FDA Tries to ‘Jump Start’ Pediatric Cancer Drug Trials

ROCKVILLE, Md—A new initiative by the Food and Drug Administration seeks to move more oncology drugs into pediatric testing and onto the market. In a letter sent to drug companies and researchers, and made public, the FDA said that such an effort “merits special consideration” and notes that the “known and potential differences in the biology of pediatric and adult tumors usually will not permit the extrapolation of clinical activity from adults to children.”

The letter was issued by Richard Pazdur, MD, director of the FDA’s Division of Oncology Drug Products. [See response by pediatric researchers to the initiative.]

FDA hopes that pharmaceutical companies will work with the National Cancer Institute-sponsored cooperative pediatric oncology groups to initiate trials of adult-approved and experimental drugs.

In an interview, Dr. Pazdur emphasized that the pediatric oncology groups desire pediatric testing of new drugs early in their development. Currently, he said, the pediatric groups get new drugs only after they have been studied extensively in adults. “We look at this new initiative as an effort to unify the pediatric community, advocacy community, regulatory authorities, and the NCI to work together with the sponsors to foster pediatric oncology drug development.”

Most pediatric cancer patients are treated in cooperative group trials, which is the reverse of adult medical oncology. “Participation in phase III trials probably represents the standard of care in pediatric oncology,” Dr. Pazdur says.

Only 14 drugs have ever won marketing approval for use in pediatric cancer patients, and no such drug has gotten FDA’s okay since 1990, when the agency allowed the marketing of Vumon (teniposide). The number of approved drugs currently in use in adult cancer patients is around 80, Dr. Pazdur said.

Pediatric cancer experts regard the dearth of new drugs for their patients as a serious problem. “So the FDA took on the responsibility of attempting to jump start this process,” Steven Hirschfeld, MD, PhD, a pediatric oncologist in the NCI’s Division of Oncology Drug Products, told ONI in an interview.

A Lucrative Carrot

FDA plans to use a potentially lucrative carrot to encourage companies to develop treatments for pediatric cancers—a provision in the Food and Drug Administration Modernization Act (FDAMA) of 1997 that allows a 6-month extension of a company’s patent or its exclusive marketing rights for a drug (see box).

Three Key Regulatory Documents

Three key regulatory documents underpin the FDA’s pediatric oncologic drug initiative.

In 1994, FDA adopted a rule that allowed adult efficacy data to be extrapolated to pediatric patients for drug labeling, provided the pathophysiology of the disease and the mechanism of action of the therapy are the same in children and adults.

The Food and Drug Admin-istration Modernization Act (FDAMA), enacted by Congress in 1997, grants to drug makers that seek to bring a new pediatric drug to market a 6-month extension of their patent protection or exclusive marketing rights to the drug, whichever is more beneficial. A company can take advantage of this provision twice, each time for a different pediatric indication for the drug.

A 1998 FDA pediatric rule requires that information about the potential pediatric usage of a drug under review must be provided, if the adult indication sought by the sponsor is for a disease also found in children.

Whereas the FDAMA provision offers drug companies a lucrative “carrot,” the 1998 rule is “a stick, in that, if a company fails to comply with the mandate, it can be taken to court,” Dr. Steven Hirschfeld said.

A key appeal of this provision is that pharmaceutical companies can reap this reward for developing a pediatric drug whether or not it demonstrates clinical efficacy. The law permits a 6-month extension for all indications for a drug if it is granted an exclusivity extension under FDAMA. “We are rewarding people for taking risks,” Dr. Pazdur said.

The agency will send a formal notice, known as a Written Request, to companies whose drugs may qualify for the extension. “In general, these requests will ask for early phase I studies to assess pediatric tolerability and seek potentially responsive tumors, followed, if the drug is tolerated, by appropriate phase II studies” in patients with specific diseases, the FDA letter explained.

FDA officials have been frustrated in that the FDAMA provision has proved very successful in generating new proposals for pediatric drugs in general, but of limited benefit in oncology. From August 1998 to January 2000, the FDA received 163 proposals to test pediatric drugs and issued 127 Written Requests that invoked the exclusivity provision. However, it received only five proposals for studying pediatric oncology drugs and issued only one Written Request.

Dr. Pazdur said that pediatric oncology has some “unique aspects” regarding oncology drug development. First, a relatively small number of children are affected with malignancies, compared with adult cancers. “One reason the companies are reluctant to actively develop drugs in pediatric oncology is because of the small market,” he commented. Second, he said, “there is a perception that if a drug produces toxicity in children, this will have a negative impact on the approval or subsequent marketing of the drug in adults.”

Dr. Hirschfeld added, “Part of the misconception is that the FDA has rigid regulatory requirements for oncologic drugs when, in fact, our history of regulation of cancer drugs has been highly flexible.”

FDA envisions pharmaceutical companies working with the cooperative pediatric trials groups to devise and carry out new clinical trials. The aim is to get companies involved in one or two phase I studies and, if these are successful, to commit to developing the drugs through phase II trials.

Under the FDA plan, companies whose drugs show positive results in phase II trials for indications for which no therapy exists, or which offer an improvement over existing therapy, can apply for accelerated approval. This process allows the use of surrogate endpoints and smaller numbers of patients than full approval, but requires that the sponsor carry out a phase IV postapproval study to confirm the effectiveness of its drug.