16. Appendices
Section 16 of a clinical study report holds the documentation needed to review the report and to replicate its critical analyses: the protocol that was followed, the forms the data were recorded on, the randomisation codes, the statistical documentation and the participant-level listings. The appendices fall into four groups. Where the regulatory authority permits, some are provided only on request rather than with the report, while supportive documents generally stay in the trial master file or the clinical supply database. The numbering adapts to regional requirements, and appendices held for request have to be finalised by the time the submission is filed.
What the appendices contain
E3 describes a report whose appendices contain the protocol, sample case report forms, investigator-related information, information related to the test drugs or investigational products including active controls or comparators, technical statistical documentation, related publications, patient data listings, and technical statistical details such as derivations, computations, analyses and computer output.
The report with its appendices should provide enough individual patient data, including the demographic and baseline data, and details of analytical methods, to allow replication of the critical analyses when authorities wish to do so.
16.1 Study information
The first group holds twelve appendices of study information:
| Appendix | Contents |
|---|---|
| 16.1.1 | Protocol and protocol amendments |
| 16.1.2 | Sample case report form, unique pages only |
| 16.1.3 | List of IECs or IRBs — plus the name of the committee Chair if the regulatory authority requires it — and representative written information for patients and sample consent forms |
| 16.1.4 | List and description of investigators and other important participants in the study, including brief one-page CVs or equivalent summaries of training and experience relevant to performing the study |
| 16.1.5 | Signatures of principal or coordinating investigators, or of the sponsor’s responsible medical officer, depending on the regulatory authority’s requirement |
| 16.1.6 | Listing of patients receiving test drugs or investigational products from specific batches, where more than one batch was used |
| 16.1.7 | Randomisation scheme and codes, giving patient identification and treatment assigned |
| 16.1.8 | Audit certificates, if available |
| 16.1.9 | Documentation of statistical methods |
| 16.1.10 | Documentation of inter-laboratory standardisation methods and quality assurance procedures, if used |
| 16.1.11 | Publications based on the study |
| 16.1.12 | Important publications referenced in the report |
Annex VIII of the guideline gives guidance for Appendix 16.1.9, as well as for Section 11.4.2 on statistical and analytical issues.
The guideline’s entry for audit certificates refers to Annexes IVa and IVb, which are the guideline’s examples of the disposition of patients.
16.2 Patient data listings
The second group holds listings of individual patient data for specified groups of patients:
| Appendix | Contents |
|---|---|
| 16.2.1 | Discontinued patients |
| 16.2.2 | Protocol deviations |
| 16.2.3 | Patients excluded from the efficacy analysis |
| 16.2.4 | Demographic data |
| 16.2.5 | Compliance and/or drug concentration data, if available |
| 16.2.6 | Individual efficacy response data |
| 16.2.7 | Adverse event listings, for each patient |
| 16.2.8 | Listing of individual laboratory measurements by patient, when required by regulatory authorities |
The data listings requested as part of the report, usually in an appendix, are those needed to support the critical analyses, and they should be readily usable by the reviewer. So although it may be desirable to include many variables in a single listing to limit its size, this should not be at the expense of clarity. An excess of data should not lead to overuse of symbols in place of words or easily understood abbreviations, or to displays too small to read, and where it would, several listings are preferable to one.
16.3 Case report forms
The third group holds the case report forms, in two parts: CRFs for deaths, other serious adverse events, and withdrawals for an adverse event; and other CRFs submitted.
16.4 Individual patient data listings
The fourth group holds all individual patient data — the archival listings, requested only in the US.
The list of appendices
Section 16 should open with a full list of all appendices available for the study report. Where the regulatory authority permits it, some appendices need not be submitted with the report and are provided only on request, so the applicant should clearly indicate which appendices are submitted with it.
The CORE Reference manual has a table that lists each appendix by number and content and states whether it should be included with the report or may be omitted and made available on request at the time of filing. Its authors consider it useful to include that table in the report, so that a reader sees exactly what the appendices hold.
What belongs in the appendices
For a report’s appendices to be fit for inclusion in a marketing application, three documents have to be considered together: E3 itself, a 2004 instruction on adapting the original appendices for reports going into applications, and a 2012 questions and answers document that further clarified their content.
The resulting requirements take account of the trial master file and the clinical supply database, neither of which is submitted as part of the application. Because the trial master file is not submitted with the application, the appendices should contain all the documentation needed to review the report. To limit the appendices to the material necessary for reviewing the report, the 2012 document clarified that supportive documents such as investigator curricula vitae, ethics committee approvals, informed consent forms and batch numbers per subject are held in the trial master file or the clinical supply database and should generally not be included in the report appendices. Supportive documents should still be available promptly if a regulatory authority requests them. The writer should remind the responsible team member that the required information must be in the trial master file or the clinical supply database by the time the application is filed.
The appendices should not be bulked out with redundant documents. In a region where documents used by non-English-speaking investigators or subjects must be translated, the local-language versions must not be included in the appendices.
The impending public disclosure of full reports in 2014 prompted a shift towards moving the details of named individuals, formerly in Section 6 on investigators and study administrative structure, and the details of the sponsor signatory into Section 16.
Appendix numbering
E3’s stated objective is a single core clinical study report acceptable to all regulatory authorities of the ICH regions, with authority-specific additions taking the form of modules treated as appendices and made available on request according to regional requirements. Some data in the appendices are specific requirements of individual regulatory authorities and should be submitted as appropriate, and the numbering is adapted accordingly.
For a US new drug application, the FDA strictly requires granulated report components that use E3’s appendix numbering. The granulation goes right down to numbers such as 16.2.3, which the granulated documents have to carry. One experienced writer holds that this runs a bit counter to the general notion that E3 is not a template, and another agrees that E3 is not a template but notes that granulated documents have to fit a predefined framework. The first writer holds that what is done for the FDA has to be done for every other authority, because no one wants to prepare two versions, so that in effect E3 becomes quite a rigid template again. Granulation became a problem for one team that had prepared each report as a single PDF, when it found the FDA imposing granulated components that many others were already preparing.
For topics E3 does not specifically cover, such as pharmacokinetics, pharmacodynamics, pharmacogenomics, biomarkers and devices, it is appropriate to create new appendices. The CORE Reference manual keeps E3’s appendix numbering, except that it adds Appendix 16.1.13 for material that does not fit into the appendix numbering as it stands, such as a standalone pharmacokinetics report.
Finalising and compiling the appendices
Appendices that are to be available on request should be finalised by the time the submission is filed.
Besides its text body, a report contains multiple appendices of study-related information, among them the protocol, post-text tables and figures and individual subject data. A well-crafted text body matters for presenting the results, and regulatory guidelines also require these standard appendices to facilitate a comprehensive regulatory review. Compiling the appendices can be time-consuming and, if not properly managed, may delay the completion of the report.
Several strategies make compilation more efficient. An appendix preparation plan that details what has to be included and in what format is critical. An individual such as a medical writer should be designated as cross-functional project lead to manage the compilation. The report should follow E3 for structure and content and meet Common Technical Document submission requirements, so standard operating procedures, internal format and style standards and report templates should be developed with the publishing group. Appendix preparation must start while the trial is ongoing, so that every required document is collected, prepared, reviewed and compiled on time. Good management of the compilation, with appropriate planning, makes compilation more efficient, shortens the overall report timeline and helps the submission go in promptly.