FDA's drug approval process is caught in crossfire

In March, the FDA's Cellular, Tissue and Gene Therapies Advisory Committee endorsed approval of Dendreon's sipuleucel-T vaccine (Provenge) for treating men with metastatic prostate cancer. The committee voted 17-0 that the agent is safe, and 13-4 that it is effective.

However, neither of the two small studies presented by Dendreon in support of approval met the primary endpoint of progression-free survival, and overall survival was significant only in post hoc and combined analyses.

At least one dissenter said that approval should be delayed until Dendreon completes its phase III IMPACT study of Provenge in men with hormone-refractory prostate cancer, to answer lingering questions about the drug's ability to improve overall survival.

Two months later, counter to its advisory committee's recommendation, FDA denied approval of the vaccine, citing a need for more data on overall survival. FDA has agreed with Dendreon to accept either a positive interim or final analysis of survival from the IMPACT study to complete the licensure of the agent.

The denial of approval for Provenge set off strident protests from advocates who believe the drug should have been approved based on the available data. These advocates' voices were joined by others, including the Abigail Alliance for Better Access to Developmental Drugs, who think that terminally ill patients should have access to investigational drugs after phase I trials have shown safety. In September, the advocacy groups held a small, staged protest outside of FDA's Rockville, Maryland, offices (see photographs of the protest below, courtesy of Leslie Mulkey).

The mainstream press got into the fray, with pieces such as the Wall Street Journal Op-Ed "The FDA's deadly track record" [WSJ.com 08/14/07], in which representatives from the Abigail Alliance excoriated the FDA, claiming that Provenge was "kept away from prostate cancer sufferers because of a small but aggressive club of FDA advisors hand-picked by the director of the agency's Office of Oncology Drugs who thinks the statistics are not yet perfect enough."

The advocacy group, A Right to Live, which led the protest outside the FDA offices, insists that Provenge met the statutory requirements for immediate FDA approval.

Is a change in policy needed?

In a recent public statement, FDA commissioner Andrew von Eschenbach, MD, said, "The agency is rethinking how and when it calls upon expert panels, and which scientists are selected to participate."

For those who see bureaucracy as the culprit, the problem started in the mid-1980s when the FDA tightened its regulatory policies to ensure the safety and efficacy of drugs that made their way into the public domain. Critics of FDA's approach think that the Office of Oncology Drug Products, which was established, in part, to raise the bar for drug approval, is part of the problem.

"The creation of the new division did not address the most compelling issue, which is one of policy," Philip S. Schein, MD, told ONI. Dr. Schein, who is a past ASCO president and ODAC chair, believes that the process of evaluating safety and efficacy and how we bring drugs to market needs to be reevaluated. In his view, benefits derived from approval of promising cancer therapies based on early efficacy data outweigh potential risks, especially for patients with advanced disease and limited therapeutic options.

"This could be accomplished through a more liberal application of the accelerated approval mechanism, or adoption of the approach the Europeans have recently taken with their new Conditional Marketing Authorization procedure," Dr. Schein said.

He explained that the European Medicines Agency has recognized that patients with life-threatening diseases, such as cancer, have expectations that potentially important new treatments will not be delayed by an overly cumbersome regulatory review process, and that advances in science might provide measures for an early assessment of efficacy.

The Conditional Marketing Authorization process allows approval of a new therapy for a 1-year period, renewable annually, when data demonstrate a positive benefit-to-risk balance. The drug sponsor is assigned specific obligations to be carried out post-conditional approval, which are directed to the provision of comprehensive data relating to safety and efficacy.

Dr. Schein stressed that accelerated assessment, if suitably applied, carries the prospect of better aligning the critical needs of the cancer patient with the requirements of a regulatory agency.

He mentioned that a scientific discovery is not meaningful to patients and their families unless it makes its way through trials to the public in the form of an approved therapy in a timely manner.

"The process of clinical trials itself does not fulfill that requirement. Only FDA approval and establishing a drug's true value in clinical practice does," he said.