Clinical research serves as the foundation for advancing medical knowledge, improving patient care, and ensuring the safety and efficacy of new investigational products. As a result, clinical trials must be performed to the highest degree of scientific and ethical standards, for results to be recognised as credible and the trial deemed as successful. One document which plays an essential role in the safety, traceability and overall validity of a clinical trial is the Statistical Analysis Plan (SAP).
The SAP is a document outlining the planned statistical methods and procedures undertaken to analyse and interpret the data collected during the lifespan of a clinical trial. The SAP should be specific and highly detailed, offering a clear description of any data manipulation or analyses required to meet trial objectives and endpoints. To ensure high reliability and validity of the clinical trial, the SAP should be written and finalised as close to the beginning of the clinical trial as possible but can be amended at any point before First Patient First Visit (FPFV) for unblinded open trials and database Lock (DBL) for blinded trials, to document any updates occurring throughout the trial. It is essential that the SAP is transparent and reproducible as it is a key contributor to the writing of Tables, Listings and Figures (TLFs) for inclusion in the Clinical Study Report (CSR), which ultimately concludes the success of the investigational product.
During a clinical trial, several crucial documents guide the process and ensure the integrity of the study:
Following Database Lock, the planned datasets and TLFs are produced based on the SAP and TLF Shells.
The optimal time to create the SAP is before data collection begins, ideally during the trial design phase and before First Patient First Visit (FPFV). Benefits to developing the SAP early in the trial include:
Creating the SAP as early as possible in the clinical trial enhances SAP robustness, but the deadline for finalising the SAP will depend on the nature of the trial. For blinded trials, the SAP must be finalised prior to DBL to ensure that planned analyses are not changed after the final data are collected. However, for unblinded or open-label trials, the primary endpoints must be well established in the SAP prior to the recruitment of the first patient, to minimise bias and enhance result credibility.
Understanding the timing of when to submit the SAP to regulatory authorities like the FDA, CHMP or MHRA (for the US, Europe and UK respectively) is highly important for achieving success in a clinical trial. While the SAP should be written and finalised as early in the trial process as possible, it is important for SAP submission to occur prior to database lock (DBL) for most blinded studies. For studies which are unblinded or have complex/adaptive designs, earlier submission may be required, sometimes during the initial protocol submission or at key milestones, such as the end-of-Phase II meeting. Ensuring timely submission of the SAP to the FDA, CHMP or MHRA helps to align the trial's statistical approach with regulatory expectations and facilitates a smoother review process.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines are a set of internationally recognised standards and recommendations which guide the development, testing, approval, and monitoring of new pharmaceutical products. The ICH was established to harmonise regulatory requirements across different countries, particularly in the United States, Europe, and Japan, and to ensure that pharmaceutical products are safe, effective, and of high-quality.
The following three guidelines are of key interest and should be closely adhered to when writing the SAP:
The SAP should serve as a blueprint for all analyses, ensuring that any details relating to data manipulation and analyses methods are planned out before data collection begins. As a result, the following details are recommended to be included when writing a SAP:
The SAP must be written by a statistician or a biostatistician who has expertise in the relevant field of trial. However, the process often involves collaboration with other contributing key stakeholders, who are listed below:
While the primary author of a SAP is the statistician or biostatistician, the creation of the plan is often a collaborative effort with any or all of the above disciplines to ensure that the SAP is comprehensive, scientifically valid, and aligned with the trial goals.
An estimand is a precise description of the treatment effect within a clinical trial. Contributing attributes to estimands include:
Estimands play a fundamental role during the writing of the SAP as they directly influence the design, conduct, and interpretation of statistical analyses. Specific components of the SAP which may be influenced by estimands include:
Estimands provide additional clarity and precision relating to what is being measured in clinical research, helping to reduce ambiguity, and ensuring that the selected statistical analyses align with trial objectives. Estimands also improve consistency between analysis methods and the goals of the trial, as well as improving adherence to regulatory and scientific standards by ensuring the transparency and reliability of results.
Interim analyses are any planned analyses conducted at predefined points before the trial is completed. Motivations for planning interim analyses during a clinical trial include early detection of treatment efficacy or futility, which could lead to early termination of a trial if the investigational product is assessed as either beneficial or futile. Interim analyses also allow the sample size to be adjusted if the effect size and power differs to what was originally planned, as well as assessing if the trial is likely to meet its planned objectives.
However, there can be drawbacks to planning interim analyses which should be considered at the time of writing the SAP. Conducting multiple analyses throughout a clinical trial without adjustment can raise the alpha spend, which increases the chance of Type I error (false positives). Conversely, numerous interim analyses can also increase beta spend if not adjusted for correctly, which can result in a loss of power for the trial. Hence, consideration of statistical methods and spending functions (e.g.: the O’Brien-Fleming method or the beta spending function) must be considered at the time of writing the SAP to balance the benefits of early decision-making with maintaining trial integrity.
Clinical research is vital for advancing medical science and improving health-related quality of life. It is essential that clinical trial research in humans is performed in a safe environment which protects patient safety while accurately measuring treatment efficacy. The SAP is a key document in this process, playing a crucial role in determining the success of the investigational product, while maintaining high reliability and robustness of results.
The SAP requires input from qualified collaborators but ultimately must be written by a qualified statistician or biostatistician and meet relevant regulatory guidelines. The SAP must be detailed and comprehensive with clear instructions for suitable statistical techniques and data manipulation, which will contribute to the credibility and overall success of a clinical trial. Transparency and reproducibility are essential for honest and reliable results, for which a well-written SAP is a key contributor.
At Quanticate, our expert statisticians and biostatisticians are committed to delivering comprehensive and meticulously crafted Statistical Analysis Plans (SAPs) that ensure the credibility and success of your clinical trials. With extensive experience in adhering to regulatory guidelines and employing advanced statistical methodologies, we are here to support you in every stage of your trial.
For more information on how we can assist with your SAP or our other biostatistical services, please contact Quanticate or submit an RFI.