This International Conference on Harmonization ICH document makes recommendations on information that should be included in a core clinical study report of an individual study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects. The guideline is intended to assist sponsors in the development of a report that is complete, free from ambiguity, well organized and easy to review. This International Conference on Harmonization ICH document makes recommendations for strategies to permit clinical data collected in one region to be used to support drug and biologic registrations in another region while allowing for the influence of ethnic factors. Good Clinical Practice GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects. Compliance with GCP assures that the rights, safety, and well-being of trial subjects are protected and that the clinical trial data are credible. This International Conference on Harmonization ICH guidance provides a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in those jurisdictions.
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This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Extensive and complete documentation must be submitted for obtaining a marketing authorization of an investigational medicinal product in the European Union, Japan, or the United States. One of the most critical of the documents submitted as part of the Common Technical Document, masterpiece of a marketing authorization application, is the Clinical Study Report, which represents the integrated full report of efficacy and safety data for an individual study of a therapeutic or diagnostic agent.
Some of the studies conducted during product development may ultimately not contribute to the evaluation of the effectiveness of a product for a specific indication. In these cases, abbreviated Clinical Study Reports are required to be submitted to the regulatory authorities. A guideline issued by the Food and Drug Administration of the United States in is the only document available from a regulatory authority that recommends which sections can be included in an abbreviated Clinical Study Report.
This article describes which sections have to be included in abbreviated Clinical Study Reports written during clinical development of new medicinal products for human use. Extensive and complete documentation must be presented for a marketing authorization of an investigational medicinal product IMP for human use in the European Union EU , Japan, or the United States.
The documentation to be submitted to the regulatory authorities has to prove the quality, safety, and efficacy of the new drug. The compilation of these reports forms the basis of the Common Technical Document CTD 1 , 2 Figure 1 , which has become an internationally agreed format for the preparation of a well-structured presentation for applications to be submitted to regulatory authorities in the regions where ICH is applied 4.
Sponsors should pay keen attention to the guidelines established by the ICH to insure a speedy and efficient review of their submissions. One of the most critical documents submitted as part of a CTD is the Clinical Study Report CSR , which represents the integrated full report of the efficacy and safety data for an individual study with a therapeutic or diagnostic agent.
The different CSRs produced during the clinical development of a medicinal product are included in module 5 of the CTD 3. The particular location of a CSR within the CTD is determined by the primary objective of the study: eg, efficacy and safety, pharmacokinetics, or pharmacodynamics Box 1.
Each CSR should appear in only one section, and when the study has several objectives, it should be cross-referenced in the other sections. Moreover, the CSRs also have to be cross-referenced in module 2. During the more than ten years of use of this guidance document, the regulatory authorities and the industry have worked to refine some of its ambiguities and redundancies, and have allowed the template to evolve into a well-structured, highly intuitive format for the presentation of clinical results.
The CSR integrates the clinical and statistical descriptions, presentations, and analyses into a single integrated report, incorporating tables and figures. This integrated report not only outlines the original plan of the protocol, but also describes in more depth and explains any practices in the clinical trial that were different from those originally planned.
By reading the CSR, one can understand why and how the study was conducted, the types of data collected and analyzed, and the nature and extent of the conclusions that may be drawn from the results. The results of pivotal clinical trials and human pharmacology investigations that contribute to the evaluation of effectiveness and safety for a proposed indication or that otherwise support information included in the product labeling are to be presented as a full CSR, which addresses all the elements of the template report described in the ICH E3 guideline Table 1.
An issue of concern among users of the template provided by the ICH E3 guideline is whether, or how much, is one allowed to deviate from the structure of the guideline. While this approach ensures consistency in data presentation and contributes to the ready access of information by reviewers, it holds some limitations. For instance, pharmaceutical companies are often confused as to where to present the results of pharmacokinetic analyses.
The template provides a section number While there is no formal prohibition to alter the structure of the ICH E3 template, sponsors must consider the implications of following a different structure from the standpoint of consistency with other documents, integration of non-standard templates into electronic document management systems, ease of review, and regulatory agency expectations.
Nevertheless, current overall experience shows that the ICH E3 guideline is a valuable tool for the comprehensive presentation of clinical data. The CSR has to be written following a modular approach that includes a core report, which gives the information necessary for assessing the results of the study, and the appendices, which contain additional information such as protocol, protocol amendments, sample case report form, investigator-related information, technical statistical documentation, related publications, patient data listings, and related computer printouts from the clinical study database, among others.
To allow navigation in the e-format for future electronic applications the so-called electronic CTD or e-CTD, now applicable in the United States but yet in development in the EU , the CSR has to integrate all parts of the report in a unique document eg, in portable document format [pdf] files : the core report with the 15 main sections and the appendices section Therefore, only-based-in-paper documents eg, signature pages have to be scanned and converted to electronic format.
During product development, studies may be conducted that ultimately do not contribute toward the evaluation of the effectiveness of a product for a specific indication. Abbreviated reports should be submitted for these studies, and also for studies for which the reviewer needs sufficient information to determine that the results do not cause any doubts about the effectiveness claims.
However, a full description of safety aspects should be included in these cases. If an abbreviated report is submitted, there should be enough detail of design and results to allow the regulatory authority to determine whether a full report is needed.
The only relevant information on the content of an abbreviated CSR that is available in the ICH E3 is that such an abbreviated report should contain all the safety information included in a full report.
Only the FDA seems to have promoted a guideline to solve the question of abbreviated CSRs, with no further initiatives from European regulatory authorities. This guideline, although not strictly supported from a European regulatory point of view, currently forms the only basis available for defining in a direct and clear way the structure and content of abbreviated CSRs.
In agreement with what is defined in the ICH E3 approved in , ie, three years before this FDA guideline , abbreviated reports should be submitted for studies that are not intended to contribute to the evaluation of product effectiveness or provide definitive information on clinical pharmacology, but about which the reviewer needs sufficient information to determine that the study results do not, in fact, cast doubts on the effectiveness claims or the description of the clinical pharmacology.
Abbreviated reports should contain all the safety information included in a full report. This FDA guideline is the only official document available from a regulatory authority that recommends which sections may be included in an abbreviated CSR Box 2. Briefly, this guideline recommends to drastically reduce the contents of sections 9 Investigational Plan , 10 Study Patients , and 11 Efficacy Evaluation. In the case of the investigational plan, the information should be directed to the overall study design features and to the changes in the planned analyses.
With respect to the study patients, only disposition is recommended to be included. Finally, section 11 Efficacy Evaluation may be replaced by a summary of the efficacy evaluation preferably in table form with enough information for the reviewer to determine whether the study results are germane to the overall evaluation of effectiveness and to use in the review of the integrated analysis of effectiveness, if necessary including means, confidence intervals, P values, standard errors, etc.
Section Any additional information pertinent to the evaluation of safety should also be included. Individual patient listings of efficacy data are not necessary. The summary should contain enough information for the reviewer to determine whether the study results are germane to the overall evaluation of effectiveness and in the review of the integrated analysis of effectiveness, if necessary including means, confidence, intervals, P values, standard errors, etc.
Several guidelines applicable to the clinical development of IMPs for human use eg, ICH M4E, ICH E3 define abbreviated clinical study reports as useful in cases where the study is not pivotal for claiming the effectiveness of a product in a Marketing Authorization Application or when the study was discontinued early due to, for instance, lack of efficacy.
However, scant information is available on which sections are required to be included in these abbreviated clinical study reports. The single guideline available was issued in in the United States by the FDA, but no similar initiatives appear to have been produced in the European setting.
While waiting regulatory initiatives in Europe to promote a definitive guideline on the content and structure of abbreviated clinical study reports eagerly expected for a long time by pharmaceutical companies and other biomedical centers involved in drug development , our recommendation is to follow the FDA guideline in those cases where, according to the local regulatory authorities, an abbreviated report could be submitted.
All three authors work as medical writers for Pharmaceutical Industry in Spain but have no relevant financial interests in this manuscript. National Center for Biotechnology Information , U. Journal List Croat Med J v. Croat Med J. Author information Article notes Copyright and License information Disclaimer. Received May 21; Accepted Sep All rights reserved.
This article has been cited by other articles in PMC. Marketing authorizations for investigational medicinal products: common technical document and clinical study reports Extensive and complete documentation must be presented for a marketing authorization of an investigational medicinal product IMP for human use in the European Union EU , Japan, or the United States. Open in a separate window. Figure 1. ICH E3 guideline 1. Title Page 2.
Synopsis 3. Table of Contents 4. List of Abbreviations and Definitions of Terms 5. Ethics 6. Investigators and Study Administrative Structure 7. Introduction 8. Study Objectives 9.
Investigational Plan Study Patients Efficacy Evaluation Safety Evaluation Discussion and Overall Conclusions Reference List Important Publications Referenced in the Report X Other CRFs Submitted. Abbreviated clinical study reports Two guidelines are available on the structure and content of CSRs 5 or on the appendices to be submitted in a Marketing Authorization Application for an IMP 6.
Conclusion Several guidelines applicable to the clinical development of IMPs for human use eg, ICH M4E, ICH E3 define abbreviated clinical study reports as useful in cases where the study is not pivotal for claiming the effectiveness of a product in a Marketing Authorization Application or when the study was discontinued early due to, for instance, lack of efficacy.
Competing interests All three authors work as medical writers for Pharmaceutical Industry in Spain but have no relevant financial interests in this manuscript. References 1. Molzon JA. The International Conference on Harmonization common technical document — global submission format? Food Drug Law J. Todic M. Dossier for marketing authorization in the European union. Bosn J Basic Med Sci. ICH M4E.
Common technical document for the registration of pharmaceuticals for human use-efficacy. Clinical overview and clinical summary of module 2. Module 5: clinical study reports. London: European Medicines Agency; Molzon J. The common technical document: the changing face of the New Drug Application. Nat Rev Drug Discov.
ICH topic E3.
U.S. Food and Drug Administration
ICH E3 Structure and content of clinical study reports