Call for congressional hearing on Provenge approval process re-ignites FDA conflict-of-interest controversy

January 1, 2008

A call for a congressional hearing has put the FDA drug approval process under scrutiny for possible conflict-of-interest vio-lations.

A call for a congressional hearing has put the FDA drug approval process under scrutiny for possible conflict-of-interest vio-lations. In a letter sent to House Energy and Commerce Committee Chairman John Dingell (D-Mich), congressmen Dan Burton (R-Ind), Mike Michaud (R-Maine), and Tim Ryan (D-Ohio) said, "There is reason to believe that serious ethics rules were violated by two FDA advisory panel members in their decision, and that these decisions played a role in the subsequent decision not to approve Provenge."

Provenge, Dendreon's sipuleucel-T vaccine for treatment of metastatic prostate cancer, was denied FDA approval last year because of lack of data showing improved overall survival.

The Provenge issue was originally pursued by the advocacy group CaretoLive, in a federal lawsuit against FDA commissioner Andrew C. von Eschenbach, MD; Richard Pazdur, MD, head of FDA's Office of Oncologic Drugs; and panel member Howard Scher, MD, chief of the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center.

The lawsuit cited the three for their alleged "improper conduct...and inappropriate actions," among other alleged activities having to do with the decision not to approve Provenge.

However, some leading oncologists say these strong allegations levied against FDA and its advisory panels are driven more by self-interest and passion than by scientific reason.

Defenders of the advisory panel system point out that FDA seeks out the nation's leading experts, and, for good reason, these experts are often the same people sought by pharmaceutical companies as advisors.

"The potential inquiry is very disappointing to me as I think that the physicians on the advisory panel were trying to do the right thing and are being hammered for it. They simply were addressing the results of the study that were presented. I would like to know who sponsored this inquiry and what their conflicts of interests are." Derek Raghavan, MD, PHD, director of the Taussig Cancer Center, told Oncology News International.

Expert panels under fire

Although the well-publicized drama following the FDA denial of Provenge served as the flashpoint for this latest attack on FDA advisory panels, critics have long contended that conflicts are clearly avoidable.

In an interview with ONI, Harold J. Burstein, MD, PHD, of Dana-Farber Cancer Institute, said the suggestion that there is "no one" without ties to industry suitable for a review panel is troubling.

"It's is a sad commentary on our so-called experts that so many are tainted by relationships with industry. Patients and clinicians, along with FDA and third-party payers, should expect more from those given responsibility for developing standards of therapy for cancer patients," Dr. Burstein said.

He added that "there are, of course, many experts without conflicts of interest who would be more than capable of joining advisory panels."

Over the past several years, there have been numerous reports criticizing FDA's dependence on advisory panels. For instance, in October 2007, the Eastern Research Group, Inc. (ERG) filed its report to the FDA-Measuring Conflicts of Interest and Expertise on FDA Advisory Committees-in which the researchers found "substantial conflicts of interest for many members of FDA's advisory committees."

Ezekiel J. Emanuel, MD, PHD, chair of the Department of Bioethics at The Clinical Center of the National Institutes of Health, told ONI that FDA drug reviews must retain public trust, and if conflict of interest is influencing or is seen to influence reviews, it will undermine public trust.

Although Dr. Emanuel stressed that there are problems with the approval process, he said, "We need to be sure that we do not attack decision-makers just because we don't like the decision."

How much disclosure is necessary?

In the letter calling for an ethics hearing, the three congressmen concluded that prostate cancer activists have raised serious questions about two academic medical oncologists who voted against Provenge on an FDA panel in March- Maha Hussain, MD, professor of internal medicine, University of Michigan Medical School, and Dr. Scher.

According to the letter, Dr. Scher was a lead investigator for a competing prostate cancer drug in development by Novacea Inc., and is listed as an advisor to a large venture-capital firm that is also a major investor in Novacea.

FDA contends that it screens advisory committee members in relation to an upcoming drug or biologic product advisory committee meeting for conflicts of interest by requiring disclosure of the member's "current and past involvement in matters involving the product at issue, competing products, or matters involving other 'affected firms' as determined by FDA."

For example, if an advisor's duties as a member of a scientific advisory board included "providing advice to that firm on the product or competing product, he or she should report it," FDA said. If the duties did not involve such advice, FDA said the advisor would not be required to report the financial relationship with the firm.

Critics of FDA point out that whether or not Dr. Scher disclosed his potential conflicts of interest, the fact that he was a lead investigator in a clinical trial of a competing prostate cancer drug should certainly have been reason enough to exclude him from the FDA-appointed advisory panel.

When asked to comment on this issue a spokesperson for Dr. Scher replied, "Your question is really a matter for the FDA. As you may know, Dr. Scher was asked to participate in an FDA advisory panel. Dr. Scher disclosed all pertinent information that was required by and consistent with FDA conflict of interest guidelines."