Most anticancer drugs that enter clinical testing in children and adolescents fail to reach late-phase trials or earn pediatric regulatory approval, according to the authors of new research.
Over a 15-year period, only 17.7% of anticancer drugs that entered pediatric-eligible clinical trials advanced to a pediatric phase 3 trial. The 10-year cumulative incidence of pediatric FDA approval was just 12.0% compared with 38.7% for adult FDA approval over the same window.
In addition, more than one third of drugs that started pediatric clinical trials had no additional pediatric trials within a 5-year period.
“In the context of cancers seen in children and adolescents, enrollment to clinical trials of drugs that will not advance further delays or prevents enrollment to trials of drugs that are more likely to be successful,” wrote lead author Samantha D. Martin, MD, of Dana-Farber Cancer Institute, Boston, and colleagues.
The study was published in Cancer.
Why lag behind development for adults?
According to Martin and colleagues, developing pediatric anticancer drugs presents distinct challenges compared with drugs for adults. From a scientific standpoint, childhood cancers are rare and biologically heterogeneous. Pediatric trials also present complex ethical concerns that may impede enrollment. Combined with poor commercial prospects, these factors yield low investment from pharmaceutical companies, resulting in relatively slower development than adult agents.
Principal author Steven G. DuBois, MD, also of Dana-Farber, has published multiple studies characterizing this gap.
For instance, a 2019 study found that the median lag between first-in-human and first-in-child trials for oncology drugs that eventually won FDA approval was 6.5 years, with a range up to 27.7 years.
A more recent analysis revealed that only 1.4% of new anticancer drugs entering clinical testing in any age group reached pediatric FDA approval within 10 years.
How was this study conducted?
The current study built on the above findings by analyzing the clinical and regulatory timelines of 191 anticancer agents, all of which initiated a first trial involving patients younger than 18 years between 2005 and 2020.
Almost two thirds of the agents were small molecule inhibitors. Only 11% were FDA approved in adults at the time of their initial trial in children and adolescents.
What were the key findings?
Ten years after the initial pediatric-eligible trial, the cumulative incidence of subsequent pediatric phase 1, 2, and 3 trials was 56.1%, 63%, and 17.7%, respectively.
Pediatric regulatory approvals were even less common.
Among drugs not already approved when their initial pediatric-eligible trial started, the 10-year cumulative incidence of subsequent pediatric FDA and European Medicines Agency (EMA) approval was 12% and 5.6%, respectively. Adult approvals were far more common, with cumulative incidence at 10 years of 38.7% for the FDA and 31.7% for the EMA.
Drugs that entered pediatric testing in a phase 1/2 or phase 2 trial were more likely to reach subsequent approval than drugs starting in phase 1, as were drugs already FDA- or EMA-approved in adults.
“These results may reflect a greater a priori expectation of clinical benefit in the trial and argue for more initial dose confirmation studies in pediatric oncology,” Martin and colleagues wrote.
Are approvals starting to catch up?
The new findings track with longstanding concerns in the field, said Theodore Laetsch, MD, director of the developmental therapeutics program at Children’s Hospital of Philadelphia and co-leader of the pediatric oncology program at the Abramson Cancer Center at the University of Pennsylvania, both in Philadelphia.
“[T]his study is absolutely correct that most drugs that are studied in children don’t reach a phase 3 trial or approval, and that pediatric drug development still lags that in adults,” Laetsch told Medscape Medical News.
However, this pattern could be changing, he added.
“An important caveat to this work is that the pace of new drug approvals by the FDA for children and adolescents has significantly accelerated over the last decade,” Laetsch said.
He cited a presentation at the recent AACR Annual Meeting by Elizabeth Fox, MD, senior vice president for clinical trials research at St. Jude Children’s Research Hospital, Memphis, Tennessee.
“Through incentives and hard work, we have seen exponential growth recently in FDA approvals for [pediatric] drugs,” Fox said during her presentation in San Diego. “It is real progress. When you look at the past 3 years, we are consistently having drugs approved for children with cancer.”
What’s holding back pediatric development?
According to Laetsch, two main constraints are still holding back the pediatric pipeline: poor funding specifically for pediatric drugs and a small market size.
“This can result in business decisions to discontinue drug development if there is a negative study in adults, even if the drug is showing promise in pediatric cancers,” Laetsch said.
Jennifer Foster, MD, director of the Developmental Therapeutics Program at Texas Children’s Cancer and Hematology Center and associate professor of pediatrics at Baylor College of Medicine, both in Houston, pointed to the same structural reality.
“Drug development is largely driven by the potential for commercialization,” Foster told Medscape Medical News. “Pediatric programs therefore depend on adult drug development and are often delayed, deprioritized, or abandoned if adult indications fail, since the small pediatric cancer market makes it difficult to justify the high costs of development and long-term product maintenance.”
Foster pointed to scientific barriers as well.
Pediatric cancers are biologically diverse, individually rare, and, unlike many adult cancers, may lack clearly validated drug targets, making it harder to identify and prioritize the most relevant therapies, she said. Meanwhile, the rapid expansion of complex new treatment modalities has broadened the oncology pipeline but also complicated the choice of which agents to test in children.
“Together, these factors create a system where many drugs enter pediatric testing but fail to advance despite scientific potential,” she said.
What could improve development?
Both experts suggested that regulatory and structural changes are needed to accelerate development of anticancer drugs for children and adolescents.
The RACE for Children Act, a 2017 law that requires sponsors of certain adult cancer drugs to plan and conduct studies in pediatric patients, has increased planning for pediatric studies; however, “those requirements primarily require early phase trials and do not require further development of the drug for children beyond that,” Laetsch said.
Foster called for global coordination and earlier integration of pediatric work into drug development plans: “A coordinated approach that prioritizes efficiency, collaboration, and patient access is needed to improve pediatric drug development.”
The study was funded by Alex’s Lemonade Stand Foundation for Childhood Cancer. Bourgeois reported receiving grant or contract funding from Burroughs Wellcome Fund. DuBois reported receiving consulting fees from Bayer, Amgen, Jazz Pharmaceuticals, Inhibrx, EMD Serono, and Merck, and grant or contract funding from Alex’s Lemonade Stand Foundation for Childhood Cancer. The other study authors, Foster, and Laetsch reported having no relevant financial relationships.
https://www.medscape.com/viewarticle/few-pediatric-cancer-drugs-reach-phase-3-or-approval-2026a1000fsh
