Controversy is a fact of life for pharmaceutical companies and the Food and Drug Administration but the saga of an investigative immunotherapeutic agent for advanced prostate cancer has been unusually contentious.

The struggle to gain FDA approval for sipuleucel-T, to be marketed as Provenge by Dendreon Corp., has included a raucous FDA meeting, picketing in Washington, congressional lobbying, and a lawsuit.

A final decision about whether to approve the drug now awaits interim findings from a 500-patient phase III trial, but in the meantime, the dispute has ignited activism reminiscent of the efforts to get HIV drugs “fast tracked” in the 1980s.

The dispute has raised questions about whether biologic agents can be judged by the same efficacy standards as traditional drugs, particularly when the goal is to treat terminal patients with few alternatives.

It has also generated concern in some scientists about the increasing influence of “antiscience” voices in American life. And finally, it has highlighted media pressure on the scientific community to justify established principles guiding medical policy decisions in the face of tearful families and angry investor campaigns.

It began March 29, when officials of the Seattle-based biotech firm presented to the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee the results of two fast-tracked, phase III parallel studies of their biologic agent in a total of 225 men with asymptomatic, hormone-refractory, metastatic prostate cancer.

Sipuleucel-T would be the first oncologic drug in a new class, designed to stimulate a patient's immune system with a “vaccine” made from his own peripheral blood mononuclear cells, including antigen-presenting cells. The cells would be extracted by plasmapheresis and flown to a centralized laboratory, where they are activated with a recombinant fusion protein containing prostate antigen fused to GM-CSF, an immune cell activator. Within 3 days of collection, the cells are reinfused into the patient in an outpatient procedure.

After the March meeting, at least two committee members, oncologist Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and Dr. Maha Hussain, professor of internal medicine and urology at the University of Michigan, Ann Arbor, wrote to the FDA to express concern about the implications of approving the drug based on the evidence. The letters were leaked and reprinted, first in The Cancer Letter, then online.

Dr. Scher said inconsistent trial data “do not constitute 'proof' of benefit or justify a conclusion that they are 'reasonably likely' to predict benefit. … The only conclusion is that the survival difference observed may have occurred by chance alone.”

The company had argued that the survival results were “clinically meaningful, significantly persuasive, and internally consistent in the intent-to-treat population.”

A 4.5-month survival benefit from a drug with few side effects is urgently needed by prostate cancer patients, who now gain only about a 2-month survival advantage from docetaxel (Taxotere), a drug with side effects that many patients find debilitating.

On May 9, the FDA rejected the committee suggestion to approve sipuleucel-T, requesting more data from Dendreon.

The decision sparked a debate about whether the FDA's restraint represented a scientifically valid concern about the efficacy of a treatment that failed to pass muster in clinical trials, or a risk-averse philosophy depriving patients of treatments that offer them their only hope of prolonged survival.

Within the month, Dr. David Penson of the University of Southern California, Los Angeles, presided over a press briefing at the annual meeting of the American Urological Association marked by frustration about the decision. He listed three reasons the FDA might reject a recommendation to approve a drug: safety, efficacy, and politics. “[We] were really hoping this would be approved, because these patients have so few other options,” he said.

After the July 30 filing of a federal lawsuit by Care to Live, an Ohio nonprofit organization seeking an emergency injunction that would make the drug available to cancer patients, an FDA spokeswoman said the agency could no longer comment on the issue. A U.S. Court of Appeals, District of Columbia Circuit, in early August ruled that patients do not have a constitutional right to unapproved drugs, in a suit brought by the Abigail Alliance for Better Access to Developmental Drugs. The Alliance has vowed to appeal.

Dendreon announced that the FDA had decided to accept either a positive interim or final analysis of survival from its ongoing, phase III, 500-patient IMPACT study as the basis for amending the Biologics License Application that was filed on a fast-track basis in early 2007, possibly paving the way for approval as soon as 2008.

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Activists demand FDA approval of Provenge during a Sept. 18 protest in front of the agency's offices in Rockville, Md. Sheri Mattes/Elsevier Global Medical News

Tempers Flare Over Fate of Prostate Cancer Drug