1. Nonclinical Information in the Common Technical Document: Opportunities for Content Reuse
Peggy Zorn, MPI Research
Susan Mattano, Pfizer, Inc.

2. Common Technical Document
Module 1
Regional
Administrative
Information
1.0
CTD Table of Contents 2.1
Nonclinical Sections
CTD Introduction 2.2
Clinical
Overview
2.5
Nonclinical Overview 2.4
Module 2
Quality
Overall
Summary
2.3
Nonclinical Written and Tabulated Summaries 2.6
Clinical Summary
2.7
Module 3
Quality
3.0
Module 4
Nonclinical
Study Reports
4.0
Module 5
Clinical Study Reports
5.0

3. Relationship of Nonclinical Content in the CTD
2.4
Nonclinical
Overview
2.6.1 Nonclinical Introduction
2.6.2 & 2.6.3
Pharmacology Written / Tabulated Summaries
2.6.4 & 2.6.5
Pharmacokinetics Written/Tabulated Summaries
2.6.6 & 2.6.7
Toxicology Written/Tabulated Summaries
4.2.1
Pharmacology Study Reports
4.2.2 Pharmacokinetics Study Reports
4.2.3 Toxicology Study Reports

4. Overview of Nonclinical Sections in the CTD
Nonclinical sections include Pharmacology, Pharmacokinetics and Toxicology
Breakdown of nonclinical information in Modules 4 and 2 is identical, detail level is different
Module 4 provides detailed data on study level
Module 2 provides summarized information by study type and discipline
2.4 Nonclinical Overview is the primary nonclinical summary document, providing integrated overall analysis of nonclinical information in the CTD; document structure also mirrors structure found in M4 nonclinical study reports and M2 nonclinical written summary documents
Nonclinical information in the CTD is often the most “reusable” between regions

5. What’s Included in Nonclinical Sections of the CTD?
Module 2
2.4 Nonclinical Overview
2.6.1 Introduction
2.6.2 Pharmacology Written Summary
2.6.3 Pharmacology Tabulated Summaries
2.6.4 Pharmacokinetics Written Summary
2.6.5 Pharmacokinetics Tabulated Summaries
2.6.6 Toxicology Written Summary
2.6.7 Toxicology Tabulated Summaries
Module 4
4.2.1 Pharmacology study reports
4.2.2 Pharmacokinetics study reports
4.2.3 Toxicology study reports
4.3 Literature References

6. Toxicology Information Breakdown
Module 4
4.2.3 Toxicology study reports
Single-Dose Toxicity
Repeat-Dose Toxicity
Genotoxicity
Carcinogenicity
Reproductive and Developmental Toxicity
Local Tolerance
Other Toxicity Studies
Toxicology study reports generally include abstract, methods, results, conclusions and summary and individual data listings

7. Toxicology Information Breakdown
Module 2
2.6.6 Toxicology Written Summary
Brief Summary
Single-Dose Toxicity
Repeat-Dose Toxicity
Genotoxicity
Carcinogenicity
Reproductive and Developmental Toxicity
Studies in Juvenile Animals
Local Tolerance
Other Toxicity Studies
Discussion and Conclusions
Tables and Figures
Note breakdown of Toxicology Written Summary directly mirrors breakdown of Toxicology study reports in Module 4

8. Toxicology Information Breakdown
Module 2 Nonclinical Tabulated Summaries
Tabulated summary is created for all toxicology studies included in Module 4
2.6.7 Toxicology Tabulated Summaries
Toxicology Overview
/3 Toxicokinetics Studies & Data
Toxicology Drug Substance
Single-Dose Toxicity
/7 Repeat-Dose Toxicity
/9 Genotoxicity
Carcinogenicity
Reproductive and Developmental Toxicity
Local Tolerance
Other Toxicity Studies
Study-level tabulated summaries

9. Toxicology Information: Opportunities for Content Reuse
Text and data included in Toxicology study reports form the basis for the Toxicology Written and Tabulated summary documents provided in Module 2
Abstracts from the Module 4 Toxicology study reports can be reused directly in corresponding sections in the Toxicology Written Summary
Toxicology tabulated summaries can be populated directly from protocol/study information and raw data captured in data collection systems and/or study reports
Addition of system to capture noteworthy findings provides opportunity for further automation

10. 2.6.7.1 Toxicology Overview Tabulated Summary Sample

11. 2.6.7.7 Repeat-Dose Pivotal Tabulated Summary Sample

12. 2.6.7.7 Repeat-Dose Pivotal Tabulated Summary Sample (continued)

13. 2.4 Nonclinical Overview Primary nonclinical summary document
Nonclinical Overview Structure
Overview on Nonclinical Testing Strategy
Pharmacology
Pharmacokinetics
Toxicology
Integrated Overview and Conclusions
References

14. Toxicology Information: Opportunities for Content Reuse
2.4 Nonclinical Overview
Contains major sections for Toxicology
Breakdown of major sections mirrors breakdown of toxicology study reports, written summary and tabulated summaries
Paying careful attention to how study reports, written summary and tabulated summaries are structured can lead to opportunities for direct population of several 2.4 Nonclinical Overview sections

15. Implications for Pharmacology and Pharmacokinetics Sections in CTD
Same opportunities demonstrated for Toxicology also exist for Pharmacology and Pharmacokinetics Sections
Breakdown of Module 4 study report mirrors sections included in Module 2 Written Summaries
Study reports can form basis of information for Module 2 Written and Tabulated Summaries
Opportunity to directly feed sections from Written Summaries to Nonclinical Overview
Integrated approach to development of all nonclinical sections can lead to significant content reuse opportunities

16. Nonclinical Information Flow in the CTD
Nonclinical Summary Documents
Study data collection systems containing general protocol/study information and raw data
Study Reports
Nonclinical Overview
Abstract
Report Body
Summary Tables
Written Summaries
Individual Listings
Electronic capture of Noteworthy Findings
Tabulated Summaries

17. Additional Opportunities for Reuse of Nonclinical Information in the CTD
Investigator’s Brochure compilation
Annual Reporting
Product Labeling
Direct submission of nonclinical datasets using SEND standard (second FDA pilot in planning stages)

18. How Can Technology Help?
Nonclinical sections have to be built from the beginning with content reuse in mind
Manage, collect and summarize study information, raw data and findings in electronic format, preferably using standard database formats
Use of “Smarter” document technologies
Use of XML to “code” documents to pave way for reuse
Document templates that are prepopulated with information from other finalized documents and/or authoritative database sources
Leverage full capabilities of document management/publishing systems to centrally store attributes, link documents and publish “virtual” documents created from information pulled from various source documents
Automated adherence to submission document guidelines (fonts, margins, page orientation, bookmarking, hyperlinking, etc.) through use of standardize stylesheets and advanced document automation

19. Implications for Document Management and Submissions Publishing
Much of the structure and metadata required for document management systems is embedded in the CTD
More automated submission assembly can be facilitated by fully utilizing CTD structures
Document management systems can be a major driver in enabling content reuse across the CTD if appropriate functionality is utilized/developed

20. In Conclusion …
Deliberate planning to enable content reuse is necessary
Making full use of existing databases and document management systems, in conjunction with smarter document technologies, can significantly increase content reuse
Using CTD structures and terminology whenever possible in systems enables automation
Increasing content reuse won’t eliminate work associated with authoring submission documents, but it has the potential to dramatically increase accuracy and efficiency
Lessons learned with content reuse for nonclinical information in the CTD are easily applied to other areas of the CTD