Washington Editor

BETHESDA, Md. - After a decade of clearing certain oncology drugs under accelerated approval guidelines, the FDA is asking companies to explain why it takes so long to successfully complete confirmatory efficacy studies.

Richard Pazdur, director of the FDA's Division of Oncology Drug Products at the Center for Drug Evaluation and Research, called a two-day meeting of the Oncologic Drugs Advisory Committee (ODAC) to take up the issue of lengthy confirmatory or post-marketing studies that often end in failure for reasons other than efficacy of the drug.

Accelerated approval drugs are cleared on a surrogate endpoint that is "reasonably likely" to predict clinical benefit. Such approval gives the agency authority to require confirmatory studies. (See BioWorld Today, March 13, 2003.)

A few ODAC members said the snail's pace of many post-marketing studies should be blamed on individual companies for failing to properly plan the trials and for having no motivation to complete them. "You've already approved the drug - it's on the market and the company is making money," said Silvana Martino, panel member and head of medical oncology at the John Wayne Cancer Institute at the St. John's Health Center in Santa Monica, Calif. "The common theme I've seen in the last two days is that companies don't have the same due diligence in post-marketing studies as they would if they were trying to get the drug on the market for the first time."

On the contrary, George Ohye, panel member and retired senior vice president for regulatory affairs at Johnson & Johnson in New Brunswick, N.J., said companies are committed to post-marketing studies because they have an obligation to patients and the FDA. "I haven't seen any company fail to act with due diligence," he said. "Why would they? They'll be dealing with the FDA for a long time in other drugs, so why wouldn't they do the trials?"

Others, including Stephen George, a panel member and professor of biostatistics at Duke University in Durham, N.C., said companies seeking accelerated approval should be required to submit a plan along with the application.

"I wouldn't approve an accelerated drug without a plan," he said. "If you're going to go for accelerated approval, then go for it - but it's not a second prize to regular approval."

The discussion surrounded Subpart H, which was added to the new drug application regulations in 1992, allowing accelerated approval for diseases that are serious or life threatening. The regulations generally apply to new drugs that appear to provide benefit over available therapy. Indeed, accelerated approval provides quick access to the newest drugs. (Accelerated approval is typically granted on single-arm trials.)

"Maybe we shouldn't call it accelerated approval - maybe conditional approval or premature approval," said Otis Brawley, panel member and associate director for cancer control and professor at Emory University School of Medicine in Atlanta. "I know one company that advertises for you to buy this hot, new drug because it went through the FDA on accelerated approval. That sounds like the drug is so good that it went through quickly."

When asked whether accelerated approval could be explained on labels, Pazdur responded that labels do carry a disclaimer, but "it may be lost on the vast majority of people. If you don't work with the FDA, you probably don't understand it."

The Challenge Of Post-Marketing Trials

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.

Clearly, companies run into a number of problems in all clinical trials. Take, for example, the situation with London-based SkyePharma Inc. and its injectable chemotherapeutic, DepoCyt.

SkyePharma representative Steven Howell, professor of medicine at UCLA, San Diego, on Thursday brought ODAC up to speed on post-marketing commitments for DepoCyt, a sustained-release formulation of cytarabine, for patients with lymphomatous meningitis - an orphan indication with 1,200 cases per year.

DepoCyt received accelerated approval April 1, 1999, based on data from a pivotal trial of 28 patients with lymphomatous meningitis supported by data from a Phase I trial (19 patients), two additional pharmacokinetic trials (11 and 13 patients), a randomized, prospective-controlled trial (61 patients) and a subsequent open-label trial (89 patients) in solid tumor neoplastic meningitis.

While SkyePharma, and then-partner Chiron Corp. of Emeryville, Calif., had every intention of initiating the Phase IV trial following approval, the companies hit a snag in October 1999 when it was discovered that batches of product failed to meet regulatory specifications. DepoCyt was pulled from the market and re-launched after a 16-month hiatus. (Enzon Pharmaceuticals Inc. of Bridgewater, N.J. now owns North American rights) (See BioWorld Today, March 5, 2001, and Jan. 3, 2003.)

The hiatus accounts for part of the slow Phase IV, but the other problems, Howell said, relate to issues common among companies trying to conduct confirmatory trials. Patient accrual due to competition with other trials and a reluctance to join a randomized trial are among the reasons, he said.

Nevertheless, Howell told the panel the current accrual rate is approximately 4.7 patients per month in the company's post-marketing study, compared to 2.6 patients per month it accrued in its pivotal trials for DepoCyt.