Thursday, June 21, 2007

The Provenge Brawl: Two Wrongs Do Not Make a Right

The controversy, to use a polite word, over how the US Food and Drug Administration (FDA) has handled a proposed immunotherapy treatment for prostate cancer, Provenge (?Sipuleucel-T?, manufactured by Dendreon) has been striking. To start, let me quote from an article in the Philadelphia Inquirer,

In a small study, the median survival of men treated with Provenge was 26 months, just 4.5 months more than patients receiving a placebo. A survival edge in a second small study could have been by chance. And Provenge did not achieve one of its primary goals of delaying disease progression.

Yet the 4.5-month survival benefit was almost double that of Taxotere, a treatment with tough side effects that is the only other option for advanced, progressing cancer.
The FDA's expert advisory panel voted unanimously that Provenge is safe but voted only 13-4 that it was effective.

Prostate cancer activists have raised questions about two of the negative voters - academic medical oncologists Maha Hussain and Howard Scher. Both were granted conflict-of-interest waivers and have been members of an FDA advisory committee that evaluates conventional cancer drugs.

In an unusual move, both wrote letters to top FDA officials complaining about the advisory committee that recommended approval of Provenge.

Yesterday about 100 activists from 19 organizations rallied in Washington. The activists are petitioning Congress - and pressuring the FDA - to approve marketing of the promising prostate cancer "vaccine," while its manufacturer, Dendreon Corp., completes a 500-patient study.

Afterward, six of them met with FDA Commissioner Andrew von Eschenbach - who himself has been treated for prostate cancer.

The FDA's delay, the activists believe, could add years more to Provenge's long development odyssey.

'You're talking a minimum of two more years,' declared rally leader Thomas Farrington, founder of the Prostate Health Education Network, aimed at African American and other men at high risk of the disease. 'Since prostate cancer kills 27,000 men a year, you're talking 54,000 deaths.'
But the controversy is even more pointed than that, this week, Diedtra Henderson wrote in the Boston Globe,

When federal regulators delayed approving a promising new prostate cancer therapy, patients and the drug’s advocates reacted with more than disappointment.

They took a page from the playbook of AIDS activists and took to the streets and to the Internet, mounting an unusually intense lobbying campaign to pressure the Food and Drug Administration to reverse its stance on Provenge, the experimental cancer drug.

Blogs and websites are uniting disappointed cancer patients and disillusioned investors who put money on Seattle-based Dendreon Corp.’s Provenge, believing it could rally the body’s immune system to combat cancer.

Some, however, question whether some Provenge advocates are too aggressive. Some patient advocates say the FDA should be guided only by science.

'Do people in this country really want drugs to be approved by riot?'’ asked Abx bey Meyers, president of the National Organization for Rare Disorders. 'Every other patient organization is going to go down there and have a March on Washington and use political pressure to get their drug approved. That’s not what the American people want.'

Dr. Howard I. Scher, a Memorial Sloan-Kettering Cancer Center researcher whose image is featured on Vestal’s MySpace page and who was pilloried on the InvestorVillage website, received additional security during a recent cancer conference after receiving e-mails from Provenge supporters that he considered threatening.

Paul Goldberg, editor of The Cancer Letter, a weekly newsletter that reprinted letters from Scher and other Provenge skeptics, received a spate of irate e-mail messages, including one that said: 'I hope the entire male staff at the Cancer Letter is diagnosed with Prostate Cancer.'

Another Provenge supporter told him about her idea to create 'it squads,' people assigned to chat up FDA advisers during meeting breaks, Goldberg said.

‘‘The idea of a ‘hit squad’ is really unpleasant,’’ he said. ‘‘The idea of a committee member getting threats, being approached on the way to the restroom, at coffee breaks — this is about science.

‘‘Or it should be about science. That’s how patient interests are protected.’’

And Adam Feuerstein, a senior writer for TheStreet.com, received at least 100 e-mails, some of them anti-Semitic, after writing about Provenge and suggesting that investors ‘‘ditch Dendreon’’ stock.

It actually gets worse than that. According to the New York Times,

Two prominent prostate cancer experts have been threatened for opposing approval of a controversial new drug and are being protected by bodyguards as they attend the nation’s largest cancer conference here.

The experts, Dr. Howard Scher of Memorial Sloan-Kettering Cancer Center and Dr. Maha Hussain of the University of Michigan, received e-mail and other threats, according to spokeswomen for Sloan-Kettering and for the cancer conference.

When he gave a talk at the conference on Sunday, Dr. Scher was accompanied by three men wearing suits and earphones, but not conference name badges, which attendees must wear.

A spokeswoman for the oncology association said it had been working with the two doctors and was increasing security at the conference.

Christine Hickey, a spokeswoman for Sloan-Kettering, said Dr. Scher had received e-mail messages and phone calls, including one e-mail entitled 'our murder.' A copy of his biographical page on the Sloan-Kettering website was vandalized.

It is not known who sent the threats. However, it is clear that the doctors’ public stance against the drug, Provenge, has inflamed the passions of some men with prostate cancer and patient advocates, who say the drug would offer hope to desperate patients with few or no alternatives.

'ntimidation or harassment is going to make qualified people think twice about serving in national positions,' Dr. Hussain said....
A quick internet search did reveal that both Dr Hussain and Dr Scher did have conflicts of interest.

Dr Hussain acknowledged receiving consulting and lecture fees and holding stock in Sanofi (the forerunner of Sanofi-Aventis) in 2004 [Petrylak DP, Tangen CM, Hussain MHA et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513-1520]; receiving research funding from Bristol-Myers-Squibb in 2005 [Hussain M, Bhandari MS. Epothilones and the next generation of phase III trials for prostate cancer. Brit J Urol 2005; 96: 296-302.]; owning stock in AstraZeneca in 2006 [Hussain M, Tangen CM, Higano C et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metatstatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006; 24: 3984-3990.]; and receiving research funding from Genentech in 2007 [Hussain MHA, MacVicar CR, Petrylak DP et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute Trial. J Clin Oncol 2007; 24: 2218-2224.]

Dr Scher acknowledged research funding from AstaZeneca, Bristol-Myers-Squibb, Novartis Pharmaceuticals, and Millenium Pharmaceuticals; consulting fees from Bristol-Myers-Squibb, Conforma Therapeutics, Genentech, Novartis, ProQuest Investments, and Wyeth-Ayerst Pharmaceuticals; membership in the speaker's bureau for AstraZeneca; and stock holdings or option holdings in Cell Therapeutics, Vidamed, ProQuest, Conforma, and Genta [Shaffer DR, Scher HI. Prostate cancer: a dynamic illness with shifting targets. Lancet Oncology 2003; 4: 407-413.]

But while we're on the topic of conflicts of interest, the Boston Globe article also noted,

Dendreon is among the drug industry sponsors that have provided funding for a patient advocacy group that [Thomas] Farrington founded.

What a mess.

On one hand, this appears to be yet another in our series of stories about FDA advisory panels that include members with conflicts of interests (see recent post here). The presence of such conflicts naturally raise questions about whether the actions of the panels are influenced by their members financial entanglements, thus challenging the validity of the whole process. In my humble opinion, I think that to restore integrity in its advisory panels and its operations in general, the FDA should not allow people with conflicts of interest to serve on these panels.

On the other hand, the advisory panel's decision unleashed far more than scientific or clinical criticism, or concerns about how its members' conflicts may have affected its decision. It unleashed not just political pressure, but apparently threats of intimidation by "hit squads" and ominous emails, to the extent that the conflicted panel members felt they needed bodyguards. Intimidation of this nature is plain wrong, and surely will not lead to a climate in which policy makers will make the best decisions for patients and the public at large. Such threats deserve investigation, and anyone who was waving the bloody shirt in a way that might have inspired people to make such threats ought to be ashamed. Two wrongs here surely do not make a right.

3 comments:

Anonymous said...

This needs to be looked at in the broader context of the chaos in the medical industry. The July 22, WSJ story Hard Case: When Academics Double as Expert Witnesses highlights the work of William Clark and his conflicts concerning fees paid, during or after, testifying on behalf of a siren maker, that there was no work related hearing loss to fireman. In the same issue we see the headline Ruling on Drug Pricing Faults Three Companies.

My wife recently received an unsolicited letter from an IM outlining the poor care she was receiving from her current physician, and the need to immediately, space is limited, sign up for a series of ultrasounds. In a low tone a radio ad warns of the dangers of PVD, peripheral vascular disease. No prescription is needed, as the hospital will conduct the test and their specialist will review the test results.

One has to question the very veracity of a system so plagued by self-serving conflicts and the relentless and ruthless pursuit of profits. Personal attacks, undermining patient confidence in their current physicians, and now physical intimidation have become the norm. Science has simply become a sideline to manipulating the message to protect entrenched interest.

My personal view is that the vested interest in medicine, are the very interest, that will not allow the needed reform to take place to not only control cost, but ultimately provide better patient care.

Steve Lucas

Tony F said...

A compilation of Conflict of Interest (COI) for Scher who sat on the Provenge March 29 FDA Advisory Committee and who voted “YES” that Provenge was substantially safe and “NO” that is showed substantial efficacy. Sources are public information available on the internet.

Scher reported only 3 COI’s to the FDA in his Waiver Application permitting him to sit in judgment of Provenge’s FDA AC which appears to be composed of ownership of 1 stocks and 2 competing industry interest.

Internet research shows the following for Scher thus far:

1. NOVACEA: grants & research support; STUDY CHAIR of DN-101; 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 MYERS SQUIBB: consultant, grants & research

6. MILLENNIUM PHARMCEUTICALS: grant of research support

7. COUGAR BIOTECHNOLOGY: principal investigator; advisory board;

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. DEPARTMENT of DEFENSE: Principal Investigator PC Clinical Trials-P1 and P2

14. MEDIVATION, INC: principal investigator MDV3100

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

16. PROQUEST INVESTMENTS: consultant, scientific advisory board; LIMITED PARTNER FINANCIAL interest

NOTE: Items 1 & 16 above, again!

There appears to be a significant and disturbing difference between his 3 disclosures to the FDA and the alleged 16 COI’s found so far on the internet. It seems incomprehensible for someone with the training and education Scher has to “forget” so many apparent COIs… that is simply beyond all reasonableness and suggests intentional dishonesty or deceit.

Even more disturbing is the FDA’s Office of Inspector General and others at the FDA to whom this information has been supplied and their apparent failure to investigate these charges that Scher has more COI’s than he disclosed to them. When such information is provided and such allegations of potential federal law violation is involved, any ordinary citizen has the right to expect our government to investigate such allegations timely and thoroughly.

As a “temporary government employee” at the FDA, he is obligated, under Federal law, to provide full and complete disclosure. If he didn’t, he may have the potential for liability for law violation(s) as well as for providing false data to the FDA under which he secured a waiver in order to participate on the Provenge AC meeting March 29th.

Why hasn't the media looked further into these allegations to either acknowledge them as being true or refuting them as false?

Anonymous said...

The Unreachable Availability of Provenge

Terminal patients are those who are not expected to live due to usually illness such as advanced cancer. If the patient has 6 months or less to live, those patients are considered terminally ill. Regardless, if a patient is terminal, they are without a cure or a tolerable treatment for their illness. Since such patients will likely die in a short period of time, treatment options, even if unproven, are often desired by such patients. This is understandable, because at such a severe stage of illness, such as prostate cancer, possible extension of their lives with comfort is worth it to them, regardless of lack of evidence of proof of whatever treatment that may be advantageous to them regarding these issues. The FDA, however, claims authority on the treatment options of such patients, although that administration has proven itself over the years to be rather inadequate with its frequent drug recalls and black box warnings, and they do these things only under pressure from the public, usually. So, the FDA may not be an ideal judge regarding such issues as treatment options for very sick patients.
Prostate cancer is rather frequent, with between 10 to 20 percent of men predicted to acquire the disease during their lifespan, resulting in about 30,000 deaths a year from this disease. It is the third most common cancer one can acquire, and the United States has the most cases diagnosed n the world, which usually strikes men past the age of fifty. One million do have prostate cancer in the United States, and about thirty thousand will die from the disease each year. Furthermore, there are different stages of prostate cancer, and the more severe the prostate cancer cases are, the higher of what are called Gleason Scores will be, and the severe cases are the most difficult to treat, of course.
Yet innovation still exists in medicine. A few years ago, a small Biotechnology company called Dendreon was working on a conceptually new treatment for the worst prostate cancer patients, and this treatment therapy created by Dendreon was named Provenge. Provenge is the first immunotherapy biologic treatment for the progressed prostate cancer patients. Usually, these patients are unresponsive to usual treatment methods for prostate cancer, and are left with chemotherapy, specifically a hazardous drug called Taxotere, as their only treatment option at such a traumatic stage of prostate cancer. Understandably, most patients at this stage refuse treatment entirely, largely due to the brutal side effects of such chemotherapy treatments as Taxodere, which include cytotoxic side effects and haematological adverse events. The immunotherapy method developed by Dendreon requires the removal of white blood cells of the diseased patient and, after altered, are re-injected into this patient now designed to attack within the diseased body what is called PAP, which is on prostate cancer cells only. This treatment requires only three such injections in a period of six weeks. This results in life extension twice that of Taxodere, and Provenge is free of the discomfort of the only other treatment of Taxotere. The medical community and survivors of prostate cancer were elated and waited with great anticipation for access to this treatment method.
Fortunately, as the years passed, Provenge, by 2007, had convinced others of its safety and efficacy in its benefit for severe prostate cancer patients. This caused great joy to such patients and their families. Perhaps greater elation was experienced by the caregivers and specialists of such a disease, such as Urologists and other caregivers who treat such patients. While Provenge was on fast track status at this time at the FDA, as they at the time agreed with the benefits of this new therapy, the FDA panel recommended with clarity the approval of Provenge based on its proven and superior efficacy and safety that was demonstrated in its trials, as they announced in March of 2007. Lifespan extension of severe prostate cancer patients was twice as long with Provenge versus Taxotere, which is the only other treatment indicated for this stage of prostate cancer that had only superficial efficacy, and is free of the toxic effects of this chemotherapy agent.
Now for the bad news: With great shock and surprise, the FDA agency rejected the approval of this great treatment for very sick patients due to, they said, ‘lack of data’ in May of 2007. This contradicts their favorable opinion of Provenge weeks before delivering this terrible news. Especially when one considers the FDA Commissioner is a prostate cancer survival himself! Many found this ruling completely unbelievable.
Soon after this judgment was passed by the FDA, conflicts of interest were discovered by others. For example, a member of the FDA agency who was evaluating Provenge, Dr. Scher, was found to have a financial commitment to a future competitor of Provenge that was being produced by a company called Novacea, and this company had signed a co-promotion agreement with Schering to provide support for this similar prostate cancer drug treatment being developed by this company. Dr. Scher never disclosed this conflict during the approval process of Provenge. As it turns out, this anticipated prostate cancer drug made by Novacea was discovered to have serious flaws, and Schering pulled out of the agreement with Novacea. In addition to this incident and before May of 2007, baseless letters were anonymously delivered to the FDA stating negative qualities about Provenge that were without Merit and speculative claims about the treatment were fabricated in these letters, it is believed Oncologists were speculated to lobby and pressure the FDA not to approve Provenge due to anticipated revenue loss. Yet overall, the disapproval by the FDA of Provenge angered and saddened many, and a newly formed advocacy group called Care to Live filed a lawsuit against the FDA for their clear lack of etiology for not approving Provenge, as they should have, according to the data about the therapy last year.
Terminal patients, I surmise, desire comfort during their progressive disease that has placed them in the last chapter of their lives, and certainly should have a right to choose any treatment that possibly could benefit them. Clearly, because of their lack of desirable and beneficial treatment options, most are willing to assume any risks of unapproved, yet potentially and likely beneficial treatments such as Provenge. Because they have a terminal illness, these benefits provided by Provenge take priority over any possible safety issues of unapproved treatments for them. The controversy could be concluded by a terminal patient signing a waiver of some sort, perhaps, stating that they are responsible for the consequences of an unapproved treatment regimen such as Provenge. Yet the FDA, with reckless disregard and with deliberate intent, denied what likely was a great treatment therapy for these very ill patients. Several have concluded that the FDA ultimately harmed others more by not approving Provenge, or offering any valid explanations explaining their action. Thier action was irrational, as one considers the agreement of the FDA and others regarding the need of the benefits provided by Provenge for the sickest of the sick with advanced prostate cancer.
The FDA does in fact presently have the ability to grant what is called conditional approval for such treatment methods as Provenge at this time, and why they have not remains completely unknown. What is known is that they are accelerating and worsening the illness, an illness the FDA pledged to protect so long ago. So now the FDA appears to be a bought, corrupt, and incompetent administration without loyalty and dedication to the public and its health, but with what appears to be overt collusion with venture capitalists and corporations. This needs to be corrected in any way possible for the lives of others- regardless of their own present health state today. Because of the FDA's flaws in the past regarding drugs taken off the market along with increasing black box warnings of other drugs, which happens often with both, the individual should be the deciding factor in such matters of deciding thier treatment course presently, along with their health care provider, due to this unreliable administration called the FDA.
“Facts do not cease to exist because they are ignored.” --- Aldous Huxley
Dan Abshear