Washington Editor

WASHINGTON - Companies required to conduct postmarketing studies should expect to find themselves under closer scrutiny by the FDA and the public as the government begins tracking progress on such trials in the Federal Register.

In compliance with the FDA Modernization Act of 1997, the FDA is mandated to publicly post updates for products cleared under accelerated approval guidelines as well as those cleared via the normal regulatory process with a voluntary or agency-requested postmarketing commitment.

The FDA has begun listing the status of such commitments in the Federal Register report and on its website at www.fda.gov/cder/pmc. The site will be updated each July, October, January and April.

The apparent need for such policing has grown out of the snail's pace in completing the trials combined with the agency's failure to enforce rules around the requirements.

Indeed, in mid-March, the FDA's Oncologic Drugs Advisory Committee summoned several companies saddled with postmarketing commitments to provide updates and explanations as to why those studies often were taking a decade to complete. (See BioWorld Today, March 14, 2003, and March 13, 2003.)

Officials from various companies said it is difficult to get researchers and patients interested in Phase IV studies.

For example, 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. He 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.

James Pluda, representing Gaithersburg, Md.-based MedImmune Inc., told the panel it probably would take the company six or more years to finish a postmarketing study on Ethyol (amifostine) because an adequate patient count would be 1,150 (2,000 if survival is the endpoint), and that number is not easy to accrue. Ethyol is used for reduction in cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced non-small-cell lung cancer and for moderate to severe dry mouth or xerostomia in postoperative patients undergoing radiation treatment for head and neck cancer. (See BioWorld Today, June 9, 1999, and Sept. 23, 1999.)

Both Ethyol and Ontak were approved under Subpart H, which was added to the new drug application regulations in 1992, and allows accelerated approval in 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 for which the new drug appears to provide benefit over available therapy. (Accelerated approval typically is granted on single-arm trials.)

The FDA has the discretion to require a postmarketing study (either a new trial or completion of an ongoing trial; the regulations state that postmarketing studies usually would be under way) to demonstrate that treatment with the drug is associated with clinical benefit.

But under regular approval, the FDA may request a postmarketing study to develop information that is important for improving the use of the product, product quality, or consistency in product manufacturing, according to the agency.

At the ODAC meeting, Richard Pazdur, director of the FDA's Division of Oncology Drug Products, Center for Drug Evaluation and Research, said the agency has not been "dogmatic" in forcing companies to abide by deadlines and guidelines related to confirmatory studies.

That's clearly true, considering statistics provided by the agency Thursday.

Of required postmarketing biological studies, 67 (30 percent) have not started; 102 (46 percent) are ongoing; 17 (8 percent) are delayed; two (1 percent) have been terminated without a final study report; and 35 (16 percent) have either been completed or terminated, the FDA said.

Of required postmarketing drugs studies, 820 (61 percent) have not been initiated; 285 (21 percent) are ongoing; 25 (2 percent) are delayed; eight (1 percent) have been terminated before completion but the manufacturers have not submitted a final study report; and 201 (15 percent) have either been completed or stopped, the FDA said.

Manufacturers also are required to submit annual status reports on study commitments for approved drugs and certain biologics. According to the FDA, in drugs, 289 (22 percent) of reports are overdue; in biologics, 77 (35 percent) of reports are overdue.

On the positive side, the Federal Register includes a list of 349 completed postmarketing commitments for drugs and 52 for biologics. Two hundred forty (69 percent) of the drug studies and 47 (90 percent) of the biological studies met the commitments.

If a confirmatory study fails, the FDA has the option of pulling the product from the market or working with the company to design another trial.

In a House Energy and Commerce Committee meeting last year, Janet Woodcock, CDER's director, said she could not recall a time when a product was pulled from the market because of a company's failure to complete a Phase IV study. (See BioWorld Today, Aug. 22, 2002.)

The FDA does not have that kind of authority, an attorney told BioWorld Today.