Dendreon: The FDA's Commissioner Doth Protest Too Much!

| About: Dendreon Corporation (DNDN)
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In his latest The FDA this Week: Andy's Take: FDA Advisory Committees: A High Priority, April 18, 2008, FDA Commissioner Andrew von Eschenbach, MD, had the following to say:

Many of you may not be aware of the great lengths we at the FDA go to to (sic) ensure the integrity of our advisory committees—to assure that we get good information and advice. FDA carefully scrutinizes each committee member for potential conflicts of interest—we review who they work for, any contract work they’ve done, and even any investments and stock they or their family members hold. We weigh the potential for those financial holdings to bias their participation with the need for their expertise and determine whether they should participate, and issue a waiver if appropriate. When a waiver is granted, we then share this information publicly so that others know what conflict might exist.

Given the revelations surrounding the multiple conflicts of interest (COIs) that have come to light in the wake of the scandal involving certain members of the Provenge Advisory Committee meeting of March 29, 2007, one is apt to ask: Where was the commissioner back in early 2007, when the rules governing COI that now are in force were being considered for implementation?! It was clear to many, including Steve Usdin, Washington Editor of BioCentury, The Bernstein Report on BioBusiness, that certain members of the forthcoming Provenge Advisory Committee would not qualify for participation under the new rules. Writing in the March 26, 2007 edition, he said:

When FDA’s Cellular, Tissue and Gene Therapies Advisory Committee meets this week to discuss whether the agency should approve the first cancer vaccine, a product that could establish proof of principle for an important new therapeutic class, several of the votes will be cast by internationally respected experts who were invited to join the committee on an ad hoc basis because of their specific expertise.

The picture might look quite different if FDA’s new draft guidance for determining conflict of interest and eligibility for participation on its advisory committees were in force. Under the proposed policies, three of the invited experts probably would be ineligible to vote on Provenge sipuleucel-T from Dendreon Corp. (DNDN, Seattle, Wash.).

And two might be completely barred from participating in the discussions.

In particular, running test cases for the new rules on three Advisory Committee members, he concluded the following:

Dr. Maha Hussain: “The waiver notes that Hussain is the principal investigator on a research contract awarded by a competing company for a product that is not related to Provenge. Under the draft guidance this probably would not be considered a conflict. However, the fact that her husband owns stock in three competing companies, valued at $15,000-$300,000, would at minimum prevent her from voting. If the total value of the stock exceeds $50,000, Hussain wouldn’t even be at the table if the new policy were in effect.”

Dr. Howard Scher: “Under the draft guidance, Scher either would be prevented from voting or excluded from the meeting.

“He owns stock in a firm that competes with DNDN valued at $5,000-$100,000. In addition, Memorial Sloan-Kettering has a grant from a competing company valued at $100,000-$300,000 to study a licensed, approved drug in prostate cancer trials.”

Dr. Savio Lau-Ching Woo: “One standing member of the committee, Savio Lau-Ching Woo, was also granted a waiver for the Provenge meeting. Woo, professor of gene and cell medicine at Mount Sinai School of Medicine, reported that an affected company has licensed a gene therapy technology he invented. It is being studied in prostate and other cancers.

“Although Woo has received less than $15,000 from the patent license in the last 12 months, he would be prohibited from voting if the draft guidance were in effect.”

All three of the Advisory Committee members cited above voted YES on the first question (regarding Safety; the vote was 17-0 in favor of the drug being safe), and NO on the second question (regarding the drug evidencing “Substantial Efficacy,” the federal standard (the vote was 13-4 in favor of the drug evidencing substantial efficacy)).

Importantly, two of the Advisory Committee members above, Drs. Scher and Hussain, went on to write letters to the FDA, disparaging Provenge and calling for non-approval of the immunotherapy…letters that were leaked immediately upon their receipt at the agency (if not before) to the non-peer-reviewed The Cancer Letter. Who asked Dr. Scher to write his letter and what part was played by personnel at the FDA and NCI in helping Dr. Scher write his letter? (A draft of Dr. Scher’s letter (version 3) was found on the computer of a researcher at the National Cancer Institute [NCI] and at least one other NCI researcher attended a meeting at the FDA to discuss the development of Dr. Scher’s letter.) These questions never have been answered by the FDA or NCI. Nor has the person or persons responsible for leaking the letters written by Drs. Scher and Hussain (as well as a third letter written to the FDA by Dr. Thomas Fleming) to The Cancer Letter ever been identified and prosecuted.

Also problematic is this statement made in Dr. von Eschenbach’s latest “Fireside Chat”: Each year the US Food and Drug Administration expends considerable resources convening over 60 advisory committee meetings. This is part of our commitment to engage a wide range of scientific expertise to inform our regulatory decision making process. This is the right thing to do for we must keep up-to-date with the rapidly-changing world of science related to the products we regulate. [emphasis added]

The majority of those on the Provenge Advisory Committee were immunologists…they were the ones who were “…most up-to-date with the rapidly-changing world of science related…” to Provenge and immunotherapy. Contrary to Dr. von Eschenbach’s assertion above, however, the FDA did not listen to these experts. Instead, for reasons known only to those within the FDA, the agency, in the case of Provenge, let itself by swayed by the minority. If you want proof of that statement, the FDA admitted as much in an e-mail the agency sent to Mr. Stephen D. Study after he questioned it, on behalf of his father (who passed away from prostate cancer on March 27, 2008, almost one year to the day from the date of Provenge Advisory Committee meeting) when the FDA refused to approve Provenge on May 8, 2007. Here's that text of that e-mail:

To Stephen D. Study:

Thank you for your recent email to FDA’s Center for Biologics Evaluation and Research [CBER] regarding Provenge. CBER is one of six centers within FDA, responsible for the regulation of biologically-derived products, including blood intended for transfusion, blood components and derivatives, vaccines, allergenic extracts, tissue, and cell and gene therapy products.

I share with you the goal of safe and effective treatment choices for all cancer patients and FDA does this in the context of being a science-based regulatory agency whose mission is to both promote and protect the public health. In reviewing marketing applications for new medical products, our medical and scientific experts objectively evaluate all the data submitted and base their decisions on the available scientific evidence. Often we call upon independent outside experts for their advice. In this instance, we sought the advice of an FDA advisory committee. The majority of the advisory committee members indicated that the data submitted for Provenge supported its effectiveness; however, several members expressed significant concerns about the strength of these data. FDA factored the advisory committee discussions into its decision regarding this application. As noted by Dendreon, the manufacturer of Provenge, FDA determined that additional scientific data is required before a definitive decision can be made. The public and patients we serve deserve such a rigorous and disciplined effort to both protect and promote their health. FDA is committed to working with Dendreon to quickly obtain and review new information as it becomes available. [emphasis added]

You can contact Dendreon directly for any clinical trials using Provenge [].

Patricia H. Harley
Consumer Safety Officer
Food and Drug Administration
Center for Biologics Evaluation and Research
Office of Communication, Training and Manufacturers Assistance
Division of Communication and Consumer Affairs

It often is said that the true measure of a person (or in this case, an agency) is how they behave when the “policeman” is not around. Dr. von Eschenbach and the personnel involved in the submittal, review, and approval of waivers for Drs. Scher, Hussain, and Woo, among others, knew well the COI rules that were being considered at the time. In good conscience, they should have refused to approve all three of these waiver requests. That they did not speaks volumes regarding the bankrupt ethics of the Federal agency charged with the health and welfare of the American People. Unfortunately, more than 28,000 men with prostate cancer, many of whom could have been helped by Provenge, have paid the ultimate price for the FDA’s incompetence since the agency sent Dendreon a “Complete Response” (“Approvable”) on May 8, 2007.

In many other countries of the world, given the FDA’s handling of the Provenge application described above, a person in Dr. von Eschenbach’s position would have resigned in disgrace long ago.

Disclosure: The writer owns shares of Dendreon (NASDAQ:DNDN).