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Are New Templates Needed to Fill Master Protocols for Integrated Research Platform Trials?

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Integrated research platform trials have recently generated more awareness in light of upcoming changes to the International Council for Harmonization’s (ICH) regulatory guidance document on good clinical practice, ICH E6 (R2). While it was last updated in 2016, a draft for R3 was endorsed in May 2023.1 The results of a 3.5-year study recently published in Trials highlighted the process of stakeholders from the EU Patient-Centric Clinical Trial Platforms (EU-PEARL) developing new templates to fill master protocols for integrated research platforms (IRPs) that address their current needs.2

“Recently, there has been heightened awareness of the importance of platform trials IRPs designed to evaluate multiple therapies simultaneously,” the study authors wrote. “The use of a single master protocol as a key source document to fulfill trial conduct obligations has resulted in a re-examination of the templates used to fulfill the dynamic regulatory and modern drug development environment challenges.”2

According to the study authors, a number of backgrounds were represented by members of EU-PEARL in the development process, including regulatory medical writing and biostatistics. Stakeholders included academic hospitals, pharmaceutical companies, non-governmental organizations, patient representative groups, and small- and medium-sized enterprises.2

“Complexity occurs in two dimensions in platform clinical trials: the protocol and the operations. Trials that are complex in any one of these dimensions require special flexibility to easily adapt to variability and change, including in the technologies built to support the trial,” the authors wrote. “IRP protocol complexity covers specifics in the study design and can be related to the treatment, patient flow through the study, and point-in-time complexities. Protocol complexities might include multiple treatment arms, variable visit schedules, or personalized medicines.”2

Following the development of a 3.5-year plan, members of EU-PEARL decided to incorporate certain elements of available TransCelerate templates. In August 2020, the members contacted TransCelerate for approval to base their own master protocol templates on several of TransCelerate’s.2

At the end of the 3.5 years, EU-PEARL developed five templates for sponsors developing their own platform trials: a master protocol template, an intervention specific appendix or sub-protocol template, a template for the statistical analysis plan, a data monitoring committee charter template adjusted for the purpose of conducting a platform trial, and a guidance for supplementary information to the CTR Cover Letter (Clinical Trials Regulation—Regulation EU No 536/2014).2

EU-PEARL focused on a few key considerations while developing these templates, including the use of statistical procedures and non-concurrent controls. Members also considered regulatory feedback from EMA and had interactions with the FDA. Finally, the EU-PEARL patient and community engagement group provided insights into the development of the templates.2

Looking forward, EU-PEARL developed a sustainability plan for the generic templates. This includes a regular review of the master protocol templates and communication to their user communities on at least a yearly basis once the ICH M11 protocol template guidance is finalized at a future date.2

“Furthermore, the suite of templates should increase the quality and enhance consistency within and between sponsors,” the authors concluded. “It may also benefit systematic reviewers in their review of platform trials, which will also contribute to the development of a trust-enhanced environment.”2

References

1. ICH Harmonized Guideline Good Clinical Practice (GCP) E6(R3). International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. May 19, 2023. Accessed March 28, 2024. https://database.ich.org/sites/default/files/ICH_E6%28R3%29_DraftGuideline_2023_0519.pdf

2. Gidh-Jain, M., Parke, T., König, F. et al. Developing generic templates to shape the future for conducting integrated research platform trials. Trials 25, 204 (2024). https://doi.org/10.1186/s13063-024-08034-8