NEWS

Accelerated Approval Regulations May Need Overhaul, Panel Suggests

Joel B. Finkelstein

Accelerated approval has allowed many orphan drugs to come to market sooner—and in some cases, perhaps too soon, said oncology experts who advise the U.S. Food and Drug Administration.

Accelerated approval allows drugs for life-threatening diseases, including cancer, to be given marketing approval by the FDA based on data from less rigorous studies than are required for full approval. The approval is given on the condition that companies conduct postmarketing confirmatory studies.

Those studies have proven difficult to complete and are raising some ethical concerns as companies move them overseas in attempts to meet accrual targets.

After hearing presentations about several such efforts, members of the Oncologic Drug Advisory Committee (ODAC) called for revisions to the study requirements meant to move the drugs from accelerated to full approval status.

"I like what we have done in terms of making these drugs available to more patients, but in the process we have lengthened the study process," said ODAC member S. Gail Eckhardt, M.D., a program director at the University of Colorado's cancer center in Aurora.

In some cases, FDA requirements for subsequent randomized, blinded trials may have made accrual difficult.

"We have a situation where this drug is out in the marketplace, and there is no clear line between clinical agents and research agents," said ODAC Chair Silvana Martino, D.O., director of the breast cancer program at the Angeles Clinic and Research Institute in Santa Monica, Calif.



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Silvana Martino

 
In other instances, the agency has approved drugs based on scarce data, said ODAC experts.

"In granting accelerated approval, the question is what is the shortest amount of time we can get the minimum amount of information to justifying full approval," said Antonio Grillo-Lopez, M.D., chair of the Neoplastic and Autoimmune Diseases Research Institute in Rancho Sante Fe, Calif.

There may also be artificial barriers that have been created in setting up this process, the panel agreed.

"We have 10 years of experience with [the regulation]. It seems to me that it's time to revisit the benchmarks," said Maha Hussain, M.D., a clinical professor at the University of Michigan.

That doesn't mean loosening the standard; it may mean just taking another approach.

"One could envision setting up a body of data requirements for full approval of these agents. That could be a constellation of data that does not necessarily have to be randomized but needs to be done in a high-quality manner," said Eckhardt. Sometimes single-arm or registry trials may be appropriate, she said.

Similar Problems

Since 1995, the FDA has granted accelerated approval for 29 new indications. Ten of those indications have since been granted full approval, two indications were eventually restricted to patient subpopulations, and one indication was withdrawn, according to agency officials.

There are still 16 indications for which confirmatory data are pending. At the recent meeting, ODAC members heard presentations on trials for six drugs that received accelerated approval: Doxil (doxorubicin liposome injection) for AIDS-related Kaposi sarcoma, Ontak (denileukin diftitox) for refractory CD25-expressing cutaneous T-cell lymphoma, Mylotarg (gemtuzumab ozogamicin) in relapsed CD33-positive acute myeloid leukemia, Depocyt (cytarabine liposome injection) for intrathecal treatment of lymphomatous meningitis, Celebrex (celecoxib) for prophylactic treatment of familial adenomatous polyposis, and CamPath (alemtuzumab) for refractory B-cell chronic lymphocytic leukemia.

All the studies are taking longer to complete than expected. Company researchers explained the types of problems that have faced, including difficulty accruing subjects from such small patient populations, the need to expand trials overseas, and finding endpoints that were both measurable and reflected clinical benefit.

Doxil received accelerated approval for use in AIDS-related Kaposi sarcoma in 1996 just as highly active antiretroviral therapy (HAART) was coming into widespread use. With HAART, rates of Kaposi sarcoma in AIDS patients dropped off from thousands of new cases a year to just about 300–350 patients now, lead researcher Wayne Rackoff, M.D., told the panel.

Not only has accrual been affected, but the original design of the study is making it difficult to prove clinical benefit, despite experience from the field that strongly supports findings of a substantial palliative effect in a disease that is often painful and disfiguring, he said.

Given that Doxil has proven safe in other indications, it may be enough to show that the drug can reduce the severity of lesions in patients who have no other chemotherapeutic options, said Michael Perry, M.D., director of the hematology–medical oncology division at the University of Missouri.

"This is not a home-run drug, but we are treating very symptomatic patients," he said.

Ligand researchers have faced similar problems in their postmarketing study of denileukin diftitox, said Andres Negro-Vilar, M.D., Ph.D., executive vice president of research and development at Ligand Pharmaceuticals.

In their attempt to conduct a relatively large trial in cutaneous T-cell lymphoma patients, the researchers enrolled patients at study sites all over the world.

"We realized it would be difficult to maintain active sites in the U.S.," he said.

As the study progressed, all of the U.S. sites dropped out, while new ones were eventually added in South America and Eastern Europe.

Studying drugs exclusively overseas may foster the misperception that studies that ethically can't be done here are still OK to test in foreign countries, said David Kelsen, M.D., chief of gastrointestinal oncology services at Memorial Sloan-Kettering Cancer Center in New York.

These deadly diseases can also present a conundrum in deciding what constitutes effectiveness, as in the case of celecoxib for FAP, a rare genetic disorder that is currently treated with prophylactic colon resection.

Although studies in teenagers with the disease show that celecoxib reduces the number of colon polyps, it's unclear whether the FDA would consider that endpoint as a clinical benefit, said Craig Eagle, M.D., oncology research director for celecoxib maker Pfizer.

Good Effort

Despite these problems, the panel gave the companies an "A" for effort.

"We saw companies that really are trying hard, doing the right things, are really learning a lot of good lessons here, and are moving in the right direction," said Bruce Cheson, M.D., head of hematology at Georgetown University's Lombardi Comprehensive Cancer Center in Washington, D.C.

That conclusion compares favorably with what ODAC saw just a couple of years ago, said Donna Przepiorka, M.D., Ph.D., professor of medicine at the University of Tennessee in Memphis.

"I was struck by the presentations today in comparison to the presentations in 2002. In the previous presentations, there was a lot of foolishness and foot-dragging on the part of the pharmaceutical industry, which was definitely not the case here," she said.

Given the difficulty of completing trials, ODAC members said they may not be as quick to recommend approval of drugs under the accelerated mechanism in the future.

"There are drugs for which there was more emotion than anything else pushing them through the system. I would like to put a plea in for putting our heads before our hearts," said Cheson.

It's harder to pull drugs off the market than to keep them off until more data are available, the experts said.

"Speaking for the committee, our concern is, does the FDA have the guts to take the drugs off the market for something other than toxicity? That really is the issue here," said Martino.

When a drug does receive accelerated approval, there need to be better assurances that postmarketing studies will be completed, the panel said.

"Everybody puts a lot of work into this, particularly the FDA and the companies, and it's a shame when resources are wasted. But the worst resource to waste is a patient going on a clinical trial that never gets completed," said Cheson.



             
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