A CMC Reviewer s Perspective on the Quality Overall Summary. Arthur B. Shaw, Ph.D. FDA/CDER/ONDQA FDA DMF Expert June 15, 2010.

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1 A CMC Reviewer s Perspective on the Quality Overall Summary and Module 3 Arthur B. Shaw, Ph.D. FDA/CDER/ONDQA FDA DMF Expert June 15, 2010 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. ( DIA ) DIA), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. For work prepared by US government employees representing their agencies, there is no copyright and these work products can be reproduced freely. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. 2 1

2 Module 1 Admin ESub overview Module 2 Summary Includes Quality Overall Summary (QOS) Module 3 Quality Module 4 Safety Module 5 Efficacy Modules 1, 4 and 5 These modules contain important information related to CMC Module 1: Letters of Authorization to other applications, particularly Drug Master Files (DMFs) Modules 4 and 5: Information about batches used for safety studies and clinical trials. Important if there are issues regarding impurities and/or formulation changes during development. 2

3 Module Letter of Authorization (LOA) Submission by the owner of information, ato giving g authorization for the information to be used by another. Include in DMF Statement of Right of Reference Submission by recipient of a Letter of Authorization with a copy of the LOA and statement of right of reference. Include in NDA/IND. Do NOT place in S.2 or P [next slide] 1.14: Claim of categorical exclusion or environmental assessment Section 1.11 Information amendment: Information not covered under modules 2 to 5 From Guidance for Industry: Providing Regulatory Submissions in Electronic Format Human Pharmaceutical Product Applications and Related Submissions Using the ectd Specifications Page 11 You should include documents that are provided in information amendments in the appropriate module using the appropriate headings to describe the subject matter. In the unusual case when information amendments do not fit appropriately under any heading in the CTD, you should place the documents in module 1 under the heading information amendment: Information not covered under modules 2 to 5. 3

4 Scanned Images vs Text or OCR From the ECTD Guidance (Page 6) Scanned documents submitted electronically as images are not as useful for review as documents that are text based. Image-based documents are more difficult to read and cannot be electronically searched. It takes longer to print image-based documents, and they occupy more storage space than text-based t documents. For these reasons, we strongly urge that you provide text-based documents, rather than image files, whenever possible. Module 2 Module 2 (QOS) is the basis for the Question- based Review (QbR) used by the Office of Generic Drugs (OGD) I have no experience using it for a QbR Can be useful to get an overview of the application but not as the basis for the review. For Phase 1 INDs Module 3 without QOS is acceptable. Don t submit everything in the QOS. 4

5 One Single PDF Document vs Separate PDF Documents For small submissions, such as Phase 1 IND, single PDF document MIGHT appear to be acceptable but it isn t. The whole point of breaking the outline into separate sections is to avoid having to resubmit entire document when amendments are filed. Module 3 The most granular of the technical modules. Permits replacement of individual sections as updated. Can be challenging for reviewer since the reviewer has to go up and down the sections. 5

6 Links Internal links can be very useful, including to other Modules Useful to be able to link Batch Analysis to batches used for safety studies and clinical trials. If a different formulation was used during clinical development, link to P.2. Pharmaceutical Development Stability Data Provide data in tabular format. Clearly identify package type, strength. Useful to provide data by attribute in addition to by batch. Have SAS Transport files available as needed. Used for statistical analysis if needed. 6

7 Health Level 7 (HL7) Standards Develops standards for healthcare industry New FDA standards model Collaborate with standards development organizations like HL7 Adopt standards as appropriate Structured Product Labeling (SPL) Annotated Electrocardiogram (aecg) Various clinical data standards (e.g. CDISC) Regulatory Product Submission (RPS) which represents the evolution of the ectd HL7 Stability Model XML-based approach based on model created by FDA s Jon Clark & Naiqi i Ya Version 1 XML Schema approved and adopted as an ANSI standard in 2005 Industry-FDA working group established to test standard and associated Implementation Guide Version 2 submitted 7

8 FDA-Developed Sample Viewer Life Cycle Management Powerful tool, particularly for CMC. Permits tracking of tentative specs as they evolve, changes in manufacturing procedures Useful both pre-and post-approval 8

9 Post-Approval Submissions Relation to lifecycle management When constructing initial NDA submission consider impact on sections likely to be changed. What if baseline submission is not original NDA? What and when to back-populate? Post-Approval Submissions (contd) Supplements Consider adding a change history table to each document Module 1: Summarize ALL changes in cover letter Module 2: Use only when extensive changes Not for all data supporting the changes Module 3: Supporting data go here. Include only files that have been changed 9

10 Post-Approval Submissions (contd) Provide references to approved information Include baseline file if not already submitted Use Replace or Append Example: Add a new manufacturing site. Append another document containing additional site to existing document or replace existing list with a new list? Make changes to Module 3 documents obvious Tabular comparison, highlighting, Word s Track Changes, Best Practices Summary Include meaningful links & bookmarks Confirm that links work Include header or footer that identifies the file, and its version Limit submission of many small files Include short descriptive backbone file titles Be consistent Perform QA in the role of a reviewer Use related sequence number appropriately Facilitate comparisons of what s new/what s old 10

11 Conclusion Electronic submissions are a useful tool to permit easy access to information for reviewers but the submitter must follow the Guidances to facilitate review. Norman Schmuff Virginia Ventura Mark Seggel Acknowledgments 11