Dendreon: The Provenge Approval Scandal, One Year Later

| About: Dendreon Corporation (DNDN)

It all began so gloriously on February 9, 2007, when the Food and Drug Administration [FDA] and the National Cancer Institute [NCI] held their groundbreaking seminar on immunotherapies: Bringing Therapeutic Cancer Vaccines and Immunotherapies Through Development to Licensure. Hosted by Andrew C. von Eschenbach, M.D., who was sworn in as the 20th Commissioner of the U.S. Food and Drug Administration on December 13, 2006, the theme of the seminar was summed up (search on 'February 9, 2007') by Dr. von Eschenbach as follows:

Cancer vaccines and immunotherapy are ready to move beyond proof of concept studies, and we are ready to move them to the patients as safe and effective treatments for cancer. Therefore our primary focus over the next few days is to share our collective expertise and find solutions to the challenges of bringing cancer vaccines and immunotherapies through development to licensure.

The intent, simply put, was to find ways to develop therapies that stimulate a patient’s own immune system to fight cancers. Importantly, for an agency that frequently is viewed as a roadblock to the introduction of innovative, novel treatments for life-threatening diseases, Dr. von Eschenbach stressed that under his direction, the "FDA will be a bridge to the future, not a barrier."

As it turned out, Dr. von Eschenbach’s talk of the FDA being a “bridge to the future” was a cruel joke. Events almost exactly 3 months later would show his “bridge” to be nothing more than agency’s euphemism for Saint Benezet's bridge in Avignon, France…a bridge that only extends halfway across the Rhône.

Specifically, on Tuesday, May 8, 2007, despite a positive Provenge Advisory Committee [AC] meeting on March 29, 2007, which saw the AC members vote 17-0 that Provenge was “safe”, and 13-4 that the drug exhibited “substantial efficacy” (the federal standard), the agency issued Dendreon (NASDAQ:DNDN), the drug’s developer, a Complete Response (“Approvable”) letter.

Dendreon announced the FDA’s decision on the following day. The immunology world was stunned!

Wednesday, May 9, 2007, is now, in fact, referred to as Black Wednesday. It was so-named by Dr. Mark Thornton, a former medical officer in the FDA Office of Oncology Products who today volunteers as president of the Sarcoma Foundation of America.

In an op-ed piece for the Wall Street Journal published on May 14, 2007, he wrote:

May 9, 2007, should be cited in the annals of cancer immunotherapy as Black Wednesday. Within an eight-hour period that day, the FDA succeeded in killing not one but two safe, promising therapies designed and developed to act by stimulating a patient's immune system against cancer. The FDA's hubris will affect the lives and possibly the life spans of cancer patients from nearly every demographic, from elderly men with prostate cancer to young children with the rarest of bone cancers.

Thus it was remarkable that in the last several months two different biotech companies, with products utilizing two completely different cancer immune approaches, came before the FDA's Advisory Committee Meeting for judgment. The first product, Provenge, made by the Dendreon company, is a cellular therapy that tackles prostate cancer. The results of the Provenge clinical trial in men with prostate cancer who had failed all other therapies appeared before the committee that advises on cell-based cancer products for the FDA Center for Biologics. This committee was comprised of immunology and oncology experts… [The second product discussed, Junovan, is made by the IDM company.]

In the span of eight hours, the dawn of a new era in cancer immunotherapy was driven back into the night. It will be years before we know the full impact of these decisions and how many cancer patients, young and old, have had their lives cut short as a result. For now, however, one thing is clear: While our lawmakers obsess over FDA "safety reforms," no one is holding this government agency accountable for its complicity in stalling therapies for life-threatening diseases.

Two points are worth emphasizing:

  1. Since the FDA sent Dendreon its Complete Response letter, more than 30,000 men have died of prostate cancer. Many of those could have been helped by Provenge; and
  2. To reiterate Dr. Thorton’s conclusion: “no one is holding this government agency accountable for its complicity in stalling therapies for life-threatening diseases.”

Indeed, over the last year, despite (1) a lawsuit filed against the FDA, Dr. Andrew von Eschenbach, Dr. Rickard Pazdur, and Dr. Howard Scher, among others, by CaretoLive, (2) calls for a congressional investigation, (3) multiple articles in major U.S. newspapers and on the Internet, citing the many ethical and legal irregularities associated with the matter; (4) protests in front of the FDA; and (5) countless letters written to the U.S. Attorney General, the U.S. Securities and Exchange Commission, the U.S. Department of Health and Human Services’ (HHS’) Office of the Inspector General (OIG), the FDA (including the office of FDA Ethics), the U.S. Attorney in New York City, the General Accountability Office’s (NYSE:GAO) Fraudnet, and others, there is nothing—ABSOLUTELY NOTHING—to suggest that the U.S. government even is looking into the ethical and legal violations surrounding the conduct of certain participants in the Provenge AC meeting and in the events that unfolded thereafter.

Particularly glaring is the U.S. government’s apparent refusal even to investigate egregious conflicts of interest (COIs) uncovered in the case of Dr. Howard Scher. Dr. Scher, you may recall, was co-lead on the phase III trial of Asentar, Novacea’s drug for prostate cancer, at the time that he sat on the Provenge AC. This fact was not disclosed on his waiver request (.pdf warning). Further, at the time of the Provenge AC meeting, Dr. Scher was a member of the Scientific Advisory Board of ProQuest Investments of Princeton, NJ; there is some indication from information found on the internet that he also is or was an officer in that investment house as well as a member of its board of directors. Importantly, at the time of the Provenge AC meeting, ProQuest Investments owned slightly more than 8% of Novacea and a Proquest Investments’ officer sat on the board of directors of Novacea.

Even more astounding is the fact that just 3 weeks after the FDA sent Dendreon its Complete Response letter, Novacea and Schering-Plough signed a co-development agreement for Asentar that would have been worth up to $440M to Novacea. It’s almost certain that the deal would not have been completed for this price, if it were to have been completed at all, had Provenge been approved! (Since then, the Asentar trials have been terminated because of the higher death rate in the Asentar arm of the trial; the Proquest Investments’ officer has resigned from Novacea’s board of directors; and Schering-Plough has terminated its co-development deal with Novacea.)

So, what have we heard from HHS Office of the Inspector General, Hon. Dan Levinson?


Nothing, unless you count that fact that on the one year anniversary of the Provenge AC meeting, he sent two agents from the FDA’s Office of Criminal Investigations to All Seasons Florist in Rockville, MD, to intimidate and question its owner and operator, Hermine (Amy) Khatchatoorian, regarding who sent Dr. von Eschenbach flowers to commemorate the anniversary (here and here). By the time the agents had shown up, however, the FDA already had donated the two-dozen, white, long-stemmed rose arrangement in a white vase to a local nursing home. (One presumes that the flowers were forwarded with the compliments of the commissioner!)

It would be unfortunate if Mr. Levinson met the same fate as met the former Inspector General [IG] of the Securities and Exchange Commission [SEC], Mr. Walter Stachnik. As you may recall, the SEC’s former IG resigned after a Senate report concluded that “[T]he SEC’s Office of Inspector General failed to conduct a serious, credible investigation of [Gary] Aguirre’s claims” that he was fired for pursuing a case of insider trading at the SEC too aggressively.The U.S. Senate report was released on August 3, 2007. Mr. Stachnik resigned that afternoon, (according to this Forbes story, he had held that position since its creation in 1989). By the way, on Thursday, August 9, 2007, SEC Commissioner Roel C. Campos resigned as well.

Interesting, too, is the fact that just last week, a Federal judge in Washington, D.C., ordered the SEC to turn over thousands of pages of transcripts, trading records, e-mails, and other documents it tried to hide from Mr. Aguirre, who is battling the Commission over its treatment of him back in 2005. The agency has until May 23 to turn over the sought-after papers. Further, according to Forbes, it has to prove that it did a thorough search of items “allegedly missing from the personnel file it turned over to Aguirre already.”

Are there some lessons here for the FDA? Here are two, for starters:

  1. Houses of cards tend to come down very quickly, once the underpinnings give way!
  2. Sooner or later, the truth will out. You can’t stall forever. The FDA, with the help of the Department of Justice [DOJ], has been thwarting CareToLive’s Freedom of Information Act [FOIA] requests for certain papers thought to be in the possession of Dr. Richard Pazdur. Even Dr. von Eschenbach’s office has responded to the organization’s FOIA requests. So one has to wonder…what do Dr. Pazdur and the agency have to hide from CareToLive? And why is the very agency of the Federal government, the DOJ, an agency that should be investigating the alleged ethical and legal violations surrounding the conflicts of interest and the handling of the Provenge application, aiding and abetting those that are thwarting CareToLive’s FOIA requests?

What about those calls for a congressional inquiry into the handling of the Provenge drug application?

As readers may know, on December 13, 2007, Representatives Michael Michaud, Dan Burton, and Tim Ryan wrote to the Honorable John Dingell, Chairman of the House Committee on Energy and Commerce, expressing serious concerns about the failure of the FDA to approve Provenge.

“While much has been written on both sides of the issue about the effectiveness of the therapy known as Provenge,” said the three congressmen, “there is reason to believe that serious ethics rules were violated by two FDA advisory panel members in their decision and that these violations played a role in the subsequent FDA decision to not approve Provenge at this time.”

Specifically, they continued:

[P]rostate cancer activists have raised questions about two of the negative voters [at the March 29, 2007, AC meeting], academic medical oncologists Maha Hussain and Howard Scher. Dr. Howard Scher is lead investigator for a competing cancer drug made by Novacea and is listed as an adviser to a large venture capital firm that is also a major investor in Novacea. We believe the FDA should not be appointing scientists leading the testing of a rival drug for another firm onto the advisory committee evaluating Provenge nor should the FDA appoint an adviser to a large investor in such a competitive firm as a panel member. It is important that Congress examines possible ethical violations of these panel Members considering the viability of potentially important life-saving drugs.

Simply put, the three congressmen (and other congressmen who supported them, including Hon. Patrick Murphy) were asking the Committee to investigate the COIs of Drs. Hussain and Scher. Note that they were not asking the Committee to force the FDA to approve Provenge; protocols already are in place to address that issue later this year or in 2009.

On February 13, 2008, Chairman Dingell’s House Committee on Energy and Commerce responded to the call for hearings in the matter of conflicts of interest (COIs) regarding how the FDA handled Dendreon’s (DNDN) application for Provenge by rejecting the request on the basis of two arguments:

  • “FDA has not yet made a final decision on this product, and it is the practice of this Committee to allow a regulatory agency such as FDA to complete its statutorily-mandated processes and render a final decision before initiating formal investigative action.”
  • “A preliminary investigation into the record of the March 29, 2007, Open Session of the Cellular, tissue and Gene Therapies Advisory Committee that reviewed Provenge shows that the two advisory panel members you mentioned in your letter [Dr. Howard Scher and Dr. Maha Hussain] were granted waivers in compliance with the conflict of interest rules in force at that time.”…”Importantly, since the advisory panel that considered Provenge met, a new law strengthening conflict of interest provisions now governs FDA advisory panels.”

Clearly, neither statement has anything whatsoever to do with the original request for hearings made on December 13, 2007! And so, for whatever reason, the Committee was given a flawed recommendation by its staff…one that not only ignored the bases for the request for hearings, but the evidence as well.

So, we sit and wait…for the interim look at the Provenge data expected later this year and for a recalcitrant U.S. government, primarily HHS and the FDA, to investigate a decision that has impacted – and will continue to impact – the lives of hundreds of thousands of men across the United States every year.

All of which has led many an observer of this scene to utter the following comment under their breaths: “You’re doing a great job, Andy!”

Disclosure: Author has owned shares of Dendreon since 2006

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