Surgery News - October 2007 - (Page 4)

NEWS SURGERY NEWS • O C T O B E R 2 0 0 7 Furor Erupts Over Fate of Prostate Cancer Drug A final decision about whether to approve Provenge awaits interim findings from a phase III trial. B Y B E T S Y B AT E S Else vier Global Medical Ne ws ontroversy is a fact of life for pharmaceutical companies and the Food and Drug Administration, but the ongoing 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 been marked by a raucous FDA meeting, picketing in Washington, congressional lobbying, a federal lawsuit, conspiracy theories, conflict of interest allegations, death threats against scientists, investor fury, scientists’ indignation, and the employment of bodyguards at a major cancer meeting. 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 Provenge controversy has ignited activism among prostate cancer patients, their families, and investors that is reminiscent of the highly charged battles 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 who have few alternatives. It has generated concern by some scientists about the increasing influence of “antiscience” voices in American life, from the highest reaches of government to physician-patient bedside deliberations. 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 organized at lightning speed over the Internet. The controversy 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 customized “vaccine” made from his own peripheral blood mononuclear cells, including antigen-presenting cells. Extracted by plasmapheresis, the cells are 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 after collection, the stimulated cells are reinfused into the patient in an outpatient procedure. Following the March FDA committee meeting, at least two committee members, Dr. Howard I. Scher, an oncologist at Memorial Sloan-Kettering Cancer Center in New York, and Dr. Maha Hussain, pro- fessor of internal medicine and urology at the University of Michigan, Ann Arbor, sent letters to the FDA to express their concern about the implications of approving the drug based on the evidence. The letters were leaked and widely reprinted, first in The Cancer Letter and then online. Dr. Scher’s letter stated that inconsistent trial data “do not constitute ‘proof ’ of benefit or justify a conclusion that they are ‘reasonably likely’ to predict benefit. Consequently, the only conclusion that can be reached 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 position that Greg Schiffman, chief financial officer for Dendreon, reiterated in an interview. Years ago, when the small phase III trials were designed, using time to progression as a surrogate for survival was “pretty typical,” Mr. Schiffman said. Research has since shown that survival is a better benchmark, and it is the primary end point in Dendreon’s larger Activists demand FDA approval of Provenge during a protest phase III trial, he in front of the agency’s offices in Rockville, Md. explained. At the FDA committee meeting, Dr. probably works, is clearly safe, and doesn’t Mark Frohlich, vice president of clinical af- detract from quality of life. These pafairs for Dendreon, said that survival is the tients are desperate. They are very excit“least biased, least variable, and most clin- ed that a drug may extend their lives 3-4 ically meaningful” end point, and on that months with minimal side effects. Dr. Mark Thornton, writing in the Wall measure, sipuleucel-T succeeded, the Street Journal on May 14, accused comcompany maintained. A 4.5-month survival benefit from a mittee members of “kneeling before the drug with few side effects is urgently need- altar of statistics” in failing to recommend ed by prostate cancer patients, who now approval of Provenge or another investigain only about a 2-month survival ad- gational drug, Junovan, an immunothervantage from docetaxel (Taxotere), a drug apeutic treatment for osteosarcoma. “In the span of 8 hours, the dawn of a with side effects that many patients find debilitating, advocates and company ex- new era in cancer immunotherapy was driven back into the night,” said Dr. perts emphasized. On May 9, a day dubbed “Black Wednes- Thornton, former medical officer for the day” in an opinion piece in the Wall Street FDA’s Office of Oncology Products, senior Journal, the FDA rejected the committee vice president for the biopharmaceutical recommendation to approve sipuleucel-T corporation GenVec, and an adviser to the and requested more data from Dendreon. advocacy group Abigail Alliance for Better The decision sparked a debate in the on- Access to Developmental Drugs. Quickly, other established advocacy cology community and beyond about whether the FDA’s restraint represented a groups such as the Prostate Cancer Rescientifically valid concern about the effi- search Institute became involved in the cacy of a treatment that failed to pass quest for approval. “Provenge was a little bit different for muster in clinical trials, or a risk-averse philosophy depriving desperate patients of us,” PCRI spokesperson Jan Manarite said treatments that offer them their only hope in an interview. “It was a different type of drug, and the of prolonged survival. Within the month, Dr. David Penson of public outcry was huge. Overwhelming,” the University of Southern California, Los she said. Questions of efficacy and cost that arose Angeles, presided over a press briefing at the annual meeting of the American Uro- during the FDA panel meeting and after- logical Association marked by frustration about the FDA decision. Dr. Penson listed three reasons the FDA might reject an advisory committee’s recommendation to approve a drug: safety, efficacy, and politics. “No one’s arguing safety. It was 17-0,” he said. “Efficacy? The panel voted 13-4. Maybe it wasn’t a slam dunk, but it wasn’t close, either,” he said. He paused. “Politics I can’t comment on,” he said. “Urologists and medical oncologists were really hoping this would be approved, just because these patients have so few other options. We’re still left with this terrible problem, a man who has advanced prostate cancer, and a chemo regimen which, while it does extend quantity of life, it doesn’t help quality of life,” Dr. Penson said. Dr. Penson’s own review of the data would have convinced him to approve the drug, he said. “Here’s a treatment that ward “are all important concerns, but concerns that should never be more important than the individual,” she added. Outside the small circle of established patient advocacy groups, however, the dialogue soon turned vitriolic, especially within the anonymous confines of Internet chat rooms and blogs. A Dendreon investor’s much-visited MySpace page began playing Mozart’s Requiem I while displaying a cartoon of a grinning Grim Reaper carrying a scythe labeled “FDA.” An image of a mature antigen-presenting cell stands next to toppled cemetery crosses. Web sites erupted with accusations of conflict of interest aimed at committee members who had questioned whether the data justified approval of Provenge. Their photographs, and those of FDA administrators, were accompanied by inflammatory statements about their motives and character. The New York Times reported on June 3 that serious threats had been made against Dr. Scher and Dr. Hussain. Bodyguards appeared at the annual meeting of the American Society of Clinical Oncology (ASCO) in early June in Chicago, where both oncologists were due to speak. Nor was the press immune. Coverage of the controversy by The Cancer Letter, a weekly publication about academic, industry, and research news, generated an e-mail to editor Paul Goldberg expressing the wish that he and all male members of his staff be diagnosed with prostate cancer. “This is not the level of discourse you would hope people would be using in the discussion of whether a drug should be approved,” he said in an interview. Following 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 that the agency could no longer comment on the Provenge 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.) Meanwhile, 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 so

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Surgery News - October 2007

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