It is imperative to include a biostatistician or a statistical expert during all stages of a trial, i.e. design, conduct and analysis. The designated biostatistician assumes the ultimate responsibility of all statistical aspects of the trial, including the preparation of the Statistical Analysis Plan (SAP). Critical statistical aspects pertaining to the trial, are included in the SAP, which is developed prior to data analysis. The type of statistical analysis to be used for a particular trial is pre-specified. This is done to ensure that, the knowledge of the results does not impact or influence the analysis or the presentation of the findings. Finalisation of the SAP is one of the key milestones in a trial, and is also sought during the publication process. The other key documents pertaining to data and analysis is the Data Management Plan and the Database Design and Development. It is critical that these are developed and personnel involved in data handling and analysis are adequately trained, with the help of these documents and their respective SOPs.

Many (but not all) clinical trials especially randomised trials, will have a Data and Safety Monitoring Board (DSMB) who will review trial data at pre-determined frequencies (like, interim analysis or after the recruitment of xx number of participants), to monitor the safety and progress of the trial. It is the responsibility of the trial statistician to ensure that the plan for analysis for the DSMB report is prepared and reviewed by the members of the DSMB, as early as possible. Generally, the DSMB report contains two sections – closed or confidential section (reviewed only by the independent members of the DSMB and the trial statistician), and an open section (this is open to review by members of the Trial Management Group and Trial Management Teams).

Interim analyses comparing outcome measures between randomisation arms should not be performed, except for the purpose of the DSMB reports. The final report must include the dates of interim analyses and the reason for these analyses.

During trial close-out, all unresolved data queries must be resolved, so that the database can be locked. The database lock ensures that the data is clean for analysis. It is recommended that all analyses are verified by a senior statistician, prior to the preparation of the report and any publication.

Clinical trials are considered to provide the highest level of evidence, in terms of efficacy of an intervention. Clinical trial results that are reported can influence clinical practice, and therefore it becomes imperative that the statistical methods and tests applied to the trial data are appropriate. For example, a large number of trials measure multiple end points, and use multiple statistical tests to measure the differences between the groups. This may result in an increase in false positivity or a Type I error. Therefore, it is always recommended that the endpoints are divided into primary and secondary endpoints, during the trial design phase. And, if this is not possible, then, multiple endpoints should be adjusted with the help of adjustment methods. According to the ICH E9 guidelines, if for a clinical trial multiple endpoints are not adjusted, then the reason for not doing so must be clearly mentioned in the manuscript or the final report. This is also a recommendation by the CONSORT statement.

It is also recommended that, the tables included in the statistical report, should be based on direct output from the statistical program used. If this is not possible, then, it should be ensured that the tables included are carefully verified with the log files. Any deviations or amendments (post hoc analysis) from the analysis plan specified in the SAP, should be justified and reported in the final report and all subsequent publications.

The results of the statistical analyses should be presented in such a manner that it facilitates the interpretation of their clinical importance. Missing, unused and spurious data must be accounted for during the statistical analyses. All such omissions should also be documented, to enable review. More importance should be given to confidence intervals, or magnitude of treatment effects, as compared to significance tests. The final report should be reviewed and endorsed by a senior statistician, other than the trial statistician, prior to its release.

Reference and Further Reading:

• Good Clinical Practices for Clinical Research in India, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2001, available online (last accessed on 26.02.2019).
• ICH Harmonised Guideline, Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), current step 4 version, dated 9^th November 2016, available online (last accessed on 26.02.2019).
• ICH Harmonised Tripartite Guideline, Statistical Principles for Clinical Trials, E9, current step 4 version, dated 5^th February 1998, available online (last accessed on 26.02.2019).
• MRC Clinical Trials Unit at University College London SOP for Statistical Principles (version 5.0), 2017.
• For randomized clinical trials, one may refer to the CONSORT This is an evidence-based, minimum set of recommendations for reporting of randomized trials.
• Charan, J., & Saxena, D., 2012, Suggested statistical reporting guidelines for clinical trials data, Indian Journal of Psychological Medicine, 34(1), 25-9, available online (last accessed 26.02.2019) – the authors of this article have highlighted some of the most common issues related to inappropriate use of statistical methods, especially for articles published in the Indian Medical Journals.
• Please also refer to the following elements of the routemap: Statistical Analysis Plan, Data Management Plan and Database Design, Development and UAT.

Reports

Various types of reports are submitted to the regulatory agency, the ethics committee, oversight groups, and the sponsor throughout the lifecycle of a trial. Whether the trial has been completed or prematurely terminated, the sponsor must ensure that the clinical trial reports are prepared, and submitted as per the regulatory requirements of the country.

Premature termination

For all trials, the ethics committees, all participating sites and participants enrolled in the trial, must be informed of the premature termination or discontinuation of the trial.

If a regulatory trial is prematurely discontinued (for any reason), a summary report should be submitted to the Licensing Authority i.e., Central Drugs Standard Control Organization (CDSCO), within three months. The sponsor shall also submit records relating to any order issued for premature termination of the trial, with a summary of the reasons to Ethics Committee.

The content of this summary report should include information on the following:

• Number of participants exposed to the investigational product
• Dose and duration of the exposure
• Details of Adverse Events/adverse drug reactions if any. This information should be in accordance to Table 5 of the Third Schedule (page 218) of the New Drugs and Clinical Trial Rules, 2019
• Reason for discontinuation of the trial or non-pursuit of the new drug application.

Annual Report

Ongoing clinical trials are reviewed at regular intervals by the Ethics Committee (EC) that has granted the approval. The frequency of this review is decided by the EC, depending on the level of risk, type of trial to be conducted, and other safety concerns that the EC may have. This is also known as ‘continuing review’. In certain instances, the EC may grant an approval subject to the annual review of the trial. The Principal Investigator of the trial is required to submit an Annual Report to the EC in the prescribed format.

Final Report (Clinical Study Report)

This is a complete and comprehensive description of the trial, after its completion. The final report is also referred to as a Clinical Study Report. The format, structure and content of this report for a trial, should be as per Table 6 of the Third Schedule (page 219) of the New Drugs and Clinical Trial Rules, 2019. This template can be used to develop the report. It is recommended that the template is customised as per the trial, and requirements of the regulatory agency and ethics committee.

References, Resources and Further Reading

• New Drugs and Clinical Trial Rules, 2019, G.S.R. 227(E), Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, available online (last accessed on 03.04.2019).
• Good Clinical Practices for Clinical Research in India, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2001, available online (last accessed on 26.02.2019).
• Format for Premature Termination / Suspension / Discontinuation Report, published by the Indian Council of Medical Research in 2018, available online.
• Format for Annual Report, published by the Indian Council of Medical Research in 2018, available online.
• Further reading for Clinical Study Reports: Structure and Content of Clinical Study Reports (E3), ICH Harmonised Tripartite Guideline, current step 4 version, dated 30 November 1995, available online.
• Format for Final Report (study completion report), published by the Indian Council of Medical Research, 2018, available online.
• ICH Harmonised Tripartite Guideline, Structure and Content of Clinical Study Reports, E3, 1995, available online.