The lessons
Platform trials are most intensive in the startup phase
The nature of platform trials means that, operationally, many standard or streamlined practices in the startup phase are not usable or require considerable reworking. The sponsor must be able to rely on a flexible, operationally competent, and lean team during the startup phase to work efficiently with regulatory authorities and implement required amendments (e.g., refining randomization ratios, or perfecting rules for treatment arms).
Vendors need to be carefully managed
Often, many vendors are required for platform trials, and they may not have appropriate pricing structures or sufficient supplies needed for successful execution. Furthermore, their services may be diminished or unnecessary depending on the outcome of certain sections of the platform trial. PSI has very good connections with vendors; however, we still had to work through face-to-face meetings to change their understanding of the concept of a clinical trial, and ensure they were flexible in a way that suited the trial protocol.
Working with a draft protocol is frequently unavoidable
Unlike “traditional” clinical trials, platform trials evolve over time. The trial protocol is designed to change, allowing for the treatment of as many patients as possible while still gathering the necessary data required for approvals. Regulatory authorities will review protocols at different stages, and potentially in parallel; however, sites and vendors can be uncomfortable working with draft protocols.
Close support for PIs driving the trial is crucial in helping relevant stakeholders understand the draft protocol and enabling them to implement any necessary amendments. Some CROs are unable to work with early draft protocols; however, PSI has flexible systems in place and has experience initiating trials based on draft protocols. The sooner the trial can start (which, in theory, is faster with a draft protocol), the sooner problems can be solved, lessons learned (as built into the protocol design), and life-altering treatments made available.
Randomization and data management systems need to be fit for purpose
Very specific, complex randomization systems are required for platform trials. Dynamic allocation according to changes in the trial design (i.e., adding new arms to evaluate a new drug or removing an arm to halt the exploration of one intervention) must be seamless, and the data produced must be of use (i.e., remain statistically valid). Patients should also be fairly assigned to an appropriate arm, based on ethical guidelines, and often should remain blinded.
Data management systems must be able to handle increasingly complex data and remain robust enough to maintain integrity when modifying the trial protocol and study arms. PSI worked closely with the sponsors and, where necessary, helped develop randomization protocols and select the appropriate data management system to avoid problems down the line.
Close communication with regulatory authorities is key
Closely monitoring feedback from relevant authorities across the trial’s geographical area and implementing changes can be time-consuming, potentially leading to the need to stop site selection in a country where the obstacles can’t be overcome.
As mentioned earlier, protocols can be in draft stages, and regulatory authorities have more opportunities and are more likely to request information and amendments. PSI’s early and frequent engagement with regulatory authorities is crucial, especially in countries where platform trials are not yet established.
Site ethics review boards have their own individual needs
Platform trials are beneficial for sites as they don’t impact pre-existing reimbursement contracts. Many sites are excited about running a platform trial and having the opportunity to evaluate advanced therapies. However, individual ethics review boards can pose a challenge.
Sites must be willing to follow the protocol exactly as described, i.e., per regulatory authority approval. Identifying sites where protocol execution could be at risk is important – and pivoting to other sites is vital to keeping platform trials on track. Simply, each site should be considered individually, rather than assuming that a regulatory authority’s decision for a country is a nationwide green light.
Site engagement activities are required to inform and educate all stakeholders
By design, prior data feeds into the platform trial, and changes to the protocol can happen. Sites can be “switched on/off” depending on several factors, so ensuring comprehensive education for patients, their healthcare team, and caregivers means they fully understand the positives and potential drawbacks of enrolling in such a trial.
Pioneering first-in-indication platform trials
In short
The evolution of the platform trial
The framework for clinical trials has been evolving continuously, especially in recent decades. However, newer challenges, including personalized treatment, competitive therapeutic marketplaces, and long drug development cycles, often render the “traditional” clinical trial suboptimal.
Current thinking centers on a Master Protocol – a protocol that allows one or more interventions to be assessed in one or more patient populations under a single, unified trial structure [1]. Use of a Master Protocol has several advantages: having a single trial evaluate multiple parameters reduces the length of timelines; shared control groups reduce redundancy (i.e., fewer patients will receive a placebo/SoC); and ongoing assessment means new trial arms can be introduced without halting the study.
Under a Master Protocol, a basket trial investigates a single drug (or combination) in different disease populations; and an umbrella trial investigates multiple drugs in a single disease population. A platform trial can combine features of both basket and umbrella trials, however the focus is on the longitudinal nature of the trial [1, 2]. Efficacy and safety can be evaluated at multiple timepoints, and new arms (and new therapies) can be added or removed as needed. Platform trials are patient-centric by nature [3]; patients who enroll have access to a range of treatment options. However, a set of preconditions must be met for a platform trial to be viable, foremost being that the sponsor must have multiple molecules ready for assessment.
Platform trials were initially developed for oncology studies [4], where rapid deployment of a therapy is crucial in patients with frequently limited lifespans – other therapeutic areas are not currently well-served by platform trials, and the relevant regulatory agencies are often not ready for them.
When two different, biopharma sponsors approached PSI for their help in running two of the first platform trials in their respective indications, this knowledge informed our approach to the challenge from day one. Having a comprehensive yet flexible and adaptive protocol that evaluates multiple molecules in a platform trial can mean more patients are reached sooner with a potentially life-altering therapy.
Running platform trials presents novel challenges, but lessons learned from PSI’s previous experience in on-time delivery in this indication served the sponsors well. These two platform trials are currently enrolling; to reach this stage, several challenges had to be overcome.
The lessons
Platform trials are most intensive in the startup phase
The nature of platform trials means that, operationally, many standard or streamlined practices in the startup phase are not usable or require considerable reworking. The sponsor must be able to rely on a flexible, operationally competent, and lean team during the startup phase to work efficiently with regulatory authorities and implement required amendments (e.g., refining randomization ratios, or perfecting rules for treatment arms).
Vendors need to be carefully managed
Often, many vendors are required for platform trials, and they may not have appropriate pricing structures or sufficient supplies needed for successful execution. Furthermore, their services may be diminished or unnecessary depending on the outcome of certain sections of the platform trial. PSI has very good connections with vendors; however, we still had to work through face-to-face meetings to change their understanding of the concept of a clinical trial, and ensure they were flexible in a way that suited the trial protocol.
Working with a draft protocol is frequently unavoidable
Unlike “traditional” clinical trials, platform trials evolve over time. The trial protocol is designed to change, allowing for the treatment of as many patients as possible while still gathering the necessary data required for approvals. Regulatory authorities will review protocols at different stages, and potentially in parallel; however, sites and vendors can be uncomfortable working with draft protocols.
Close support for PIs driving the trial is crucial in helping relevant stakeholders understand the draft protocol and enabling them to implement any necessary amendments. Some CROs are unable to work with early draft protocols; however, PSI has flexible systems in place and has experience initiating trials based on draft protocols. The sooner the trial can start (which, in theory, is faster with a draft protocol), the sooner problems can be solved, lessons learned (as built into the protocol design), and life-altering treatments made available.
Randomization and data management systems need to be fit for purpose
Very specific, complex randomization systems are required for platform trials. Dynamic allocation according to changes in the trial design (i.e., adding new arms to evaluate a new drug or removing an arm to halt the exploration of one intervention) must be seamless, and the data produced must be of use (i.e., remain statistically valid). Patients should also be fairly assigned to an appropriate arm, based on ethical guidelines, and often should remain blinded.
Data management systems must be able to handle increasingly complex data and remain robust enough to maintain integrity when modifying the trial protocol and study arms. PSI worked closely with the sponsors and, where necessary, helped develop randomization protocols and select the appropriate data management system to avoid problems down the line.
Close communication with regulatory authorities is key
Closely monitoring feedback from relevant authorities across the trial’s geographical area and implementing changes can be time-consuming, potentially leading to the need to stop site selection in a country where the obstacles can’t be overcome.
As mentioned earlier, protocols can be in draft stages, and regulatory authorities have more opportunities and are more likely to request information and amendments. PSI’s early and frequent engagement with regulatory authorities is crucial, especially in countries where platform trials are not yet established.
Site ethics review boards have their own individual needs
Platform trials are beneficial for sites as they don’t impact pre-existing reimbursement contracts. Many sites are excited about running a platform trial and having the opportunity to evaluate advanced therapies. However, individual ethics review boards can pose a challenge.
Sites must be willing to follow the protocol exactly as described, i.e., per regulatory authority approval. Identifying sites where protocol execution could be at risk is important – and pivoting to other sites is vital to keeping platform trials on track. Simply, each site should be considered individually, rather than assuming that a regulatory authority’s decision for a country is a nationwide green light.
Site engagement activities are required to inform and educate all stakeholders
By design, prior data feeds into the platform trial, and changes to the protocol can happen. Sites can be “switched on/off” depending on several factors, so ensuring comprehensive education for patients, their healthcare team, and caregivers means they fully understand the positives and potential drawbacks of enrolling in such a trial.
Key takeaways
Platform trials are a vital development in rapidly bringing the right treatments to the right patients and reducing unnecessary investment. Platform design doesn’t negatively impact site selection or enrollment — simply, in this time where platform trials aren’t commonplace, more investment is required during study startup and enrollment.
Learn more about PSI's experience executing trials with innovative adaptive designs
Abbreviations
CRO, contract research organization;
SoC, standard of care.
References
1. Roustit, M., et al., Platform trials. Therapie, 2023. 78(1): p. 29–38.
2. Lu, C.C., et al., Practical Considerations and Recommendations for Master Protocol Framework: Basket, Umbrella and Platform Trials. Ther Innov Regul Sci, 2021. 55(6): p. 1145–1154.
3. Koenig, F., et al., Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL. eClinicalMedicine, 2024. 67.
4. Hau, P. and Frühwald, M.C., Platform trials for rare cancers-A complex innovation to accelerate knowledge. Neurooncol Pract, 2024. 11(4): p. 365–366.
Share