeof Nonclinical Data (SEND):Past, Present and FutureThomas Papoian, Ph.D., D.A.B.T.Senior Pharmacologist / ToxicologistDivision of Cardio-Renal Drug ProductsCDER/FDAJune 27, 2005DIA MeetingWashington, D.C.

## Disclaimer

- The views expressed in this presentation are those of the speaker.
- They do not necessarily reflect the “official” views of the Food and Drug Administration (FDA).

## Overview

- CFR requirements for data submission
- Current approaches to data submission in CDER
- Overview of SEND
- Completed pilot project with industry participants
- Software tools
- Next steps
- Conclusions

## Code of Federal Regulations (CFR) Requirements for Submission of Animal Toxicity Data to CDER

**INDs**: 21 CFR 312.23(a)(8)(ii)(b)
- The sponsor should submit, for each animal toxicology study that is intended to support the safety of the proposed clinical investigation, _**a full tabulation of data**_ suitable for detailed review.
**NDAs**: 21 CFR 314.50 (d)
- The application is required to contain the technical sections described below. Each technical section is _**required to contain data**_ and information in sufficient detail to permit the agency to make a ***knowledgeable judgment*** about whether to approve the application or whether grounds exist under section 505(d) of the act to refuse to approve the application.

## Current Formats for Submission  of Animal Toxicity Data to CDER

- Paper Submissions
- Being phased out, but still common and even desired by reviewers
- Electronic Submissions (eNDA Guidance 1999)
- PDF files
- Datasets (*optional*):
- SAS Transport files
- eNDA Guidance gives *examples* of meta-data options (e.g., animal ID, dose, duration, test name, results, units, etc.)
- Datasets for statistical analysis of tumor incidences from carcinogenicity studies to be submitted _exactly_ as described in guidance (Appendix 1, p.61).

## Datasets

- Currently, viewing and analysis of *nonclinical* datasets requires use of JMP/SAS software
- Advantage: powerful programs for data analysis
- Disadvantage: difficult to use for most pharm/tox reviewers
- Therefore, nonclinical datasets _not_ generally preferred or requested by most review divisions
- Goal should be to *encourage* use of datasets to enhance submission and review process

## Advantages of Developing Data Standards

- Improves data exchange between CROs and companies for later submission
- Improves data exchange between FDA and industry
- Both companies and reviewers can communicate more precisely with regards to what data was submitted
- Increases efficiency of submissions
- Need for redundant data submission is minimized
- Reduces review time and increases review efficiency
- Data of interest  and issues of concern can be more easily addressed by reviewers independently without need for contacting company
- Validation of data _before_ submission becomes possible
- Supports FDA’s efforts (with NCI and IBM) to develop a repository for all submitted data (i.e., Janus Data Warehouse)

## Advantages of Developing Data Standards (cont)

- Allows development of *specialized* software to:
- Enable reviewers to replicate company’s tables and graphs (as both line listing and summary tables)
- Enables reviewers to view and subset any data (i.e., by dose, time, test, gender, etc.)
- Having *specialized* software is _key_ to pharm/tox reviewer acceptance and use of datasets
- Does _not_ change company’s study design, conduct, or data capture methods (i.e., remains flexible)

## Clinical Data Standards

**HL7** (Health Level 7):
- ANSI-accredited Standards Developing Organization
- “Provides standards for the exchange, management and integration of data that support clinical _patient care_ and the management, delivery and evaluation of _healthcare services_.”
**Ex**: Patient records, insurance companies (Medicare/Medicaid), most major hospitals, etc.
- Not *originally* designed for clinical trial data

## Clinical Data Standards (cont)

**CDISC** (Clinical Data Interchange Standards Consortium):
- “Non-profit organization committed to the development of industry standards to support the electronic acquisition, exchange, submission and archiving of _clinical trials data_ and _metadata_ for medical and biopharmaceutical product development.”
- CDISC has formal liaison to HL7 through Regulated Clinical Research Information Management (RCRIM) Committee.

## Nonclinical Data Standards 

**SEND** (Standard for Exchange of Nonclinical Data):
- Part of CDISC
- Developed by SEND Consortium
- Members from industry, CROs, vendors, and FDA
- Format follows CDISC’s clinical model
- Defines domains and variables for submission of data generated from animal toxicity studies
- SEND part of SDTM (Study Data Tabulation Model) as overall model for _both_ clinical and nonclinical data
- Each with own Implementation Guide (I.G.)

## SEND (cont)

- SEND Implementation Guide v2.1 (March 2005):
- Includes single- and repeat-dose toxicity, carcinogenicity, and rodent micronucleus
- Includes detailed description of variables and domains with examples
- Currently, does _not_ include animal toxicity data generated from reproductive toxicity, safety pharmacology, or *in vitro* toxicity studies
- SEND v1.8 (May 2005)
- Current working version
- To include:
- Reproductive toxicity
- Safety Pharmacology
- PK/TK Parameters

## SEND(Specific Domains v2.1)

- Animal Disposition
- Body Weights
- Clinical Pathology
- Clinical Signs, Physical and Ophthalmoscopic Exam
**Comments**
- Drug/Metabolite Levels
- ECG Test Results
**Exposure**

- Food and Water Consumption
- Group Characteristics
- Macroscopic Findings
- Microscopic Findings
- Organ Weights
- Subject Characteristics
- Study Design Summary
- Vital Signs

**Domains are a collection of observations with a **_**topic**_**-specific commonality:**
- (Interventions, Special Purpose, and Findings)

## SEND(Domain Categories)

- Interventions domain (Exposure):
- Dose, duration, route, vehicle, etc.
- Special Purpose domain (Comments):
- Used to explain unusual findings or provide additional information about findings (e.g., faulty reagent; gavage error; etc.)
- Findings domains (All Others):
- Test name, _all_ results, units, date/time of observation, etc.

## SEND (cont)

- All datasets (one per domain) can be pre-screened by a validator tool *before* or *after* submission
- All study data then deposited into FDA database repository
- Selected data accessed through web-based software tools

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

- Asked for volunteers from industry to submit sample nonclinical (i.e., *animal toxicity*) datasets using SEND format
- Provided opportunity for industry participants to become familiar with proposed nonclinical data standards at early stage of development
- Used to test SEND model and associated software tools
- Pilot completed (March 2005) for general toxicology (i.e., single/repeat-dose toxicity and carcinogenicity studies)

## SEND Pilot Participants

- Amgen
- AstraZeneca
- Aventis
- Bristol-Myers Squibb
- Eli Lilly & Co.
- GlaxoSmithKline
- Merck
- Pfizer
- Sanofi-Synthelabo

## Software Tools

- Will enable reviewers to *easily* locate the data for *basic* data viewing, analysis and graphing
- Data converted from *single* observation per row format to more traditional view of *multiple* observations per row
- Software tools for loading, viewing and analyzing data being developed through CRADA with **PharmQuest, Inc.**

## Clinical Signs Domain (SEND)

## Clinical Signs (from Dataset)(One observation per row)

## Clinical Signs (from Database)(Multiple observations per row)

## ToxVisionTM (Key Features)

- Validates and loads data files into FDA database repository
- Data from each domain viewed in separate web-browser windows for easy side-by-side comparisons
- Data viewed as either individual values or as group means
- Data views can be further subsetted based on gender, dose group, time scale (e.g., days or weeks), selected time points, test category (e.g., hematology), or specific test (e.g., ALT)
- Option to view displayed data in graphical (chart) format
- Individual data entries can be excluded for calculation of means and SD.
- “Animal Profile” functionality displays all data for one animal in a single window
- Exports tumor data from carcinogenicity studies for statistical analysis

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## Next Steps

- SEND v2.1 “Comments” period completed (April 2005)
- Additional SEND “Comments” can be submitted to CDISC’s Discussion Forum
- SEND Team working to incorporate additional types of animal toxicity studies into SEND I.G.
- Reprotox, safety pharm, and PK/TK
- FDA and NCI working to implement Janus Data Warehouse and associated software tools
- NCI considering *early* implementation of ToxVision prototype for animal toxicity data submissions

## Conclusions

- Use of SEND as a *nonclinical* data submission format would offer significant advantages over current methods, including:
- Data validation *before *or* after* submission
- Data storage, retrieval, display and analysis using *specialized* software
- Overall use of data standards and associated software tools should result in a more *effective* and *efficient* submission and review process that would benefit industry, FDA, *and* public alike.

## Acknowledgements

**PharmQuest:**
- Seema Handu
- Hemant Gokhale
**CDISC/SDS Team:**
- Wayne Kubick (Lincoln Technologies)
- Fred Wood (P&G)
**CDER/FDA:**
- Randy Levin (Medical Informatics; Health and Regulatory Data Standards / OC)
- Norman Stockbridge (DCRDP / CDER)
- Lois Freed (DNDP / CDER)
**SEND Pilot Participants**
**SEND Consortium / Team**

## Thank you!