Washington Editor

BETHESDA, Md. - A senior FDA official said the agency hasn't been dogmatic in forcing companies to abide by deadlines and guidelines related to confirmatory studies following accelerated approval of a drug or biologic. But a series of missteps over the past 10 years has prompted the agency to take a look at the accelerated approval process in order to find ways of improving it.

The agency's Oncologic Drugs Advisory Committee (ODAC) on Wednesday began a two-day meeting to discuss the matter and to hear brief presentations by several companies in the process of conducting these post-marketing studies.

"Accelerated approval does not end with approval of the drug," Richard Pazdur, director of the FDA's Division of Oncology Drug Products, Center for Drug Evaluation and Research, told panel members. "We have not insisted that post-marketing studies be under way before approval because we didn't want to deny access to the drug. There needs to be strategies in place for confirmatory studies and we need potential alternatives if the first confirmatory study fails. And this needs to be an integral part of the process."

At issue is Subpart H, which was added to the new drug application regulations in 1992, allowing "accelerated approval" for diseases that are serious or life threatening. Under the regulations, accelerated approval may be granted on the basis of a surrogate endpoint that is "reasonably likely" to predict clinical benefit in indications where the new drug appears to provide benefit over available therapy. (Accelerated approval is typically granted on single-arm trials.)

However, after approval, the FDA has the discretion to require a post-marketing study (either a new trial or completion of an ongoing trial; the regulations state that post-marketing studies would usually be studies under way) to demonstrate that treatment with the drug is indeed associated with clinical benefit.

Such a task is time consuming, costly and often difficult, according to FDA officials and company representatives who have navigated those waters.

Illustrating the point, Gordon Bray, senior medical director of clinical research at San Diego-based Ligand Pharmaceuticals Inc., briefed ODAC on confirmatory commitments for Ontak (denileukin diftitox), a fusion therapy for the treatment of persistent or recurrent cutaneous T-cell lymphoma. Seragen Inc., a wholly owned subsidiary of Ligand, received approval for Ontak in 1999. Since then, Ligand has taken over all development responsibility, Bray said.

At the time of approval, 73 patients had been accrued in the follow-up. Since then, 105 of the 195 needed patients have been accrued. Bray expects the company to hit its targeted completion date of 2006. (The study was halted at one point while the agency and company negotiated increasing enrollment from 120 to 195.)

And there were other stumbling blocks associated with the trials, Bray said. Patients often decline to participate in placebo studies because of symptoms associated with the disease and investigators are reluctant because the patients are usually late stage.

Indeed, MedImmune Oncology Inc., of Gaithersburg, Md., is facing accrual problems similar to those experienced by Ligand.

The drug in question is Ethyol (amifostine), acquired by MedImmune in 1999 via its purchase of U.S. Bioscience Inc. Ethyol is approved for reduction in cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced non-small-cell lung cancer (NSCLC) and for moderate to severe dry mouth or xerostomia in post-operative patients undergoing radiation treatment for head and neck cancer. (See BioWorld Today, June 9, 1999, and Sept. 23, 1999.)

But it's the first indication that commands post-marketing commitments. James Pluda, of MedImmune, told the panel the main problem in finishing the trial (likely to take six and one-half years) is accruing patients - the necessary study would require 1,150 patients (more than 2,000 if survival is the endpoint) to fulfill the accelerated approval challenges.

"It would be helpful if ODAC can suggest any alternative solutions for approaches to the completion of the application for NSCLC," Pluda said.

Otis Brawley, panel member and associate director for cancer control and professor at Emory University School of Medicine in Atlanta, wondered about the ethics of post-marketing trials.

"Some are taking 10 to 12 years and the idea of accelerated approval was to get the drugs approved early and these [confirmatory trials] are competing with pivotal trials that tell us more," Brawley said. "I would say most doctors and other people don't know the difference between accelerated approval and regular approval, but talk about a conflict of interest - you can either sell the drug or put someone in a trial and give it to them for free."

And in another instance of post-marketing commitments, Steven Hamburger, representing Johnson & Johnson Pharmaceutical Research & Development LLC, of Raritan, N.J., discussed Phase IV commitments associated with Doxil (doxorubicin HCI liposome injection), in the treatment of chemotherapy-refractory AIDS-related Kaposi's sarcoma. The FDA issued Doxil accelerated approval in December 1995, and subsequently, the company initiated a Phase IV commitment trial.

The FDA was unable to interpret clinical benefits in the Phase IV due to the introduction of highly active antiretroviral therapy for the treatment of HIV in the trial, resulting in a non-approvable letter on the supplement, Hamburger said. Hamburger said the company had difficultly conducting a randomized trial because of the availability of Doxil in the marketplace.

J&J and the agency are negotiating another design.

So how does the FDA respond to failure to prove efficacy in the randomized trial or failure to complete the trial? Pazdur said the agency continues to work with the company.

"If you fail, we may start the process to remove the drug," Pazdur said. "But this is not necessarily a knee-jerk reaction."

When asked how many products have been pulled following failure on accelerated approval, Pazdur said he wasn't sure of any in the oncology and HIV/AIDS fields, but added, "We want alternative plans in the event of a failure."

From 1992 to 2002, 19 treatment indications for anticancer drugs or biologics have been granted under Subpart H. Of these, four have been subsequently converted to full approval.