FDA Reviews Its Policies With Cancer Patient Advocates

August 1, 2001

WASHINGTON-The Food and Drug Administration (FDA) plans to review potential new endpoints for use in approving cancer drugs. The decision-making process will include public discussions involving practicing oncologists, academic physicians, the pharmaceutical industry, and advocacy groups.

WASHINGTON—The Food and Drug Administration (FDA) plansto review potential new endpoints for use in approving cancer drugs. Thedecision-making process will include public discussions involving practicingoncologists, academic physicians, the pharmaceutical industry, and advocacygroups.

Richard Pazdur, MD, director of FDA’s Division of OncologyDrug Products, described the agency’s plans during a meeting between severalFDA officials and cancer patient advocates. The session provided insights intocurrent FDA thinking and activities regarding the oncologic drugs approvalprocess.

Traditionally, FDA has relied largely on survival data as theprimary endpoint for approving drugs. But drug companies and advocates haveurged the use of other endpoints, including time to progression, response rates,and quality of life. "We know there is a significant debate, and we wouldlike to discuss this in a larger forum," Dr. Pazdur said, adding that thereis discussion within FDA itself on the issue.

If the FDA concludes that new endpoints may be appropriate, itwill then take them to a meeting of the agency’s Oncologic Drugs AdvisoryCommittee (ODAC) for further discussion and a recommendation vote on whether thecommittee believes the FDA should adopt the endpoints.

The question-and-answer session touched on a number of otherissues:

Expanding Trial Eligibility

Dr. Pazdur said he wouldlike to see a broadening of eligibility of many trial protocols to includepatients representative of those who will eventually use the drug in thepostapproval setting.

"Once a drug is approved, it is not limited to patientswith 0 or 1 performance status," he said. "By having less restrictiveentry criteria, we will get a better picture of how a drug works in thepopulation that will actually use it."

By accruing only excellent-performance patients, trials cannotassess symptom improvement because such patients have few or no symptoms, Dr.Pazdur noted. "Our idea in approving a drug is to demonstrate clinicalbenefit," he added. "People have focused on survival advantage, butclinical benefit may be the improvement or delay of symptoms."

FDA has talked with the pharmaceutical industry about thepossibility of doing two trials of a drug—one in less advanced stages of adisease and the second in symptomatic patients to assess clinical benefit, Dr.Pazdur said.

"A drug’s efficacy may not be optimally observed inpatients who have a poor-performance status or are highly symptomatic. This is aconcern of many sponsors," he commented.

Patricia Keegan, MD, deputy director of clinical trials designand evaluation at FDA’s Center for Biologics Evaluation and Research, agreedwith Dr. Pazdur’s statement. She added that there is also a perception byclinical researchers and drug companies "that it’s got to be thisway." Dr. Keegan emphasized that FDA does not write clinical protocols."We give comments about things that are not acceptable from a scientificpoint of view, and I think we are willing to rethink these issues," shesaid.

Need for Two Phase III Trials

FDA wants pharmaceuticalcompanies to conduct phase III trials of a drug, but many now carry out only onesuch trial and hope that it will yield "eye-popping" results, Dr.Pazdur said. Often, the results prove marginal or there are seriousmethodological problems with the single study, but the sponsor nonethelesspursues submission of a new drug application (NDA).

"We are then in a quandary because we must have proof ofthe drugs’ safety and efficacy to approve it. Most importantly, patients losebecause a potentially effective therapy is not available. The company losesbecause of the revenue loss if the drug is not approved."

Problems With Chemoprevention Trials

Drugs to preventcancer or treat precancerous conditions pose difficult issues for FDA in termsof deciphering how to judge their effectiveness and long-term safety. "Whatare the trade-offs of giving a drug or product to people who, at this point,have no disease? That is what we really need to know," Dr. Keegan said."Some issues—problems in terms of sample size, follow-up, and otherthings—seem almost insurmountable."

Such studies would require trials of great length and patientsize. "Proof has to be very rigorous, because you are asking people to takemedications for a prolonged time," Dr. Pazdur said. "Surrogate markersfor chemoprevention trials, for the most part, are still under development anddiscussion."

ODAC’s Evolving Role

Dr. Pazdur acknowledged that hisdivision is bringing fewer cancer drugs before ODAC and that the committee’srole may evolve from that of prior years.

"One has to remember that in the name ‘ODAC’ is theword ‘advisory,’" he said. "We are using our consultantsthroughout the review process and not simply at the ODAC meeting. We arediscussing thematic issues of how a drug should be approved and what areappropriate endpoints. We will take drugs to them with which we have specificproblems and feel we need a public hearing."

FDA brings in outside advisors at several stages of its reviewof a cancer drug, allowing the agency to make more rapid decisions, Dr. Pazdursaid. He cited as an example the recent rapid approval of imatinib mesylate,also known as STI-571 (Gleevec), for chronic myeloid leukemia. "It isobvious from the trial data that STI-571 is effective," Dr. Pazdur said."We do not want to unnecessarily delay approval of drugs when there iscompelling data to expedite our review process."

Quality-of-Life Data

Advocates and pharmaceuticalcompanies both want quality-of-life (QOL) data considered by FDA during the drugreview process, but the agency has been reluctant to use such data in grantingmarketing claims.

"It certainly seems like a logical way to go," Dr.Keegan said. "Nobody wants to approve a drug that doesn’t make people’slives better, and this looks like the obvious way to do it. We have just had alot of difficulty figuring out the best way to get reasonable information."

The agency’s concern in looking at QOL data, she said, is that"it is often very hard to interpret exactly what it means. In a trialdirected at arthritis, you have a large population that stays on study a long,long time, and you don’t lose anybody. That is not often the situation withcancer trials. We end up with lots of missing data points, and we know, in ourhearts, they are not just missing at random."

Dr. Pazdur said that FDA is interested in QOL measures as a wayof assessing clinical benefit. "The problem is that the tools to measurequalify of life have methodological problems, including missing data and thedifficulties of interpretation," he added.

He pointed out that the agency has been encouraging sponsors to"pick a few symptoms to measure from the patient’s perspective. Let’sget them involved in a prospective evaluation of symptoms. Is your coughimproved? Can you walk better? Can you sleep? Obviously, the patient is the onlyperson who can measure these things."