Comments and Responses

Below are a list of all comments received during the 6-week open comment period on CORE Reference and our responses to them.

The guidance provided here, "In general, do not repeat in-text tabulated summary data by additionally describing it in text" would seem to be a proscription against any text that includes data from the study.

Perhaps this is intended to prevent repeating, in text, virtually all of the numbers in an in-text table, which I agree is egregious and pointless.

However, the guidance as written would seem to ban even a simple text summaries of typical in-text table, eg:
"Most subjects were women (78%), and mean (SD) age of all subjects was 68.5 (2.9) years."
"Efficacy was demonstrated by a statistically significantly higher response rate of the primary efficacy endpoint in the active drug group (83.5% vs 13.2%, p < 0.001)."
"The A and B treatment groups showed similar rates of all AEs (58% vs 57%, respectively), treatment-related AEs (8% vs 9%), and SAEs (1% vs 1%)."

Is the intent that the text for the results sections of CSR should not include sentences such as the above, which would "...repeat in-text tabulated summary data by additionally describing it in text"?

Thanks very much, and thanks for all your hard work in completing the CORE Reference.

It is important to understand that CORE Reference cannot ‘ban’ or ‘proscribe’. CORE Reference makes suggestions for good CSR authoring practice. It is up to the end user to make choices on if or how they implement particular suggestions. We believe that the CORE Reference text as written is reasonable because we prefix the statement with the words ‘In general…’ In an earlier draft of CORE Reference, the text read ‘Do not laboriously repeat…’ Our intent is to counsel against repeating virtually all of the numbers in an in-text table in the text of the report. Simple text summaries, as you ably provide in example form in your comment, are reasonable to include in text. Thank you for your appreciation of our work.

Action: Text to be changed in next version of CORE Reference to: "In general, do not exhaustively repeat in-text tabulated summary data by additionally describing it in text. Lean in-text summaries of key in-text table data should, however, be considered."

Does CORE reference also apply for reporting the results of non-interventional studies?

Thank you for your comment, Racha. As stated on the first page of the document, CORE Reference is aimed at interventional studies only. Separate non interventional reporting guidelines are available but reviewing these was outside of the remit of the CORE Reference project.

Heading of Section 9.5 “Efficacy and Safety Variables”, does not adequately support the studies with PK, PD, PK/PD as primary or secondary objectives (mainly Clinical Pharmacology studies). Suggestion to either expand this heading to include these variables or keep it more generic, like “Study variable(s)”

In CORE Reference Section 9.5, the text on lines 4 and 5 immediately below the Section 9.5 title states ‘The title of this section (Efficacy and Safety Variables) may be renamed to reflect characteristics of the study. For example, if the study measures drug concentration (pharmacokinetics [PK]), pharmacodynamics (PD), including, for example, an exploratory biomarker, or pharmacoeconomic parameters, adapt the title to ‘Efficacy, Safety and Other Variables’. ‘Other’ variables may be specified in the title.’ The Mapping Tool is intended to support CORE Reference utility and, as such, should be used in conjunction with it. We therefore consider that the clear explanation in CORE Reference means that no change to the Mapping Tool is necessary.

The section heading “PHASE OF DEVELOPMENT” mentioned in the example synopsis could be misleading. Phase of development can be interpreted as the phase of the study for which the CSR and study is being drafted or can be interpreted as development phase of the program. Therefore suggest to have a clear heading “Study Phase”.

As stated in the CORE Reference Preface, page iv, point 4: ‘Unless otherwise stated, CORE Reference terminology is per Clinical Data Interchange Standards Consortium (CDISC) Clinical Research Glossary. Applied Clinical Trials, December 2011. http://www.cdisc.org/system/files/all/standard_category/application/pdf/act1211_011_043_gr_glossary.pdf See CDISC definitions for ‘Clinical research and development’; ‘phase’; ‘Phase 0’; ‘Phase 1’; ‘Phase 2’; ‘Phase 2A’; ‘Phase 3’; ‘Phase 3B’; ‘Phase 4’ and ‘Phase 5’. The existing text in CORE Reference seems sufficiently clear, given that the document being written is an individual clinical study report. We do not consider that any change to CORE Reference is necessary.

“BACKGROUND AND RATIONALE FOR THE STUDY” In addition to study objectives, endpoints, variables, here we introduce the term “rationale for the study”. Shouldn’t this be included in the main CSR together with the “Introduction” section, maybe as a subsection? The text on rationale of the study can be then directly incorporated into the CTR.

The rationale for the study is covered in the protocol and, in our opinion, does not need to be wholly repeated in the CSR, although some elements that are pertinent to reporting are included in, for example, Section 9.2 (Discussion of Study Design). The suggested section title ‘Background and rationale for the study’ within the Synopsis, is so named because it derives from Clinical Trials Regulation (CTR) EU No. 536-2014: http://ec.europa.eu/health/files/eudralex/vol- 1/reg_2014_536/reg_2014_536_en.pdf Annex IV Section A page L 158/69, point 5,which requires inclusion of ‘General information about the clinical trial (including information about main objectives of the trial, trial design, scientific background and explanation of rationale for the trial; date of the start of the trial, measures of protection of subjects taken, background therapy; and statistical methods used)’ in the summary of results. For clarity, we will omit the words ‘and rationale’ from the title. Action: Synopsis header ‘Background and rationale for the study’ to be changed in next version of CORE Reference to: ‘’Background for the study’.

I disagree with the suggested strategy of only listing the PIs in the List of Investigators, 'in the spirit of ICHE3 Q&A'. Please remain loyal to the text of the guidelines, including the Q&A, and do not extrapolate 'in the spirit.' FDA inspectors expect the full list of investigators, and use this list extensively to check against CVs, 1572s, Financial Disclosure and other documents submitted. Furthermore, the List of Investigators is expressly mentioned in the ICHE3 Q&A document among the documents that should be included in the CSR (without any mention of abbreviating it). The purpose of the CORE Reference document should be to consolidate and navigate the various requirements, not change them.

Thank you for calling this to our attention. While the 2012 Q & A says Investigator CVs may not be necessary, the guidance specifically states to retain the list of investigators. Action: CORE Reference Page 16, line 12/13 text ‘…abbreviated for studies with many centres to only PIs of each centre’ will be deleted and Comment A82 will be removed in the next version of CORE Reference.

I commend this effort for its thoroughness and vision. However it is essential for its usability that the designated quotes from the various references are literal quotes, not paraphrasing, interpreting, extrapolating or abbreviating. In addition, comments should be restricted to annotating the guidance text, not actually recommending ways to change it. The document would be a very useful tool if it stuck to this scope, bearing in mind that there are numerous additional guidances that have not been addressed in detail, and new requirements emerging all the time.

Thank you for your comments. The ICH E3 quotes within CORE Reference are literal quotes. It was not always quite so straightforward to include ICH E3 Q & A text in literal form because of the way the Q & A was written. Our approach was therefore to add clarity where we thought this was needed, and share suggestions and insights to allow pragmatic CSR authoring. The individual CSR author may decide if they wish to take note of these or not. The suggestions or insights presented in CORE Reference were consensus-based, and were not restricted to the views of the authors of CORE Reference. This was achieved through a lengthy and rigorous Stakeholder review process taking many months. The 6-week open comment period post-publication was intended to add value to the document. Only detailed pointers can inform follow-up of any specific omissions. We state that in addition to the ICH E3 and ICH E3 2012 Q & A guidance, we include regional guidance (EU and US) - see Hamilton et al launch publication: http://dx.doi.org/10.1186/s41073-016-0009-4. We did this to the best of our ability, and if there are omissions, we are glad to hear about them so that going forward we can update the resource. We believe that CORE Reference sticks to its intended scope. Any such document can only ever be a reflection of the wider regulatory environment at a particular point in time as there is no reliable method to predict future requirements. This seems to us self-evident. We recognise that, like guidance and regulation, the CORE Reference is a living document. As declared up-front, our intent going forward is to update CORE Reference on an ‘as-needed’ basis.

Removal of CVs does not apply in all cases, so this needs to be clarified and considered carefully. For instance for non-US trials that are not conducted under an IND, or global trials in which non-US sites are not submitted under the IND, the FDA requires CVs for all PIs and sub-investigators. See FDA 21 CFR 312.120, including also the FAQ document on this.

We have already drawn attention to this exact point in a single comment that precedes the Appendices section. It may be that it needs to be repeated at the exact relevant places in CORE Reference so that readers do not overlook it. Comment A574 on page 84 states: ‘See FDA Guidance on FDA Acceptance of Foreign Clinical Studies not Conducted Under an IND – Frequently Asked Questions: http://www.fda.gov/downloads/RegulatoryInformat ion/Guidances/UCM294729.pdf Additional appendix requirements may be necessary e.g. Investigator CVs, and action dates of IRB/IEC approvals (e.g. initial approval date, date of approval of study amendments/modifications), master ICF...’ So Comment A84 remains valid, but should make reference to CFR (FDA 21 CFR 312.120). Action: Comment A84 and Comment A582 will be updated as follows in the next version of CORE Reference: ‘The requirement for CVs in Appendix 16.1.4 has been removed as per the ICH E3 2012 Q & A which states that CVs can be included in the TMF only. However, be aware that CVs may be required in Appendix 16.1.4 for certain types of studies. See for example CFR (FDA 21 CFR 312.120) Foreign clinical studies not conducted under an IND: http://www.ecfr.gov/cgi-bin/text-idx?SID=f2e58b62de98ab01488b698c776a80b5&mc=true&node=pt21.5.312&rgn=div5 and the associated FAQs: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294729.pdf Section B.1 Investigator Qualifications. Check specifically if your study type must include CVs in Appendix 16.1.4 and include them if necessary.’

I disagree strongly with the CORE interpretation of ICHE3 and Q+A that the reporting of important PDs is limited exclusively to the PDs that are requested in Annex VI of ICHE3 (Annex III of the CORE), which is intended to be about the statistical analysis data sets, not to define the subset of important PDs. In most trials, this is a small subset of all the PDs that fulfil the ICHE3 (+Q+A) definition of important: 'may significantly impact the completeness, accuracy and/or reliability of the study data or that may significantly affect a subject's rights, safety or well-being.' In many trials, exclusion from efficacy analyses is not relevant, so restricting reporting to only these would greatly undermine the PD reporting. Furthermore, the CSR is not solely designed to capture efficacy data, but also to accurately report the conduct of the trial, including issues related to ethics (informed consent), IMP, reliability of the procedures at the investigational site, safety issues, etc. in order to assess GCP compliance overall. The minimalistic approach suggested here is not in line with ICHE3 (which provides limited 'examples'), nor inspections, where GCP inspectors expect to find relevant important PDs, e.g. relating to timing of consent, late SAE reporting, drug delivery or storage issues, and many other PDs identified during site inspections to be reflected in the CSR.

Thank you for spotting this. Obviously, important protocol deviations are not limited to those resulting in exclusions from the efficacy analysis. The cross-reference to Annex III from Section 10.2 is simply an artefact. Action: Page 50, line 6 text ‘An example of such a listing is provided in Annex III’ will be deleted in the next version of CORE Reference.

Please call attention to the issues with the Study Tagging Files when suggesting to create new appendices, and reference the FDA Guidance on this, as it is not without complications.

You refer here to the ICH E3 Q & A point about Appendices and in particular point 4 (2) entitled ‘In a region where study tagging files are used’. The complete ICH E3 Q & A text on this is: ‘In a region where study tagging files are used. It is recommended that a file tag option from the “valid values list” be used, for example, safety report, antibacterial, special-pathogen, etc. (see Specifications for Study Tagging Files, http://www.ich.org/products/electronic-standards.html ). Alternatively, if a file-tag that adequately describes the material you are planning to submit is not available, you may request that a new file-tag be made available. This request should be submitted to your regional authority. In the event that this change cannot be accommodated within your timeframe you may place the document with the main body of the report, i.e., the document would be tagged with the “study-report-body” file-tag. The nature of the information should be contained in the title of the document that is provided through the eCTD. Please refer to the most recent version of the “valid values list”, as it is periodically updated as changes are requested’. Action: We will call attention to the above ICH E3 Q & A text on page 84 of CORE Reference in the next version of CORE Reference.

Once again, ICHE3 Q&A does not stand alone, nor is it quoted accurately here. The Q&A document states 'Supportive documents such as...should generally not be included...'. Please remain loyal to the text. Furthermore, for non-US trials, master SI/IC forms are still required by the FDA under 21 CFR 312.120 (and the FAQ document on this).

This is already covered in Comment A574 on page 84 as explained above. Comment A578 remains valid, but should make reference to CFR (FDA 21 CFR 312.120). Action: Comment A578 will have the following text appended: ‘…which states ‘Supportive documents, such as … informed consent forms… are in the TMF … and should generally not be included in the CSR appendices’. However, be aware that ICFs may be required in Appendix 16.1.3 for certain types of studies. See for example CFR (FDA 21 CFR 312.120) Foreign clinical studies not conducted under an IND: http://www.ecfr.gov/cgi-bin/text-idx?SID=f2e58b62de98ab01488b698c776a80b5&mc=true&node=pt21.5.312&rgn=div5 and the associated FAQs: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294729.pdf Section 8 Description of how informed consent was obtained. Check specifically if your study type must include ICFs in Appendix 16.1.3 and include them if necessary.’ In addition, page 85 Appendix 16.1.3 boxed italicised text will be adapted to exact Q & A wording and will include the word ‘generally’.

Once again, ICHE3 Q&A does not stand alone, nor is it quoted accurately here. The Q&A document states 'Supportive documents such as....should generally not be included...'. Please remain loyal to the text. Furthermore, for non-US trials, CVs are still required by the FDA under 21 CFR 312.120 (and the FAQ document on this).

This is already covered in Comment A574 on page 84 as explained above. Comment A582 remains valid, but should make reference to CFR (FDA 21 CFR 312.120). Action: Comment A578 will have the following text appended: ‘…which states ‘Supportive documents, such as … investigator CVs… are in the TMF … and should generally not be included in the CSR appendices’. However, be aware that CVs may be required in Appendix 16.1.4 for certain types of studies. See for example CFR (FDA 21 CFR 312.120) Foreign clinical studies not conducted under an IND: http://www.ecfr.gov/cgi-bin/text-idx?SID=f2e58b62de98ab01488b698c776a80b5&mc=true&node=pt21.5.312&rgn=div5 and the associated FAQs: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294729.pdf Section 8 Section B.1 Investigator Qualifications. Check specifically if your study type must include CVs in Appendix 16.1.4 and include them if necessary.’ In addition, page 86 Appendix 16.1.4 boxed italicised text will be adapted to exact Q & A wording and will include the word ‘generally’.

I am keen to implement CORE Reference within my company and have been selling it as best I can but need to provide others with more reassurance. Please could you provide any comments to the following:
1. Feedback on adoption by pharma companies/CROs so far
2. Have there been any endorsements/comments from MHRA/other RAs etc. since launch?
3. Was there any TransCelerate involvement in putting CORE Reference together?
4. Was there any discussion of CORE Reference at DIA?

It is good to hear from you, Becky, and to have your support; the BWG thank you for your efforts to increase uptake of CORE Reference. We know for sure that interest grows daily as reflected in the download counter displayed clearly on the website. These are not just page hits but actual downloads of the PDF, which as of 15 July 2016, are around the 1650 mark. Further, below are the BWG’s responses to your comments: Re. 1. We are in the process of posting support and adoption comments and have now received these from several organisations who have already adopted CORE Reference into their SOPs. We anticipate that more will follow. At the July 2016 ExL conference in Florida, Aaron Bernstein’s (BWG team member) presentation on CORE Reference was attended by approximately 50 heads of MW departments and senior-level medical writers. Multiple audience participants openly declared their company’s support and adoption of CORE Reference into their SOPs during the Q&A. Our advice is to watch the website and keep an eye on the ‘Adoption and Support’ page. Re 2. No such post-launch comments have been received to date. ICH has made it clear that they wish to remain insular in developing guidance and have stated in a letter to Sam Hamilton (Chair CORE Reference project) received August 2015, that they do not plan to update ICH E3. Health Canada (an ICH regulator) was a CORE Reference Stakeholder, and our point contact, Dr Celia Lourenco, who headed the 5-member HC Stakeholder team is listed by ICH as a ’Standing Regulatory Member Representative': http://www.ich.org/fileadmin/Public_Web_Site/ABOUT_ICH/Organisational_changes/ICH_Permanent_MC_Rep_23Oct2015.pdf Re 3. Yes. An important CORE Reference Stakeholder was the DIA MW Community 18-member CORE Review Task Force. Members of this group were also on the TransCelerate team [NOTE: to my knowledge, TransCelerate did not take on the ICH E3 – only the ICH E6 in the context of protocol modeling; I am therefore not sure how relevant TransCelerate is to the CSR/CORE Reference], and brought cross-fertilisation of ideas to the project through their insightful comments. BWG’s Strategist, Art Gertel, was also a consultant on the TransCelerate CPT initiative, and Tracy Farrow (BWG team member with special responsibility for transparency and disclosure) was on the ACRO Stakeholder Group for the TransCelerate CPT initiative. The cross-functionality of individuals involved in the development of CORE Reference and TransCelerate’s CPT project has brought value to the CORE Reference project in our view. Re. 4. Yes. Tracy Farrow presented in April 2016 at DIA in Hamburg. She discussed CORE Reference in her presentation ‘The impact of clinical trial data disclosure on trial-related documents: Redaction requirements and future document structure’. Tracy reported the warmth with which CORE Reference was received by the audience in this open forum, and furthermore in informal discussions held more widely around the DIA conference. Although there were no formal presentations of CORE Reference at this year’s DIA Annual Conference, Art Gertel received many positive comments in the course of private conversations. This was also true at a DIA Medical and Scientific Communications Meeting in March 2016 and at the AMWA Carolinas Chapter Conference in May 2016.