one-size-fits-all approach to biopharma R&D no longer fits the technology-savvy, diversified world of drug development. Limited resources, patient recruitment challenges, and other barriers have forced the biopharma R&D industry to explore alternative trial designs, which this article illustrates along with some recently developed tools to enable their implementation.

In 2019, the EU Innovative Health Initiative (IHI), formerly known as the Innovative Medicines Initiative (IMI), provided a grant to EU Patient cEntric clinicaAl tRial pLatforms (EU-PEARL), a public-private consortium for knowledge sharing and science-driven debate, to shape the future of clinical trials by making them more efficient, potentially shortening the timeline to develop and bring new medicines to market for patients. A total of 36 organizations representing patients, clinicians, sponsors, academia, researchers, and health authorities were members while EU-PEARL was active through the end of spring 2023.

EU-PEARL decided to develop a generic framework and tools to conduct patient-centric collaborative integrated-research platform trials for any disease. A platform trial is a disease-focused, adaptive, randomized clinical trial that compares multiple interventions against a control group. In a platform trial, interventions can enter and leave throughout the lifetime of the trial, either simultaneously or sequentially.

What questions should one ask to determine if a platform trial is more appropriate in place of a standard protocol evaluating a single intervention?

• Will multiple populations and/or multiple study interventions or combinations be evaluated?
• Will study arm/cohorts be added/removed in an adaptive manner?
• Will the same endpoints be analyzed for all study arms/cohorts?
• Are the recommended Phase 2 dose(s) of each study intervention and preliminary efficacy established?

If the answer is “Yes” to most questions, a platform trial may be appropriate.

Designing and Implementing Master Protocols in Platform Trials

EU-PEARL quickly identified that creating and implementing a master protocol (a protocol designed with multiple substudies) is a more standardized approach and can benefit those conducting platform trials with acceleration, efficiency, and flexibility.

Master protocols have become an important research tool for conducting adaptive and collaborative complex trials. They enable the simultaneous evaluation of a single intervention in multiple indications (basket trials), multiple interventions available for investigation at the same time in a single disease population (umbrella trials), or multiple, simultaneous, and possibly differently timed interventions examining a specific clinical condition (platform trials). Master protocols are often conducted as a series of substudies within a single clinical trial infrastructure, often involving multiple investigational product contributors or with a single sponsor with a broad portfolio in a disease area. Master protocols provide governance for the entire study, give an overall picture of what is common to all intervention cohorts, and include common study design elements.

While master protocols can offer increased flexibility and efficiency, they can also contain extensive details and be challenging to review due to their complex and innovative designs. During initial development, master protocols require in-depth collaboration and forethought about study aspects that will remain constant or can change over time to create well-organized protocols that can be easily maintained and implemented. A master protocol can become unreadable if details are added to it every time a new intervention is implemented, which is why the master protocol should be treatment-agnostic.

Fortunately, in their efforts to optimize master protocol approaches, EU-PEARL had a head start based on the prior work of TransCelerate BioPharma’s Clinical Content & Reuse Initiative, formerly known as the Common Protocol Template Initiative. This initiative has enhanced clinical trial processes by providing harmonized structure and proposed model content within clinical trial documents (e.g., protocol, statistical analysis plan, clinical study report) that can be reused throughout the project lifecycle to enable digitization and traceability through automation. TransCelerate’s Common Protocol Template contains harmonized content aligned with ICH guidelines to facilitate the creation, review, and implementation of protocols. It has been widely adopted for traditional clinical trials and is extensible to master protocols.

EU-PEARL agreed to develop and make publicly available guidance and templates for a master protocol, Intervention-Specific Appendix (ISA) (i.e., substudy protocol), the EU CTR Cover Letter, Statistical Analysis Plan (SAP), and Data Monitoring Committee (DMC) charter. TransCelerate was invited to join the working group with a request that the applicable deliverables be based on TransCelerate’s Common Protocol Template V8 and its SAP V3.

The ISAs detail what is specific to a targeted population and the relevant intervention. ISAs added as interventions are chosen and become available and are ready to enter the platform study, therefore avoiding major protocol amendments to the master protocol. Recognizing the complexity which can come with multiple ISAs, the team developed a recommendation for structured comments to be added to the cover letter to the submission, allowing for easy reference between the whole clinical trial platform and substudies and a way to track amendments.

The project’s kickoff in November 2019 focused on developing a set of provisional templates. The first step was creating a glossary with terminology and trial scenarios. Shortly after, a stakeholder workshop was conducted to help inform the refinement of the provisional templates into the final versions. EU-PEARL also hosted a patient advisory group to obtain feedback on the design.

“It was essential to convene a patient advisory board to understand the areas that most concern patients when participating in a clinical trial. Then we can build those elements into the design of the clinical trials and tools from the start,” said Peter Mesenbrink, executive director of biostatistics at Novartis and the leader of the work package within EU-PEARL that developed the templates. “Compared to traditional trials focusing on a standalone treatment, platform trials give patients the option of which potential treatments they may receive. Our efforts built this optionality into the informed consent process and the design of the protocols. For example, a patient can choose to be potentially randomized into a subset of the substudies within the master protocol based on their individual preferences,” said Mesenbrink.

Input from the patient advisory group and the Clinical Trials Facilitation Group (CTFG) helped focus discussions beyond the content included in the master protocol and included substantive discussions on why the protocol was being designed in a certain way. The group examined the master protocol at 360 degrees, assessing how each stakeholder typically structures their protocol and where inefficiencies may lie.

“These deliverables were co-designed by those that develop and write protocols, those that conduct platform trials and statisticians, and regulatory professionals who receive and review these protocols,” said Cecile Spiertz, a former EU-PEARL leader and current vice president of development operations at Exscientia. “These content discussions helped us to push our collective thought process and think more broadly rather than for creating a research trial infrastructure and documents for one specific asset. The project also developed four master protocol designs for tuberculosis (TB), major depressive disorder (MDD), nonalcoholic steatohepatitis (NASH), and neurofibromatosis (NF). Feedback from those work packages along with feedback from operationally running platform trials (i.e., REMAP-CAP, ALS HEALEY, UCL) was incorporated in the design. The TransCelerate team helped tease out where we could impact the whole clinical trial enterprise.”

Lessons Learned

Creating the master protocol and its supporting assets required ingenuity from participating members. EU-PEARL was established in November 2019. By March 2020, COVID-19 had spread, making face-to-face meetings impossible. The group was forced to adapt, and a virtual-only environment actually ended up benefiting the project.

“Normally, you plan for in-person workshops,” said Spiertz. “This project was different because we were able to reach out to the whole world, not just those that had a travel budget. We had to revisit how these projects usually get done but also had a wider input on our vision, goal, and the tools we are developing. People dialed in from all over the world.”

The group’s willingness to be flexible and adapt to change positively benefited the master protocol development as well.

“For a master protocol to enable platform trials to run correctly, we had to undertake a mindset shift and identify which parts of the protocol should be consistent and where variability can occur,” said Mesenbrink. “The goal was to build a usable master protocol where protocol amendments and changes are focused on appendices, not the main trial and substudies.”

Results

In 2021, the first version of the Platform Trials Best Practice Tool (download here), the interim version of the templates, and Software Implementation of Statistical & Simulation Processes were released. The following year, the second stakeholder workshop convened to prepare to release the final IHI templates to the public in 2023. Accompanying this framework were integrated research platforms for use in four therapeutic areas: TB, MDD, NASH, and NF.

The resulting final master protocol template provides the overall picture of what is common to all intervention cohorts. It also allows for an easy comparison of the whole trial and across all substudies and tracking of amendments. You can access the EU-PEARL’s Suite of Master Protocol deliverables here.

The timing was fortuitous, as the International Council for Harmonisation (ICH) released its M11 Clinical Electronic Structured Harmonised Protocol Template (CESHarP) for public comment in 2022 to help ensure that protocols are prepared consistently and provide a harmonised data exchange format acceptable to health authorities. EU-PEARL’s efforts ensured that the new master protocol template aligned with this evolving regulation.

Call to Action

The development of this suite of materials would not have been possible without collaboration across the biopharma R&D industry to enable the advancement of science and new ways of working. To aid organizations in the use of master protocols, TransCelerate is hosting a webinar on September 10, 2024, at 9:00AM ET. Interested participants can register here.