1. TOPIC: ICH E3 Medical Writing SIAC Helle Gawrylewski, et al April 20, 2005

2. 2 The Achievement of E3 First major effort to harmonize marketing applications; among the first ICH guidances Guidance has been successfully used since its release Forms the foundation of a CTD The E3 working group’s effort should be commended

3. 3 But… Questions Exist In an informal SIAC survey of 20+ companies and freelance writers, virtually every CSR Table of Contents showed variations in structure Be assured our MW group does not request E3 be opened for revision We propose that certain aspects of E3, particularly its relationship to the eCTD, be clarified

4. 4 Main Topic for Discussion Diametrically different views of the E3: As a guideline As a template An official position from ICH needs to be communicated The trend: clear specification of file structure while retaining flexibility within a file, with regard to content.

5. 5 Guideline or Template? Those who see the guidance as a guidance have successfully designed templates to accommodate most study types, including abbreviated reports Others interpret E3 as a rigid template, including software vendors, QA auditors, and a proportion of companies in the US Some HA in Europe question CSR structure if numbering is not exactly as in E3 Colleagues in Asia-Pacific often interpret E3 literally

6. 6 Guideline or Template? STF documents refer to and appear to recommend E3 numbering No reference to the allowed modifications is linked to the actual E3 official copy No forum for official answers

7. 7 Guideline or Template? The guidance was designed to specify minimum required content As a “template” it is not user friendly Questions arise when sponsors attempt to force a report into an E3 “template” A clear and publically available position from ICH would be useful

8. 8 Case in Point CTD and eCTD allow and recommend the synopsis as a separate document Some see that as a conflict with E3 and expect a synopsis within the CSR and another copy preceding the CSR, defeating the purpose of tagging and reusing elements But argumentation for a reasonable approach is not officially found in ICH documents, or at least this is not being understood

9. 9 General Questions E3 at times appears incompatible with rigidity of electronic requirements, eCTD Overall structure and numbering in E3 sometimes confusing How best to adapt E3 to Phase 1 reports? How to submit a Synoptic Report or Abbreviated Report in an eCTD?

10. 10 Other Discussion Topics Appendix Contents Appendix Headings Clarification of terms Signatures required in the CSR vs linked to Mod 1 Within the text: Duplication of information Missing sections, like concomitant meds? Possibility to add topics, like Outcomes variables? Reordering of sections?

11. 11 Specifics – Some Examples: Perceived E3/eCTD incompatibility No possibility to include or attach entire separate reports, ie, for microarray, health outcomes, special studies data, as is possible in paper CSR Appendices Numbering in E3 applied to eCTD study tagging files but— Location of information such as PK and immunogenicity are not specifically identified Uncertainty about placement for this material in the eCTD Many issues have been solved by ICH M2 EWG (v 2.6) but resolutions are not well understood or communicated

12. 12 Specifics (cont’d) Sections that appear to contain duplicated material—combine? Section 9.5.1: Efficacy and Safety Measures Section 9.7.1: Statistical and Analysis Plans Sections 9.4.1, 9.4.4, 9.4.5: Treatment, contain redundant information Acceptable to change order within text, like Section 9.5 to make a more logical presentation?

13. 13 Specifics (cont’d) Acceptable to add sections for following missing information: Prior and concomitant medications? Withdrawals due to safety issues? PK/PD/Immunogenicity? Pharmacogenomics? Allowing flexibility within the text (file) allows writers to streamline text

14. 14 Specifics (cont’d) Protocol deviations—How much detail? Clarify the following re: Appendices 16.1.1 = Final protocol or all versions? 16.1.3 = Master IC or IC from each site? 16.1.4 = CVs of PIs only or include subinvestigators?

15. 15 Specifics (cont’d) Title page—Regulatory Department instead of author of report? Signature of responsible medical officer in report with link to separate location for PI or CI? What are allowable modifications for Phase 1 studies, including oncology MTD studies, to accommodate PK results. Reconcile FDA Guidance on Abbreviated CSRs to fixed format of eCTD

16. 16 Questions About Terms Terms “Selection Criteria” same as “Inclusion Criteria”? Or is meaning different? (From Japanese Medical Linguistics Inst) In synopsis: Methodology, is this study design, investigational plan, rationale? Test product (in synopsis) vs treatments studied, test drug, investigational product, medicinal product. Reference therapy vs control therapy later Terms not consistent in E3 or across later guidances

17. 17 Change Control of Terms Support the proposal for a Change Control Process for ICH terms, including the topic of headings for E3 Appendices Maintenance Process for ICH Terminology Lists Process needs to be linked to the standardization efforts of the HL7\CDISC RCRIM Group and the Protocol Representation Group (and Glossary effort)

18. 18 Current Situation Varied interpretations mean widely varying CSR content and location of information Many companies spend time and effort collecting, processing, and submitting unnecessary documents We need to remember the segments still requiring and submitting paper documents

19. 19 Common Goals Guidelines for CSR that: Allow adequate and concise reporting of study data Allow consistent and predictable location of information Are compatible with other formats, such as eCTD Remain flexible enough to accommodate device, Phase 1, oncology MTD, other types of studies Are a win/win solution– consistency can assist reviewers and streamline compilation for sponsors

20. 20 MW SIAC Requests that ICH: Establish official Q & A process for E3 Reconstitute an expert working group to provide official responses Answer first: Is E3 intended to offer guidance or be a template? Post answers to questions in a central location MW SIAC has compiled questions and will provide the list Medical Writers need to be included in the EWG

21. 21 Those Who Contributed Barbara Kamm Nancy Katz Linda Wood Peggy Boe Art Gertel Jean Soul-Lawton Virginia Watson Chris Preston Cathy Stein-Izsak Sandy Hecker MaryAnn Foote Christina Rogers Elizabeth Ashraf Ellen Hodosh Scott Cain Cara E Willoughby Ruth Starzyk Nikola Bulow Gerri Smoluk Takumi Ishida Gail Head

22. Thank you, Merci, Domo Arigato G ozaimas For your attention and consideration. Special thanks to Justina Molzon, who participates in our SIAC.