For any clinical regulatory writer, compiling the appendices for a clinical study report (CSR) can feel like a daunting task, but it doesn’t have to be. To make this task easier and less time consuming you need to start thinking about it before you even begin to write the CSR.
This blog describes a possible workflow for publishing a final CSR in modular format, ie, individual PDF files for the CSR body (Sections 1 to 15, excluding synopsis), CSR synopsis, and each CSR appendix (16.X.X).
- Create a list of everything needed for the final CSR Section 16 appendices using the ICH E3 and ICH E3(R1) guideline(s). (Note Following the R1 guideline can make the publishing process easier, as it allows certain items to be excluded from the CSR appendices if they are included in the Study TMF). ICH E3 also contains guideline numbering.
- Share the list with the appropriate person (eg, Project Manager), who should provide each required document as it becomes final. Ideally, use Microsoft (MS) Word versions or pdfs and avoid scanned documents. MS Excel files or scanned documents should not be included unless there is no other option. If scanned files are to be included, they should be scanned using optical character recognition (OCR) where possible.
- When feasible, review the Statistical Analysis Plan (SAP) and check that the tables, listings and figures are correctly numbered (see item 1).
- Compilation of an appendix can begin as soon as the relevant final appendix material has been received. Each modular appendix file should contain a cover page and table of contents (TOC) created within MS Word. For appendices that are not applicable, a cover page should still be present, and relevant text (eg, ‘Not applicable’) should be included on the cover page.
- For each appendix file, update the TOC with details as per the content of each appendix and convert the TOC text to blue font.
- Ensure that all document properties and personal information metadata are removed from the MS Word file.
- Ensure all documents for each modular appendix (cover page, TOC, and appendix content) are converted to PDF format and combined using Adobe Acrobat or a pharmaceutical/biotechnology specialised Adobe Acrobat plug‑in software, such as TRS ToolBox. The FDA and ICH guidelines for submission ready files, include PDF specifications (eg, the properties of PDFs should be as follows: saved and set to Adobe 5 [PDF 1.4] or higher, files optimised for fast web view, no password protection, all fonts embedded, correct page orientation, text searchable wherever possible [ie, avoid scanned documents], scanned documents have a resolution of 300 dpi and are black and white [where possible], no PDF larger than 100 MB). The guidance documents also list which fonts are acceptable (eg, Times New Roman is fine, Cambria is not).
- Delete any unnecessary blank pages.
- Ensure each modular CSR file is named in accordance with appropriate naming conventions.
- Ensure bookmarks and hyperlinks are present within each modular appendix file for each item listed on the TOC. All bookmarks and hyperlinks should be set to the correct destination and set to magnification level ‘inherit zoom’. Bookmarks and hyperlinks can be added within Adobe Acrobat or using an Adobe Acrobat plug-in software.
- Consistency in whether the bookmarks are collapsed or expanded should be maintained between all modular files. The Medical Writer should consider the usefulness to the reviewers of how to present bookmarks (ie, collapsed or expanded).
- For each appendix file, check the TOC and update to ensure that it contains correct page numbering. Page numbering can be updated using the Edit tools within Adobe Acrobat or using an Adobe Acrobat plug-in software.
- When each appendix file has been converted to PDF, and bookmarked and hyperlinked, add the header and footer to every page of each modular PDF appendix file using Adobe Acrobat or using an Adobe Acrobat plug-in software. The header and footer detail should be consistent with that used in the CSR body. Each page of each modular CSR file is internally paginated (ie, pagination starting again within each PDF file). The page number is normally present in the footer.
- Ensure that any external hyperlinks to modular appendices files referenced in the CSR TOC or CSR body are correctly linked (link to correct file and set to magnification level ‘inherit zoom’).
- Ensure file properties of each appendix file are set to ‘Bookmarks Panel and Page’, ‘Single Page’ and ‘100% zoom’ by selecting File > Document Properties and amending details within the ‘Initial View’ tab.
- Finally, you should ask a colleague to perform a quality control check on the entire document.
International Council for Harmonisation (ICH) guideline Efficacy 3 (E3) Structure and Content of Clinical Study Reports
ICH E3 Guideline: Structure and Content of Clinical Study Reports Questions & Answers (R1).
FDA Guidance for Industry Providing Regulatory Submissions in Electronic Format – General Considerations (Draft Guidance)
ICH M2 EWG Electronic Common Technical Document Specification and Guidance for Industry
ICH M4 (R3) Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use
Authors note: This blog was originally published on 10/05/2011 and has since been updated.
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