Pediatric Drug Trial Priority Should Be Vincristine/Actinomysin-D, Cmte. Says

A combination drug trial evaluating vincristine and actinomysin-D should be the top priority among off-patent drugs for a pediatric study, FDA's Pediatric Oncology Subcommittee recommended Oct. 9.

"The committee was supportive of these drugs but far more supportive if there was a strategy in which we could study them together," Subcommittee Chair Victor Santana, MD, St. Jude Children's Research Hospital, said.

"If the opportunity exists to do that in a reasonable study design...we can get two bangs for the same buck," Santana said. "That probably could move us up in the list of drugs that could be studied."

FDA convened the committee to discuss the National Cancer Institute's recommendations of vincristine and actinomysin-D as the top two off-patent oncology drugs in need of pediatric studies as mandated by the Best Pharmaceuticals for Children Act.

Under the act, the National Institutes of Health, in consultation with FDA and the U.S. Pharmacopoeia, is required to develop and prioritize a list of off-patent drugs for which additional studies are necessary in the pediatric population (¹ (Also see "Pediatric Labeling Negotiations Limited To 6 Months In Reauthorization Bill" - Pink Sheet, 14 May, 2001.), p. 21).

The bill includes a provision for funding the studies if manufacturers of off-patent drugs decline to conduct them. A request for contract proposals would be issued to entities that have expertise in the conduct of pediatric clinical trials, including universities, hospitals, contract research organizations and pediatric pharmacology research units.

FDA will publish the study results for comment, after which the agency could request labeling changes from the manufacturers.

NCI recommended that vincristine and actinomysin-D be the top priorities based on their broad use in the pediatric population and their "substantial variability in dosing for infants and young children in current pediatric protocols," voting consultant Malcolm Smith, MD/PhD, National Cancer Institute, said.

Smith also suggested that study of the off-patent drugs could build upon ongoing clinical trials.

Phase III trials evaluating new agents generally include "use of off-patent agents that have been inadequately characterized across the entire pediatric age range. Children enrolled in these trials could participate in studies to evaluate the pharmacology of specific off-patent agents. And you could use population PK methods," Smith said.

"The advantages to this approach are that it reduces costs. The study participants are already identified from an ongoing clinical trial data collection," Smith said. "You're building on clinically important standard treatment regimens and so the data that you collect have in turn applicability," he added.

The committee agreed with NCI's selections but recommended evaluating the agents in a single study because they are often used in combination.

"I would strongly urge the panel to consider studying those two compounds," subcommittee member Patrick Reynolds, MD, Los Angeles Children's Hospital, said.

"When you want to think about what compounds to study, you think about compounds when they start losing efficacy or a compound that starts demonstrating toxicity. That's exactly what happened with actinomysin. It started demonstrating toxicity in a very young population," Reynolds added.

Subcommittee member Peter Adamson, MD, Children's Hospital of Philadelphia, noted that actinomysin-D is always administered with vincristine. "As a single study we should be able to figure out with the same specimens what's going on," he said. "I don't know if I would try to separate them out because...actinomysin-D is always given with vincristine."

Smith noted that combining the agents in a single study "would be a great use of resources in terms of minimizing the burden all along."

FDA's Office of Counter-Terrorism and Pediatric Drug Development Deputy Director Rosemary Roberts, MD, noted that "from a regulatory perspective, we would really have to think outside the box to figure out how to do these trials" for a combination of the products.

The trial request sent to the drug manufacturers has to be identical to the trial ultimately conducted by NIH if the companies decline, she noted.

Conducting a single study involving vincristine and actinomysin-D would presumably enable NIH and FDA to conduct trials with other high priority drugs either concurrently or soon thereafter, the committee agreed.

Members of the committee suggested that cisplatin (Bristol-Myers Squibb's Platinol and generics) be considered a high priority for additional study. "When it comes to dosing and what makes pediatric oncologists more nervous, cisplatin is probably at the top of the list when it comes to the concern of long-term toxicity," Adamson said.

The committee recommended that NIH and FDA consider off-patent drugs that have demonstrated efficacy within pediatric population when prioritizing the agents.

"We really should be selecting drugs from the off-patent list in which there is a track record that they're efficacious. So ultimately if we get the answer that we want, it would prove the safety and the efficacy and we won't be compromising anything for our patients," Santana said.

"Feasibility is also a consideration," FDA Division of Oncologic Drug Products Medical Officer Steven Hirschfeld, MD/PhD, said. The agencies should consider, for example, "if assays exist for one drug over another or if the conditions favor the study of one drug over another. In order to establish the credibility of the program, that could be a consideration."

Other factors that the agencies should consider include drug toxicity, frequency of use, use in special pediatric populations, and the cost impact of adding to ongoing clinical trials.