1. 1 Optimal Strategies for Preparing Integrated and Clinical Summaries for a New Drug Application: Making it Work Under Any Circumstance Lisa A. Pierchala, MPH Principal Medical Writer MMS Holdings, Inc.

2. 2 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”), its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners. Disclaimer

3. 3 Integrated documents vs summary documents Integrated Summary of Safety (ISS) and Summary of Clinical Safety (SCS) –Overview of content –Ideal timing for document preparation –Other alternatives for timing of document preparation Integrated Summary of Efficacy (ISE) and Summary of Clinical Efficacy (SCE) –Overview of content –Ideal timing of document preparation –Other alternatives for timing of document preparation Conclusion Overview of Presentation

4. 4 Integrated documents vs summary documents ISS and SCS –Overview of content –Ideal timing for document preparation –Other alternatives for timing of document preparation ISE and SCE –Overview of content –Ideal timing of document preparation –Other alternatives for document preparation Conclusion Overview of Presentation

5. 5 Integrated summaries (ISE and ISS) reside in Module 5.3.5.3 –Format and Content of the Clinical and Statistical Sections of an Application (Clin-Stat guidance) includes outlines of the ISE and ISS; updated in International Conference on Harmonization (ICH) M4 guidance Clinical summaries (SCE and SCS) reside in Module 2.7 (2.7.3 and 2.7.4, respectively). –ICH M4E Guideline describes the structure and format of the clinical data (both efficacy and safety) in an NDA, including summaries and detailed summary reports Integrated Documents vs Summary Documents

6. 6 The FDA requires the ISS and the ISE in addition to the SCS and SCE (SCS and SCE alone do not satisfy regulatory requirement). The SCS and SCE are usually derived from the ISS and ISE. Integrated Documents vs Summary Documents Source: http://pixshark.com

7. 7 SCS and SCE are not intended to provide the same level of detail as presented in the ISS and ISE. – ISS and ISE are intended to be comprehensive, integrated analyses of all relevant data from the clinical study reports. –SCS and SCE provide a more succinct summarization of key clinical information. Integrated Documents vs Summary Documents

8. 8 Integrated documents vs summary documents ISS and SCS –Overview of content –Ideal timing for document preparation –Other alternatives for timing of document preparation ISE and SCE –Overview of content –Ideal timing of document preparation –Other alternatives for timing of document preparation Conclusion Overview of Presentation

9. 9 Summarizes data relevant to safety in the intended population. Display of safety related data including: –Extent of exposure –Common AEs and changes in laboratory examinations –Deaths, SAEs, and other significant AEs ISS/SCS – Overview of Content

10. 10 Content and organization of the SCS approximately follows the ISS. What to omit from the ISS: –Not all tables in the ISS need to be included in the SCS –May omit some pooled populations –May omit full presentation of subgroups –May omit some special safety topics ISS/SCS – Overview of Content

11. 11 Key inputs will limit availability to start writing documents ISS/SCS – Ideal Timing for Document Preparation ISS Pivotal CSR(s) All Other CSRs (ex. ongoing long-term safety studies with interim data cut) Pooled TLGs SCS

12. 12 Will present “ideal” scenario for ISS and SCS preparation assuming: –Shell/TOC, 2 drafts, QC, final draft –All inputs are available at the time of writing draft 1 of the documents For alternatives for timing of ISS and SCS preparation, will modify assumptions including: –Shortened durations –Parallel development of ISS and SCS –One less draft of the SCS –Writing from draft tables ISS/SCS – Ideal Timing for Document Preparation

13. 13 Staggered writing of ISS and SCS ISS/SCS – Ideal Timing for Document Preparation Write shell Review shell Incorp shell changes/ write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCS Determine SCS content ~ 15 d~ 5 d ~ 20 d ~ 10 d ~ 5 d ~ 10 d ~ 5 d Overall time frame: ~ 100 days Not drawn to scale! Receipt of final pooled TLGs

14. 14 Staggered writing of ISS and SCS Benefits Content for ISS has largely been determined by the time you start writing the SCS; more straightforward to write the SCS and ensures higher quality. Minimal overlap between the 2 documents prevents reviewers from having to request the same revisions multiple times for the same text in both documents. Drawbacks Overall duration to write the 2 documents is longer. Changes requested to later draft of SCS cannot be applied to ISS. ISS/SCS – Ideal Timing for Document Preparation

15. 15 Shorter durations in the timeline ISS/SCS – Alternatives for Timing of Document Preparation Write shell Review shell Incorp shell changes/ write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCS Determine SCS content ~ 10 d~ 5 d ~ 15 d ~ 5 d ~ 10 d ~ 3 d~ 5 d~ 3 d~ 5 d Receipt of pooled TLGs Overall time frame: ~ 76 days Not drawn to scale!

16. 16 Shorter durations in the timeline Benefits Overall duration to write the 2 documents is shorter. Drawbacks These documents can be HUGE and the same amount of work will need to go into them regardless of the number of days provided to write. This is the first time integrated data across the program are available. Time is needed to fully review and describe data. Risk to quality. Employee burnout. ISS/SCS – Alternatives for Timing of Document Preparation

17. 17 Parallel writing of ISS and SCS ISS/SCS – Alternatives for Timing of Document Preparation Write shell Review shell Incorp shell changes/ write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCS Determine SCS content ~ 15 d~ 5 d ~ 20 d ~ 10 d ~ 5 d ~ 10 d ~ 5 d Overall time frame: ~ 80 days Not drawn to scale!

18. 18 Parallel writing of ISS and SCS Benefits Overall duration to write the 2 documents is shorter. Drawbacks The text for the same data is being written twice in 2 different documents, therefore, there will likely be discrepancies in content. The reviewers are reviewing the same/similar text at almost the same time; challenging to ensure that appropriate changes are being made in both documents. SCS is finalized first. Changes requested to later draft of ISS cannot be applied to SCS. ISS/SCS – Alternatives for Timing of Document Preparation

19. 19 One less draft of the SCS ISS/SCS – Alternatives for Timing of Document Preparation Write shell Review shell Incorp shell changes/ write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes QC Final SCS Determine SCS content ~ 15 d~ 5 d ~ 20 d ~ 10 d ~ 5 d ~ 10 d ~ 5 d Receipt of pooled TLGs Overall time frame: ~ 90 days Not drawn to scale!

20. 20 One less draft of the SCS Benefits Overall duration to write the 2 documents is shorter. Drawbacks Reviewers only have 1 opportunity to review the SCS. Requires a commitment from the team to provide a very detailed review of a critical submission document. ISS/SCS – Alternatives for Timing of Document Preparation

21. 21 Writing from draft TLGs ISS/SCS – Alternatives for Timing of Document Preparation Write shell Review shell Incorp shell changes/ write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCS Determine SCS content ~ 15 d~ 5 d ~ 20 d ~ 10 d ~ 5 d ~ 10 d ~ 5 d Overall time frame: ~ 100 days Receipt of draft pooled TLGs Receipt of final pooled TLGs

22. 22 Writing from draft TLGs Benefits Overall duration is not shorter, but you can start Draft 1 sooner, therefore finishing sooner. Drawbacks If corrections are made to tables between draft and final, an additional step needs to be added to ensure data in the document is accurate. Risk to quality. ISS/SCS – Alternatives for Timing of Document Preparation

23. 23 Integrated documents vs summary documents ISS and SCS –Overview of content –Ideal timing for document preparation –Other alternatives for timing of document preparation ISE and SCE –Overview of content –Ideal timing of document preparation –Other alternatives for timing of document preparation Conclusion Overview of Presentation

24. 24 Summarizes efficacy and other information (ie, demographics, baseline disease characteristics, etc) from controlled studies and other pertinent studies that evaluated efficacy specific to the indication. SCE provides summaries of data, not a complete presentation of all integrated data that is presented in the ISE. ISE/SCE – Overview of Content

25. 25 Content and organization of the SCE approximately follows the ISE. Differences between content of ISE and SCE: –Detailed descriptions of analytical methods included in the ISE –SCE may omit some secondary or exploratory analyses that may be included in the ISE –SCE may focus only on dose(s) sought for approval –Tables and figures should be used to enhance understanding of the data; lengthy tables should only be included in the ISE ISE/SCE – Overview of Content

26. 26 Pooling of data “Individual controlled studies to a great extent speak for themselves with respect to their ability to provide evidence of effectiveness required by law.” Studies are not always pooled – depends on the design of the studies. “…particular attention should be paid to statistical considerations, selection bias in choosing studies, etc.” Guideline for the Format and Content of the Clinical and Statistical Sections of an Application (FDA) ISE/SCE – Overview of Content

27. 27 Key inputs will limit availability to start writing documents ISE/SCE – Ideal Timing for Document Preparation ISE Pivotal CSR(s) Other CSRs (ex. long-term efficacy studies with interim data cut) Pooled TLGs SCE Pop PK

28. 28 Often more variability in when inputs are available for writing of efficacy documents: –Programming of pooled TLGs can begin at database lock of final pivotal study(ies); pooled TLGs may be available before final CSR(s). –If minimal data is being pooled (ex: only pooled data for subgroups), the majority of the ISE writing can begin once final pivotal CSRs are available. –Population PK reports can take a significant amount of time after database lock of final pivotal study(ies); often the last piece received for the ISE/SCE. ISE/SCE – Ideal Timing for Document Preparation

29. 29 Many of the scenarios described for the ISS/SCS can also be duplicated for the ISE/SCE (are not repeated in subsequent slides): –Shortened durations –Parallel development of ISE and SCE –One less draft of the SCE ISE/SCE – Ideal Timing for Document Preparation

30. 30 Will present “ideal” scenario for ISE and SCE preparation assuming: –Shell/TOC, 2 drafts, QC, final draft –All inputs (final pivotal CSRs and final pooled TLGs) are available at the time of writing draft 1 of the documents For alternatives for timing of ISE and SCE preparation, will modify assumptions including: –Writing from draft CSRs with final pooled TLGs available OR writing from draft TLGs with final CSRs available –Varying when final inputs are available. ISE/SCE – Ideal Timing for Document Preparation

31. 31 Staggered writing of ISE and SCE ISE/SCE – Ideal Timing for Document Preparation Write shell Review shell Incorp shell changes/ write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final ISE Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCE Determine SCE content ~ 15 d~ 5 d ~ 20 d ~ 10 d ~ 5 d ~ 10 d ~ 5 d Overall time frame: ~ 100 days Not drawn to scale! Receipt of final CSR(s) and final pooled TLGs

32. 32 ISE/SCE – Ideal Timing for Document Review Staggered writing of ISE and SCE (with all sources available) Benefits Content for ISE has largely been determined by the time you start writing the SCE; more straightforward to write the SCE and ensures higher quality. Minimal overlap between the 2 documents prevents reviewers from having to request the same revisions multiple times for the same text in both documents. Drawbacks Overall duration to write the 2 documents is longer. Changes requested to later draft of SCE cannot be applied to ISE.

33. 33 ISE/SCE – Alternatives for Timing of Document Preparation Writing from draft CSRs with final pooled TLGs Write shell Review shell Draft 1a Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCS Determine SCS content ~ 15 d~ 5 d ~ 15 d ~ 10 d ~ 5 d ~ 10 d ~ 5 d Overall time frame: ~ 100 days Receipt of draft CSR(s) and final pooled TLGs Draft 1b ~ 5 d Receipt of final CSR(s) Not drawn to scale!

34. 34 ISE/SCE – Alternatives for Timing of Document Preparation Writing from draft CSRs with final pooled TLGs Benefits Overall duration is not shorter, but you can start Draft 1 sooner, therefore finishing sooner (ie, not waiting for the pivotal CSR(s) to be final). Preparation of ISE and SCE is still staggered. Drawbacks If there are changes between the draft and final CSR(s), an additional step needs to be added to ensure data in the document is accurate. Risk to quality.

35. 35 ISE/SCE – Alternatives for Timing of Document Preparation Writing from draft pooled TLGs with final CSRs In general, the timing is the same as in the previous example –If there are changes between draft and final TLGs, an additional step needs to be added to confirm that the information in the document is accurate.

36. 36 ISE/SCE – Alternative for Timing of Document Preparation Write shell Review shell Prepare Draft 1 Review draft 1 Incorp draft 1 changes; incorp final TLGs Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCS Determine SCS content ~ 15 d~ 5 d ~ 15 d ~ 10 d~ 15 d~ 5 d ~ 10 d ~ 5 d Overall time frame: ~ 100 days Receipt of final CSR(s) Receipt of final pooled TLGs Not drawn to scale! Varying when final inputs are available

37. 37 ISE/SCE – Alternative for Timing of Document Preparation Write shell Review shell Prepare Draft 1 Review draft 1 Incorp draft 1 changes; incorp final TLGs Review draft 2 Incorp draft 2 changes QC Final ISS Write draft 1 Review draft 1 Incorp draft 1 changes Review draft 2 Incorp draft 2 changes QC Final SCS Determine SCS content ~ 15 d~ 5 d ~ 15 d ~ 10 d~ 15 d~ 5 d ~ 10 d ~ 5 d Overall time frame: ~ 100 days Receipt of draft CSR(s) and draft pooled TLGs Receipt of final pooled TLGs Not drawn to scale! Receipt of final CSR(s) Varying when final inputs are available

38. 38 ISE/SCE – Alternative for Timing of Document Preparation Varying when final inputs are available Writing from draft pooled TLGs or draft pivotal CSR(s) is an option and when these inputs will be received can vary. Time must be given to verify the ISE/SCE against the final CSR(s) and final pooled TLGs to ensure data in the document is accurate. Risk to quality.

39. 39 Integrated documents vs summary documents ISS and SCS –Overview of content –Ideal timing for document preparation –Other alternatives for timing of document preparation ISE and SCE –Overview of content –Ideal timing of document preparation –Other alternatives for timing of document preparation Conclusion Overview of Presentation

40. 40 Overall Summary Staggered preparation of the ISS/SCS and ISE/SCE is an optimal approach for preparing the documents. Utilizing the alternatives for timing of document preparation depends on the level of risk that a Sponsor is willing to assume. It is possible to combine multiple approaches (ex: shorter durations + one less draft of the SCS), depending on how aggressive the Sponsor is willing to be. Conclusion

41. 41 Lisa A. Pierchala, MPH Principal Medical Writer MMS Holdings, Inc. Join the conversation #DIA2015 Thank You