Pediatric Brain Tumor Populations Too Small For Non-Inferiority Trials – Cmte

The heterogeneity of pediatric brain tumors generally precludes the use of non-inferiority trials to support approval, FDA's Pediatric Oncology Subcommittee determined.

Given that only 3,000 to 3,500 children are diagnosed annually with brain tumors, "can we ever really even consider doing the non-inferiority trial for any condition given the numbers and confidence levels?" committee consultant Roger Packer (Children's National Medical Center) asked. "The answer is we can't ever do a true non-inferiority trial."

The Pediatric Subcommittee of FDA's Oncologic Drugs Advisory Committee met Dec. 6 to discuss endpoints for trials to support approval of pediatric brain tumor therapies. Potential brain tumor endpoints were discussed at an FDA workshop in January, but the pediatric population was not specifically addressed (¹ (Also see "Progression-Free Survival Is Meaningful Endpoint For Glioma Trials" - Pink Sheet, 6 Feb, 2006.), p. 15).

For tumor types with high survival rates, drugs would typically require a randomized, controlled non-inferiority trial for approval on the basis of a reduction in the collateral neurotoxicity of treatment.

However, the committee concluded that it is not plausible to conduct such a clinical trial within a pediatric brain tumor subpopulation that would produce sufficiently robust results to support approval.

"There are probably only a couple of tumor types in which we could really be talking about these kind of trial designs ... and I think as the biology progresses ... we're beginning to segregate those patients in a number of different ways," committee consultant Mark Keirnan (Harvard University) said.

In addition to potential trial populations being increasingly segmented by histology, classification, location, etc., demonstrating a treatment effect in non-inferiority trials of less toxic therapies is often complicated by using a comparator with a high or un-established effect.

"Maybe we should think about other designs and not get worried about this [non-inferiority] study we could never do," Packer said.

The committee noted a significant discrepancy between the standard of evidence FDA requires for regulatory decision-making and what the oncology community considers to be clinically meaningful.

"The people that are dealing with doing these trials are not trying to get approval from you guys to put a label on a drug. They are trying to convince themselves that they are helping these children," committee consultant James Boyett (St. Jude Children's Research Hospital) said. "You have a much higher standard if you are trying to label a drug for an indication, and that's not what's going on here."

The committee asked FDA if it would be willing to forgo the use of the typical "adequate and well-controlled trials" required for marketing approval in favor of trials that are sufficient for oncologists to use for treatment decisions, but do not pass regulatory muster.

"Believe it or not, there is a fair amount of flexibility at the agency," Office of Oncology Products Deputy Director Karen Weiss said, adding that sponsors that are unclear about regulatory standards should discuss their trial design with the agency.

FDA also asked the committee to assess the value of developing risk-based categories for considering primary efficacy endpoints for pediatric brain tumors.

The committee suggested that a survival endpoint is appropriate for high-risk patients, and morbidity endpoints can be examined for conditions in which high survival rates have been achieved.

However, the panel noted that due to the differences between and within pediatric tumor types, endpoints cannot be consistently applied across categories, and there should be flexibility to select an endpoint for the specific clinical condition under evaluation.

Most trials in pediatric brain tumors evaluate survival and are not powered to provide insights on secondary endpoints such as neurological toxicity.

"Although neurotoxicity doesn't seem to be the primary objective...it should be incorporated in all our ongoing trials just so we have this data to look back on later on," National Cancer Institute Neuro-Oncology Branch Physician Kathy Warren commented.

- Brian Marson