What is a Clinical Study Report?

The clinical study report is a document prepared for submitting clinical trial results to the regulatory authorities for product approval. This document is so crucial at each product development phase that the regulatory authorities make their sole decision to approve the product for further development or marketing based on the clinical study reports. This is because clinical study reports answer basic questions related to product development, such as:

• What was the importance of the clinical trial?
• What is the role of the sponsor’s product in the market?
• How can this product contribute to healthcare?
• What were the important objectives of the trial?
• How were these objectives achieved?
• What were the clinical trial results in terms of safety, efficacy, pharmacokinetics, pharmacodynamics, etc.?

Understanding the Importance of a Clinical Study Report

As per the US FDA and CFR guidelines, clinical study reports are required to be submitted for each clinical trial. Therefore, these reports should present an adequate and well-controlled study by presenting details regarding study design, study conduct, and statistical analysis. These details help the regulatory authorities evaluate and determine the characteristics of a study.

As per 21 CFR 314.126, the characteristics of an adequate and well-controlled study include the following, which need to be presented in the clinical study report¹:

• A clear statement of the objectives of the study
• Summary of applied analysis for the study results
• Precise description of study design (including duration of treatment period(s), type of treatment, sample size, interim analysis, etc.)
• Description of assigning subjects to groups (such as randomization or non-randomization, inclusion of stratification, etc.)
• Description of procedures used to minimize bias (such as blinding)
• Explanation of the variables measured in the study and methods of assessing these variables in subjects
• Details of results and analytical methods used to evaluate these results (such as statistical methods)

Besides this, the ICH E3 clearly states to prepare and provide a clinical study report as per the ICH E3 guideline, whether the clinical study is completed or prematurely terminated.²

How do you write a clinical study report?

The clinical study report writing begins with writing a shell (methodology sections) with the help of source documents such as the study protocol, statistical analysis plan, randomization schedule, etc.³

After the arrival of tables, listings, and figures (TLFs), the rest of the sections containing results are written. The sections containing results are written after a thorough understanding of the study output. Most of the time, results for the overall study population and safety are written first for this purpose. Moreover, this enables the writer to know the safety issues that may have arisen and led to patient discontinuations or withdrawals. This is followed by writing efficacy and/or pharmacokinetics and/or pharmacodynamics sections.

Lastly, the discussion and conclusion sections are written. Both of these sections are written to justify the study objectives and endpoints.

What is the purpose of a clinical study report?

The purpose of a clinical study report is to compile the clinical trial results into a single document and communicate them to the regulatory authorities. Eventually, the clinical study report becomes a part of the common technical document for an investigational product and helps in getting approval for marketing of the investigational product.

Who signs a clinical study report?

As per Appendix 16.1.5 of the ICH E3 guideline⁴, the principal or coordinating investigator(s) or sponsor’s responsible medical officer (depending on the regulatory authority’s requirement) signs the clinical study report. Further whoever signs the clinical study report confirms that they have read the report and confirms that to the best of their knowledge, it accurately describes the conduct and results of the study. In today’s scenario of the digital world, both handwritten signatures and digital signatures work for the signature page of clinical study reports.

There is guidance from the FDA on the use of electronic systems, electronic records, and electronic signatures in clinical investigations.⁵ As per this guidance, the FDA considers electronic signatures generally equivalent to paper records and handwritten signatures on paper only if electronic signatures and their associated electronic records meet the requirements of 21 CFR Part 11.

What are the types of clinical study reports?

Clinical study reports are categorized based on the type of results they comprise. The FDA’s guidance on the Submission of Abbreviated Reports and Synopses in Support of Marketing Applications provides detailed information on these clinical study reports.⁶ Usually, full clinical study reports are submitted; however, abbreviated reports and synopses are submitted when full reports are not required and applicable. Below is detailed information on each type of clinical study report.

Full Clinical Study Reports

Full clinical study reports are submitted for studies that contribute to the effectiveness data as well as the safety data of the investigational product. The format and content to be used for these full study reports are clearly stated in the ICH E3 guideline.⁴ Full clinical study reports are also submitted for controlled studies that⁶:

• Report data on investigational products for rapid development programs and orphan indications
• Provide the basis for the dose recommendation
• Support an intended comparative claim
• Provide support for the approval of product for different indications or dosage forms or regimens
• Provide effectiveness data for the indication that failed to show an effect
• Provide clinical pharmacology and biopharmaceutics data to support labeling statements

Abbreviated Clinical Study Reports

It clinical study reports are submitted for studies that provide all the safety information of the investigational product; however, these reports do not aim to cast doubt about the effectiveness of the investigational product. Abbreviated clinical study reports are also submitted for studies that⁶:

• Contains data on related indications that do not claim marketing approval
• Provide or not provide efficacy data for different indications, but contribute towards critical information about investigational product safety (for example, data from studies where enrollment approached or exceeded the size of the efficacy trials)
• Contain data of doses or dosage forms but do not intend for marketing (unless there is efficacy data involved)
• Are negative studies (studies failing to show investigational product effect); however, the format to display efficacy data should be discussed with the regulatory authority in advance
• Presenting bioavailability/bioequivalence data that does not assess the performance of material used in clinical trials relative to dosage forms intended for marketing
• Are stopped for safety reasons or due to futility

Synoptic Clinical Study Reports (or Synopsis)

Synoptic clinical study reports or synopsis are submitted for studies presenting safety data of the investigational product. The format of the synopsis remains the same as provided by the ICH E3 guideline. The synopsis is also submitted for studies that⁶:

• Provide data on unrelated indications for which no marketing approval is being sought
• Provide data about evaluating the routes of administration of the investigational product but no marketing approval is being sought
• Are incomplete, i.e., studies that have enrolled less than one-third of planned patients and stopped
• Are phase-1 safety-tolerance studies
• Have no relevant conclusions due to defects in design, conduct, data handling, or analysis
• Are evaluating dosage forms no longer under development
• Are considered discontinued
• Are from abandoned indications

Conclusion

The regulatory authority has guided the industry on each type of clinical study report. It is the sponsor’s decision about which clinical study report will fit best according to the type of study to submit to the regulatory authority. It is always a better approach to discuss the matter directly with the regulatory authority in advance to smooth the review process later.

References

1. Code of Federal Regulation. Part 314.126 Adequate and well-controlled studies. ecfr.gov. Published 01 March 2017. Accessed August 29, 2023. https://www.ecfr.gov/current/title-21/section-314.126
2. International Council for Harmonization. Integrated Addendum To ICH E6(R1): Guideline For Good Clinical Practice: E6(R2). database.ich.org. Published November 9, 2016. Accessed 29 August, 2023. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
3. Hamilton S. Effective authoring of clinical study reports: A companion guide. 2014; 23(2): 86-92. https://journal.emwa.org/regulatory-writing-basics/effective-authoring-of-clinical-study-reports-a-companion-guide/article/1681/2047480614z2e000000000211.pdf
4. International Conference on Harmonization. Structure and content of clinical study reports E3. database.ich.org. Published 30 November, 1995. Accessed 29 August, 2023. https://database.ich.org/sites/default/files/E3_Guideline.pdf
5. Food and Drug Administration. Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations Questions and Answers Guidance for Industry. fda.gov. Published March 2023. Accessed August 29, 2023. https://www.fda.gov/media/166215/download
6. Food and Drug Administration. Submission of Abbreviated Reports and Synopses in Support of Marketing Applications Guidance for Industry. fda.gov Published August 1999. Accessed August 29, 2023. https://www.fda.gov/files/drugs/published/Submission-of-Abbreviated-Reports-and-Synopses-in-Support-of-Marketing-Applications..pdf