Industry experts tout potential for master protocols in pediatric clinical trials

Regulatory NewsRegulatory News | 07 September 2022 | By

Using master protocols in pediatric clinical trials could speed the development of drugs for pediatric indications that already have development programs for adults, according to a recent paper written by industry representatives and published in Therapeutic Innovation & Regulatory Science.
A master protocol framework would potentially have “great benefit” because stakeholders could use shared control groups, operate more efficiently in the clinical setting and use Bayesian analysis to assess primary outcomes with a lower the number of enrolled participants, Robert M. Nelson, MD PhD, of Johnson & Johnson, and co-authors from Janssen Research & Development and Eli Lilly and Company, said.
The pediatrics space has seen little use of master protocols—usually in pediatric oncology, in rare, and ultra-rare diseases. However, master protocols could be applicable in other situations where clinical trials are conducted in small pediatric populations, they argued.
Master protocols have been a subject of increased discussion, as regulators and industry look to improve the drug development process. Both the FDA and the EMA have recently released guidance documents on master protocols. (RELATED: EU regulators offer new guidance on complex clinical trials, Regulatory Focus 3 June 2022; RELATED: FDA issues new COVID-19 master protocol guidance, Regulatory Focus 17 May 2021)
Master protocols in pediatrics should consider the context of the drug being developed, whether trials will have a common control group, how a centralized infrastructure could improve executing the master protocol and conducting sub-studies, and the regulatory submission process for the regulatory authority, the authors said.
Shared placebo arms can help reduce the issues associated with clinical trials where no treatment of a disease can alter that disease’s course, but many pediatric clinical trials opt to use a historical active or placebo control group in lieu of a concurrent control group. While not having a shared control group reduces the benefits of having a master protocol, the authors said, the shared infrastructure and protocol still confer operational advantages and make Bayesian analyses easier to conduct.
A “plethora” of master protocols were in use in clinical trials during the COVID-19 pandemic, the authors noted, but problems arose when a lack of infrastructure led to issues with data quality in the trials, such as treatment arm randomization and inadequate power. Creating the infrastructure and framework to evaluate more than one drug a single disease or multiple drugs with the same mechanism of action would be beneficial for cross-company platform trials, they explained.
“Pediatric platform trials could leverage Bayesian statistical analyses, as well as operational efficiencies, to streamline the process for data generation and analysis,” Nelson and colleagues said. “This would be enabled by building the infrastructure necessary to generate high quality and interpretable data acceptable to health authorities.”
Janssen and Lilly have been building such a cross-company pediatric platform trial for Crohn’s disease where recruitment of pediatric participants with inflammatory bowel disease is difficult because eligible patients are rare, and parents often are unaware of clinical trials being conducted. The two companies are working together to develop a master protocol involving Janssen’s Tremfya (guselkumab) and Lilly’s experimental monoclonal antibody mirikizumab governed by a contract research organization (CRO) that allows for management of two separate treatment arms conducted by the companies, including randomization to each treatment arm. Outcomes will be compared with a meta-analysis of an adult placebo control arm. The Bayesian platform-level analysis will “borrow” information from both treatment arms to generate a sufficient sample without the companies having to share patient-level data, the authors said.
Nelson and colleagues acknowledged the work needed to create and implement a master protocol in pediatrics “should not be underestimated.”
“Building the collaborative infrastructure for the design and implementation of pediatric master protocols would benefit the movement toward wider use and acceptance. The ultimate goal would be to reduce the delay in pediatric marketing approvals when compared to adults so that children have access to safe and effective medications in a timelier manner,” the authors wrote.
Ther Innov Regul Sci Nelson et al.


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