A lack of suitable pediatric patients to participate in clinical trials is already an issue. With the RACE for Children Act we expect to see an increase in the number pediatric oncology studies to be conducted globally in order for Sponsors to comply with RACE.
Given the rarity of pediatric cancers and the limited number of potential patients to participate in these trials, it is likely that more complex protocol designs will be utilized. Master protocols are one option and are encouraged by the FDA who have issued draft guidance on master protocols for oncology products. The guidance defines a master protocol as ‘a protocol designed with multiple sub-studies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes with the overall trial structure’. The aim is to expedite drug development through more efficient clinical trial design. Master protocols are designed to study either multiple therapies, with direct comparison to competing therapies, or to their respective controls in parallel, or multiple diseases. They can be split into three distinct types:
Given the advances in identifying tumor mutations for targeting therapy, oncology trials are well suited to master protocol designs. There are a large number of similar or same in class IMPs and matching of target therapies in theory should speed up early phase clinical testing. The large number of possible IMPs also raises the question of need for prioritization which itself requires industry coordination and cooperation and master protocol use may help with such prioritization. Use of master protocols should also limit exposure of children to potentially ineffective therapies by avoiding unnecessary duplication of studies. Master protocols can also provide efficiencies such as a common screening platform, a shared control arm, which is recommended to be standard of care, and more efficient use of trial set up, although the initial set up may be more time consuming than a stand-alone trial.
However, they pose challenges. Pre-planning and discussion with all stakeholders are important. The master protocol design requires flexibility but also a clear overall plan. This may include criteria for future IMPs and changes in controls, patient populations and study arms, plans and guidance for oversight to allow for changes to be made during the study, clear stopping rules for cohorts, and clear end points for the trial and each cohort.
A major consideration for the conduct of master protocols is the fact they may involve direct comparisons of competing therapies. This requires there to be extensive pre-trial discussions among those Sponsors contributing IMPs for the trial with multiple targeted therapies. This is to address concerns such as timing of study reporting to prevent possible unblinding issues, avoid introducing bias to the ongoing trial and also commercial sensitivities. Other areas for discussion include publication rights and data use.
It should also be noted that the FDA guidance strongly recommends that the master protocol should be the only trial conducted under an IND. This raises the question when there are multiple collaborators of who will be the IND holder.
There have been successful studies conducted using master protocols in adult oncology studies such as the I-SPY 2 platform trial and the LUNG-MAP umbrella trial, both of which involve multiple Sponsor companies collaborating and are public-private partnerships.
The National Cancer Institute Pediatric MATCH study is running under a master protocol and was launched in 2018.
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RACE Act is significantly changing clinical development. Are you ready?
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