Executive Summary

In addition to reviewing proposed lists of targets for relevance to pediatric cancer, advisory committee will discuss possible criteria for prioritizing same-in-class agents for evaluation and ways to promote international collaboration and global development; proposed list of substantially relevant targets is growing.

A US FDA advisory committee’s views on the development and implementation of a list of pediatric cancer molecular targets also could influence how studies among multiple agents in the same class are prioritized and coordinated on a global basis.

The Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee will meet June 20 to review FDA’s proposed lists of molecular targets considered to be substantially relevant, or not relevant, to the growth and progression of pediatric cancers. The panel will discuss the agency’s approach to developing the lists and proposals for adding or deleting target candidates in the future.

The lists, which FDA must publish on its website by Aug. 18 but update regularly, will help determine when sponsors of certain cancer drugs must conduct pediatric studies.

Committee members will discuss “considerations other than scientific relevance that FDA will include in decision-making with respect to the need and timing of pediatric evaluation of specific new drug and biologic products,” the agency’s briefing document states.

The committee also will discuss possible criteria and mechanisms for prioritizing select targeted new agents for pediatric evaluation, with an eye toward avoiding unnecessary duplication of clinical trials of same-in-class agents. In addition, FDA seeks panel comment “on process development aimed at enhancing international collaboration between clinical trial networks to facilitate global cancer drug development for children in light of currently non-aligned regulatory requirements.”

Third Public Meeting On FDARA Provision

The advisory committee meeting marks another step in the US regulator’s implementation of an FDA Reauthorization Act (FDARA) provision aimed at extending the Pediatric Research Equity Act’s reach to cancer. (Also see “Pediatric Cancer Study Requirements Added To FDA User Fee Bill” – Pink Sheet, 11 Jul, 2017.)

Under FDARA, applications for novel drugs and biologics submitted after Aug. 18, 2020 must include reports on a “molecularly targeted pediatric cancer investigation” if the product is intended for treatment of an adult cancer and directed at a molecular target that FDA determines to be “substantially relevant” to a pediatric cancer.

Applications submitted after Aug. 18, 2020 must include reports on a “molecularly targeted pediatric cancer investigation” if the product is intended for treatment of an adult cancer and directed at a molecular target determined to be “substantially relevant” to a pediatric cancer.

The agency was tasked with developing a list of molecular targets “substantially relevant to the growth and progression of a pediatric cancer” and that may trigger study requirements under FDARA, as well as a list of molecular targets for which pediatric cancer study requirements will be automatically waived.

FDA already has participated in two public meetings on the development of the molecular target lists and implementation of the FDARA provision.

At a February meeting hosted by Friends of Cancer Research, stakeholders discussed proposed frameworks to guide determination of whether molecular targets are substantially relevant, or not relevant, to the growth or progression of pediatric cancer. (Also see “Pediatric Cancer Studies: US FDA Promises Flexible Approach On Requirements” – Pink Sheet, 22 Feb, 2018.) These general frameworks are included in the agency’s briefing document for the advisory committee meeting.

At an April workshop, FDA unveiled its initial draft lists of relevant and nonrelevant molecular target candidates. However, discussion at that meeting moved beyond the lists themselves to issues such as the need to prioritize targets and compounds for pediatric study and global coordination. (Also see “US FDA’s Pediatric Cancer Targets List Spurs Questions On Breadth, Prioritization” – Pink Sheet, 26 Apr, 2018.)

Preclinical Studies Ripe For International Collaboration

At the advisory committee meeting, the panel will hear presentations from academia and industry representatives on prioritization of targets and molecules for pediatric studies, and on international collaboration and global coordination.

FDA appears to view nonclinical studies as particularly ripe for international collaboration.

“Because of the potential importance of nonclinical evaluation in contributing to the evidence base for relevance of a molecular target, every effort should be made to ensure sponsors expedite early nonclinical investigation, which could be in collaboration with academic research teams with pediatric expertise in nonclinical testing,” the briefing document states.

“The creation of these collaborations and/or partnerships, ideally international in scope, should be explored further as they will be crucial for early testing of nonclinical models, such as patient-derived xenograft models.”

Target Lists Are Growing

FDA’s proposed lists of molecular targets have grown since the drafts were unveiled ahead of the April meeting.

The list of substantially relevant targets now includes 177 target candidates or groups of targets, up from approximately 140 with the initial draft. The current list is broken down into the following categories: gene abnormality (54); cell lineage (39); tumor microenvironment and immunotherapy (19); and others (65).

The list of nonrelevant targets for which studies would be automatically waived now includes nine candidates, up from six initially proposed.

The agency’s briefing document counters a suggestion by some stakeholders at the April meeting that a threshold level of evidence should be required to include a target on the lists.

“Defining a specific evidence standard for determination of target relevance is not feasible for several reasons, including the different classes of targets, variability in evidence base that may exist among targets and between specific target classes.” — FDA

“FDA has the regulatory authority to determine whether adequate evidence is available to define a target as substantially relevant to require pediatric investigation of a drug directed at that target,” the briefing document states.

“Defining a specific evidence standard for determination of target relevance is not feasible for several reasons, including the different classes of targets, variability in evidence base that may exist among targets and between specific target classes, and the fact that emerging science evolves making pre-defined qualifications based on peer-reviewed publications or publicly available registry data difficult.”

FDA said the proposed framework of factors and characteristics to guide a determination of whether a molecular target is substantially relevant should not be interpreted as a checklist. “It is important to note that the totality of evidence available may be considered when guiding discussion to determine target relevance,” the agency said. “Additionally, the presence of a single factor or a combination of factors may not be sufficient to define relevance.”

Similarly, the agency does not attempt to define what “adequate evidence” means in the context of determining that a molecular target is not relevant to pediatric cancer.

“Molecular targets which lack sufficient evidence to make a determination of ‘substantially relevant’ or ‘not relevant’ will not be included in either list. Decisions regarding relevance of these targets to the growth or progression of pediatric cancers will be made when there is an adequate evidence base to make such a determination,” FDA said.

Keeping The Lists Timely

The briefing document notes that three distinct approaches for updating the list have been suggested:

• A semi-annual public workshop at which stakeholders could discuss potential changes to the list;
• A transparent nomination process open to sponsors and academic investigators; and
• A mechanism by which clinical investigators and sponsors could request a meeting with the agency to discuss new data that may warrant a change in a target’s classification.

“Information from these sources could then be assessed by the FDA, with possible input from the Pediatric Subcommittee of the ODAC, to determine whether there is sufficient new evidence to support changing the relevance status of the target of interest,” the agency said.

The briefing document suggests other considerations may impact whether a sponsor will be required to conduct pediatric studies, even for a target on the substantially relevant list.

“Additional factors that may require consideration when seeking to utilize the list of molecular targets for decisions regarding pediatric evaluation include analysis of clinical benefit and risk, the availability of pediatric formulations, and the adequacy of patient populations when planning clinical trials,” FDA said. “These factors may vary with each targeted product under consideration for pediatric study and will be assessed and subject to multi-stakeholder discussion.”

https://pink.pharmaintelligence.informa.com/PS123317/Pediatric-Cancer-S…