By Deborah Borfitz

July 11, 2019 | The current lag time between first-in-human and first-in-child clinical trials for kids with cancer is concerning to Steven G. DuBois, M.D., a pediatric oncologist who leads the early phase clinical trials program at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. One of the downstream consequences of not having a clinical trial available, or not having an anticancer drug FDA-approved for a pediatric indication, is that physicians' only choice is off-label prescribing, he says.

Data on off-label use of novel anticancer agents isn't collected in a systematic manner that benefits future children, notes DuBois. "Once a drug is FDA-approved for an adult indication, it opens up the potential for off-label prescribing in the pediatric space that can then make a clinical trial of that agent more challenging to run."

In a study DuBois co-authored in the May issue of the European Journal of Cancer (DOI: https://doi.org/10.1016/j.ejca.2019.02.011), the median lag time from first-in-human to first-in-child trials of oncology agents ultimately approved by the FDA between 1997 and 2017 was pegged at 6.5 years. "One of the things I worry very much about, as it pertains to pediatrics, is we don't have data that informs safe dosing of these medicines," he says. "If there is strong rationale that a particular agent, based on its mechanism of action, will potentially benefit a child with cancer, then we need to get that agent into pediatric clinical trials much more quickly, even as early as end of the adult phase I."

Some may argue the existing time gap is appropriate to ensure the safety of a vulnerable population, believing pediatric studies shouldn't begin until the agent is on the path to market approval based on adult trials, DuBois says. In many ways, the underlying issues parallel those of pregnant women—namely, misperceptions about ethical requirements, the administrative burdens of involving them and general reluctance of potential trial partners to get involved in a less familiar area of drug development.

The study results describe the current state of affairs in the absence of a uniform accepted interval between first-in-human and first-in-child clinical trials, DuBois says. It provides a benchmark against which to evaluate recent initiatives designed to hasten drug development relevant to children with cancer.

Only six of 117 oncology drugs included children in the initial FDA approval, he says, highlighting the challenge of getting therapies for rare pediatric cancers to market. The six were treatments for acute lymphoblastic leukemia, the most common type of childhood cancer, and neuroblastoma, the most common solid cancer of childhood. "Most cancers taken care of in pediatric oncology are less common types of cancer."

Regulators appear to be growing more flexible, DuBois adds. "After data cutoff for the analysis just published, there was an additional FDA approval of a drug called larotrectinib [a NTRK inhibitor granted orphan product designation] based on a dataset of 55 patients, which is pretty remarkable."

Moving forward, first-in-human oncology studies are also expected to more often include adolescents as a result of initiatives such as ACCELERATE, aimed at improving global development of new pediatric oncology drugs, says DuBois.

In the US, implementation of the RACE for Children Act begins in August 2020, which will strengthen the requirement that new cancer therapies with potential biological relevance to pediatric cancers be evaluated in children, he continues. The FDA will no longer automatically grant waivers to companies developing an agent exclusively for an adult indication, such as prostate cancer, if the mechanism of action has relevance to pediatric cancer.

A significant number of pediatric trials have already gotten off the ground thanks to the advocacy work of academically affiliated clinical trial networks and cooperative groups with industry sponsors, DuBois adds. Within the next decade, he is hopeful the lag time between first-in-human and first-in-child trials will have significantly narrowed.

Clinical trials are standard practice in pediatric oncology, says DuBois. But options for children in the relapse phase are limited largely to early-phase studies where therapeutic effects and dosing are still being evaluated.