Testing Cancer Drugs in Children

A subcommittee of the Oncologic DrugsAdvisory Committee (ODAC) recently spent a day discussing the similarities anddifferences between pediatric and adult hematologic malignancies. It was thesecond session in a series intended to advise the Food and Drug Administration(FDA) on how to apply its 1998 Pediatric Rule regarding the testing of cancerdrugs in children. The rule states that "there is a federal mandate toperform pediatric studies if the indication under review for a marketing licenseexists in children."

Subcommittee members and a panel of cancer specialistsaddressed application of the rule in three areas: myeloid leukemia andmyelodysplastic syndrome, lymphoblastic leukemia, and lymphomas.

Ethical Dilemma

In his introductory comments, David G. Poplack, MD, professorof pediatric oncology at Baylor College of Medicine, touched on a fundamentalissue of testing new drugs in children that are intended for adult use. He citedacute lymphocytic leukemia (ALL), for which conventional cytotoxic therapy has agood survival record in youngsters. If a new drug shows promise in adults, itcan be a challenge for pediatric clinical researchers to decide whether to testit in children, he said.

"On the one hand, you can say, how is it ethical tochange the regimen?" said Dr. Poplack. "However, you can make a strongargument to the contrary. We know that many curative therapies are associatedwith toxicity. If you have something that is more specific—that may have fewertoxicities—you may be ethically bound to study that drug vs the combinationtherapies that may cure ALL but have high toxicities."

Although the FDA relies on ODAC for advice and guidance inapproving the marketing of cancer drugs and biologic agents, as well as otherissues relating to its regulatory responsibilities, the agency is under noobligation to accept any ODAC recommendation.

Questions Posed by the FDA

In opening the advisory meeting, FDA medical officer StevenHirschfeld, MD, PhD, noted that "many therapies are administered tochildren without adequate study" and "many therapies are not madeavailable for pediatric study until after adult marketing studies arecompleted." The question for the subcommittee, he added, was: "Howshould the 1998 rule be applied for hematologic malignancies?"

Prior to discussing each of the three agenda topics, thesubcommittee heard presentations by specialists in the area. The panel thensought to provide guidance on questions posed by the FDA staff. "We arelooking for recommendations and the scientific data to support them,"Richard Pazdur, MD, director of the FDA’s division of oncology drug products,told the panel.

There was a strong consensus that the French-American-British(FAB) classification system was inadequate for relating adult and pediatricmyeloid malignancies. "There’s a wealth of data and it’s now widelybeen shown that that classification should not be used for makingdecisions," said Sharon B. Murphy, MD, PhD, chief of the division ofhematology/oncology at Children’s Memorial Hospital in Chicago. "I’vedecided I am going to stop teaching the FAB classification."

Asked what general principals could be used to relate adultand childhood myeloid malignancies, Dr. Michael J. Borowitz, MD, PhD, suggestedthe answer was clear in cases where the two shared a common translocation."My bias is that in cases where you can’t truly demonstrate that it isMDS [myelodysplastic syndrome]-related AML [acute myelogenous leukemia]—andtherefore a disease that is more likely to be seen in adults—you should err onthe side of saying the leukemias are the same, unless you have compellingevidence that they are different," added Dr. Borowitz, professor ofpathology at Johns Hopkins University.

Increased Inclusiveness Urged

Dr. Murphy opined that if a drug is aimed at general AML,rather than a specific molecular target, then the adult and childhood diseasesshould be considered the same. Cells can have the same malignant phenotype, evenif they don’t share the same translocation, noted Samuel Waxman, MD, professorof medicine at Mount Sinai School of Medicine. "If the drug is beingtargeted to a specific malignant phenotype, that principle should hold, whetherit is an adult or pediatric case," he said.

Donna Przepiorka, M, PhD, associate professor of medicine atBaylor College of Medicine, urged as much inclusiveness as possible. "Andif we have a targeted therapy, it should be targeted to both populations whohave that target," she said.

One oncologist questioned whether the FDA should mandatecancer-drug trials in pediatric cases. "It seems to me the issue goes backto how early or how rapidly the drug can be applied to children, and that ismore a consequence of dosing," said Charles Schiffer, MD, chief ofhematology/oncology at Wayne State University School of Medicine. "Fortraditional cytotoxic agents, and maybe even biologics, that is something thatneeds a focus."

Some panel members suggested that acute lymphoblasticleukemia in children may be different from that in adults. "Some studiesshow there are clearly differences in the translocations that are seen in adultcells and pediatrics," Dr. Borowitz said. "There’s not much data,and it is somewhat early to make that definitive conclusion." Anotherparticipant argued that "absent clear difference between adults andchildren, my bias is to say they are the same." The panel recommendedconsidering ALL as the same indication in children and adults, recognizing thatthere are differences in the distribution of subtypes and responses to therapyby age.

The panel also agreed that Hodgkin’s lymphoma isessentially the same disease in children and adults. Many non-Hodgkin’slymphomas, Dr. Murphy suggested, may be different in children and adults. Dr.Robert E. Hutchinson, MD, a clinical pathologist at the Upstate MedicalUniversity in Syracuse, NY, discussed various categories of lymphomas.

Further Similarities Noted

Stefania Pittaluga, MD, PhD, of the National Cancer Institute’scancer therapy evaluation program, said that Burkitt’s lymphoma is quitesimilar in the two age groups. "There might be some subtle differences withBurkitt’s, but I think that overall clinically, their behavior is much moresimilar." The panel recommended that anaplastic lymphoma, diffuselarge-cell lymphoma, Burkitt’s lymphoma, and lymphoblastic lymphoma could beconsidered the same in adults and children.

Robert Arceci, MD, PhD, director of pediatric oncology at theJohns Hopkins Oncology Center, summarized the discussion by pointing out theneed for cooperation and prioritization of potential studies. He alsorecommended that for vaccine development, shared surface antigens may providesufficient basis for doing both adult and pediatric studies.