Pediatric Oncology Labeling Should Reflect Exploratory Approach – Pazdur

Oncologic drug pediatric labeling should reflect the exploratory nature of the field, FDA Oncologic Drug Products Division Director Richard Pazdur, MD, said during an advisory committee meeting March 4.

"The problem [in pediatric oncology], as in adult oncology, is that you don't know in what indications this drug is going to work," Pazdur said. "The game plan was to be a little more exploratory."

"What we put in the label, we have to have an understanding of how useful it would be. If we start putting every negative Phase II trial in a label, it could become quite unmanageable."

FDA does not expect that the label would be a repository for all the clinical data regarding a product. However, members of the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee felt there should be a forum for pediatric data if it is not included in the product label.

"We need to find a way, if you go out there and request studies, to provide an additional mechanism for pediatric data," subcommittee Chair Victor Santana, MD, St. Jude Children's Hospital, said. "You have to find a way to reflect the information. If the label doesn't allow us then we should find another way."

Adding Phase II data to the label, when there is not yet a related adult indication, may not provide useful information, subcommittee guest Malcolm Smith, MD, National Cancer Institute, suggested. "The challenge to FDA would be to make that information publicly available and the details that you need to interpret what that Phase II result means," Smith said.

The Pediatric Oncology Subcommittee also discussed extrapolation of data from adult conditions for pediatric labeling. The subcommittee previously recommended at a November 2001 meeting that to extend efficacy from an adult indication to a pediatric population using extrapolation, pediatric dosing studies and a demonstration of clinical proof of concept should be performed (¹ (Also see "Pediatric Access To Unapproved Drugs Is Next Topic For Oncology Subcmte" - Pink Sheet, 3 Dec, 2001.), p. 27).

In the situation where the same disease is present in adults and children and extrapolation is used, the subcommittee recommended that dosing and safety information should be included in the label. However, if the dose is derived from an adult population with no additional pediatric data, then it should be excluded from labeling, the members said.

If pediatric dosing and safety data are available but clinical proof of concept has not been established, the subcommittee said the dosing and safety information could be added to the label, but should not include data from Phase II trials in other indications. This could arise if the studies were done in children with diseases other than the one that is being considered for an indication.

In situations where there is no evidence of clinical benefit in children and there are data on a lack of activity, the subcommittee suggested there should be a statement in the label that "no meaningful clinical activity has been observed."

"I think there should be a statement that there's no demonstrated activity and not include in the label any dosing information which I think would only be of interest to clinical investigators," ODAC member Gregory Reaman, MD, Children's Hospital National Medical Center, said.

The subcommittee also agreed the label could include a statement when no safety or efficacy data in pediatric patients are available. FDA said the purpose of the statement would be to distinguish between data that have not been submitted to FDA, no data and negative data.

"We don't have the ability to distinguish among those possibilities," FDA Medical Review Officer Steven Hirschfeld, MD/PhD, said. The default statement that safety and effectiveness have not been established is "perhaps not sufficiently informative," he said.

In an article that will appear in the March 15 issue of the Journal of Clinical Oncology, Hirschfeld et. al., reported that just 15 of the 100 drugs approved by the Division of Oncology Drug Products have pediatric use information.

"The FDA has a desire to be flexible and practical in accepting data intended to support a marketing claim," the article states. "The FDA recommends discussion with a pediatric cooperative group to use their expertise and resources to assist with study design and patient accrual and further recommends meeting with the FDA to review the specifics of any proposal."

FDA hopes that its regulatory initiatives will increase the submission of pediatric data. The Best Pharmaceuticals for Children Act, signed into law Jan. 4, 2002, reauthorizes the pediatric exclusivity program (² (Also see "Barr Expects Metformin Launch By Early February; Pediatric Bill Signed" - Pink Sheet, 14 Jan, 2002.), p. 5).

"We have issued 30 written requests for pediatric studies in oncology," Hirschfeld said. "As far as we know, they have all been accepted and are being acted on."

FDA presented an overview of five pediatric submissions it has received, but did not identify the products. In the first case where extrapolation was used to support efficacy for hematologic malignancies, two Phase I studies in 39 patients demonstrated safety similar to adults and pharmacokinetic parameters were similar to adult values, but the mean therapeutic dose was not reached.

In the next case, the company submitted a pediatric Phase II pharmacokinetic trial in malignant and non-malignant life-threatening conditions that were similar to the adult conditions. Smaller children required a higher dosage, the study found; that recommendation was added to labeling along with safety data from the study.

The third case involved solid tumors and hematologic malignancies found only in pediatric patients, while the drug's approved indications occur only in adults. The sponsor submitted a Phase I dose finding study and a Phase II open-label tumor response trial. While tumor responses were seen in some of the pediatric tumors, the data were not included in labeling because no extrapolation could be made from the adult diseases to support the pediatric data.

In another case, in solid tumors and hematologic malignancies, Phase II data showed a lack of activity in pediatric patients. As a result, a brief description of the study with the negative efficacy data was included in the drug's labeling, but dosing and pharmacokinetic data was excluded.

The last case involved a submission for a spectrum of diseases, including the approved adult indication. The sponsor submitted Phase I-II trials in patients with relapsed or refractory CNS and solid tumors.

The product did not show efficacy in the disease that also exists in adults, but responses were seen in a disease that occurs primarily in children for which there is an available therapy. FDA has not decided what information, if any, should be placed in the label.