ÎÛÎÛ²ÝÝ®ÊÓƵ

Summary

This project will develop comprehensive, consensus-driven guidance for Statistical Analysis Plans (SAPs) in Adaptive and Platform Trials (APTs). The guidance will cover both interim and final analyses to enhance the quality and timely implementation of these complex trials. It will also include recommendations for the proportionate release of interim information from ongoing APTs without compromising trial integrity.

Background

The increasing need for efficient and innovative trial designs to rapidly evaluate investigative treatments and expedite clinical decision-making for the quick benefit of patients has led to the growing use of Adaptive and Platform Trials (APTs). APTs have already proven their efficiencies. Adaptive designs allow for pre-specified changes to trial design aspects (trial adaptations) based on accrued interim outcome data while maintaining valid conclusions. Examples of trial adaptations include early stopping of ineffective treatment arms, early trial stopping upon gathering sufficient evidence to reach conclusions, or allocating more participants to promising treatment arms. Platform trials further enhance this flexibility by enabling the addition of new treatment arms to an ongoing study, with or without interim analyses.

While APTs offer clear benefits, their inherent flexibility and statistical efficiency introduce considerable operational and statistical complexities across the design, conduct, analysis, and reporting stages. Trial adaptations should be accounted for in all these stages to yield valid, trustworthy, and interpretable results, and to maintain public confidence in the generated evidence. Therefore, timely access to high-quality Statistical Analysis Plans (SAPs) for APTs, addressing both interim and final analyses alongside detailed protocols, is vital for enhancing transparency and facilitating accurate interpretation of results.

However, current SAP guidance does not adequately address the specific considerations posed by APTs. Many publicly available APT-SAPs, including related reports of published results, provide insufficient detail on statistical methods. This makes it difficult to interpret reported results and reproduce methods and findings – hindering the credibility of reported results. This lack of transparency undermines public trust and contributes to research waste. In addition, there is a notable absence of guidance on the proportionate level of interim information that can be released (e.g., to trial participants, patients, investigators, or the research community at conferences) from ongoing APTs without compromising trial integrity.

Aims/Objectives

This project focuses on improving the quality of APT-SAPs for ongoing and future trials. The aim is to develop a comprehensive consensus-driven APT-SAP guidance for interim and final analyses. Specific objectives are to:

1. Develop a consensus-driven minimum set of essential items for APT-SAPs using a Delphi process followed by an international consensus meeting;
2. Provide practical examples and an annotated template to facilitate the immediate production of high-quality APT-SAPs;
3. Establish recommendations for releasing trial information from ongoing APTs while maintaining integrity;
4. Engage international, multidisciplinary, and cross-sector stakeholders throughout the process to maximise the quality of outputs and research impact.

Methodology

This project comprises two interconnected work packages (WPs), conducted concurrently, to address the above aim and objectives.

Work Package 1: APT-SAP Guidance

This WP focuses on developing comprehensive and consensus-driven guidance for APT-SAPs. This will be achieved through a rigorous, multi-stage Delphi process¹, as recommended by the EQUATOR Network². The initial stages will involve a thorough literature review and expert consultations to inform the drafting of checklist items for the APT-SAP guidance. These items will then be assessed and refined through a 2- to 3-round Delphi survey involving a diverse group of international stakeholders, including statisticians, trialists, regulators, reviewers, journal editors, and patient representatives. The findings of the Delphi survey will be discussed and finalised at an international consensus meeting, leading to the creation of a draft APT-SAP checklist. This draft will undergo pilot testing on real APT trials to ensure its suitability before the final guidance and an annotated SAP template, complete with detailed examples for easy implementation, are produced.

Work Package 2: Ongoing Trial Findings Disclosure Recommendations

WP2 aims to establish best practice recommendations for releasing trial information and results from ongoing APTs. This will begin with a survey to understand current practices regarding the disclosure of interim information, data and results in ongoing APTs. The survey will explore motivations for sharing interim information, the nature of the information disclosed, who it is shared with, when it is shared, and the factors considered when sharing interim information. 

The survey will be followed by 2-3 focus groups of diverse international stakeholders in trials research. The findings from the survey of current practice and these focus groups will be discussed at a dedicated workshop involving diverse international stakeholders (including trialists, funders, regulatory representatives, investigators, those serving on trial monitoring committees, and PPI representatives) to share perspectives and propose potential recommendations. Feedback from project partners will then be incorporated to refine these recommendations, ultimately providing researchers with practical guidance on sharing appropriate interim information from ongoing APTs while maintaining trial integrity and minimising the risk of introducing biases in the conduct of APTs.

Importance

High-quality APT-SAPs are crucial for the timely delivery of both interim and final analyses, thereby optimising research resources. Furthermore, they enhance the transparency and reproducibility of methods and results, ensure the reliability of reported findings, improve the interpretation of results, prevent misleading conclusions, and minimise the misuse of APT results in evidence synthesis. These benefits will directly impact patients, researchers, regulatory agencies, funders, and the public. The research outputs will also indirectly advance research knowledge, improve patient outcomes, inform policy decisions, and reduce research waste. Finally, appropriate disclosure of interim information in ongoing APTs will maximise intended benefits while preserving trial integrity, ultimately supporting better-informed practice.

Project Team

To maximise the quality, accessibility, impact, and widespread adoption of the resultant guidance, we have assembled a cross-sector, multidisciplinary, and diverse team of national and international experts in APTs, including PPI representatives, to drive and support the project throughout. This carefully curated team, comprising the PMG and project partners, brings comprehensive expertise and robust support to every stage of the process.

For any queries about APT-SAP, please email Dr Munya Dimairo:

• m.dimairo@sheffield.ac.uk

APT-SAP Core Group

• Dr Munyaradzi Dimairo, The University of ÎÛÎÛ²ÝÝ®ÊÓƵ (co-lead)
• Prof Christina Yap, Institute of Cancer Research (co-lead)
• Dr Xiaoran Lai, Institute of Cancer Research
• Isabelle Wilson, The University of ÎÛÎÛ²ÝÝ®ÊÓƵ
• Jasmine Allender, The University of ÎÛÎÛ²ÝÝ®ÊÓƵ

APT-SAP Project Management Group

• Israel Maia, HCor Research Institute
• Associate Prof Franz Koenig, Medical University of Vienna
• Dr Sofia Villar, MRC Biostatistics Unit
• Prof James Wason, Newcastle University
• Prof Susan Todd, University of Reading
• Prof Thomas Jaki, University of Regensburg
• Prof Christopher Weir, University of Edinburgh
• Prof Derek Stewart, PPI representative
• Roger Wilson, PPI representative

APT-SAP Advisory Group

• Dr Kert Viele, Berry Consultants
• Assistant Prof Jay Park, McMaster University
• Prof Deborah Ashby, Imperial College London
• Prof Louise Brown, University College London
• Associate Prof Sean Ewings, University of Southampton
• Prof Ed Juszczak, University of Nottingham
• Dr Peter Mesenbrink, Novartis Pharmaceuticals Corporation
• Laura Moretti, Institute of Cancer Research
• Prof Hisham Mehanna, University of Birmingham
• Prof Jeremy Chataway, University College London
• Prof Andrew Tutt, Institute of Cancer Research
• Assistant Prof Florian Klinglmueller, Austrian Medicines and Medical Devices Agency
• Dr Olga Kholmanskikh, Federal Agency for Medicines and Health Products
• Dr Khadija Rantel, Medicines and Healthcare products Regulatory Agency
• Dr Quynh Lan Nguyen, Paul-Ehrlich-Institut

Funding

APT-SAP project is funded by UKRI (UKRI615 / APP42050) MRC-NIHR BMBR Develop guidance for better research methods. The MRC-NIHR funded Trials Methodology Research Partnership (TMRP) provided additional funding to support part of WP2.

References

¹

²