Where a clinical study report's requirements come from
What a clinical study report must contain, and who can require one, is decided by several documents and authorities together. ICH E3 defines the report, ICH E6(R3) sets the sponsor's reporting duties and adds content of its own, the TransCelerate template is used at the user's discretion, and the authority that receives the report may set its own format or appendix list.
What ICH E3 sets out
ICH E3 describes the structure and content of clinical study reports of studies evaluating therapeutic, prophylactic or diagnostic agents. The report it describes is an integrated full report of an individual study conducted in patients, in which the clinical and statistical description, presentations and analyses are combined in a single report. Such a report should not be derived by simply joining a separate clinical and statistical report. E3 is intended to help sponsors develop a report that is complete, free from ambiguity, well organised and easy to review. Its guidance is detailed and is intended to notify the applicant of virtually all of the information that should routinely be provided, so that post-submission requests for further data clarification and analyses can be reduced as much as possible.
E3 is aimed mainly at efficacy and safety trials, but its basic principles and structure can be applied to other kinds of trials, such as clinical pharmacology studies, where a less detailed report might be appropriate depending on the study's nature and importance. For very large trials, some of E3's provisions may be impractical or inappropriate, and E3 encourages contact with the regulatory authorities to discuss an appropriate report format when such trials are planned and when they are reported.
Specific requirements for data presentation and analysis may depend on specific situations, may evolve over time, may vary from drug class to drug class, may differ among regions and cannot be described in general terms. So it is important to refer to specific clinical guidelines and, whenever possible, to discuss data presentation and analyses with the reviewing authority. Detailed written guidance on statistical approaches is available from some authorities. E3 should be used in conjunction with other ICH guidelines.
ICH E3 is a harmonised tripartite guideline. It reached Step 4 of the ICH process at the ICH Steering Committee meeting on 30 November 1995, and at that step it was recommended for adoption to the regulatory bodies of the European Union, Japan and the USA. E3 was finalised in 1995 and adopted by 1996 in all three ICH regions, the European Union, Japan and the United States. By standardising the criteria for a clinical study report, E3 enables the same report to be submitted to the regulatory bodies in all three ICH regions, so that a separate report need not be submitted to each region.
In 2014 the regulatory and ethical basis for writing clinical study reports lay in Section 5.22 of ICH E6, and ICH E3 gave the authoring guidance. The definitive guidance for writing the report in 2014 was ICH E3, published in 1995, with its supplementary questions and answers published in 2012, and a complete understanding of the report's text requirements needed both.
ICH E6(R3) and the sponsor's reporting duties
ICH E6(R3) defines a clinical trial or study report as a documented description of a trial of any investigational product conducted in human participants, in which the clinical and statistical description, presentations and analyses are fully integrated into a single report. An interim clinical trial or study report is a report of intermediate results and their evaluation, based on analyses performed during the course of a trial.
Under E6(R3), the sponsor should ensure that clinical trial reports, interim reports included, are prepared and provided to the regulatory authorities as the applicable regulatory requirements demand, whether the trial is completed or prematurely terminated, or an interim analysis is undertaken for regulatory submission. The sponsor should also ensure that reports in marketing applications meet the standards of ICH E3 or are otherwise in accordance with applicable requirements, and E6(R3) notes that, under E3, abbreviated trial reports may be acceptable in certain cases. Where a coordinating investigator is involved in the trial, consideration should be given to their being a signatory on the report.
E6(R3) also names content the report should carry. The sponsor should describe in the report the quality management approach implemented in the trial. The sponsor should summarise and report the important quality issues, including instances in which acceptable ranges are exceeded, together with the remedial actions taken, and document them in the report. Deviations from the planned statistical analysis, and changes made to the data after the trial has been unblinded, should be reported in the clinical trial report.
The TransCelerate common CSR template
The TransCelerate common CSR template is used at the discretion of the user.
The receiving authority's format and appendix requirements
E3's objective is to allow the compilation of a single core report acceptable to all regulatory authorities of the ICH regions, with each authority's specific additions consisting of modules considered as appendices, available on request according to regional regulatory requirements. Some data in its appendices are specific requirements of individual authorities and should be submitted as appropriate. The European Medicines Agency issued regional guidance in 2004 on adapting the appendices of reports included in marketing authorisation applications.
China's SFDA required a report generally compliant with E3, and it also required these appendices:
- each ethics committee's approval letter for the study, with a list of site qualifications
- the ethics committees' approval letters for every protocol amendment
- the principal investigators' qualifications, such as good clinical practice and SFDA training certificates and medical licences
- certification of analysis and pre-production records for the investigational products, placebo included
- package insert sheets for the comparator and the investigational product, where marketed
- an individual by-site summary table for multicentre trials
- a statistical report
Japan required a report compliant with E3.
Switzerland did not require a report in E3 format. Whether a trial was commercial or non-commercial, and whether it ended normally or was discontinued early, a final report always had to be submitted to Swissmedic within six months of the end of the study, the time limit VKlin laid down. Swissmedic stipulated no binding format for the report, but it had to be in line with ICH good clinical practice requirements and with current medical and scientific standards. Many Swiss sponsors still produced an E3-compliant report, particularly where the trial was planned to be used in a marketing authorisation application somewhere, while many others took the shortcut of submitting a publication instead of a report.