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

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

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

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

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

Toxicology Information Breakdown Module 4 4.2.3 Toxicology study reports 4.2.3.1 Single-Dose Toxicity 4.2.3.2 Repeat-Dose Toxicity 4.2.3.3 Genotoxicity 4.2.3.4 Carcinogenicity 4.2.3.5 Reproductive and Developmental Toxicity 4.2.4.6 Local Tolerance 4.2.4.7 Other Toxicity Studies Toxicology study reports generally include abstract, methods, results, conclusions and summary and individual data listings

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

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 2.6.7.1 Toxicology Overview 2.6.7.2/3 Toxicokinetics Studies & Data 2.6.7.4 Toxicology Drug Substance 2.6.7.5 Single-Dose Toxicity 2.6.7.6/7 Repeat-Dose Toxicity 2.6.7.8/9 Genotoxicity 2.6.7.10 Carcinogenicity 2.6.7.11-2.6.7.15 Reproductive and Developmental Toxicity 2.6.7.16 Local Tolerance 2.6.7.17 Other Toxicity Studies Study-level tabulated summaries

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

2.6.7.1 Toxicology Overview Tabulated Summary Sample

2.6.7.7 Repeat-Dose Pivotal Tabulated Summary Sample

2.6.7.7 Repeat-Dose Pivotal Tabulated Summary Sample (continued)

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

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

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

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

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)

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

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

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