WASHINGTONThe 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.
Richard Pazdur, MD, director of FDA’s Division of Oncology Drug Products, described the agency’s plans during a meeting between several FDA officials and cancer patient advocates. The session provided insights into current FDA thinking and activities regarding the oncologic drugs approval process.
Traditionally, FDA has relied largely on survival data as the primary endpoint for approving drugs. But drug companies and advocates have urged the use of other endpoints, including time to progression, response rates, and quality of life. "We know there is a significant debate, and we would like to discuss this in a larger forum," Dr. Pazdur said, adding that there is discussion within FDA itself on the issue.
If the FDA concludes that new endpoints may be appropriate, it will then take them to a meeting of the agency’s Oncologic Drugs Advisory Committee (ODAC) for further discussion and a recommendation vote on whether the committee believes the FDA should adopt the endpoints.
The question-and-answer session touched on a number of other issues:
Expanding Trial Eligibility
Dr. Pazdur said he would like to see a broadening of eligibility of many trial protocols to include patients representative of those who will eventually use the drug in the postapproval setting.
"Once a drug is approved, it is not limited to patients with 0 or 1 performance status," he said. "By having less restrictive entry criteria, we will get a better picture of how a drug works in the population that will actually use it."
By accruing only excellent-performance patients, trials cannot assess symptom improvement because such patients have few or no symptoms, Dr. Pazdur noted. "Our idea in approving a drug is to demonstrate clinical benefit," he added. "People have focused on survival advantage, but clinical benefit may be the improvement or delay of symptoms."
FDA has talked with the pharmaceutical industry about the possibility of doing two trials of a drugone in less advanced stages of a disease and the second in symptomatic patients to assess clinical benefit, Dr. Pazdur said.
"A drug’s efficacy may not be optimally observed in patients who have a poor-performance status or are highly symptomatic. This is a concern of many sponsors," he commented.
Patricia Keegan, MD, deputy director of clinical trials design and evaluation at FDA’s Center for Biologics Evaluation and Research, agreed with Dr. Pazdur’s statement. She added that there is also a perception by clinical researchers and drug companies "that it’s got to be this way." Dr. Keegan emphasized that FDA does not write clinical protocols. "We give comments about things that are not acceptable from a scientific point of view, and I think we are willing to rethink these issues," she said.
Need for Two Phase III Trials
FDA wants pharmaceutical companies to conduct phase III trials of a drug, but many now carry out only one such trial and hope that it will yield "eye-popping" results, Dr. Pazdur said. Often, the results prove marginal or there are serious methodological problems with the single study, but the sponsor nonetheless pursues submission of a new drug application (NDA).
"We are then in a quandary because we must have proof of the drugs’ safety and efficacy to approve it. Most importantly, patients lose because a potentially effective therapy is not available. The company loses because of the revenue loss if the drug is not approved."
Problems With Chemoprevention Trials
Drugs to prevent cancer or treat precancerous conditions pose difficult issues for FDA in terms of deciphering how to judge their effectiveness and long-term safety. "What are 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 issuesproblems in terms of sample size, follow-up, and other thingsseem almost insurmountable."
Such studies would require trials of great length and patient size. "Proof has to be very rigorous, because you are asking people to take medications for a prolonged time," Dr. Pazdur said. "Surrogate markers for chemoprevention trials, for the most part, are still under development and discussion."
ODAC’s Evolving Role
Dr. Pazdur acknowledged that his division is bringing fewer cancer drugs before ODAC and that the committee’s role may evolve from that of prior years.
"One has to remember that in the name ‘ODAC’ is the word ‘advisory,’" he said. "We are using our consultants throughout the review process and not simply at the ODAC meeting. We are discussing thematic issues of how a drug should be approved and what are appropriate endpoints. We will take drugs to them with which we have specific problems and feel we need a public hearing."
FDA brings in outside advisors at several stages of its review of a cancer drug, allowing the agency to make more rapid decisions, Dr. Pazdur said. He cited as an example the recent rapid approval of imatinib(Drug information on imatinib) mesylate, also known as STI-571 (Gleevec), for chronic myeloid leukemia. "It is obvious from the trial data that STI-571 is effective," Dr. Pazdur said. "We do not want to unnecessarily delay approval of drugs when there is compelling data to expedite our review process."
Advocates and pharmaceutical companies both want quality-of-life (QOL) data considered by FDA during the drug review process, but the agency has been reluctant to use such data in granting marketing claims.
"It certainly seems like a logical way to go," Dr. Keegan said. "Nobody wants to approve a drug that doesn’t make people’s lives better, and this looks like the obvious way to do it. We have just had a lot 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 trial directed 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 with cancer trials. We end up with lots of missing data points, and we know, in our hearts, they are not just missing at random."
Dr. Pazdur said that FDA is interested in QOL measures as a way of assessing clinical benefit. "The problem is that the tools to measure qualify of life have methodological problems, including missing data and the difficulties 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’s get them involved in a prospective evaluation of symptoms. Is your cough improved? Can you walk better? Can you sleep? Obviously, the patient is the only person who can measure these things."