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PHARMA: Wall Street, Cancer, and the FDA: A Cautionary Tale by Maggie Mahar

Maggie Mahar  writes on healthcare, economics and public policy. Her work has appeared in The New York Times, Barrons, Institutional Investor and may other publications. A regular contributor for THCB, her most recent book is "Money-Driven Medicine: The Real Reason Healthcare Costs So Much." She was recently named a fellow at The Century Foundation.

Only in America do physicians
who evaluate new drugs need bodyguards.

You may have read about the
brouhaha surrounding Provenge, a vaccine designed to extend the lives
of men suffering from late-stage prostate cancer. In March, a Food and
Drug Administration (FDA) advisory panel voted 13 to 4 to recommend
approval. The next day, shares of Dendreon, the drug’s sponsor, doubled.

But shareholders did not celebrate
for long. Two of the dissenting votes were cast by the panel’s two
prostate cancer specialists: Sloan-Kettering’s Howard Scher and the
University of Michigan’s Maha Hussain. And they did not just vote
“no”—following the hearing, both wrote to the FDA arguing that
Dendreon offered no solid evidence that Provenge works.

The FDA listened. And in May
it told the company it wouldn’t approve the drug until it had   more
data. That is when the two oncologists began receiving threatening e-mails,
phone calls, and letters. Many were anonymous.

No doubt much of the hate mail
came from investors who had watched Dendreon’s shares climb from $5
in early January to $25.25 in late March—before plunging to $3 and
change. One Alabama shareholder expressed his feelings on his MySpace
page, where he asks “Hey, Hey, FDA, How Many Dads Did You Kill Today?”
while images of Hussain and Scher flash across a backdrop of crooked
crosses. Mozart’s “Requiem” plays in the background.

The response illustrates how,
in a money-driven health care system, those who view health care as
a profit center strive to dictate social policy. From their point of
view, the FDA should approve any product that Wall Street finds attractive—and
then let the market decide whether or not the drug is both safe and
effective. What they ignore is that, unlike other consumers, sick patients
are not in a good position to comparison-shop. They must rely on the
doctors and scientists who serve on FDA panels to sort through the hundreds
of offerings that drug makers hope to bring to market. For even if a
drug makes it to Phase III trials, this is no assurance that it is safe—or
that it will work. Indeed, a recent study shows that fully 40 percent
of new drugs fail in that final stage of testing
.

So far, the FDA has not bowed
to investor pressure regarding Provenge, but the e-mails and phone calls
were too menacing to be ignored. When Hussain and Scher attended the
conference of the American Society of Clinical Oncology last month,
both asked for extra security guards. At that point, Hussain began wondering
whether she should continue as an FDA adviser.

Patients also protested the
FDA’s decision. Many had pinned their hopes on Provenge because it
is one of a group of new cancer drugs under development that uses the
patient’s own cells to create a vaccine designed to mobilize the patient’s
immune system to attack the cancer. The notion that the body might “heal
itself” is enormously seductive. For more than a century, oncologists
have dreamed of such a solution. But thus far, as Dr. Steven A. Rosenberg
of the National Cancer Institute confirmed in an e-mail to me last week,
“there are no therapeutic vaccines that have been shown to be effective.”

This is not what patients want
to hear. But while many were crushed by the FDA’s decision, patient
advocates such as PSA Rising disown the hate mail. "Folks, this is not grassroots
cancer patient activity, it’s . . . naked grassroots investor activity,”
wrote Jaqueline Strax, the editor of PSA Rising, in her newsletter for
prostate cancer survivors. “Ironically, some investors have whined
that prostate cancer patients are not helping THEM on behalf of Dendreon.” Roman">

Meanwhile, shareholders charged
that Sloane-Kettering’s Scher nixed the drug because he is the lead
investigator for a rival product. To drive this point home, earlier
this month Provenge activists
raised $24,000 on the Dendreon message
board at Investor Village to buy a half-page ad in the Washington
Post
headlined
“Prostate Cancer Victims Face Needless Suffering and Premature Death.”

Could this be true? Knowing
how much misinformation swirls around any new cancer drug, I decided
to take a close look at the transcript of the FDA hearing and find out
more about the scientific evidence
behind Provenge. 

This is when my skepticism
turned to shock. First, I learned that Dendreon has done two clinical
trials attempting to show that Provenge slows the progress of the cancer.
And that both failed. That’s right—the studies offered absolutely
no proof that the drug put a brake on the disease.

“It’s not clear why the
FDA panel was even voting on the drug—Provenge had already been check-mated,”
says Paul Goldberg, who broke the story by printing Scher’s letter
to the FDA in The Cancer Letter, a weekly newsletter about the
politics of cancer. . . .

In the meantime, “the stock
has become the momentum trading vehicle of 2007,” TheStreet.com’s
Adam Feuerstein wrote earlier this month. “A stock that will be pumped
and dumped based on the flimsiest of rumors and lowest-common denominator
reporting.” 

Inevitably, the Wall Street
hype spills over into the mainstream media, where dying patients, willing
to grab at any thread of hope, read about a drug and begin to believe
that, if they could just get access to the “newest new thing,” it
might save their lives. (In fact, even the company claims only that
the average patient might win an extra 4½ months.) Those who
“pump” the stock do patients a cruel disservice.

Ultimately, Scher and Hussain
were not the only ones who would be  intimidated by the Wall Street community.

I’ve written the full story of Provenge, discussing how it passed
the FDA panel, and whether individual patients should have the right
to gamble their lives on an unproven drug at http://www.tcf.org

Read the extended version of the story at http://www.tcf.org/Publications/HealthCare/healthbeat.pdfPlease return here to comment

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53 replies »

  1. Any more comments? You got shut down with your silly article and lack of factual data to back up your position. IMO
    I did not mean for a “personal attack” on you. If I had, I would have said: you “were” rather than “I think” as I was trying to realize and understand why you would take such a position without being educated on the statistics. I however think Walldiver summed it all up fairly well why you psotion yourself as you did.(see below)
    I would seriously like to see an intelligent rebuttal to the real facts such as those presented by Walldiver , tallhoriz, Paul and others that you conveniently avoided. All thus far have been strongly refutted by Scher , Hussain , Flemming and others.
    And I highly doubt that there were any real threats made upon Dr. Scher and Hussain. Where is the proof? Show me the proof in the police reports? I found none in the public record. Sure the NY times etc reported but they failed to site any proof other that from a spokesperson from MSKCC. Who of course virtually works for Scher.
    It makes for great news headlines thus I see why a reporter would like to report it. To bad that the news is based on no known public facts. And even you try to spin it; you are spinning rumors. (really helps your validity as a journalist; NOT)
    I would also like to add that I have no investment in Dendreon . I know Provenge should have been approved and that it will in the interim in 2008. But men are dying earlier than thy need be. No one ever thought of Provenge as a cure! I have people that love me and I know they would not mind if I was dying to have a few extra months with me as I would with them.
    So we can all laugh at those who say we will see at the interim if Provenge really works. If you knew anything about biostatistics you would already know that it does work. But I suppose if your ignorance of the statistical facts was not clouding your judgement that you would have nothing to bitch about.
    CD
    From Walldiver:
    http://investorshub.advfn.com/boards/read_msg.asp?message_id=21928141
    OT-Nmstav, sometimes I’m disappointed in my fellow progressives. The truth should take precedence over all issues. One shouldn’t reflexively take a political position on an issue based solely on what one’s ideological counterparts are saying, without looking objectively at the underlying facts. Right now, the FDA is under attack from some right-wing think tanks for not allowing limited approvals of some cancer treatments…so people on the left like Maggie automatically start out with the opposite view, use specious arguments that confuse “median” with “average,” and then change the subject when you call them on it…and then say that an extremely close miss on an endpoint means that there was “no effect” on that endpoint.

  2. Uh, Maggie; I wouldn’t want to be called a cold lonely woman either (wtf??!!), but in the name of using precise terminology, there is no cure for prostate cancer with distant metastasis – not all prostate cancer. I know you know this. Interestingly, Lance Armstrong had practically the only solid cancer that CAN be cured when widely metastatic – testicular – but he is still a lucky man.

  3. Bev M.D.–
    Thanks–you make the best point about why investors
    are inevitably biased, like anyone else with a financial interest in the outcome of a FDA decision.
    I’d urge everyone to look at http://www.aamc.org/research/coi/science.htm on conflict of interest.
    I also think that FDA reform is coming, and that ultimately physicians and scientists with a financial interest will no longer be sitting on panels.
    The piece on hospital architecture (on the same site)
    also is interesting. I can see the argument that private rooms make medication mix-ups less likely. But I’m still concerned that too much money is being spent on hospital amenities while too few hospitals have the healthcare IT that they need . . . Also, hospitals are
    being built in some parts of the country where we don’t need more hospital beds. (Southern California is a good example.) But once they are built, the beds will be filled. (Build them and they will come.) And often they will be filled by patients who don’t really need to be inpatients, exposing those patients to all of the risks of being in a hospital while also wasting billions of dollars that could be used for preventive medicine, heatlhcare IT, etc. . .
    Carey D. I don’t see any point in going round and round over the same issues. I suggest that everyone wait for
    results from the randomized controlled trail that the company is now doing. Then we will find out how effective Provenge is. At this point, no one knows for sure–including me.
    It is true that while we are waiting, people will die of
    Prostate cancer. BUT THOSE PEOPLE WOULD HAVE DIED OF PROSTATE CANCER ANYWAY. THERE IS NO CURE FOR PROSTATE CANCER. EVEN THE COMPANY DOES NOT PRETEND THAT PROVENGE WILL SAVE LIVES. THE COMPANY CLAIMS ONLY THAT PROVENGE MAY GIVE PATIENTS A MEDIAN AVERAGE OF AN EXTRA 4.5 MONTHS.
    Finally, Carey D. I don’t respond to personal attacks.
    But I’d like to thank everyone else for your comments and opinions.

  4. Carey D.;
    The reason why investors should have no say in this process, among other reasons, is found in the American Association of Medical Colleges link I cited above:
    “The (scientific) evidence suggests that self interest has a tendency to bias independent judgement in unconscious ways.”
    You may fairly argue that the two docs are in no better position than investors due to their own purported conflicts of interest. But don’t set investors up as people with a right to sit at the FDA’s conference table. Much less threaten the people who do sit there.
    I agree the FDA has been fairly hopelessly politicized in the past several years and that must be changed. This includes COI on the part of physicians (see the link I cited.) But it must also be changed to keep Wall Street OUT, not let them in!

  5. Maggie,
    You seem to be a great writer. You are so wonderful.
    However you seem to only be trying to prove the only reason people are actively trying to change the “non-approval” of provenge is because they are all bitter investors.
    “I’d also note that once again, it turns out that many of the most vociferous critics of the FDA decision are not patients, but investors” M.Mahar
    So what? Investors are more informed than any other group when it comes to the many aspects of Provenge and it CR letter.
    The investors are not just investors, they are among others things Cancer survivors, Prostate cancer patients,doctors, Nurses, Professors,lawyers, professional biotech traders, other healthcare professionals.
    It is these investors that are well informed of not just the science but also the workings of Wall Streets hedge funds, the sec and the FDA. They study all angles thoroughly. (now they must study COI’s thoroughly)
    How many PC patients do you know? I know more than a few and the ones that are not investors just think they have been screwed over by the FDA (the others know it) but know nothing about how the stock has been manipulated and the implications of virtually half the sock (~40M shares) being shorted.
    They also are in no condition to fight , they depend on the fairness of the FDA to make decisions for them. They do not count on the FDA letting doctors with extremely blatant Financial Conflicts of Interest sitting and persuading the outcome of the drugs they depend on. They have no energy to fight the likes of you who only wishes to see the investors suffer rather than the patients survive longer.
    Why do you not reply to walldivers post’s intelligently rather than choose to pick away at parts superficially?
    Why do you not dispute the points he has made?
    You said you would get back to the other points? when .
    All of the posts have been saved and are there for others to look back at and see that you never have debated the real facts but rather keep coming back with lame rebuttals about investors.
    I think I know why, because all you want to do is try and make the story 100% about disgruntled investors that cannot accept the decisions of the FDA.
    You most likely feel the same way all the investors, advocates do and know that the patients and future patients have been screwed over and think the FDA made a serious mistake. However,I think you are a cold lonely woman that is actually the bitter one and must find a fight.
    I think maybe someday you can actually write an intelligent piece that is from your heart and not your kulo.

  6. Maggie;
    I found a link to the American Association of Medical Colleges which cited a symposium on the “science of conflict of interest”. It won’t solve everyone’s assertions on this particular issue, but it does indicate the profession is taking notice. Change will no doubt follow, after a lot of kicking and screaming.
    http://www.aamc.org/research/coi/science.htm
    In addition, Maggie, regarding the issue of private rooms, which you and I both thought wasteful, here is information from the same organization that has changed my mind:
    http://www.aamc.org/newsroom/reporter/june06/patients.htm
    Data is everything; not just throwing around opinions.

  7. Here are the main points that Maggie can’t address inteligenly.
    1)Missed end points have nothing to do with Provenge’s FDA review. The FDA knew about the failed end points but still encouraged DNDN to file the NDA and gave it fast track priority. Provenge was to be judged on survival data.
    2)The FDA appointed a panel of expert with great expertise in oncology, immunology, statistics etc… voted overwhelmingly to approve Provenge 13-4 efficacy for survival and 17-0 safety.
    3)This is the first time in its history that the FDA went against the apointed panel recommendation for a drug adressing terminaly ill patient.
    4)Two oncologist with documented professional and financial conflict of interest were allowed on the panel.
    5)The two oncologist werent satisfied with voting no. They launched an unprecedented campagne to influence the FDA final decision in doing so they highjacked the process from the other member of the panel and wrongly affectd the FDA decision.
    6)On survival, which is what provenge was supposed to be judged on. There is subtantial evidence of efficacy as the stats indicate and as the panel voted.
    7)Oncologist have a vested interest in defeating Provenge. They have done that in the past (see NY times article that I posted earlier). Scher and Hussein are the worst example of such oncologist.
    8) Maggie has yet to tell me why I should beleive her rather then the panel of experts in imunotherapy, oncology and statistics that voted 13-4 for efficacy and 17-0 for safety.
    9)Maggie has yet to articulate why she is siding with the conflicted minority of experts.
    10)Maha Husein, Maggie Mahar, relationship??? LOL
    Tall

  8. Hang it up Maggie, you are on the wrong side of the argument. You have no conterpoints to the very reasoned arguments that a few of the posters have put in front of you. My total investment in DNDN at the height of the PPS was less the 1% of my portfolio. I explained to you my interest in Provenge, but of course you chose to ignore that and again you refuse to respond to my main question / point. It is apparent that you have no interest in intelligent debate.
    Wall,
    Thank you for your contributions to this discussion. But please don’t waste anymore of your time responding to Maggie. She will never admit that she’s got it wrong.
    Tall

  9. Maggie, from your last couple of posts it appears that this subject is starting to push your emotional buttons. Perhaps the oncologists in the thread who weighed in on the side of Provenge were the tipping point.
    To address a couple of your points: when Dr. Fleming strongly came out against Iressa approval for third-line non small-cell lung cancer (NSCLC) back in 2002/03, he did have a strong biostatistical case. The ODAC panel had recommended approval based on the 10% objective response rate (ORR) surrogate endpoint in one or two single-arm trials. The ORR was much lower than Astra Zeneca expected, or hoped for. In addition, Iressa was being tested in an ongoing, randomized Phase 3 trial with an enrollment target of over 750 patients. Results were expected in late 2004/early 2005. However, ODAC members voted thumbs up because 3rd-line NSCLC patients are extremely sick (already having failed two previous treatments), and typically only live 4 to 5 months. Pazdur stalled as much as he could after the panel meeting, actually ruling it should not be approved. The nonapproval went up the line to FDA Commissioner McClellan, who overruled Dr. No. Iressa was granted accelerated approval for marketing under Subpart H, with ultimate final approval contingent upon the overall survival results in the ongoing Phase 3.
    That ongoing Phase 3 failed to attain stat sig in Dec 2004 (p=0.11, median survival benefit of only 2 weeks). So, Drs. Fleming and Pazdur were “vindicated.” Iressa was effectively pulled from the market by the FDA. There had been another approval of an EGFR inhibitor (Tarceva) in 2nd/3rd-line NSCLC a few weeks before, so Pazdur felt there was no longer an unmet medical need in this indication. However, despite my already owning stock in Tarceva’s developer OSI Pharma (which went up 20 points on the Iressa trial news), I believed it was a mistake a few months later when Pazdur pulled Iressa from being marketed to new patients. He should have kept it on the market for patients refractory to Tarceva treatment. Iressa did work, and work well, for approx 10% of those who received it. Oncologists would know within a month or less if their patient would respond to Iressa, so cost would not be a major issue. Again, a p value of 0.11, while a miss, isn’t chopped liver. Especially if you’re one of those patients who responds to Iressa but don’t respond to Tarceva. Despite their being similar molecules with similar methods of action, different people react differently.
    You also seem stuck on the Provenge primary endpoint of TTP. You labeled the 0.052 p value in time to progression as a “fact that the trials showed absolutely no sign that Provenge slowed the course of the disease…” So, how is it that a 0.050 p value is absolutely a sign of slowing the course of the disease, but a 0.052 p value is absolutely not a sign? A little bit stark, but this is the logic that you’re using when you equate an extremely close miss on statistical significance in slowing the course of the disease with “absolutely no sign that it slowed the course of the disease.”
    As for the crossover, there is considerable pressure from regulators and patient advocacy groups on companies testing oncology treatments to incorporate crossover designs into their trials. A crossover component is not a “poor design” as you label it, but rather ethical and compassionate behavior. And, it does make it more difficult for a survival trial to achieve statistical significance if the product being tested is effective. The two recent biologics approved for kidney cancer (Sutent and Nexavar) both had crossover designs into the trial, and most patients in the control arms were allowed to cross over after progression when the trials were unblinded and PFS had been proven significant. Both of these drugs had p values in the PFS endpoint with multiple zeroes to the right of the decimal. Crossover severely weakened the overall survival p values in the trials.
    All this shows is that if you can still achieve stat sig survival in a randomized Phase 3 with a crossover component built in to the design, then you have a very effective drug.

  10. Let’s start with The Cancer Letter. No, it’s not Barron’s or The New York Times.
    Barron’s and The New York Times turn to The Cancer Letter as an expert source. See for example, the Times
    quoting The Cancer Letter in this story: ANDREW POLLACK, “Studies Show Anemia Drugs May Harm Cancer Patients”, New York Times, February 27, 2007,
    Link: http://www.nytimes.com/2007/02/27/health/27drug.html?em&ex=1172725200&en=b255f2891d666d3c&ei=5087.
    I’d also note that once again, it turns out that many of the most vociferous critics of the FDA decision are not patients, but investors (tallwhenhorizontal).
    To be fair, some physicians also feel that FDA was mistaken. (Though most haven’t disclosed whether they own the drug or would profit by administering it–so that’s still a bit of an open question.)
    I’d also note that the members of the FDA panel who voted for Provenge were hardly universally enthusiastic (as some commenting here have suggested.) As The New York Times reported at the time:
    “The advisory panel to the Food and Drug Administration voted 13 to 4 that there was “substantial evidence” that the treatment was effective in men with advanced prostate cancer and 17 to 0 that the therapy was safe.
    The votes increase the likelihood of F.D.A. approval for the therapy, Provenge, by the agency’s May deadline. *****Still, even panel members who voted for the drug expressed some reservations about the strength of the data. That could leave the door open for the agency to reject Provenge until a bigger trial, now under way, is completed in 2010.” http://www.nytimes.com/2007/03/30/health/30vaccine.html?ex=1185768000&en=fcc2eacc67e87282&ei=5070.
    So it was hardly a great surprise when the FDA decided to ask for more information. If you read the NYT, you knew that was likely to happen.
    But some investors just
    can’t admit it when they have lost money–and so they go into denial. (For stories, Google “TheStreet.com” and Provenge)

  11. Maggie,
    As expected you didn’t answer my main question. Why I should beleive you rather then 17 people that are far more skilled then you are in imunotherapy, oncology and statistics that voted 13-4 for efficacy and 17-0 for safety??? I even add flemings and make it 13-5…Why?
    You say that the panel composition was to blame for the positive vote. Who would be more expert on judging an imunology drug, imunologist or oncologist with an agenda to protect their turf?
    Here is an article from the NY times that illustrate the foolishness of your argument.
    ****
    2 potent cancer drugs works, but rarely used
    By Alex Berenson
    NEW YORK TIMES NEWS SERVICE
    July 14, 2007
    The patients’ stories sound nearly impossible.
    After an hourlong infusion, Linda Stephens, 58, has been cancer-free for seven years. Dan Wheeler, three years. Betsy de Parry, five years. Before treatment, the trio had late-stage non-Hodgkin’s lymphoma, a cancer of the immune system, and a grim prognosis.
    All three recovered after one dose of Bexxar or Zevalin, both federally approved drugs for lymphoma. And all three can count themselves as lucky.
    Not just because their cancers responded so well. But because they got the treatment at all.
    Non-Hodgkin’s lymphoma is the fifth-most common cancer in the United States, with 60,000 new cases and almost 20,000 deaths a year. But fewer than 2,000 patients received Bexxar or Zevalin last year – about 10 percent of candidates suitable for the drugs.
    “Both Zevalin and Bexxar are very good products,” said Dr. Oliver W. Press, a professor at the University of Washington and chairman of the scientific advisory board of the Lymphoma Research Foundation. “It is astounding and disappointing” that they are used so little.
    The reasons that more patients don’t get these drugs reflect the market-driven forces that can distort medical decisions, Press and other experts on lymphoma treatment say. The result can be high costs but not necessarily the best care.
    Although the two drugs have not been clinically proven to prolong survival compared with other therapies, patients are more likely to respond to them than to standard treatments. Trials to test whether Bexxar and Zevalin do have a survival benefit are nearly complete.
    Other, more thoroughly tested lymphoma drugs are preferred as first-line treatments. But doctors often repeatedly prescribe such drugs after they have lost their effectiveness – and when Bexxar and Zevalin might work better.
    “Oncologists use everything in their cupboard before they refer,” Press said. “At least half the patients who get referred to me have had at least 10 courses of treatment.”
    When Bexxar and Zevalin were approved, analysts expected they would be used widely. But the drugs have run into an obstacle that so far has been impassable. Because they are radioactive, they are almost always administered in hospitals, not doctors’ offices. As a result, cancer doctors are not paid by Medicare and private insurers for prescribing the drugs, as they are when they give patients a much more common treatment, chemotherapy.
    In addition, most oncologists outside academic hospitals treat many different cancers and may be only vaguely familiar with the drugs, said Dr. Andrew D. Zelenetz, chief of the lymphoma service at the Memorial Sloan-Kettering Cancer Center. “There are a number of barriers,” Zelenetz said.
    Press and Zelenetz acknowledge they have financial incentives to support the drugs. Press has been paid to speak at medical education seminars sponsored by the makers of the drugs, and Zelenetz is paid when the companies sponsor clinical trials at Memorial Sloan-Kettering.
    Both said the money was a fraction of their overall income and had not colored their views.
    Some patients say they would not have received Bexxar and Zevalin if they had not demanded them. Wheeler, of Kalamazoo, Mich., said he received Bexxar in April 2004 only after insisting on it when his lymphoma recurred.
    “I told my local oncologist, ‘I want Bexxar; you give me a referral,’ ” Wheeler said. “I’ve been a real pain.”
    Zevalin and Bexxar are the first in a new class of drugs called radioimmunotherapies. They deliver radioactive particles directly to cancerous cells to kill them. Idec, a San Diego company that is now part of Biogen Idec, invented Zevalin. Corixa, a Seattle company bought by GlaxoSmithKline, developed Bexxar. Both drugs are expensive, costing about $25,000 per treatment. But one dose is usually sufficient. The cost of the drugs is similar to a full four-month regimen of chemotherapy and Rituxan, another lymphoma treatment.
    For decades, lymphoma has been treated with chemotherapy, drugs that attack cancer cells but that can have severe side effects. Alongside chemotherapy, most patients receive Rituxan. It was discovered by Idec, the same company that found Zevalin, and is marketed in the United States by Genentech, the world’s largest biotechnology company.
    Since it was approved in 1997, Rituxan has become standard treatment for newly diagnosed lymphoma patients, based on clinical trials showing that it makes chemotherapy more effective.
    Rituxan is the top-selling cancer drug worldwide, with sales in 2006 of $4 billion. A typical course of treatment costs $20,000.
    Doctors agree that Rituxan is an excellent drug, with only minor side effects for most patients. Still, the few head-to-head clinical trials that have been conducted show Bexxar and Zevalin are as effective as Rituxan, if not better.
    The Food and Drug Administration approved Zevalin in 2002 and Bexxar in 2003 for the treatment of slow-growing lymphoma that had failed previous treatments.
    Wall Street analysts projected that Zevalin would reach $100 million in sales in 2003. But the drug hit roadblocks immediately. Its five-figure price caused insurers to balk, and its radioactivity made some oncologists worry it might prevent them from giving other treatments later.
    Prescribing Zevalin also requires oncologists to coordinate care with the hospitals that administer it. To get either Zevalin or Bexxar, patients first receive a low-radiation diagnostic dose, then imaging scans, then a high-radiation therapeutic dose, which comes a week after the first dose. Over the next weeks, the patient’s red and white blood cell counts must be monitored.
    The back-and-forth makes the treatment complicated to oversee, said Dr. Joseph M. Connors, a lymphoma specialist in Vancouver, British Columbia. “The doctors looking after people tend to turn to tools that they themselves know how to use and are familiar with,” Connors said.
    For most oncologists, infusions of chemotherapy, Rituxan and other drugs remain their primary source of income. Even so, Connors said, doctors might turn to Bexxar and Zevalin if the drugs are proven to extend survival over older treatments. While preapproval trials showed the drugs shrank tumors more frequently than Rituxan and suggested patients would survive longer, the test groups were too small to confirm it.
    Connors said Idec and Corixa should have designed their clinical trials to prove – not suggest – the drugs increased survival.
    Two clinical trials meant to answer that question are under way, but their results have not been reported. Until they are, doctors will be reluctant to use Bexxar and Zevalin, Connors said.
    Meanwhile, patients who have benefited from Bexxar and Zevalin say they cannot understand why they are not more widely used.
    Betsy de Parry received Zevalin in 2002, when she was 52. She had already failed chemotherapy and Rituxan.
    But she responded quickly to the injection and has remained cancer-free.
    “It’s not that I believe that radioimmunotherapy is right for everybody,” she said. “I just think that patients, all patients, should know their options.”
    ******
    The other agument that you make or I should say Flemming makes and you repeat is that Provenge in both trials missed the end points. Well as I already said, everyone in the world and their dogs already knew that going in, including the FDA. In fact the FDA, knowing all this granted them Fastrack status and accepted their NDA. The panel was to review the data and render an opinion on the merrit of the survival data and they did by an overwhelming majority. To go back and argue the missed endpoints is worthless. Move on and judge the survival data. A majority of experts already have and deemed it substantial.
    tall
    Ps: Your standard reply to anyone that questions your logic is that they must own DNDN? Well big surprise, you caught me I own DNDN, as I do a bunch of other stocks.
    For the record, I am happily retired and my DNDN holdings have little to no impact on my finacial well being. I got interested in the stock becasue my Fathere in Law has prostate cancer. It came back twice already and he is on hormone therapy now. If that’s unsuccesfull or if it comes back again, he will have no option. He is a very proud man and didn’t even want to take the hormone therapy. I know he will not put up with the toxicity of Taxotere. SO I was hoping that Provenge would have been approved by know and wanted to see it applied for even earlier stages.
    SO Maggie, please grow up. Thanks.

  12. 1. AIPC patients are typically elderly TERMINAL cancer victims with an approximate 18 month expected life-span and often other compounding illnesses.
    2. SURVIVAL trumps all surrogate endpoints in clinical trials as several oncology meetings this year have espoused which is a substantial CHANGE from the “old” ways of looking at cancer treatments (chemo) and their results such as TTP.
    3. IMMUNOTHERAPY cancer treatment signs and symptoms appear to be significantly different from CHEMOTHERAPY treatments. Our nations best and brightest–including Federal government physicians and researchers–are currently recommending that IMMUNOTHERAPY be assessed differently from Chemo… something that is NOT being done presently.
    4. THREATS to Drs Scher and Hussain: No question, such tactics are immoral and illegal and, if true, should be investigated and punished to the full extent of the law whether they come from cancer patients (and families), investors, advocates or whomever.
    You report Sloan Kettering reports some are email. Those are more than easily traceable across the internet by law enforcement personnel. Have those two physicians made police/law enforcement reports of these alleged threats? No one–reputable or not–in the media has reported from either physician any call for law enforcement investigation.
    If not, why not?
    If anyone received such alleged multiple death threats and took them seriously enough to comment about them publicly in the media as Scher and Hussain have as well as to secure bodyguards, doesn’t common sense suggest that one would also discuss the matter with law enforcement?
    5. SCHER COI: This topic, while talked about in generalities herein seems to be lacking in specifics.
    Scher seemed to represent to the FDA via his Feb 2007 Application for a Waiver to serve on the Provenge Advisory Committee that he has 1 stock ownership (between $5,000 and $100,000) and 2 “Grants (Related)” each between $100,000 and $300,000.
    Publicly available information shows these apparent Scher COIs (so far): [Particular attention is directed to items 1, 2 and—especially–15, but ALL—in totality– are important and telling, imo]
    1. Novcea: STUDY CHAIR of DN-101; Grants & Research support
    2. Medivation, Inc: PRINCIPAL INVESTIGATOR MDV3100;
    3. Innovive Pharmaceuticals: PRINCIPAL INVESTIGATOR
    4. Infinity Pharmaceuticals: PRINCIPAL INVESTIGATOR
    5. Cougar Biotechnology: PRINCIPAL INVESTIGATOR; Advisory Board
    6. Department of Defense: PRINCIPAL INVESTIGATOR PC Clinical Trials-P1 and P2
    7. Bristol Myers Squibb: Consultant, Grants & Research support
    8. Millennium Pharmaceuticals: Grant of Research support
    9. sanofi-aventis: Grants & Research support
    10. Genta: Scientific Advisory Board (as of March 6, 2007; since removed from web, but cached)
    11. Biogen-Idec: Joint stock with spouse
    12. Pfizer: Joint stock with spouse
    13. Pharmion: Financial Conflict of Interest per Scher quote in MedPage
    14. GPB Biotech: Financial Conflict of Interest per Scher quote in MedPage
    15. PROQUEST INVESTMENTS: Consultant, Scientific Advisory Board; Limited Partner FINANCIAL interest
    Go back and read #15 again…. He’s reported to be a “LIMITED PARTNER” in a Proquest partnership; doesn’t that suggest FINANCIAL investment?????
    =========
    6. CONDITIONAL Approval could (and should after full 500 patient enrollment) be granted by the FDA with the follow-up 500 patient trial as a requirement for full Approval. Provenge is clearly a substantially safe treatment and patients need PROVENGE NOW; the current alternatives for cancer victims are do nothing and die sooner or chemo.
    7. You stated why would anyone want a 50-50 chance of receiving Provenge by being in a trial? It’s not 50-50; the Provenge arm will have 2/3’s of the patients and the placebo arm will have 1/3. Chances are 67% of getting Provenge.
    8. QUALITY of LIFE: This horse has been well detailed above. Suffice it to re-state that Provenge is a 3 treatment immunotherapy similar to a blood infusion given over the course of a month with mild flu-like symptoms for 1 or 2 days following each treatment.
    Chemo is an extended treatment (over a year?) refused by 50% or more of those recommended to take it and results in about 1 to 2% of the TERMINAL cancer patients who take this treatment dying from the treatment itself and NOT from their disease. Hospitalization and added drug treatments (all expensive) to treat the horrible side-effects of chemo are often required.
    EACH patient’s Provenge treatment is specifically designed for that sole patient. This is not a cookie-cutter, one-size fits all treatment such as pills or chemo which only vary in the dosages (i.e. 2 pills/day for patient A and 3 pills/day for patient B) or treatment length—but all take the same meds.
    The treatment I would receive is based solely on immuno-activation given to my own blood. It cannot be used in anyone else’s body; their individual blood needs to be treated and then re-infused into themselves only.
    9. Mr. Edwardo Garcia of San Diego, a Provenge patient who has survived more than 5 1/2 years since treatment testified both in favor of Provenge and about his Quality of Life, especially with his grandchildren, at the FDA AC on Provenge.
    Mr. Kenneth Agnor of Chesapeake, Virginia, another Provenge treated patient, credits Provenge with arresting his prostate cancer diagnosed in 1992.
    You talk about Fleming (a Ph.D., if memory serves) and his being a cancer patient. Here’s another MEDICAL doctor and his results with MORE THAN 30 patients reported in media.
    The Norfolk, VA newspaper also reported, “Dr. Paul Schellhammer, a Norfolk urologist, oversaw the treatment of more than 30 local patients on Provenge in clinical trials several years ago and now has patients in a third study that the FDA will use to inform its decision. Schellhammer said he had been paid in the past by Dendreon for serving as an advise r [sic].”
    “When a drug improves survival, it’s a hallelujah event,” Schellhammer said. He said he has patients who were treated with Provenge “who are still alive with minimal other therapies, which just defies the odds.””
    “And, the treatment seemed to be especially patient-friendly, Schellhammer said, with little of the harshness of some chemotherapy drugs.”
    “No patient withdrew because of the side effects, which is virtually unheard of in an advanced cancer treatment trial,” said Schellhammer, who is director of the Virginia Prostate Center at Eastern Virginia Medical School and incoming president of American Urological Association.”
    This not from a statistician who crunches cold, hard numbers, but from a Physician actually working in the trenches with real, live patients!
    10. THE CANCER LETTER – It’s reportedly:
    A. NOT peer-reviewed
    B. Is run from Mr and Mrs Goldberg’s home basement in the Washington, DC area.
    C. They “are” the staff of this publication; previously, Mrs Goldberg’s father ran it.
    I believe all can agree that this is no BARRON’S- or THE NEW YORK TIMES-type publication.
    i. The 3 doctor’s anti-Provenge letters published in THE CANCER LETTER were CONFIDENTIAL letters purportedly written by them to the FDA which appeared almost evenly spaced about 1 week apart prior to the FDA’s May 9th decision.
    ii. I know, at least, the Scher and Hussain letters began with a long, detailed CV in the opening paragraph. Does it strike anyone as odd they would re-inform the FDA of their qualifications before their post-AC meeting attack on Provenge? The FDA has to be more than well-acquainted with their work and educational history; after all, didn’t the FDA invite them to serve on this important committee as “temporary government employees” as the FDA’s own paid consultants?
    Could it possibly be that these letters were NOT intended to be CONFIDENTIAL and, instead, for public consumption?
    iii. How did THE CANCER LETTER acquire copies of these 3 CONFIDENTIAL FDA letters?
    iv. Why hasn’t any law enforcement agency investigated how these CONFIDENTIAL letters to the FDA were “leaked” to THE CANCER LETTER?
    v. Such a public letter writing campaign has to be unheard of in the FDA history. Doesn’t this strike anyone as more than unusual to have 3 such letters conveniently leaked 1 week apart? Doesn’t it smack of intentional sabotage?
    ENDING:
    No matter which camp one resides in, this is a genuine tragedy for prostate cancer victim of which some 27,050 men–according to the American Cancer Society and the National Institutes of Health–will succumb to their TERMINAL prostate cancer in the next 12 months alone! It appears interim data will be at least 12 additional months away. In the event it takes the full 2 or 3 years for the complete data to be submitted to the FDA and for the FDA to act, the Death Tally will be between 54,000 and 81,000 men who will die prematurely from the FDA’s current actions.
    Is it no wonder patients, families and advocates are making this cause known to media, Congress and the FDA? Such a horrendous death toll, if noted daily by the media just like the Iraq war casualties are, would create a firestorm and clamor from the general public as well for this product to be released to those suffering such TERMINAL cancer.
    The DAILY Death Total is 82 (EIGHTY-TWO-emphasis added) men each and every day, 24 hours per day and 7 days per week and that, to me, is totally unacceptable when a “safe” product exists which will help a significant portion of these men EXTEND their lives and do so with excellent Quality of Life with the family and friends!.
    Provenge satisfied 100% of the 17 voting and FDA-invited and imminently qualified members (including Scher and Hussain) at the March 29th FDA AC meeting that it is “substantially safe” and 13 of those 17 positively voted that Provenge shows “substantial evidence of efficacy”.
    FINALE:
    September is Prostate Cancer Awareness month. Be sure that you’ve had your prostate cancer screening and insist the same for your brothers, fathers, and any other male family and friends! The life you save may be your own or that of a loved/esteemed one.
    Clearly this issue has ardent supporters on both sides; Thank You! for bringing this issue to public attention!

  13. Maggie,
    I wanted to respond to several flaws in your logic that exemplifies the problem with provenge. I am not a shareholder in the maker of provenge. I am a physician and the MD’s I know who are familiar with provenge feel, like those on the FDA panel, that it is safe and effective. Benign immunotherapy like provenge, as a part of combination therapy is almost certain to become the next dramatic evolution in standard of care treatment for cancer patients. Regardless of what the good Dr. Rosenberg emailed you I would suggest you peek at the dramatic data presented by either Drs. Jeffery Schlom of the NCI or Daniel Petrylak.
    If you think the FDA just saved us a bunch of money, think again. While there will indeed be short term savings, the FDA has just placed rigid requirements for the development of these very benign medicines on par with lifethreatening chemotherapies that will cost us many times what we have saved in the short run. Who do you think will end up paying for this? I treat cancer patients on a daily basis struggling to relieve their suffering from, among other things, side effects of chemotherapy; people with anorexia, burning up with fever. Every day we hold up immunotherapy is another day we prolong suffering and run up huge,expensive bills. Who will end up paying for this?
    You stated: “The egregious part, to me, is that investors in the company should have any say at all, or even the right to comment, on the scientific deliberations.” While you qualify your statement by saying the FDA should avoid conflicts of interest it is troubling, to say the least how you and most others gloss over the real issue here. The issue, believe it or not isn’t investors in provenge raising a fuss. In fact, activism is a part of democracy. The real issue is the fact that likely the largest investor involved here is Dr Howard Scher, a highly placed advisor for a hedge fund that is heavily invested in a potential competitor to provenge and who weighed heavily in the FDA’s decision to reject provenge. This is akin to a defendant’s sibling being on a jury resulting in a hung jury. Now you can say that the jury made the correct decision all you like but, really now, surely you see the travesty even if you don’t admit it.
    One final thought. The notion that the few naysayers were oncologists who, unlike the rest of the AC panel, actually treat prostate cancer patients and therefore are inordinately qualified is incredibly insidious, particularly in light of the conflicts of interest. All MD’s go to the same medical schools, take the same statistics courses, the same licensure exams. Most importantly, we are all trained to finally ask ourselves: what would we want if we were the patient?
    Chuck Bennett, MD

  14. Thanks for the comments.
    Tall when horizontal points out that Spike and I are not statisticians. I have studied statistics, and it’s obvious that Spike also has real knowledge of the subject.
    But let’s go back to what Fleming, a biostatistician with a national reputation says. (See my long response to Walldiver on July 25–Fleming also wrote a long letter to the FDA saying that it should not approve Provenge without further evidence.)
    What is signifiant, I think is that Fleming actually Has Prostate Cancer–which gives him quite a bit of credibilty in my mind.
    One would expect that, as a prostate cancer patient, he would be eager to have Provenge approved as soon as possible. But he understands the science behind
    randomized controlled trials, and is able to look beyond his own narrow self-interest to take a broader view when he says:
    “I strongly disagree that all patients want is a ‘choice.’ Patients want an ‘informed choice.’ How would pre-mature approval of Provenge that could diminish the likelihood of obtaining reliable results from the larger trial be in the best interests of prostate cancer patients?”
    I would also note that, not long ago, Fleming warned the FDA about another drug that they were approving. He turned out to be right. Maybe that is why the FDA felt it had to listen to him this time around.
    I also wonder why some investors are so anxious to have Provenge approved immediately. If they had faith in the drug, one would think that they would be willing to wait until the middle of next year when results from the larger, well-designed trial begin to come in. (The FDA has indicated it may approve the drug then if the results are good.)
    Perhaps some investors want to see the drug approved this year so that they don’t have to risk bad results from the larger trial? IF the drug were approved this year, the stock would soar, and they could dump it and pocket the profit witout worrying about what happens in the more definitive trial. If I sound cynical, it is because I covered Wall STreet for Barron’s for about 12 years. (I may have made this suggestion above; if so I apologize for the repetition.)
    Moreover, when Fleming says that you can’t change the end-point of a study after the fact, he is entirely right. As Spike points out above:
    “it is not appropriate to dumpster dive for new findings when the tested hypothesis failed to pan out. From everything that’s been written, Provenge was designed to slow the progess of the disease, which it did not do. So, it did something else, and nobody understands the mechanism by which it happened, and that result only was discovered after the intended study failed and the researchers had to come up with something else to make the drug look good.”
    “That’s fine,” Spike continues, “we all understand that’s how science works. But, after the unintended consequence with no understood mechanism is determined, the scientific approach is to run another study that intends to measure that specific variable and see if the result can be replicated.”
    Tall-when-horizontal–I am wondering why you are so outraged by Spike’s arugment (and my argument). Do you
    happen to own the stock (or have you ever had a financial interest in the company.)
    Ciarin and Walldiver–
    While the FDA usually follows the advice of an advisory committee, sometimes it doesn’t. This is not
    unprecedented.
    What is very unusual is the fact that the majority of people on the panel were not oncologists. In the past, when a cancer drug was being evaluated, most of the members of the panel were oncologists, many of whom
    worked directly with patients. The composition of the panel may help explain why it took so little interest in the quality of life that the average patient enjoyed
    during those extra months of life. Perhaps they just didn’t realize how painful late-stage prostate cancer can be.
    Walldiver– As you know, in everyday language “average” is commonly used to mean “median”, but you are absolutely right, here it’s a median average: half of the patients who received Provenge gained more than 4.5 months– half gained less.
    What’s important is that we don’t know whether the Provenge CAUSED increased survival. The fact that the trials showed absolutely no sign that Provenge slowed the course of the disease or the onset of pain (no lowering of PSA levels, etc.) seems to contradict the notion that it was the Provenge that caused the patients to live longer. The placebo was not inert, so there is the possibility that it harmed the patients in the control group. Or the extended survival could just have been chance. We’ll just have to wait for the results from the larger trial.
    As for the crossovers, there is another factor that
    makes the results uncertain. People like Fleming say that this is another example of how the trial was poorly designed. .

  15. Spike,
    What is your point?? The whole world knows that provenge didn’t meet the original end points, and so did the FDA. They granted fast track status and accepted the NDA. SO the FDA was already past that, it’s time you do the same. The original endpoints essentially tried to measure disease progression by measuring tumor size. Well imunotherapy takes a lot longer to work then threrapies that kill all the cells in sight regardless whether they are cancer cells or good cells (as in chemo). If they had waited a little longer before taking the measurements we probably wouldn’t be here discussing the merrits of provenge. So anyway all that is water under the bridge, the FDA agreed to that by accepting the NDA. The new basis for approval was supposed to be survival. So at least, lets discuss the proper endpoint, survival. Are you arguing that provenge did not show subtantial evidence of survival? If you are then you are disagreing with a panel of experts that voted 13-4 that provenge did show subtantial eveidence of extending life.
    Come on you and and Maggie show me your credentials, tell me why I should beleive you rather then the panel of experts in imunotherapy, oncology and statistics that voted 13-4 for efficacy and 17-0 for safety. Tell me why you are siding with a couple of doctors that had everything to lose by approving provenge.
    you have nothing to say, don’t you…
    tall

  16. Spike, please read my posts again. The p value for the primary tested hypothesis was 0.052 for time to progression. The FDA claimed it was 0.085. Either way, that was the primary endpoint, and the 0.21 p value for time to symptomatic pain was the secondary endpoint. One additional important point to make is that this trial was designed in 1999 and conducted from 2000-01 when much less was known about the chronology of hormone-refractory prostate cancer. The subsequent Taxotere trials and all of the other Phase III trials being run by other companies are designed with the pioneering Provenge trial in mind.
    Dendreon, its investors, and many patient advocates have been fully aware the whole time that its Phase 3 trials are not statistically pristine. The filing was based on the premise that for a terminal condition, Provenge showed a statistically significant survival benefit, plus every remaining endpoint that was a surrogate for survival trended in a beneficial direction. The company, its investors, and patient advocates were hoping for a positive, common sense, non-conflicted decision from the FDA in the best interests of terminal patients and their doctors, instead of one based on (1) rigid biostatistical criteria and (2) fear that the oncology cooperative groups would fund adjuvant immunotherapy trials instead of adjuvant chemotherapy trials, thus taking grant money away from the employers of prostate cancer oncologists/academicians (whose funding share increased after 2004 Taxotere approval) and putting it in the hands of urology groups (who dominated the treatment of the asympomatic stage of HRPC prior to Taxotere).

  17. tall,
    If you read the full article, she lays plenty of the blame at the feet of the FDA for allowing such a compromised person to make the decision. Plenty. But that doesn’t change the fact that the drug failed to meet the standard it said it was going to meet and the standard the trial was designed to measure: slowing the progress of the disease.
    These days, it’s a miracle the FDA turns down anything. So comparing this drug’s treatment to the treatment other drugs receive isn’t very meaningful, either.

  18. Maggie, maggie, maggie… Please take a statistics course or design of experiment course at your local city college prior to making any other comments on whether provenge will help or not. If you refuse to do so, at least side with the majority of scientists that reviewed the data (13-4 for efficacy and 17-0 for safety). For you to choose to side with the minority w/o any statistical creds to offer any inteligent points or counterpoints is useless.
    Scher has huge conflict of interests, the approval of provenge would have impacted impacted him professionaly to say nothing of his pocket book. His unprecedented campaign to influence the FDA decision given his conflicts was sickening.
    Finaly and most importantly you have failed to address the main issue. Why did the FDA, for the FIRST time in its history (for terminal diseases) go against the advise of its own panel of expert when they voted overwhelmingly in favor of Provenge aproval? Why did they allow a couple of individulas with huge COI’s to highjack the process?
    Given your previous work, I don’t expect you to rise to the challenge of answering these questions, but I thought I’ll give you a chance anyway. Thanks for the vine.
    tall

  19. walldiver,
    All conclusions seem valid once they attain significance. But someone as well-versed as you in research should know that it is not appropriate to dumpster dive for new findings when the tested hypothesis failed to pan out. From everything that’s been written, Provenge was designed to slow the progess of the disease, which it did not do. So, it did something else, and nobody understands the mechanism by which it happened, and that result only was discovered after the intended study failed and the researchers had to come up with something else to make the drug look good.
    That’s fine, we all understand that’s how science works. But, after the unintended consequence with no understood mechanism is determined, the scientific approach is to run another study that intends to measure that specific variable and see if the result can be replicated. Then, you can say whether there is a real effect or not.
    A .21 p value for the tested hypothesis isn’t that great. It’s something, but it’s still very possible that random chance generated that outcome and with such a small sample size, it doesn’t say much at all.
    Run another study that’s designed to test survival, and if it pans out, then go with it. Pharma companies bemoan how much they have to spend on clinical trials, and use that as an excuse to price-gouge consumers. This time, the consumers should at least get their money’s worth.

  20. Ugh. I see I am going to have to provide some basic biostatistical education here, as a number of the Provenge detractors keep mentioning something along the lines of “but the Provenge patients only lived an average of 4.5 months longer than those in the control arm” when making a financial or statistical argument against approval. The 4.5-month benefit in the 9901 Phase 3 trial is the MEDIAN survival benefit, not the AVERAGE survival benefit. The median survival is calculated by the measuring the number of months alive for the patient in the 50th percentile of the treatment arm, vs the # of months alive for the 50th percentile patient in the control arm. So, Provenge’s MS was 4.5 months better than the control arm’s MS.
    However, the average survival of the Provenge arm patients is likely 9 to 12 months longer than the average survival of the control arm patients. Why? Because 34% (28/82) of the Provenge arm patients survived the full 36 months of the formal followup included in the trial protocol, while only 11% (5/45) of the control arm patients did. In addition, it appears that 20/28 of those in the Provenge arm who survived the full 36 months after formal followup was stopped, went on to survive a total of least 66 to 84 months by the time of the advisory panel meeting in March 2007, according to the FDA briefing documents. So in summary, it’s quite apparent that the average survival benefit from Provenge treatment is substantially greater than its median survival benefit.
    Another point I haven’t made yet is the beneficial effect of salvage Provenge after progression for those patients in the control arm who opted to receive it. Approximately 75% (34/45) of the patients in the control arm opted to receive cross over and receive salvage Provenge after their cancer progressed, and their survival results were still counted as part of the control arm. Dendreon did not do a final, 36-month breakdown of the entire control arm between the crossovers and the non-crossovers…the only breakdown we have is from Sept 2003, one full year before the final 36-month survival numbers were calculated. Here are the Sept 2003 numbers for median survival:
    26.3 months Provenge arm
    23.9 months control arm crossovers
    19.3 months control arm non-crossovers
    That’s a 7.0-month median survival benefit for the Provenge arm patients vs the control arm patients who, upon enrollment in the trial, opted not to receive salvage Provenge after progression if they were to be randomized into the control arm. Thus it appears that Provenge achieved its statistically significant survival benefit despite having to compete with a substantial percentage of patients who received later Provenge.
    Finally, to answer Maggie’s point about the basis of Fleming’s biostatistical argument against approval: this isn’t just some random endpoint…it’s survival. Provenge showed a survival benefit at the point of each unblinding. In addition, while the progression and pain endpoints failed to reach statistical significance, Provenge did not “fail to show a benefit in these endpoints.” The median TTP was 11.7 weeks Provenge vs 10.0 weeks control (p=0.052 to 0.085), while the p value for time to pain was 0.21. Provenge in both endpoints showed a benefit and trended toward statistical significance, but did not attain it.

  21. The FDA advisory committee for Provenge voted 17-0 on safety and 13-4 on substantial evidence of efficacy. It is unprecedented in the history of the FDA that this level of support for a new treatment would not be approved. Therefore, there must be unknown factors at play in this case that led to the denial by the FDA. These factors need to be unearthed in a thorough investigation.
    Sincerely
    Ciaran N. Cronin PhD

  22. Rick and Walldiver:
    Rick is right: runaway healthcare inflation is becoming
    an enormous problem. If healthcare spending continues to soar as it has for the past seven years, it won’t be long before we have to cut back in other areas–education, defense, the environment, the arts . .
    See the longer version of this Provenge story where I
    quote a Wall Street analyst (quoted in the Wall Street Journal) saying that drug companies have gone way too far in over-pricing cancer drugs.
    WallDiver, responding to your point: FDA approval IS linked to healthcare spending. The minute the FDA approves something Medicare almost automatically covers it.
    MedPac–the advisory board that comments to Congress on
    Medicare spending–has said that Medicare needs to begin
    thinking about “cost-effectiveness” before paying for drugs.
    Is a drug that costs $40,000 to $60,000 to buy an extra 4.5 months of perhaps very painful life for the average
    patient worth it? Perhaps–but only if we are very sure
    that it does lead to an extra 4.5 months of life.
    WAlldiver, despite all of your statistical analysis you
    never responded to Fleming’s major point in his letter to the FDA (see mylong response to you above where I quote Fleming). The company’s attempt to go back and slice and dice the numbers another way after the fact just isn’t kosher.
    In addition Bev M.D. is right–Provenge is not a unique breakthrough drug. Researchers have been trying to figure out how to get the body’s immune system to fight cancer for many, many years. There are now 60 such drugs that are being tested on humans. And people like Rick (scroll up for his first comment yesterday) think
    that Provenge is not necessarily the best of the lot.

  23. First, let me make one thing clear. Provenge is NOT a cure for cancer. No one–including the company–claims that it is.
    As Bev M.D. points out: “Provenge will not save any lives so someone is misleading desperate patients if they think so.”
    The company’s best hope is that Provenge might “slow the progress of the disease”–but the manufacturer’s clinical trials failed to show that Provenge put a brake on the disease.
    Then the company went back and said “hey–in the small group of patients that took Provenge, patients survived by an average of 4.5 months longer than those who took the placebo. So maybe, even though PRovenge doesn’t appear to slow the progress of the disease, it somehow caused them to live 4.5 months longer.
    How were they feeling during those extra 4.5 months? Were they in excrutiating pain? The company says it kept no record of their quality of life. We know that the drug itself seems to have realtively few
    unpleasant side effects (except the possibilty that it
    causes strokes) but the disease itself is often very painful in the final months.
    I also tend to agree with Bev M.D. that investors “in the company should have any say at all, or even the right to comment, on the scientific deliberations. Much less threaten. Unacceptable.”
    To say that investors shouldn’t have the right to comment might seem to be going a little far (given the
    first amendment and all) but there is a definitely a problem when investors spread misleading rumors or tout a supposed cure, raising false hopes.
    Everyone needs to realize that when someone has a financial interest in a product there is an automatic conflict of interest. Whether that person is a doctor, a research scientist or a layman, it is very ,very difficult not to be somewhat biased. This is why some physicians have decided that they do not want to have any financial stake in healthcare companies.
    PSA Rising (a newletter for prostate cancer patients written by a woman whose husband died of prostate cancer) offers an example of the kind of conflict I’m talking about on May 20, 2007:
    “FoxNews (”Fair and Balanced”) aired Killer Bureaucracy: Why the FDA is Keeping Lifesaving Drugs from Cancer Patients May 19, 2007. Paul Gigot interviewed Dr. Scott Gottlieb. Scott Gottlieb MD, a stock analyst appointed to a top FDA job by President Bush in 2005, returned to Wall Street where he promotes Dendreon’s Provenge in his Forbes/Gottlieb Medical Technology Investor newsletter.”
    I then followed her link to this story about Gottlieb:
    Wednesday, August 24, 2005 –
    Wall Street biotech insider gets No. 2 job at the FDA
    By Alicia Mundy
    Seattle Times Washington bureau
    Dr. Scott Gottlieb
    Seattle Times special report: Selling drug secrets
    Only a month ago, Dr. Scott Gottlieb was a Wall Street insider, promoting hot biotech stocks to investors.
    Now Gottlieb holds the No. 2 job at the Food and Drug Administration (FDA), the federal agency that approves new drugs, oversees their safety and affects the fortunes of companies he once touted.
    Wall Street likes the appointment of Gottlieb, 33, who believes in faster drug approval and fewer news-release warnings to the public about potential side effects of drugs.
    But some medical experts are shocked by his July 29 appointment, coming at a time when the public is increasingly concerned about the safety of popular medicines. In addition, the federal government has just begun scrutinizing the growing financial ties between Wall Street firms and doctors researching new drugs.
    Gottlieb’s new job “further impedes the independence of the FDA,” said Dr. Jerome Kassirer, former editor of The New England Journal of Medicine. “Gottlieb has an orientation which belies the goal of the FDA.”
    “I’ve never heard of anything like this,” said Merrill Goozner, a director at the liberal Center for Science in the Public Interest.
    “If he’s had dealings regarding companies whose products are up for review at the agency, it strikes me as a potential conflict of interest. You want a barrier between the regulated and the regulators. It’s fundamental,” Goozner said.
    A half-dozen current or former officials at the FDA say they do not know of anyone from Wall Street moving directly into such a high-level job at the agency.
    Until last month, Gottlieb was editor of a popular biotechnology investor newsletter, Forbes / Gottlieb Medical Technology Investor. Forbes touted Gottlieb’s stock-picking success on its Web site in mid-May:
    “Special Offer: In the last few months, Dr. Scott Gottlieb recommended two cancer cure stocks to subscribers that have already climbed 38%. Click here for the latest report from Forbes / Gottlieb Medical Technology Investor, ‘Three Biotech Stocks To Buy Now.’ ”
    Now, as one of three deputy commissioners, Gottlieb will help oversee such major policies as the FDA’s fast-track approval process for drug and biotech products, a priority for many Wall Street funds and the pharmaceutical industry.
    Gottlieb said he has cut his ties to Wall Street and discontinued his newsletter. He doesn’t see a conflict between that work and his new role as a high-ranking regulator.
    “What I learned while working on Wall Street has informed almost everything that I have done since, but especially my work in the government,” he responded in an e-mail to questions from The Seattle Times. (The FDA would not allow the Times to interview Gottlieb or provide answers to questions about his background. The FDA has not released his financial-disclosure forms.)
    You’ll find the full story here http://seattletimes.nwsource.com/html/nationworld/2002450292_gottlieb24.html
    You’ll find Gottlieb’s Forbes column promoting Provenge here http://www.forbes.com/business/healthcare/2005/02/18/cz_sg_0218soapbox_inl.html
    For more on Gottlieb, search Merrill Goozner’s website, http://www.gooznews.com

  24. Most estimates of Provenge’s cost if approved are in the $35K-50K range per patient. A typical 7-month course of Taxotere would be in the $18-20K range (for the cost of the Taxotere only). This does not take into account the cost of any other drugs to be taken with Taxotere (prednisone for everyone, granted it’s generic), or the cost of drugs that need to be taken because of Taxotere toxicity (Neupogen, Epogen, etc.), nor the cost of hospitalization due to Taxotere adverse events. A large percentage of Taxotere patients have to be hospitalized and/or be administered Neupogen to increase their white blood cell count and/or Epogen to increase their red cell count. Then there are the drugs that need to be taken to alleviate Taxotere’s nausea/vomiting side effects, mouth sores…well, you get the picture. Supposedly the average cost per patient for Taxotere when the percentages of patients w/side effects and hospitalizations are factored in is in the $65K range…and Taxotere is one of the milder chemos.
    Cost has nothing to do with whether or not the FDA should approve. BMY and Imclone priced Erbitux at $8K per month, and it’s common for patients to be on Erbi for a year. It’s already approved. Agreed, at some point our health care system could collapse, but that should not factor into whether or not a drug gets approved.

  25. “Strict biostatistical rules at the expense of clinical common sense have taken over the oncologic product review process at the FDA. That’s the basis of my argument.”
    I get your point, but when we’re talking very expensive treatments, somebody somewhere eventually has to say words like “enough” and “no.” Healthcare of any kind is not in infinite supply, otherwise its price would be zero. Obviously that’s not the case. Therefore demand cannot be infinite either (i.e. everyone that wants it gets it).

  26. Maggie (I guess I can call you Maggie now, since everyone else is ;-),
    A couple points from your last reply to me:
    Re the Intermune/Actimmune example of the first Phase 3 in IPF…yes, it did fail the primary composite endpoint of progression or survival. However, it’s not quite the same situation as the Provenge 9901 Phase 3 trial. The secondary endpoint of overall survival in the Actimmune Phase 3 did not achieve stat sig for the entire intent-to-treat population (p=0.08). It did achieve stat sig in some subgroups, including the subgroup you mentioned. However, as we all know, subgroup data mining is a big no-no at the FDA.
    http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=ITMN&script=460&layout=-6&item_id=414304
    In contrast, in the Provenge 9901 trial, the stat sig overall survival endpoint of p=0.01 WAS achieved in the entire intent-to-treat population.
    Furthermore, those of us familiar with biostatistics need to remember that the p=0.05 figure for statistical significance is an arbitrary figure. I would definitely have sympathized with the Provenge bears a little more if 9901’s primary endpoint of TTP had not been close to achieving statistical significance. If the FDA had accepted Dendreon’s TTP figure of p=0.052 instead of the 0.085 p value, would everyone have considered this a miss? Unfortunately, one of the employees of the contract research organization originally entered the TTP of one of the early progressing control patients into the Provenge column, which caused a discrepancy of 0.009 (the remaining discrepancy was due to final audited results from the last enrolled and longest-progressing patients). So, the FDA strictly went by the original, unaudited figure of 0.085, which was still extremely close to 0.05. When you combine the highly significant survival p value of 0.01 with the TTP p value of 0.085, that’s a pretty strong correlation that many oncologists and urologists consider clinically significant (and there are many of these physicians who believe Dendreon got shafted).
    One more point…it is apparent from the 9901 trial results that for some HRPC patients, Provenge IS a cure. While 28/82 patients survived for three years after randomization in the 9901 trial, the survival data analysis stopped at the three-year point. The final patient was enrolled in Sept 2001, the initial patient enrolled in January 2000. As part of the FDA application, Dendreon went back and tracked those 28 patients, and found that an additional 8 had died. It appears plausible that the remaining 20 were still alive in March 2007, meaning that they have survived for 5.5 to 7 years. Not bad for the terminal stage of PCa for which 1.3-1.5 years of survival is typical.
    Strict biostatistical rules at the expense of clinical common sense have taken over the oncologic product review process at the FDA. That’s the basis of my argument.

  27. Maggie:
    Thank you for this thought provoking discussion. I would love to see you interview Steven Kanzer regarding this topic of conflicts of interest & the FDA. Steve is the CEO of Pipex Pharmaceutical, Inc. and until recently was the Vice chairman of DOR BioPharma, Inc. For anyone not familiar with Steve’s background, I suggest they spend a moment to better understand his qualifications: http://www.pipexpharma.com/bios/STEVE.html
    Back on May 9th, the FDA convened an advisory panel to consider DOR BioPharma’s GVHD drug, Orbec. Mr. Kanzer was in attendance and at one point in the afternoon abruptly engaged committee chairperson Dr. Maha Hussain in a heated exchange. You can read the transcript here: http://www.fda.gov/ohrms/dockets/ac/07/transcripts/2007-4301t1-Errata-Part4-Page-299-to-303.pdf If reading those words fail to convey just how strongly Mr. Kanzer felt, then take a glance at this photograph taken moments after his confrontation with Dr. Hussain: http://www.time.com/time/potw/20070510/ (4th of the 8 photographs).
    Days later, Mr. Kanzer resigned his post with DOR Biopharma, but his resignation letter to the board was anything but apologetic. Indeed he commented on the degree to which the FDA committee participants were conflicted: http://www.secinfo.com/dxpnj.u1u.d.htm .
    If Steve were to grant you an interview, please have him elaborate on his questioning of Dr. Hussain’s supposed communication with her colleague, the noted GVHD researcher Dr. Ferrara. Does Kanzer have knowledge of Ferrara trying to inappropriately influence Dr Hussain? Who knows what Kanzer would have said in that moment of rage, had the hotel security had not arrived when they did to remove him from the meeting.
    Corleyone

  28. This post and all the commentary illustrate a couple points:
    1. “Evidence-based medicine” is not the panacea everyone thinks it is. I read recently a cogent explanation of it, to wit, that there is the scientific evidence, and then there are the INTERPRETATION and JUDGEMENTS based on that evidence. The latter, performed by humans, are inevitably biased either consciously or unconsciously. (Or, in lay language, was it Mark Twain who said one can use statistics to prove anything.) This principle underlies all scientific disagreement, which can be honest even if passionate.
    2. Politicization of medicine, or any science, is a very, very bad thing and will not advance human knowledge. Commenters on all sides should remember this since we will all get sick someday.
    Just a couple other remarks – immunotherapy has been tried for years with melanoma with very mixed results. This is not a new idea, just a new application of it.
    Also, Provenge will not save any lives so someone is misleading desperate patients if they think so.
    The egregious part, to me, is that investors in the company should have any say at all, or even the right to comment, on the scientific deliberations. Much less threaten. Unacceptable, people.

  29. Maggie,
    Thank you for your response. In your last reply you state “no one has been able to come up with any evidence that Scher did anything immoral or illegal–and believe me, many people on Wall Street have tried”.
    An investigation is required by the FDA, OIG and the SEC into the matter of corruption and influence within the FDA, and in particular, the egregious handling of the matter pertaining denying immediate marketing approval to Dendreon’s Provenge for terminal prostate cancer. I suspect there is much greater detail that is just not available in the public domain.
    In response to your statement, “In the meantime, all of the “evidence” that I have seen suggests that we still need more information on PRovenge” let me state that Provenge could have been granted immediate marketing approval while promising to complete a phase 4 post marketing trial. Provenge has received unanimous support from the FDA that decided it is a safe treatment for AIPC; it’s most common side effects being cold and flu-like symptoms lasting for only a day or two. In contrast, chemotherapy is extremely toxic, and those toxic effects are long-lasting. Provenge has been shown in trials to extend survival by a substantial amount over the only approved treatment for late state prostate cancer, Taxotere chemotherapy.
    We should not wait another moment. Provenge should be an approved treatment for men suffering from AIPC now. This is a moral imperative. I try to live a healthy lifestyle. I exercise, I try to eat well and seldom ever take medication. Having a recognized safe treatment option, like Provenge, that trains my body’s own immune system to fight AIPC is something I would want available to me if I faced death from AIPC. The FDA’s actions needlessly delayed access to a recognized safe treatment for 30,000 men annually. Forsaking survival of terminally ill AIPC patients for financial gain is a moral injustice.
    Shame on the FDA.

  30. Bill–
    I just saw your comment. You are right that, no doubt, short-sellers made money by betting against Provenge and that they were primarily interested in making money–not whether the drug works.
    But because it is much more difficult to make money on the short side of the market than by going long, short-sellers tend to do a lot more reserach. They have to be interested in the science or they will lose their shirts. Short-sellers that I know tend to be very, very intelligent. (I think of JIm Chanos–the guy who figured out what Enron was doing.)
    Finally, people who bought Dendreon also were in it for the money. They wanted the FDA to approve the stock NOW. They wanted their payday. And, if it turned out, a year from now or two or three that the risks of the drug outweighed the benefits–well, that was not their concern.
    I’ll be back tomorrow morning to respond to any other comments.
    Again, thank you for contributing to the discussion.

  31. Thank you all for your comments.
    First, I completely agree with Merrill that the FDA should have automatically excluded Scher from the panel. By including him, the agency paved the way for all of the accusations that followed.
    Congress should pass a law banning people with any financial interest in the outcome sitting on a panel. Here I agree with Paul Haider about the importance of maintaining the integrity of the FDA.
    (As I mention in my longer post, the House has passed a bill limiting the number of people with a conflict to one per panel.) But lobbyists for the pharmaceutical industry has opposed this reform.
    Finally I truly wish Scher had turned down the invitation to sit on the panel–as Fleming did. (See my response to Walldiver above.)
    That said, no one has been able to come up with any evidence that Scher did anything immoral or illegal–and believe me, many people on Wall Street have tried.
    In the meantime, all of the “evidence” that I have seen
    suggests that we still need more information on PRovenge before the FDA approves it. As I mention in one of my responses above, the company now has a significantly larger (500 person) trial that is designed specifically to find out whether or not survival rates improve if patients take PRovenge.
    The FDA has indicated that the results of this trial will provide the evidence needed to make its decison.
    And interim results from the trial (which should be available in the middle of next year) may be enough
    to make the decision.
    Dr. Satterly–I honestly don’t know how the trial will come out. I don’t think anyone does. But unlike the earlier trials, this is a larger well-designed trial, and it’s worth waiting for the results. (See my longer Provenge story on http://www.tcf.org on what happened when breast cancer patients gained access to bone marrow therapy before
    randomized controlled trials could be done.)
    In the meantime,I find what Rick has to say very interesting. Clearly his firm does in-depth research, and I know, from writing about WAll Street for many years (at Barron’s) that the very best stock information is rarely free. You have to pay for it–by subscribing to expensive newsletters (and there are some good, honest ones) or by going to a firm like his. While some of the free information you find online or in the media is true, it is usually late. (By then, the stock is has already climbed.) And too often, free information is simply rumor–completely wrong or only half-right.
    I think it’s telling that when Rick’s firm looked at prostate cancer treatments (including Provenge) it found no solid evidence: “Our examination of the vaccine class of treatments is filled with qualifying terms like “possibly,” “data . . . not yet available,” “mixed expert opinion,” and “difficult to evaluate.”
    “In addition, Our assessment of the two vaccines (Provenge and GVAX) predicted that GVAX would fare better for a number of reasons.”
    Finally, Tom, I love your line that if people have to sell their houses to pay for Provenge “well, they can’t take their houses with them anyway.”
    And I agree that individuals don’t have a responsibility to become lab animals for society’s greater good. But the FDA does have a responsibilty to look out for society’s greater good–and that means making sure that nothing undermines randomized controlled trials.
    YOu believe that if patients had to pay for the drug out of pocket, few would do it. I think you underestimate our American fear of death.
    Moreover, I’m not at all sanguine that doctors will give patients good advice about the risks and benefits of experimental drugs. Most doctors are not researchers.
    And unfortunately, today many oncologists unintentionally give patients bad advice about new drugs because they ,too, are persuaded by media reports. There just isn’t enough time for most doctors to read the real in-depth research.
    Finally, many doctors profit
    from administering new drugs, and our fee-for-service system encourages them to “try one more thing” rather than let the patient die in peace.

  32. You said: “So far, the FDA has not bowed to investor pressure regarding Provenge,”
    There were short sales of Dendreon shares approaching 50% of the shares outstanding and there were a large number of call options sold as well at the time of the AC and the CR letter. How can you be certain that the FDA did not bow to that investor pressure? Let’s not be naive there was tremendous investor pressure on both sides of this issue. Why do the anti-Provenge investors get a pass? Did they not make huge amounts of money by the FDA’s delaying the approval of Provenge? So pro-Provenge investors are evil and anti-Provenge investors are noble.
    The anti-Provenge investors made money whether it works or not. They did not care–as long as approval was delayed or denied. If that is not “blood money,” I don’t know the meaning of the word.

  33. This situation shows why the FDA should ban all scientists/physicians with conflicts of interest from its advisory committees. Not because they are “in the bag” for the drug industry, but because it is the only way that everyone with a stake in the outcome — physicians, patients, drug companies, payors, and investors — can know that the data has been adjudicated fairly and by people without axes to grind. Howard Scher may be a great guy, and exactly right on this issue, but the fact that he is running a third stage clinical trial for a company that has also has a new drug for prostate cancer should have automatically excluded him from participating. The FDA screwed up big time in this case. They couldn’t find oncologists with clinical trial experience and without ties to prostate cancer drug makers? Absurd.

  34. I hope Matthew will forgive me for a shameless plug, but the company I work for, Decision Resources, studies drugs for the purposes of business intelligence. We directly employ over 200 experts in the field — Ph.D’s, M.D.’s, Pharm.D’s, MPH’s, MBA’s, epidemiologists, etc. — to research “the pipeline” and predict the behaviors of drugs and their markets through peer reviewed research and other methods, some proprietary.
    The information is out there. My company is not the only game in town if you want to get “inside” the emerging therapies game for profit. My advice to the folks who want to mitigate the risk of their investment is to put up or shut up. You could have bought one of our products or somebody else’s to get the accurate, unbiased information on whether sipuleucil-T (Provenge) would succeed. Our products are pricey, sure, but as those who bet and lost on Dendreon now are painfully aware, information has value, and its price may be well worth it to mitigate risk. You can’t say you’ve done due diligence if you relied only on publicly available information and sales pitches, and blaming the FDA or politics or the media after the fact is just rationalizing. Threatening scientists goes beyond the pale. The risk speculators took certainly isn’t their fault.
    In June 2006 we released a report on the prostate cancer (CaP) market, and addressed the potential of all known therapies at all known stages of development. While I can’t quote it line and verse, I can certainly paraphrase and give a few impressions for educational purposes here.
    1. CaP has high mortality, mainly afflicting the old and infirm, who usually have comorbidities or frailties that make aggressive treatments inadvisable.
    2. The CaP patient pool itself is comparatively small, with mild growth potential, driven mainly by population aging.
    3. The upside in the CaP market lies in a high unmet need in therapies. About 95 different ones are in various phases of testing, but only two are in the “vaccine” class, of which sipuleucil-T is one. GVAX (Cell Genesys) is the other.
    4. Our examination of the vaccine class of treatments is filled with qualifying terms like “possibly,” “data . . . not yet available,” “mixed expert opinion,” and “difficult to evaluate.”
    5. Our assessment of the two vaccines predicted that GVAX would fare better for a number of reasons.
    Speaking for myself as an investor — and, full disclosure, I have no interest in any biotech, nor any company that my firm does business with — if I were considering investing in Dendreon because of Provenge, it looked like relatively high risk and relatively small potential for return, even without the FDA approval hanging over it. Unfortunately hindsight is 20/20, but now that investors reading this know better information is available, perhaps they will consider investing in information before they invest in biotech.

  35. I am writing to you in response to your article, Wall Street, Cancer, and the FDA: A Cautionary Tale, dated July 25th, 2007. Dr. Howard Scher, as an employee of the FDA, has been granted a level of public trust and the stewardship of such a position demands the highest levels of ethical and moral conduct. Voting on and participating in an FDA advisory meeting in order to determine which drugs receive FDA marketing approval in which you play a decisive role in and in which you have a financial interest in (or counter interest in), is contrary to unbiased public concern and counter to the fiduciary duty Dr. Scher accepted as a special government employee and FDA panel advisor. Such conflicts of public and personal interest jeopardize the legitimacy of one proclaiming to act on behalf of the public’s best interests.
    The fact that Dr. Howard Scher sits on an advisory board to ProQuest Investments and has been granted an ownership position in ProQuest Investments, a $1 billion venture capital fund which has a major financial ownership stake in Novacea, a direct competitor to Provenge, and is allowed to participate in and vote on marketing approval of Provenge is unacceptable ethically. Furthermore, Dr. Scher’s apparent over the top crusade to deny this choice to terminally ill patients for what appears to be financial gain is immoral in light of the lack of treatment options available to terminally ill androgen-independent prostate cancer (AIPC) patients and when considering the undeniable survival benefit demonstrated in combination with Taxotere, the only FDA approved treatment for AIPC.
    The survival data shows that the patients that received Provenge had longer median survival (4.5 months) than that reported for Taxotere therapy, without having to endure 7 months of infusion therapy and coping with the poisonous toxic side effects related to Taxotere infusion. In support of its efficacy, a direct correlation between Provenge induction of immune response and survival benefit was also demonstrated in these patients. Most impressively, the data analysis also shows that when Provenge treated patients were subsequently treated with Taxotere, their median survival almost doubled (from 20 months to 35 months). This is compelling survival data further supporting the efficacy of Provenge for hormone refractory prostate cancer. In comparison, Taxotere increases median survival by only 2-3 months. This increase in survival is so dramatic and remarkable, it could not have been due to a random chance. This clearly shows that Provenge is effective at extending overall survival from AIPC beyond any reasonable doubt. This is amazing data.
    Provenge received an overwhelming vote of support from the advisory committee and recommended immediate marketing approval be granted. Both Dr. Howard Scher and Maha Hussin, each of whom voted in the minority and are very powerful members of the oncology community, launched an unprecedented PR campaign accusing those in the majority of incompetence and naiveté in matters relating to cancer products. The arrogance of this campaign overlooked the notion that survival data from Provenge may be qualitatively different from, and may need to be judged by different criteria than, survival data from chemotherapy drugs (as recognized in a July 1st National Cancer Institute research report by Jeffrey Schlom, Ph.D., chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute).
    A request for a Conflict of Interest Waiver was requested by Dr. William Freas, Director of Scientific Advisors and Consultants for CBER, on February 5, 2007. The request was concurred by Vince Tolino, Director of Ethics and Integrity, on February 26, 2007. On March 8, 2007, Dr. Howard Scher was granted a waiver by Dr. Randall Lutter to participate in Dendreon’s FDA advisory panel for Provenge because an individual with lesser conflicts of interest was unavailable. I don’t understand how the need for Dr. Howard Scher’s individual services could outweigh the above demonstrated conflict of interest created by the financial interest attributable to Dr. Scher. I can’t imagine an individual participant with more financial conflicts of interests sitting on the FDA advisory panel for Provenge. It is my fear that Dr. Scher’s financial interests have come before the best interests of terminal AIPC patients.
    There must be standards to public duty and there must be accountability and consequences for failure to meet the necessary high standards. Maintaining the integrity and dignity of the FDA is essential for maintaining high levels of public confidence in our institutions of government.

  36. Dear Ms. Mahar,
    Thank you for providing a forum in which the controversy surrounding Dendrion’s Provenge can be discussed. I have carefully reviewed your original commentary as well as all of the current replies.
    For the past 30 years I have been a practicing physician and surgeon and have VERY extensive experience in treating cancer patients with surgery, radiotherapy, chemotherapy and various combinations of them all. My interests also extend to the field of Immunology and I am well versed in the advantages and disadvantages of using immunotherapy for a wide variety of medical conditions. By way of additional disclosure, my retirement account contains a large number of mutual funds, many of which contain shares in developing bio-tech companies including Dendrion.
    After considering all the available public information on Dendrion’s Provenge, it is my professional medical opinion that the product should have been approved by the FDA after the published results of the FDA authorized AC panel to review Provenge for Safety and Efficacy. The AC panel EXPERTS voted 17-0 to CONFIRM Provenge safety and 13-4 to CONFIRM that Provenge offered “substantial evidence of efficacy,” the FDA STANDARD for approval.
    Furthermore, the CLEAR conflict’s of interest by at least two of the naysayer’s on the Provenge efficacy vote make their opposition extremely suspect.
    By any measure of reasonableness, the AC panel voted OVERWHELMINGLY to approve Provenge for treatment of deadly, late-stage prostate cancer. The FDA should have honored their support.
    Outraged prostate cancer victims and their loved ones have every reason to dispute the FDA ruling and demand a reconsideration.

  37. > So I’m afraid that a suprising number of people
    > would buy unproven drugs–even if Medicare didn’t
    > help pay for them.
    I read your long version. All I can say is liberty is messy, and people (dying anyway or no) don’t have a duty to society to serve as lab animals. On the flip side, the company has no duty to make the drug available at all, and if they want to wait until they have solid data, good on them.
    Breathless reporting in undifferentiated “media” notwithstanding, I think docs will do a good job educating patients, and the number who go for unproven drugs will be suprisingly small if they have to pay for them out of pocket. If they sell their houses, well, they can’t take their houses with them anyway.
    I think the greatest danger to scoiety’s interests here is Medicare and interference in contracts.
    t

  38. Tom–
    Thanks for your comments. The fact that the company went back and looked at another end-point is crucial.
    (See my response to Walldiver above.)
    On the question of whether an individual patient should have the right to gamble on the drug–I talk about this a bit in the longer version of this story on
    http://www.tcf.org.
    The big problem, as I see it, is that if patients are allowed to buy a drug before it gets FDA approval, how will companies get people to sign up for the randomized controlled trials that we need to get real proof of risk and benefit?
    Your suggestion that if Medicare refused to pay for such drugs, relatively few people would be able to afford them and so there would be plenty of people availale for clinical trials is appealing. But there are some problems.
    First, not all experimental drugs are as expensive as Provenge. Secondly,many dying patients are desperate enough to do whatever is necessary–sell their home, etc.–to get a drug that they believe will
    help them survive. Third, when Wall Street speculators get wind of a new drug that has even some hope of saving lives, they hype the stock, the hype spills over into the evening news, and patients believe it.
    So I’m afraid that a suprising number of people would buy unproven drugs–even if Medicare didn’t help pay for them.
    Finaly, companies are reluctant to make such drugs
    available to individuals for two reasons: a) the law says that the patient can sue the company if harmed by the drug–and there is no release that the patient can sign waiving this right and b) they are afraid that if one or two people die the adverse publicity will affect their chances of ever getting FDA approval.
    I plan to write about all of this in the near future, but in the end I think it comes down to the right of the individual (to get the drug before it is approved) vs. our societal interest in having good randomized controlled trials. From the colletive (societal) point of view, thousands of people could benefit if we stick with the randomized controlled trials before approving a drug. Meanwhile, on a case-by-case basis, companies can make an experimental drug available to individual patients on a “compassionate basis”–though many are unwilling to do this for legal and financial reasons . . .

  39. Walldiver–
    When you write: “please bear in mind that this is a terminal disease”— you seem to suggest that Provenge might save lives. The company itself only claims that
    Provenge might, at most, allow the average patient to survive a few more months. And during those few more months, many late-stage prostate cancer patients are in great pain (because the cancer has spread to the bone. The company’s clinical trial was not able to show that provenge slowed the onset of pain.)
    (I’d urge anyone really interested in the Provenge story to read my much longer post on http://www.tcf.org, then come back here to comment.)
    As the NYT points out, Scher and Hussain, who voted against the drug, treat cancer patients–and they know how much they suffer. The immunologists who voted for the drug do not treat cancer patients. And Provenge is, first and foremost, a treatment for cancer.
    I’m told that internal politics and/or confusion within the FDA made the agency decide
    to have the division run by Celia Witten, director of
    cellular, tissue and gene therapy organize the advisory panel rather than having it done by the division that oversees cancer drugs. Witten is a psychiatrist, not an oncologist.
    On the statistical debate–let me quote from a letter that Tom Fleming a professor of biostatistics at the University of Washington who regularly takes part in meetings of FDA advisory committees, and
    frequently consults for pharmaceutical and biotech companies pursuing drug approval wrote to the FDA:
    “I was kept awake the night following the
    panel[meeting that voted “yes” to recommend Provenge.] I had been invited by FDA to be screened to serve on the March 29, 2007, FDA Advisory Committee [which considered Provenge], but
    declined because I had had limited interactions with Dendreon in the capacity of critiquing available data.
    Nowthat the FDA Clinical and Statistical Briefing Documentsare in the public domain, I am at liberty to express my own serious concerns about some of the significant flawsand limitations in the clinical trials evaluating Provenge.”
    He goes on to explain that those trials were designed to show that Provenge slowed the progression of the disease and that it slowed the onset of pain. Provenge failed on both counts.
    So then the company went back and said, let’s look at survival rates and pretend that was the end-point of the trials. But the trials were not designed to show better surival rates; they were designed to show that the drug slowed the progression of the disease.
    As Fleming explains, you can’t simply go back and change the goal of the study after it has been completed: “The concerns regarding the unreliability of post-ho analyses are far more profound than that they simplyprovide a violation of statistical “rules”, as one might believe from comments by the sponsor’s consultingbiostatistician, Brent Blumenstein, (see O’Neill RT,“Secondary Endpoints Cannot be Validly Analyzedif the Primary Endpoint Does Not Demonstrate Clear Statistical Significance.” Controlled Clinical Trials 18:550-556, 1997).
    Estimates of effect of Provenge on overall survival are biased and p-values reported from
    such analyses convey a false sense of reliability of that evidence. An explanation for this bias was presented in a recent article discussing why proper adjustments must be made when multiple testing arises over the course of the trial, (Fleming et. al., “Maintaining Confidentiality of
    Interim Data to Enhance Trial Integrity and Credibility.”
    Annals of Internal Medicine, under review). That article
    states: “This bias (a form of “regression to the mean”
    bias) occurs because there is true signal and random
    noise in every estimate of treatment effect and, when
    many analyses are conducted, there is a tendency for
    those results that appear to be most favorable to be,
    at least in part, due to random overestimates of true
    effect”.
    The risk for “regression to the mean” bias is very
    substantial in the reported estimates of the survival .
    A clear illustration of this bias
    is provided by the recent experiences from the GIPF-
    001 and the GIPF-007 trials conducted by InterMune
    to evaluate Actimmune in patients with idiopathic
    pulmonary fibrosis (IPF). Like Dendreon, InterMune
    conducted exploratory analyses after their primary
    analysis of GIPF-001 established Actimmune did not
    provide a beneficial effect on the primary endpoint
    (relating to pulmonary function).
    When a survivaladvantage (2-sided p=0.004) was found in patients with mild to moderate impairment in lung function, the sponsor provided a press release indicating “The mortality benefit is very compelling and represents a major breakthrough in this difficult disease.”
    Fortunately, the sponsor eventually recognized that their post-hoc analyses of overall survival did not providereliable evidence of benefit and [conducted another trial which ] was recently
    terminated since [it turned out that the drug did not significantly improve surival.] . . .Many
    parallels between this setting and Dendreon’s evaluation
    of Provenge strongly illustrate the need to await [the results of the larger trial of Porvenge that Dendreon is now conducting.]”
    I would add that this larger randomized, controlled trial (that Dendreon is now conducting0 is designed to show whether Provenge increases survival rates. We’ll have some information by the second half of next year, and the FDA may use that data to make a final decision.
    In the meantime, if Provenge had been approved in May, the company would have hada very hard time persuading patients to enter the trial. (They need 75 more patients) If patients know that they can buy provenge on the market, how many would agree to participate in a trial where there was a 50/50 chance that they would get a placebo? Yet, without the trial, it could be years before we know whether Provenge really has any benefits and whether the benefits outweight the risks.
    This is why some prostate cancer patients were glad that the FDA did not approve Provenge in May–they don’t want anything to undermine that trial.
    Significantly, Fleming himself has prostate cancer and in his letter to the FDA, he disagrees with prostate cancer patients who say that all they want is “a choice”–the choice to take Provenge NOW even though there is no solid evidence that it will help them.
    Fleming write: “I strongly disagree with his statement that all patients want is a ‘choice.’ Patients want an ‘informed choice.’ How then would pre-mature approval of Provengethat could diminish the likelihood of obtaining reliableresults from the larger trial be in the best interests of prostate cancer patients?”

  40. Wow.
    And congratulations Maggie on The Century Foundation gig.
    As for the “90% chance Provenge caused increased survival” statistic, I looked here and didn’t see it either. As best I can tell, we can be 90% sure the Provenge patients in one study did survive longer, but we can’t say it was due to the Provenge for a number of reasons summed-up in the last paragraph. Dr. Zhen says here that the statistics are not very robust.
    I am not positive about what this means, but what jumped out at me was that the studies were designed to look for delays in disease progression, and they found nothing. But the company did notice that the Provenge group apparently lived longer, and so they latched onto that instead. One study reached significance on this score, but another did not.
    Whether or not FDA ought to agree that Provenge improves survival and does not itself kill seems a little beside Ms. Mahar’s points.
    One of them is this:
    “…shouldn’t individual patients have a right to gamble on the drug?”
    This has been the Libertarian argument. From my own point of view, there’s no particular reason why not — I do not think its right for the government to force people to be lab rats in a controlled experiment in order to have a 50/50 chance to try the drug. On the flip side, the oncologists have no obligation to begin a treatment they don’t want to begin, Dendreon has no duty to provide the drug at all, but if they do they ought to be able to charge whatever the market will bear even if there’s no proof it will help.
    What will the market bear? The 4-1/2 months’ survival is a median. Half don’t get this much, half get more. So, for a 70 year old man we’re talking about a 50/50 chance of a 39/40 chance of surviving an additional 130 days, for which Dendreon thinks it’ll get $60K. Whose money is he gambling with? Can medicine be said to be Money Driven when its always someone else’s money?
    I think all Dendreon should have to say is “There’s no particularly good evidence this will help, we want $100K for it, and you may not publish the results you get.” If the doc & patient still want it under these conditions, FDA should not stand in their way, and neither should FDA regulate the price. One hopes very few doctors would want to participate. I don’t think it would have much impact on studies if Medicare won’t pay for it.
    Back to one of Dr. Novack’s points: medical insurance contracts should somehow spell out what they’ll pay for. Even if the FDA is not allowed to consider quality of life or cost issues, insurers are. Or at least they should be. Contracts that will pay for more will cost more. If your insurance company says “For $500/month, we will pay for treatments expected to provide at least X benefit per $1,000”, or they say “For $400/month, we will pay for any treatment considered ‘standard’ for your disease state” then it seems to me the problem is self-limiting. Of course, we used to have contracts like these, but courts retroactively invalidated them and state legislatures declared them illegal. There is no reason we couldn’t have a contract that says “if standard treatments fail and you want a bite at an experimental apple, that costs you an extra $100/month, and you only get one bite.” Except for just one thing.
    It seems to me Medicare is the problem because the “Medicare Contract” is the de facto model contract for all insurance companies: private insurance contracts that don’t look a lot like it will be thrown out by courts and made illegal by legislatures. With Medigap policies added, the “Medicare Contract” is essentially “We will pay for whatever any doctor is willing to do to you and that you’ll lie still for, so long as any drugs or devices used in the process are FDA Approved, and we get the right billing codes.” FDA Approval means the new drug won’t cause any new disease, and works better than nothing (placebo). And so we have the Battle for Approval in order to permit desperate patients to spend Medicare dollars, hence, a lot of dollars, on something that works better than nothing.
    It should be up to patients (admittedly through their insurers) to apply any higher-order filter like “…and works better than an off-patent drug we already have” and maybe “our definition of ‘works’ means something like ‘reasonably expected to delay death a year'”.
    The problem with making FDA into the “rationer” of drugs by changing the approval process is that it takes away (largely theoretical at the individual level) freedom and politicizes science.
    Medical insurance, being a mechanism of collective financing, is by its nature political. The political discussion of solidarity and obligation belongs therefore at the level of CMS and the various private insurance companies. The result of this political discussion will be a different “Medicare Contract”. Eventually.
    t

  41. Let’s not forget, either, that capitalism, correctly-applied, does create incentives for creativity and innovation.
    But the craze that comes from pursuing marketshare alone is easy and quick and increasingly defensible. After all, for the last 30 years, we can say “we’ve ALWAYS done it this way.” No, we haven’t.
    We’re forgetting the fundamentals. Automobile companies make cars. Computer companies make computers. Drug companies make drugs. None of these people need do more than the best they can at what they do. Anything else is cheating all of us.

  42. Ms. Mahar, I don’t own Dendreon. I did at the time of the advisory panel meeting, but sold some of my position in April and the rest on the day of the Complete Response Letter. You are correct, I forgot that MSK had reported at least one of the threatening emails to Dr. Scher. In fact, I now remember posting that MSK had reported it. I did notice that you had to go through virtually my entire post to find something in it to rebut, without addressing the rest of it except for an “I’ll get to that other stuff later” or something along those lines.
    As for my pseudonym, it’s what everyone knows me by, and I get far too many requests about biotech investing already seeing as how I have a job in a different sector…and it would take up too much of my time.
    So again, I ask you…you have two choices: on the one hand, you have a chemotherapy drug that provided a 3.0-month median survival benefit in asymptomatic patients in the once per three week arm and a 0.5-month MS benefit in the once per week arm, and has the typical miserable chemo side effects; on the other hand, you have an immunotherapy (with a mild side effect profile) that showed a 4.5-month median survival benefit in one trial, tripling the % of patients alive after three years… and a 3.3-month MS benefit in the second, unsuccessful trial (albeit smaller size as it was halted before complete enrollment and before all patients received full treatment). Which treatment would you choose?
    Regarding the FDA’s decision not to approve, please bear in mind that this is a terminal disease, over 50% of asymptomatic patients decline Taxotere treatment, and if Provenge had been approved but the ongoing Phase 3 trial later failed the survival endpoint, the FDA could still pull it from the market. Also, please bear in mind that the immunologists on the panel voted 4-1 in favor of approval (with a 6th, non-voting immunologist also favoring approval), and Provenge does happen to be an immunotherapy.

  43. I just received this e-mail from a THCB reader. He
    gave me permission to post his e-mail here:
    “To: Maggie Mahar:
    “I originally intended to post this on the blog, but realize that the people responding to you have lawyers, and they know how to use them and there is enough in this to cause problems of liability. Thus I share this with you as a matter of respect for your work and a testimony to the fear and frustration I feel working for a non-profit hospital. Maybe I’m just a naive kook, but I’m MY naive kook. No one owns me…
    “Full disclosure: I’ve never made enough money in I.T. to invest in anything, nor am I affiliated with anyone or anything that might have a connection to this issue, aside from the fact that I, yes, own a prostate.
    “That said, Ms. Mahar, thank you for making the point that a laissez-faire approach to healthcare leaves dead and dying patients on the field as “market forces” reflecting “bad personal choices” that they could not possibly make. This is why healthcare is not a “market.”
    “As for the rest of you and your long, drawn-out, serpentine, point-by-point, lawyerly responses,I respectfully submit that you’re obfuscating and complicating a simple issue. You’re playing the old game of trying to discredit the messenger rather than address the real message, which is that focusing on payment rather than healing (note I don’t say “treatment” but actual healing) creates a tiresomely familiar context in which money, as always, calls the shots and the “invisible hand of the market” is only invisible to the extent that boardroom doors are closed.
    “Let’s be brave and stop applying inappropriate forms of arbitrary competition. Let’s focus on healing people instead of selling them.
    “Anything else is the lie, ladies and gentlemen, that profiting on other people’s misery is anything other than just that. ”

  44. Walldiver–
    Let me address the points you raise, starting with an easy one. You write “all we have is [Scher’s and Hussain’s] word that they were threatened.
    This is not true. We have the word of Sloane Kettering and the organizers of the conference as reported in The New York Times on June 4 :
    “CHICAGO, June 3 — 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 . . .
    “Christine Hickey, a spokeswoman for Sloan-Kettering, said Dr. Scher had received e-mail messages and phone calls, including one e-mail entitled “your murder.” A copy of his biographical page on the Sloan-Kettering website was vandalized . . . ”
    The Times goes on to note that “An F.D.A. advisory panel endorsed the effectiveness of the drug by a 13-4 vote in March. The panel voted 17-0 that the drug was generally safe, although there were signs it could increase the risk of strokes.
    “. . . both Dr. Scher and Dr. Hussain, who, unlike most of the panel members, actually treat patients with prostate cancer, voted in the minority. They argued that the evidence fell short of proving that the drug worked, and that they did not want to give patients false hope. ”
    On “PSA Rising,” a newletter for prostate cancer survivors written by Jacqueline Strax (whose husband died of prostate cancer)Strax wrote:
    “We first heard of a death threat against Dr. Scher from a reliable source in late April after his letter to the FDA. No indication suggested that this threat came from any patient or advocacy group. All along, invective and “rants” against Scher and Hussain have been high on investor message boards, with no such feelings expressed on a leading prostate cancer mailing, PPML at acor.org.”
    “By last week, investors were circulating Dr. Scher’s email address and phone number, urging that his office be bombarded with FAXes, and analysing an EDGAR record of his investments. Based on Scher and Hussain’s declarations to the FDA and receipt of COI waivers, Dendreon investors who allege that the two oncologists are motivated by financial interests seems to see nothing wrong with the fact that one of the clinical investigators for Provenge, Dr. Paul Schellhammer, who edited a report on the Phase III trials for publication, benefits financially from the company.”
    I’ll reply to your other points on a separate post. But
    I’m afraid the fact that you chose to ignore the widely reported corroboration of what Scher and Hussain said about being threatened undermines your credibility.
    Do you, by chance, own the stock? Do you, your employer or any member of your family have any financial connection to Dendreon?
    Finally, I wonder why you choose to use a pseudonymn

  45. Maggie says…Only in America do physicians who evaluate new drugs need bodyguards.
    Why don’t you do everyone a favor, and please ask Maha and Howard to produce police reports and copies of the emails showing they were threatened? I believe they lied about or at least exaggerated the supposed threats.
    Their integrity should be questioned…after all, they leaked their letters that were supposedly intended for the FDA to the two-bit rag the Cancer Letter….something smells here.
    Jon

  46. We give Maggie this great forum and she refuse to use it for insider trading! How will she afford those bodyguards she’ll soon be needing?

  47. Let me ask everyone involved in this discussion to
    disclose whether you, or the instituion you are affiliated with has any financial connection to
    Dendreon (own stock, done research that the company used, owned a competitor’s stock, etc.)
    For the record, I don’t own Dendreon (or any healthcare stocks.) I never invest in anything I
    might write about.
    I’m a fellow at The Century Foundation–a non-partisan, non-profit think tank and they have no financial connection to Dendreon. Nor did the foundation suggest the idea for the story.

  48. Aureus–
    You write “the science shows that there is over a 90% chance that Provenge was the cause.”
    Could you be more specific as to what you mean by “the science”? I have read most of what has been
    written about Provenge, pro and con, and have never
    seen any reference to this point.

  49. Bruce Holmes– I wonder why you do not mention that you and your wife own 2000 shares of Dendreon?
    (I found this in your letter to the University of
    Michigan: “By way of disclosure, my wife and I own 2000 shares of Dendreon Corporation.”

  50. Hi Ms. Mahar, I’d like to address your points one by one:
    -re Provenge’s safety and efficacy…the primary endpoint for the pivotal Phase 3 trial was time to progression (TTP). The p value for this endpoint according to the company was 0.052, but the FDA said it was 0.085. Either way, statistical significance would have been achieved at p=0.050. The overall survival p value was 0.01. For the previous five years or so before the March 2007 advisory panel, the FDA’s mantra was that survival is the gold standard. Any other endpoints were mere surrogates for survival, designed into pivotal trials in order to get the drug to market faster, but more open to subjective interpretation (reading of radiologic slides, patients self-survey of pain intensity).
    -The argument in favor of Provenge approval was that a TTP p value of 0.052-0.085 shows a strong enough positive correlation to the “gold standard survival” p value of 0.01. In other words, there was a 91.5 to 94.8% chance that the TTP benefit in the Provenge arm of the pivotal trial was due to the Provenge, and not random chance. Therefore, these 91.5-94.8% odds in TTP positively correlated with the 99.0% (p=0.01) odds in survival, and furthermore, this treatment has a much milder side effect profile than Taxotere chemotherapy, the only other treatment in terminal prostate cancer to show a statistically significant survival benefit. This is why Dendreon, after meeting with the FDA in late 2005, chose to file for Provenge approval in 2006, instead of waiting for survival data from the ongoing IMPACT trial.
    -the FDA’s own biostatistical analysis estimated that the chances of the pivotal trial’s statistically significant survival benefit being a “false positive” as only about 1 in 40. While not being the hoped for 1 in 1600, most patients would probably opt for a 39/40 chance of improved survival in a terminal indication such as hormone-refractory prostate cancer, especially when the alternative is a toxic chemo. While also noting that the survival analysis was post-hoc in nature, the FDA biostatistician also said, “It may be important to weigh the following points while considering the unfavorable strength of statistical evidence: 1) showing statistically significant difference in overall survival in Study 9901 and showing a trend toward improvement in overall survival in the second study; 2) showing a trend in favor of APC8015 arm in all comparisons for other important endpoints; 3) the safety profile of the product; 4) other existing effective treatments for the targeting patient population.”
    http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_03a.htm
    -It would seem to me that the FDA itself interpreted the Provenge data far more positively than you did.
    -The FDA’s own standard for approval regarding efficacy is that the product should “demonstrate substantial evidence of efficacy.” This is how the efficacy question for Provenge should have been worded. “Establishing efficacy” was interpreted by most of the advisory panel members to mean 100% certainty, a far stricter interpretation than the FDA’s own guideline. The official efficacy question was changed by Dr. Witten (Head of FDA Office of Cellular Tissue & Gene Therapy) and Dr. Goodman (Head of FDA CBER division), after clarification was requested by advisory panel chairman Dr. Mule.
    -The FDA seems to hold Dr. Alexander in higher regard as a prostate cancer expert than you do, since you didn’t include him as one…and he voted Yes. Granted, Hussain and Scher voted No, but the three other oncologists on the panel voted Yes. It’s also quite common for FDA advisory panels for cancer treatments to only have one or two experts at most in the particular form of cancer being reviewed to sit on that particular panel.
    -re Drs. Hussain and Scher needing bodyguards…all we have to go on is their word, and there was never any news about any followup from law enforcement. It’s illegal to threaten someone’s life, and IP addresses are easily traceable. The people who demonstrated at the ASCO meeting certainly did not appear to be the threatening sort, as evidenced from the various TV news feeds of the event.
    -the crux of Scher and Hussain’s argument against Provenge approval, besides their biostatistical point, was that in their opinion it would threaten the various prostate cancer trials that they and their organizations (Univ of Michigan, Memorial Sloan Kettering) were running. However, Scher did not disclose to the FDA his sitting position at the hedge fund ProQuest Investments, and its huge investment in the shares of Novacea, which benefited hugely from the nonapproval of Provenge and its positive effect on the partnership deal Novacea signed with Schering Plough a few weeks after Provenge was turned down. Many investors suspect either that Dr. Scher in the past has received consulting fees from hedge funds with a short position in Dendreon, or consulting fees from “matchmaker firms” that organize conference calls between hedge funds and clinical trial physicians.
    Anyway, I hope you look into some of the points I’ve raised here. Thanks

  51. Read this Maggie. Your article is misleading and full of inaccuracies. Apparently you don’t know much about drug approvals and you are off base on defending Hussain/Scher. Who paid you to write your drivel?
    July 20, 2007
    Mary Sue Coleman, Ph.D.
    President, the University of Michigan
    Administration Building
    503 Thompson Street
    Ann Arbor, Michigan 48109-1340
    Dear President Coleman:
    By way of introduction, I am a graduate of the University (57BBA). I subsequently served as class representative and served on the Michigan Annual Giving National Committee. My grandfather on my father’s side received a degree in engineering in 1906, my father received an MBA in 1926 (the first class in the graduate school of business), my wife graduated from the University in 1956 as did her parents. Two of our sons graduated from the University. My sister along with one of her sons graduated from the University and her husband performed his orthopedic surgery residency at the University. We are true maize and blue.
    In 1963 my grandfather on my mother’s side died of prostate cancer. In 1987 my father died of prostate cancer after receiving treatment at the University Hospital in 1986. In 2001 I experienced a prostate cancer biopsy which fortunately turned out to be negative. However, this background resulted in a substantial interest on my part in medical treatments for prostate cancer and led to my discovery of a vaccine for the disease named Provenge developed by Dendreon Corporation.
    On March 29 of this year I attended an FDA Advisory Committee meeting involved in a review of the application by Dendreon for a license to market Provenge. The Advisory Committee voted 17-0 that the vaccine was safe and 13-4 that it provided evidence of efficacy. Dr. Maha Hussain of the University’s School of Medicine was one of the 4 dissenting votes on the Advisory Committee.
    At the time I was unaware of Dr. Hussain’s connection with the University. However, during the course of the meeting I was quite astounded at the performance of Dr. Hussain which I found to be quite unprofessional.
    For whatever reason, it was app arent to me that Dr. Hussain chose to set herself up as a lecturer to the other 16 members of the panel in an obvious effort to prevent a positive vote for Provenge. It was a strikingly arrogant performance on her part in my estimation, especially since she was an appointee by the CDER division of the FDA specializing in chemotherapy, versus the CBER division specializing in vaccines and immunotherapy with Dr. Mule, a renowned specialist in the field, chairing the meeting.
    Late in the day, as the Committee was voting on the efficacy question for Provenge, an issue evolved over the proper question on which the Committee was to vote. Initially the question included the approximate wordage: did the clinical trials for Provenge “establish the efficacy of the vaccine?” However, after communication among FDA CBER staff the wording was changed to reflect the exact language in Federal Law which read: does the drug provide “substantial evidence of efficacy?”
    When it came to Dr. Hussain’s turn to vote she said words to the effect that as far as she was concerned “substantial evidence of efficacy” and “establish the efficacy” were the same thing. For someone in her position not to recognize a very important distinction in this regard was, to me, quite profound.
    Information I found after the Committee meeting indicated that Dr. Hussain had been granted a waiver of Conflict of Interest by the FDA for her participation in the meeting. Shortly after the meeting the FDA issued new guidelines for Conflict of Interest waivers which might well have prevented her participation in the Advisory Committee meeting. Her conflicts appear to me to warrant a careful review by the University whose reputation comes into question on this issue.
    I would appreciate your very considered response to this letter.
    Most Sincerely,

  52. Your article purports to be a “full story” but is rife with omission of pro-Provenge points, and outright misstates on the main point. It is not true as you have it that there is no scientific evidence that Provenge caused the survival benefit in the two studies — the science shows that there is over a 90% chance that Provenge was the cause. Your admirable goal of reducing health care costs may have misled you away from the achieving of that goal. Your support for those who succeeded in having the FDA delay approval of this immunological therapy inadvertently promotes the vested interests of Hussain, Goldberg, Scher and others in costly, less effective, more side-effect-ridden chemotherapeutic alternatives. Three of the FDA’s Advisory Committee panelists required Conflict of Interest Waivers to attend and vote. These three voted no to Provenge. The other scientists voted 13 to 1 for Provenge. Your read of them as manipulated by a rephrasing of the question to the correct FDA wording is bogus. I am a former holder of DNDN who found a higher level of cogency and altruism amongst shareholders there than in any other company I have been associated with. I respond to your story because I have a residual aversion to distortion of the facts. My family members who could benefit from market access to this treatment wish you a speedy recovery from the naysayers’ invective afflicting the considerable yet unrealized progress represented by Provenge.