Dendreon: The Provenge Approval Scandal, One Year Later

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 (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 (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!

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

Comments

[User 108506]

Be careful, your coronaries will be blocked, stress and stress does it. If you are that disgruntled then join the FDA or Congress and change something. Provenge efficacy was always scanty. How many therapeutic vaccines are on the market? How come DNDN never did a 500-1000 patient trial to began with??

[Gates]

User 108506, it is only fair that you tell us which hedge fund or chemo manufacturer you work for.

[Jack Henry]

The SEC went after Martha Stewart, who supposedly had insider information regarding the FDA decision on Imclone's drug, but will not investigate the connection between Dr. Scher and his hedge fund pals who knew the drug would never get FDA approval. Who do you think had more money at stake, Martha or the hedge funds?

[PoopDoggy]

RE: user 108506 - Andy, why don't you take Howie aside and tell him his privileges to use Dicky's computer have been suspended? I thought Howie might have some patients to see........no, wait......that was before he was outed in this whole mess...........maybe you can just get him to play Solitaire instead...

[Fireman Dan]

SCANTY????? What's scanty about 17-0, 13-4 (substantial efficacy)? What's scanty about 30,000 men dying since May 9th, 2007? Maybe, honest folks in charge of our FDA.....now that's scanty!

[User 127809]

re: user 108506 The answer to your question about why not a 500 or 1000 patient test (implying DNDN was afraid of a larger test), is COST.. These test costs are astronomical..period.....

[Frankie62]

This story is still amazing to me. What is the point of having an FDA Panel if FDA is not going to pay any attention to it? The safety and efficacy numbers from the Panel analysis show that they believed Provenge is safe and effective. FDA should have at least approved Provenge conditionally,if not outright. Instead, the panelists in the minority (and in the back pocket of big pharma) wrote scathing letters claiming the Panel was wrong in its analysis. What stupidity.

[User 190108]

cgi.ebay.com/ws/eBayIS...







FDA SAYS, “WAIT” TO DYING MEN



Nationwide Prostate Cancer Rally MAY 30th Over FDA Failure to Approve Safe, Effective Immunotherapy.



1 in 6 men get prostate cancer. 75 American men die from it every day. The FDA has not approved a treatment for stage IV prostate cancer in over 43 years.



Care To Live, a not for profit corporation, seeks transparency and accountability from the FDA, as to why they disregarded the advice of their hand selected Congressionally mandated Advisory Panel of experts, who voted Provenge overwhelmingly safe and effective. Without cause or explanation, in an unprecedented action, the FDA denied licensure. We are seeking immediate access to Provenge for all men with end stage prostate cancer.



On May 30, 2008, CareToLive will take to the streets to protest with the men desperately seeking Provenge. Over a year has passed, and 27,000 American men have died without hope, since the FDA denied the licensure of Provenge, an immunotherapy the FDA panel voted 17-0 safe and overwhelmingly voted effective. This is a noninvasive, non-toxic, immune building treatment, which works by employing your own body’s healthy cells to fight the cancer.



Men like Eduardo Garcia, who have had the 3 treatments, have gone from being incapacitated, to living healthy, productive lives, for as long as six years and counting. Dendreon, the company that perfected this treatment, also has similar treatments for breast, ovarian, colon, lung, kidney, and cervical cancers, in their sights.



The dysfunctional FDA's reason for delay has never been explained, as it was not science based, since survival and safety have clearly been demonstrated.



CareToLive filed a Citizens Petition for the FDA to reconsider the wrongful denial, (the only recourse the FDA allows), on July 26, 2007. The FDA has failed to follow Federal regulation and to this day they have not properly responded to our Petition, which seeks immediate access to Provenge for these desperate men. The FDA also refuses to respond to the CareToLive Freedom of Information Act request, which they know would prove that a few FDA insiders, who cared more about serving their own interests, rather than the best interest of the patients, purposely sabotaged Provenge.



“In memory of our members who have recently passed away, never having been given the chance Provenge recipient Eduardo Garcia had, we will continue to fight on, every day, in every way we can. Please come out and join us,” said CareToLive spokesperson, Mike Kearney.



Please join with me on May 30th, 2008, in Westlake Park, outside in downtown Seattle, Washington, from 1 PM to 3 PM, as a show of solidarity with our brothers who have been tossed aside by our incompetent, cold blooded health czars. Visit CareToLive.com for additional details.

Thank You, Jason Burdine Coordinator Seattle [e-mail]...

[MJ121983]

Anyone who argues that the results from Provenge is "scanty" must have some sort of conflict of interest.

You - can't - fake - survival.

Patients on the placebo lived a maximum of 4 years, while patients taking Provenge are still living after 5,6,7 years.

I'm not sure how you can sleep at night.

[Tony F]

Dr. Cohen has presented a fair and accurate itemization of the Provenge/FDA events.

... to expand on the allegations against Dr. Howard Isadore Scher of Sloan Kettering in NYC may have more Conflicts of Interest than the 3 (Three) he certified having to the FDA in order to sit in judgment of Provenge on the FDA Advisory Committee meeting in March '07, look at what's been found on the internet for him:

17 (SEVENTEEN) Conflicts of Interests--NOTE #1 and # 17, in particular:


1. NOVACEA: grants & research support
... STUDY CHAIR of DN-101 which is ...
... a Direct competitor to Provenge

2. GPB BIOTECH: financial conflict of interest per Scher in MedPage

3. PHARMION: financial conflict of interest per Scher in MedPage

4. SANOFI-AVENTIS: grants & research support

5. BRISTOL MYERSSQUIBB: consultant, grants & research

6. MILLENNIUM PHARMCEUTICALS: grant of research support

7. COUGAR BIOTECHNOLOGY: principal investigator; advisoryboard;

8. INNOVIVE PHARMACEUTICALS: principal investigator

9. INFINITY PHARMACEUTICALS: principal investigator

10. BIOGEN-IDEC: jointly held stock with spouse

11. PFIZER: jointly held stock with spouse

12. GENTA: scientific advisory board (as of March 6, 2007; since removed from web but
cached)

13. CONFOMA THERAPEUTICS: scientific advisory board

14. DEPARTMENT of DEFENSE: Principal Investigator PCClinical Trials-P1 and P2

15. AMBRILIABIOPHARMA INC: Principal Investigator PCK3145, Phase I/II

16. MEDIVATION, INC: principal investigator MDV3100

17. PROQUEST INVESTMENTS:
... member Board of Directors
... Scientific Advisor
... INVESTED in Novacea.

83 men die each 24 hours, 7 days a week, 52 weeks a year from Prostate Cancer....
.... some 30,000 men each YEAR!

Approve Provenge NOW!

and

Resign Dr. von Eschenback! Your stewardship of the FDA has been abysmal and continues to harm the American citizens.

[phoenix55218]

Ted, great summary of the misconduct that has occured over the past year. Many have gotten discouraged over the often slow and frequent lack of progress in the case, but, as in all things political, it requires a slow steady grind before anything is accomplished.
Best wishes.

[Konig]

My father died of prostate cancer. Other countries are leading in medicine and many Americans are willing to travel to get the best in medicine. The FDA allows genetically altered food and food that has been irradiated. Irradiation not only kills harmful bacteria, but many healthy microbes that are on the food.
The FDA has made many mistakes on approving drugs. People that are given months to live are willing to try anything to get better or live another day including: degrading, expensive, painful, radiation therapy. People in the end should be able to make their own informed choices. They should also be given choices.

[JJTERRITO]

I am a retired physician.I began my practice when there was no FDA.In my opinion it is unfortunate when government becomes involved because politics reigns supreme.Academicians have a role-teaching.The old expression "those who can do.Those who can't teach."Members of committees making judgements should have practice related experience because many on these cmommittes are too far removed from the actual practice of medicine.

[JMG]

It is unfortunate that the blog does not mention statistical issues surrounding DNDN's analysis of “success.” Most think them ivory tower nit picking. This is not true. The DNDN success claims come from looking back in their data for potential effects after the main dependent variable of interest –disease progression – didn’t pan out. Such action is perfectly ok when the purpose is to look for clues about next studies, but not legit in claiming effects in the study that was fished around in. This is because doing so can increase greatly the probability of identifying an "effect" that in truth does not exist, is just achieved by chance.
While nowhere could I find sufficient data to independently analyze, a back of envelope analysis I was able to do with what I could find – about the 34% of treatment group alive after 5 years vs. 11% of controls with 147 people studied – showed the groups survival rates substantially overlapping. I surely hope results of the larger study currently underway allow for quick approval of Provenge. But I think the FDA is correct in being careful in approval of a very expensive treatment that, from what we likely know today, may or may not be effective. I also think paranoia about panel conflicts of interest is not warranted. The panel is made up of experts who have intellectual, academic, and –not surprisingly – often financial interests in their field. As far as I can tell, all of them acknowledged areas of potential conflict as part of the panel process.

[zimmy zee]

Dendreon's CEO dumped over $2 million worth of stock right before the FDA denial. I think he's a crook and I also think he knows Provenge doesn't work.

I look for a complete failure for the current trial and bankruptcy for Dendreon.