The Provenge Vaccine & The Meaning Of Moderate
66 CommentsBy Ed Silverman // November 11th, 2010 // 9:51 am
The latest chapter in the Provenge saga emerged yesterday evening when the Agency for Healthcare and Research Quality issued an analysis of the prostate cancer vaccine, which is one of the most controversial medical and investor stories over the past three years. Not surprisingly, the report did little to quell the inflamed passions that characterize the debate over the Dendreon product.
Why? The AHRQ determined there is only “moderate” evidence that Provenge helps patients. And the analysis was released just a week before a widely anticpiated meeting to be held by the Centers for Medicare and Medicaid Services, which is conducting its own analysis to determine coverage after questions were reportedly raised several months ago by regional Medicare contractors.
The meeting, itself, is unusual in that CMS usually does not hold such gatherings to review oncology meds that are approved by the FDA. Typically, Medicare will automatically pay for such a treatment, at least for approved indications. But Provenge is far from typical - it is the first therapeutic cancer vaccine and its administration involves a complicated processs that requires using a patient’s blood.
Most likely, the meeting will be a forum for reviewing off-label use. Provenge, which costs $93,000 per patient, is only approved for people with advanced prostate cancer that resists hormone-deprivation therapy but who are not experiencing symptoms. Off-label use would involve patients who already have symptoms. CMS is supposed to determine whether coverage is reasonable and necessary, but cost is not supposed to be a factor in its decision. Nonetheless, off-label use hovers.
Ever since the CMS initiated its review, however, investors, doctors and patients have raised furious concerns that the upcoming meeting is, essentially, a stalking horse for a cost-effectiveness analysis (see here and here). Despite the price tag, some investors and analysts argue chemotherapy and subsequent treatments used to mitigate side effects can be equally, if not more expensive.
As with any med, the issue is the extent to which Provenge can make a difference. Clinical trials demonstrated the vaccine can extend lives by about four months. But the AHRQ analysis, which was conducted by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center, took issue with clinial trial design.
One point cited by AHRQ was that patients in the control arm of the trials did not receive a true placebo. Instead, they were given a sham version that was frozen so they could later be treated with Provenge. Consequently, the AHRQ gave the three Provenge clinical trials only a fair rating (see page 47 of the report).
Yet, this was not a new insight. This issue has been raised before, most recently in an editorial in The New England Journal of Medicine last summer (see here), and in fact, Wall Street was grappling with the clinical trial design in the run-up to FDA approval last spring.
And so by describing the benefit as moderate, the AHRQ analysis did not really yield any new insights. Nor did the report suggest there were new questions about survival benefit or raise any questions about side effects. This likely explains why Dendreon stock jumped last night in after-hours trading as investors sifted through the report.
The AHRQ report “is not a big deal,” writes RW Baird analyst Chris Raymond in an investor note this morning. “The worst-case fears (are) overblown.” And Leerink Swann analyst Howard Liang writes this: “W continue to believe that it will be difficult for the agency to deny coverage of on-label use of Provenge without declaring a glaring deficiency of Provenge data and in that context we view the glass half-full.”
So what next? The CMS meeting next Wednesday is likely to engender considerable discussion about wwhether reimbursement should be endorsed only for on-label use, as opposed to a wider debate over any and all reimbursement. And for those who wonder if additional clinical trials may be suggested, it is unlikely that a survial trial would be required, especially since there would likely be ethical issues.
MyPharmalot ID
My, my…one thing that seems to have been overlooked in all the noise about this report is this:
The assessment was done by a technology evaluation group at the Blue Cross and Blue Shield Association under contract to the government’s Agency for Healthcare Research and Quality.
Is this a joke? After all of the accusations related to conflicts of interest (COIs) on the part of some participants (special government employees) on the Provenge Advisory Committee meeting of March 29, 2007, and the activities of these participants and others in the government in the weeks that followed (involving leaked letters addressed to the FDA commish, relationships with a NJ investment house, co-development deals with Big Pharma, etc.), we have here a report that was prepared by none other than a national insurance company with a vested interested in NOT paying out funds for the use of Provenge in anything but the most restricted of venues. Frankly, I’m surprised that the BC/BS recommendation didn’t call for a return to leeching cancer sufferers.
What’s next? Is the US government going to commission a study on the Holocaust and let the contract for the work to the Embassy of Iran?
The fact is: with BC/BS preparing the report, the results are biased and tainted. The AHRQ report is DOA! And the whole issue not only is a waste of the taxpayer’s dollar, but a farce, to boot.
christopher chance
The 4 month survival benefit observed in the Provenge trials is not in question. The question is what can this 4 months survival difference between the study arms be attributable to. Is this the effect of Provenge on the Provenge arm or is it a reflection of the harm inflicted on the placebo arm? Since (1) Provenge comes with no mechanism of action, no anti-tumor effects, no efficacy in the absence of subsequent chemotherapy (from the TA released yesterday), and (2) the placebo patients were manipulated in unethical and unacceptable ways (part of their circulating immune cells were withheld, the rest were left to die @ 4 degrees before being reinfused, etc. etc.), the 4 month difference in survival could be equally likely due to provenge efficacy as it would be due to poor performance of the placebo patients. There is not enough data in the IMPACT trial to answer this question. And this is before getting into any of the other study design flaw which naturally chip away at the significance of the survival difference.
We must take care of our oldest patients and our cancer patients first and foremost–they deserve the best and most effective therapies. But we cannot subject them to a therapy which is medically futile at best and immunosuppressive at worst. We owe it to them.
Walter Kovacs
Since when do we derive our certainty on therapeutic efficacy and safety from financial analysts? Wall Street analysts should be listening to doctors on this topic, not the other way round. And those doctors should not be former IMPACT investigators, for obvious reasons.
FYI: Longo wrote yet another letter to the NEJM yesterday, in response to the IMPACT travesty. Here it is below:
(N Engl J Med 2010; 363:1966-1968 – November 11, 2010)
The Editorialist Replies:
Without question, sipuleucel-T vaccination produced a significant prolongation of overall survival in this study; what is troublesome is that the mechanism remains unclear.
Sipuleucel-T treatment prolonged the survival of men with castration-resistant metastatic prostate cancer without producing tumor responses or delaying tumor progression. Despite this unexpected result, in general, treatments that do not influence the tumor also do not influence survival. Indeed, even some treatments that slow tumor progression do not influence survival. Patients will be better served by defining how this agent prolongs survival rather than by labeling this outcome as an anticipatable class effect, as if such a label explained the result.
The experimental group in this study included two variables: a tumor antigen and GM-CSF. If one wished to understand the contribution of the tumor antigen to the outcome, the control group would have included GM-CSF alone, so that the tumor antigen was the only variable. To imply that such a control group has no rationale is specious.
I look forward to a formal cost-utility analysis of sipuleucel-T. Based on a 4-month survival benefit, the cost of sipuleucel-T per quality-adjusted life-year (QALY) is $279,000. Data on pharmaceutical interventions published between 2000 and 2006 showed a median incremental cost of $22,000 per QALY.1 Cancer pharmaceuticals often cost more than agents in other specialties; based on data from the literature through 2007, incremental cost-effectiveness ratios of new interventions were $22,000 per QALY for colorectal cancer, $27,000 per QALY for breast cancer, $32,000 per QALY for lung cancer, and $34,500 per QALY for prostate cancer.2 If these numbers establish a pattern, the cost of sipuleucel-T is out of line.
Dan L. Longo, M.D.
hancock
howard liang from leerink swan also said that dimebon would cure alzheimers and pirfenidone would cure IPF … both were catastrophic failures … i see he has moved on to Provenge … if they spin the wheel enough times chance are they will be right at some point, but they’re definitely not going to be right this time either … good luck to you all, and good luck to patients who opt for provenge, it’s pretty much russian roulette with a pheresis machine instead of a revolver
gogogiants
for a document which is not supposed to or allowed to make recommendations, the tech assessment surely kept making way too many references to the need for new thorough trials on provenge. how can so many people miss such a clear hint? … obviously, because they’re letting wall street read the document for them. yikes!
former FDA medical officer (retired)
Why is it that only Provenge critics are accused of working for hedge funds and having a financial interest? Aren’t hedge funds some of the biggest stock holders of Dendreon? People posting in support of Provenge probably have massive financial interests in the success of Dendreon. It’s hard to believe that that they’re patients. Patients don’t read financial blogs. No, it’s just the same people who put pressure on the FDA to approve this mediocre therapy, I’ve had enough experience with them at the FDA: they’re just wolves in patients’ clothing.
kyoto27
ED,
If this is the latest chapter in the Provenge saga…I ask a question asked in the comments:
Is this a joke? As noted, ‘we have here a report that was prepared by none other than a national insurance company with a vested interested in NOT paying out funds for the use of Provenge in anything but the most restricted of venues.’
So what’s going on here? Really going on?
Are we really supposed to embrace the Blue Cross and Blue Shield report? And why? The BlueCross and Blue Shield comments fly in the face of what the FDA asked Dendreon to do –don’t give patients a true placebo; it’s not ethical. One point cited by AHRQ was that patients in the control arm of the trials did not receive a true placebo. Instead, they were given a sham version that was frozen so they could later be treated with Provenge.
Yes, yes, so Provenge was actually competing with itself with no real placebo and managed to still show survival stats. Instead of saying Provenge was in competition with itself, the fools savaged the trials–the very trials that the FDA insisted be held.
Ed, what is really going on here? And was it ever suggested that Provenge would maybe be showing even greater survival benefits if there was a real placebo facing Provenge? Where are the headlines screaming: ‘Drug competes with self and still shows survival advantages’!
No, no..instead we are asked:
Is this really a reflection of the harm inflicted on the placebo arm? Or a reflection of the harm inflicted on Dendreon/Provenge?
There’s a good article somewhere in all of this.
ocyan
Sigh… Too much misreading of the Technical Assessment document. The authors of the TA were very clear that their rating of “Good”, “Moderate” and “Poor” included whether or not additional data could change the magnitude of the measured survival benefits and was not just about whether Provenge has been satisfactorily proven to confer survival benefits on treated patients.
Their definition of “Moderate” says this:
“Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.”
That is a fine assessment of data from trials with a protocol that allowed crossing over to both Frozen Provenge and other treatment forms. Of course, the measured survival benefits were not as clear as possible if only pure placebos were allowed. The TA document itself observed: “If the cross-over treatment has a treatment effect in the same direction as the original treatment, then in most cases a conservative bias would result, so that the usual intention-to-treat analysis of the trial would result in a conservative estimate of treatment effect.”
Now, consider the combined data from the D9901 and D9902a trials in which all patients were followed for three years. There were 12 survivors on the control arm at three years. Of those, 10 crossed over to take Frozen Provenge and only 2 were pure placebos. There should be no question there that Frozen Provenge was effective. It just was not as effective as the fresh Provenge given to patients on the treatment arm.
So, the median survival benefits measured from the trials were conservative as the TA authors observed. The trial results would have been better if no crossing over to Frozen Provenge was allowed. Of course, that would also mean that patients on the control arms of the trials would be denied a chance at life. No ethical trial designers would do that.
The FDA and Dendreon people who worked together on designing the Provenge trials saw through all such ethical issues. The FDA then granted Dendreon a Special Protocol Assessment for the IMPACT trial.
At this time, there should be no question whatsoever that Provenge works and that it has passed the most stringent scientific tests to prove it!
Stevierayjon
Dan Longo doesn’t even know what QALY!
http://www.minyanville.com/businessmarkets/articles/qaly-icer-drug-evaluation-health-care/11/10/2010/id/31045?page=full
Stevierayjon
Please add the word “is” at the end of the sentence!
christopher chance
To kyoto27: Yes, this is a joke. It’s a joke on our cancer patients. We are selling them a medically futile therapy. Thanks to you and the other investors here pretending to be enraged patient advocates.
The apparent 4 month survival benefit is an artifact due to underperformance of the placebo patients in the trial. Cells infused to the placebo patients were handled differently and may have caused harm, and this is NOT referring to the subsequent frozen product. Saying that the drug competed with itself makes no scientific sense. Administration of frozen provenge in the placebo arm is meaningless, because it was given non-randomly only to patients who were alive and healthiest at the time (obviously).
Scientist
Now, we have a big problem in America.
The FDA is the government agency responsible for approving drugs based on their efficacy and safety. In a case of Provenge (a cancer drug for treating patients with prostate cancer), we have another government agency CMS with no appropriate expertise in a drug development and approval process that is second-guessing the FDA trial design and clinical data analysis.
Furthermore, the CMS is hiring outside consultants with obvious conflict of interests.
Is CMS trying to save taxpayers money? Very doubtful. May be they should start with over $90B+ of fraud and theft associated with Medicare programs.
Furthermore, almost all new FDA approved drugs are very expensive since the FDA requires endless and cost-runaway clinical trials for drug approval. Now, we got CMS getting into the act. It appears that CMS is undermining the entire US drug development and approval process.
Now pharmaceutical industry, one of the very few productive and internationally competitive industries still left in America, is under a cloud of extinction thanks two US government agencies (the FDA and CMS). It is a very sad situation.
christopher chance
We should be thankful to the CMS in this case for having the courage to say “Enough!”. Since CBER at the FDA decided to approve Provenge in fear and under pressure, without giving the data (or lack thereof) the diligence that patients deserve, then someone needed to step up and attempt to expose this medical Ponzi scheme. Whoever started this NCA at the CMS is one of the last few american heroes.
The CMS is not the villain here, and I am sure of that because I actually know who the villain in this story is: it’s Dendreon.
Dendreon is trying to sell a medical hoax and overcharge us for it. Dendreon and the pharmaceutical industry have grown and appear “productive” because they keep spewing mediocre treatments while we have effectively issued them a credit card named Medicare. We continue to pay the bill of that credit card for them, without any longer re-evaluating what they have produced for us.
It is more likely than not that Provenge itself has zero effects on patient survival, as it has zero effects on disease progression. It is more likely than not that placebo patients in the IMPACT trial were harmed. When this is all done, those more responsible than others will be held accountable. I nominate Dr. Mark Frohlich (Dendreon CMO) for jail time for gross medical negligence. He is fully aware of the potential harm inflicted on the placebo patients in the Provenge trials, due to depletion of the circulating naive T cells; he understand this possibility very well (his former venture, XCyte, dealt precisely with T cells and their parameters). However, he is choosing to ignore the concerns.
Pelfrey1
BlueCross BlueShield Association does NOT pay claims. TEC evaluations are done by the BCBSA TEC group which perform evidence-based reviews of many pharma agents and medical technologies. Do a quick review of Medical Policies at various Blues PLANS and you might be surprised at the range of coverage of this and many other agents.
That being said, the clinical studies were of questionable design. It is still somewhat surprising that the FDA approved Provenge but the outcome of the CMS meeting to review the TEC assessment is still bound to be interesting!
Scientist
christopher chance,
I am a scientist. Scientists use hard & accurately obtained data to analyze the empirical data, make judgements, decisions, etc., Just because we do not understand something, it does not mean there is something wrong with the data. This is a natural science development process. Very often the true understanding comes later.
At the same time, your posts are nothing more than unsubstantiated speculations, insinuations, and outright lies. Shame on you.
I suggest you to take one or two tablets of Pepto-Bismol. You suffer an acute case of a mouth-diarrhea. You and you alike are destroying America.
PS
Provenge is a revolutionary drug. It has opened a new avenue in fight with cancer. It is time to look forward instead of using a rear-view mirror.
Granted, DNDN clinical trials, conducted with the FDA approval, were not perfect. I wish to see more clinical trials of Provenge vs the present standards of care vs Provenge in combo with other drugs. At the same time, we cannot deny to cancer patients drugs that do not yet provide a complete cure and/or we do not understand their mechanisms of actions.
brian
You can’t say “Build a triangle with four sides” but one can ask the impossible here. Trials present design problems, just like building a bridge or an iPod, and you solve the design problems as best you can. You can’t be infinitely light and have infinite battery life, for example. (A) You can’t do a disease trial against pure placebo when there are proven beneficial therapies. (B) If you did do a trial against pure placebo, the result would be downgraded because it was not blinded. (C) The trial design had features of a sham device trial (control arm patients went through apheresis but not the prostate specific amplification) which is sometimes the best available trial design. The main thing you get with the AHRQ report is “positional authority.” It’s like the order of a general or the statement of the pope. It is what it is because of its position. You already had all the FDA documents, long FDA label, NEJM article, and other literature. This is just one more (sometimes obvious, sometimes verbose) rehash again. It’s interesting it gets this much play when of the four authors, one is an MS, one is an RN, one has a PhD in social science. This supercedes the 20 experts at the FDA? I don’t think any of the authors has any new five year $500M drug trials run successfully, on their resume.
Scientist
brian,
your are absolutely correct.
The scientific & medical credentials of the AHRQ TA report authors are just laughable.
It is absolutely disgusting that tenth of thousands of prostate cancer patients lives will depend on conclusions of these “medical experts”.
christopher chance
dear “scientist”, your diction and your penchant for character-assassination rather than data-driven rebuttals sadly trap your alias between quotation marks. if you are a scientist, then i am mitch gold. i encourage you to read the actual tech assessment document rather than criticize the credentials of its authors. remember, the devil is in the details when it comes to provenge — big fat devil, very few details :)
christopher chance
soon, there will be a new trial for provenge, if not in the US then in the EU. but to learn from the tech assessment, we all need to first read it:
excerpt, page 34: “Interpretation of the existing clinical trials of sipuleucel-T was hampered by a study design that had the original intended purpose of assessing progression-free survival in an objective manner. This dictated measures such as blinding and placebo in order to avoid bias in the assessment of outcome. The likely presence of time-varying subsequent treatment and confounding adds further complexities. … Since it appears that sipuleucel-T has little or no effect in delaying measurable disease progression, it would be important for future trials to be robustly designed for a survival end point. … The trials should have more thorough protocols regarding the options and standard of care given to trial participants up to the survival end point.”
scientist
christopher chance,
unfortunately,the report authors do not know much about cancer disease at all. (Note, I used a cancer disease.)
Cancer patients do not die from cancerous tumors but rather from organs failure. It is well known in oncology that Progression Free Survival or Time to Progression(PFS or TTP) are not good parameters to predict overall survival (OS). Very many drugs shows excellent PFS with no OS benefits. The case and point is Avastin in breast cancer (great PFS and no OS benefits).
To make a long story short, if one can boost a cancer patient immune system and/or make tumors “less aggressive”, one can expect to observe improved OS and quality of life benefits without tumors shrinkage or even slowing tumor growth.
christopher chance
Why did Provenge seem to work in older patients (>65) but not at all in the younger ones (65) drove the survival benefit, however they all lived shorter than the younger group (65) live shorter than patients in whom Provenge did not work? … Try to make that long story short if you can, using science rather than threats and lobbying (like Dendreon does).
christopher chance
Why did Provenge work in older patients (>65) but not at all in the younger ones (65) drove the survival benefit, however they all lived shorter than the younger group (65) live shorter than patients in whom Provenge did not work? … Try to make that long story short if you can, using science rather than threats and lobbying (like Dendreon does).
Chris Chance 2.0
chris chance - you are the same troll who frequents the care to live website and whines and whines and makes statements based on an anonymous paper that is made of pure conjecture and some outright lies. the immuno-suppression theory is “interesting” but is just not feasible. many, many have already shut that POS of paper down.
unfortunately, you never seem to be able to refute those points. instead, you simply keep pointing to an annonymous paper and then close your eyes and plug your ears and rinse and rep
christopher chance
[correct version] Why did Provenge work in older patients (over 65) but not at all in the younger ones (under 65)? Shouldn’t vaccines work better in healthier and younger immune systems? The older age group (over 65) drove the survival benefit, however they all lived shorter than the younger group (under 65). How was this possible, since age is not prognostic in mHRPC? Why did the patients in whom Provenge worked (over 65) live shorter than patients in whom Provenge did not work (under 65)? … Try to make that long story short if you can, using science rather than threats and lobbying (like Dendreon does).
Chris Chance 2.0
This (annonymous paper) was a serious piece of work to support an argument that Dr. Hussain put up during the 2007 AC meeting when she said that the placebo protocol might have been active and could hurt patients. At that time, she gave no explanation of how that could be the case. Now, the argument is that it is immuno-depletion.
The basic idea is that a large number of immune cells were taken from a patient in a leukapheresis procedure. If a patient was on the treatment arm, he would get most of them back on reinfusion. However, if a patient was on the control arm, he only got back less than a third of what was taken during the leukapheresis procedure. Therefore, the immune system of a placebo patient was suppressed. That is called immuno-depletion.
The immuno-depletion attack on Provenge goes like this. Because of immuno-depletion,the placebo protocol could harm patients, especially older ones so that they could not recover and died early. In turn, because of this, a survival benefit was seen in the trials of Provenge even though Provenge might not have done anything for patients. That is, the treatment arms of D9901, D9902a and IMPACT were the true placebo arms while the control arms were giving a poison to patients.
The best evidence against this immuno-depletion hypothesis is on page 40 of the FDA Clinical Review where the survival curves for patients taking APC8015F (Frovenge), patients not taking it and treated patients were plotted on the same chart. The curve for APC8015F more or less overlaid the treatment curve, meaning that the survival profile of APC8015F patients was similar or only slightly worse than that of Provenge patients.
Now, the APC8015F patients, of course, underwent immuno-depletion at randomization and did not get back the frozen blood months later. Due to the long elapsed time, the return of this blood could not have done anything to alleviate immuno-depletion. Thus, if immuno-depletion did hurt patients, the APC8015F patients should have died much earlier than the Provenge patients. Yet, that is not the case as seen in the survival curves!
So the conclusion must be that immuno-depletion is an interesting hypothesis but the existing data have shown that it is false.
-caretolive.com
Chris Chance 2.0
Our previous blog covered the bogus report making the rounds, falsely disparaging Provenge. (see blog below Provenge is Approved but the Lies Continue)
This further dispels that bogus report. Care To Live has learned,
Dendritic/other immune cells are extravascular, not in the blood. Removing less than 3% of immune system. If you check 3 weeks after apheresis, level of immune cells in blood is same as prior to apheresis.
The immune cell count calculation within the report appears to be wrong. Based on the article, the calculation discussed the immunodepletion of the cells within the blood. However, the majority of immune cells are in the TISSUE, and not just in the blood. Dendreon measured the immunodepletion 3 weeks into the trial and that was normalized.
Within the clinical trials no increase in infection was seen between placebo arm and Provenge arm. This suggests a normalized immune system.
The survival in the control arm was no different than historical normals for Prostate Cancer.
-caretolive.com
Chris Chance 2.0
david miller also crushed this dumb paper that our buddy christopher chance loves to quote (unfortunately i dont have the miller piece to post but im sure chance has read it)
so mr chance…here is your chance to refute all these points. we all await your response.
christopher chance
Although I cannot take credit for writing the “immunodepletion paper” I love to quote it and do think that more people should actually read the whole thing (including David Miller, who should take some immunology classes: most of the naive t cells in older people are in circulation, so the older patients in the provenge trials were selectively depleted of their naive t cells; later the extravascular populations repopulate the periphery, but all the naive t cells are now gone and cannot be replaced because the thymus has involuted in old age; meanwhile the overall t cell levels appeared to have renormalized, however dendreon did not conduct any analyses of the t cell subpopulations, which would have indicated a defficiency in naive t cells. you understand?)
The reason why I love to quote this paper is because in addition to explaining the survival difference it also can answer some questions which cannot be explained by provenge efficacy alone. feel free to take a crack at answering any of these questions otherwise:
Why did Provenge work in older patients (over 65) but not at all in the younger ones (under 65)? Shouldn’t vaccines work better in healthier and younger immune systems? The older age group (over 65) drove the survival benefit, however they all lived shorter than the younger group (under 65). How was this possible, since age is not prognostic in mHRPC? Why did the patients in whom Provenge worked (over 65) live shorter than patients in whom Provenge did not work (under 65)?
christopher chance
Dear CareToLive, also, while I have you attention, would you mind disclosing your financial contributors? Just post the list on your website. If all your work is in the patients’ interest, then I don’t see any reason why you should not once and for all dispel the myth that you are funded by Dendreon. How can we otherwise take a non-profit seriously if donations are secret and not tax-deductible?
scientist
I will not waste my time answering all questions but the statement is totally incorrect.
Patients’ age is very much prognostic in mHRPC, and the disease dependence curve is quite complex.
The explanation to your questions is available using clinical studies addressing specifically mHRPC disease development vs patients age.
christopher chance
“… age is not a significant prognostic factor in prostate cancer”
Kantoff, P. et al. J Clin Onc. Vol 28:7 March 1 2010
Perhaps you should “waste you time” reading the other publications of the lead author of the IMPACT study :) He seems to think that age is prognostic in mHRPC.
When you’re done reading that paper, I will still appreciate answers to the following questions: Why did Provenge work in older patients (over 65) but not at all in the younger ones (under 65)? Shouldn’t vaccines work better in healthier and younger immune systems? The older age group (over 65) drove the survival benefit, however they all lived shorter than the younger group (under 65). How was this possible, since age is not prognostic in mHRPC? Why did the patients in whom Provenge worked (over 65) live shorter than patients in whom Provenge did not work (under 65)?
Chris chance 2.0
Mr chance - I have no ties to care to live but from what I have seen and remember, there are absolutely no ties to dendreon. They were born out of the travesty that was the disgusting corruption and awful conflicts of interest in the 2007 provenge debacle at the FDA (you know with your corrupt and GREEDY friends maha hussain, Howard scher, Tom flemming…leaked letters to the cancer letter by pazdur etc etc). In fact ctl’s pro bono counsel has spoken out against dendreon as to how they are not doing enough to get this out patients and instead just acting as a for-profit company by taking it slow.
Finally, you once again refuse to refute any of the points above. Instead you just close your eyes and plug your ears and respond with a) a potshot at miller and b) a question. Hahahahah. Refute the points please. Always wonder how people like yourself can look at themselves In the mirror everyday.
Chris Chance 2.0
once again, mr chance dissapears when asked to refute the points above.
ocyan
christopher chance, November 12th, 2010, 12:23 am
It’s disingenuous of you to select and emphasize a negative data point without discussing the entire context of how it could have randomly arisen and, therefore, was found false on a deeper analysis.
The subgroup of patients < 65 years old in the IMPACT (D9902b) trial was small and likely had significant imbalances between the trial arms. So the poor hazard ratio was just a matter of chance bound to happen when too many subgroup analysis was attempted.
However, an analysis by the FDA statistician of the pooled data from all three trials, D9901+D9902a and IMPACT, clearly showed that Provenge did help those patients. Below is a direct quote from page 38 of the FDA Clinical Review:
Reviewer’s comments: The exploratory pooled analyses in Table 14 were conducted across multiple studies to analyze the effect of age on the primary endpoint, overall survival. The above analyses of the data from all three studies (D9901, D9902A, and D9902B) support the hypothesis that the subgroup of subjects who were less than 65 years of age also benefit from treatment with sipuleucel-T. The hazard ratio in the subgroup of Study D9902B subjects who were less than 65 years of age most likely resulted from chance, related to the multiplicity of comparisons in 49 different subgroups.
Chris Chance 2.0
where did christopher chance go?
DC
As a physician I appreciate christopher chance’s examination of the harms in the so called placebo arm. This information will be passed onto patients who are being manipulated by people with conflicts of interest.
The profits of investors will suffer while the people prosper.
ocyan
DC (Double C’s?),
That you peruse an investment blog and make comments about investors says something about you. So please drop the pretense about being a physician and about caring for patients.
Now, let’s consider the so called “immuno-depletion hypothesis” that you cited to cause “the harms in the so called placebo arm” because white cells were taken away from them.
If you had a medical degree, you would be aware at least of the first basic fact about the human body below:
1. A typical person would produce about 10^11 white cells a day on the average (Normal Granulocyte Collection with a Modified Repetitive Cycle Filtration Leukapheresis, Annals of Hematology, Vol.29, No.4, 1973)
2. An average infusion of Provenge consists of about 10^8 cells (Immunotherapy of Hormone-Refractory Prostate Cancer With Antigen-Loaded Dendritic Cells, Journal of Clinical Oncology, Vol.18, No.23, 2000).
So, even overestimating 10^9 cells in a leukapheresis procedure for Provenge, only about 1 percent or less of total white cells would be extracted from a patient for each infusion. Even if the cells were never reinfused, the immune system would replace that within a day or two even for a sick patient. In fact, the leukapheresis procedure is routinely done for various purposes including blood donation with no harms known to donors.
Immuno-depletion is just a big made-up name for a non-existent condition.
ocyan
Btw, in case the notation is unfamiliar:
10^11 is one hundred billions,
10^9 is a billion, and
10^8 is a hundred millions.
So, 10^9 is one percent of 10^11.
hancock
the cell fraction depleted from the provenge placebo patients posed a QUALITATIVE not QUANTITATIVE problem. ocyan, you keep assaulting everyone and doubting their credentials, but you’re not making an effort to understand their argument: you keep saying that the cells taken out are too small a fraction of the total immune cells in the body, but that’s not what your critics are arguing. they are saying that the fraction taken out consist of a population of naive Tcells which in old age exist ONLY in circulation and CANNOT be repopulated from the tissues (so, independently of how many billions of cells are left in the tissue and can repopulate the periphery post-pheresis, they are not naive Tcells–these have been lost forever. it’s well known that the thymus is completely gone by the mid 60s, so the naive Tcells that you have at that point are all your have left and they’re precious, and they’re all in circulation).
i just went read the whole thread here and the poster above named christopher chance explains this to you (in his post above from November 11th, 2010 @ 11:38 pm). what he is saying is very clear. what you are saying is also true, but those absolute numbers that your quote have nothing to do with the problem.
Pseudoscience investigator
The MODERATE evidence as graded in that report implicates that the evidence leading to the approval was not substantial. In other words, the approval was likely premature or a mistake. At end, patients suffer or lose.
The above “Scientist” appears not a medical oncologist. The above So-So-ers for use of the product should consider to try themself first. A man on the moon without shuttle activity seen? Either dreaming or using photoshop. In this case, the survival difference appears generated from the 30% of patients in the control arm who only received 1/3 of their own cells collected from them. These 30% patients had a median survival of 11.6 months! This median survival is unlikely in patients with the early satge mCRPC. Read the online FDA reviews carefully and use your brain scientifically.
KDDublin
CareToLive through a FOIA request obtained correspondence wherein the FDA stated this about the immune depletion argument:
“[FDA is] aware of the concerns but we did not find any clinical evidence of decreased white blood cell counts in control patients following leukapheresis in the 9902B clinical studies.”
In addition the article was written with the help of Appollo Medical CEO Brandon Fradd a known short seller of Dendreon stock. A known woman who worked for the Schoenfeld hedge fund(also a known short seller of Dendreon stock) was seeking support for the bogus 27 page article at ASCO but could find no support among any of the oncologists. However the article was hijacked and distributed by a person that using a g-mail account using the name Jonathon White.
andre
Several small cap biotechs now starting immunotherapy trials in different cancers.
I think Biosante will soon restart testing of G-VAX. It didnt work the first time, but with some luck theyll succeed now.
Bavarian Nordic is also going to move ahead with a phase 3 with prostvac.
Not sure which one will be the next Dendreon, but it doesnt have to be just one. Lots of exciting new therapies for patients. Lots of companies for investors. Good news for everyone.
JWarren
when dndn said that national coverage of provenge was a sure thing, the cms responded by opening an investigation. when asco and senators asked the cms to drop the investigation entirely, instead the cms scheduled the date for a panel. when dndn bulls said that the panel would only focus on restricting off-label use, the cms published a list of questions focused on adequacy of evidence for on-label efficacy, and is even bluntly soliciting recommendations for a new trial design. come on, people, these messages from the cms are not even mixed. they’re crystal clear about where this is all headed.
Chris Chance 2.0
jwarren - funny that use “dndn”. isnt that the stock symbol??? and kdublin…nice! a “medical” report drafted by short sellers. pathetic. WHERE’s Chris Chance?
Detective
The “efficacy” as reported so far is TOXIC to our patients, to our hard-earned tax, and to clinical science intergrity.
A new Madoff version in medicine and science.
ocyan
hancock -
The math goes like this. At any given time, there are more than 10^11 immune cells and each leukapheresis procedure only takes about 10^9 or 1 percent out. Now, since the leukapheresis procedure does not select cells trained for any particular antigen, such cells will be taken at random. As such, the percentage of cells taken from any one such population (per the particular antigen) should also be minuscule.
The immunodepletion paper contains numerous errors in interpretation or over-interpretation of statistics. But the simple argument above is sufficient to dispose of it.
Btw, those who criticize Provenge proponents for having a financial interest in DNDN should read a Wall Street Journal article that just came out tonight. As it turns out, the author(s) of the immunodepletion hypothesis had a financial interest - clearly on the short side.
‘The law firm Willkie Farr & Gallagher LLP submitted a 26-page anonymous scientific analysis contending the data show the treatment may do more harm than help by weakening patients’ immune systems. The firm’s submission said it couldn’t name the author “because of the public vilification of anyone that questions Provenge.” A Willkie lawyer said the firm was acting on behalf of a client with a financial interest. ‘
ted
wow … dendreon secretly hired a lobbying group to lobby congress?
Pseudoscience investigator
Does real science need lobbying?
Some human beings are corrupted in their soul and prioritize their personal gain at the expense of patients interest and well-being. it is shameful or a crime to calibrate an ineffective therapy by lip-coloring or -covering.
Chris Chance 2.0
wow …short sellers wrote the fraudulent 27 page paper?
ocyan
The immuno-depletion argument was just brought up at the CMS meeting and was shot down just as quickly by Dr Gulley of NCI who gave my same argument above about the minute quantities of white cells extracted per leukapheresis procedure.
Dr Petrylak of Columbia University added that the control arm of IMPACT behaved similarly to the control arms of the Taxotere trials that he helped run.
The short sellers who drew up that offensive argument were apparently Summers Street Partners. Chris Chance, Pseudoscience investigator, anything to add?
Biochemist, Immunologist
Christopher Chance has clearly explained above why both you and Dr Gulley are correct that the number of cells removed is ~3%, but incorrect in your belief that this is immaterial in old people.
Dr Petrylak failed to mention that IMPACT selected for very healthy patients that SHOULD have lived a lot longer than those in the Taxotere trials. The truth will come out.
And the company STILL hasn’t explained why the old patients in the placebo group are dying 11 months shorter than the younger ones when they should have THE SAME survival. the “placebo” intervention was harmful to the older patients. that’s why. you and Dr Gulley and Dr Patrylak are simply wrong.
The truth will prevail ultimately. it has a way of getting out…..
Chris Chance 2.0
hmmmm anonymous blog poster or highly decorated doctors who actually reveal themselves. i think ill go with the latter. hope that short selling worked out for you. pathetic.
Chris Chance 2.0
if you guys are going to send someone in to sabotage the meeting, at least send someone who is capable of public speaking. that guy was shaky and awkward. definitely was fun to watch.
AKW
Why do you think we’re all coordinated? the truth is funny like that…. it finds followers all by itself.
I, for one, will reveal myself soon enough.
Oh yeah, and the truth also wins.
Pseudoscience investigator
Dan lied!
“that the control arm of IMPACT behaved similarly to the control arms of the Taxotere trials” is not truthful. Look at page 40 of the FDA review. Patients in the “placebo” arm who only got their 1/3 of the total mononuclear cells (not simply WBC) had a median survival of 11.6 months. This is totally wrong for patients with early mCRPC. please ask Dan if that is acceptable. It was those poor vulnerable patients that defined the “survival advantage” of the product in that tricky study setting. The real world will not have such patients for you to abuse or exploit!
The unilateral vocies from those with considerable conflicts of interests in the NCA meeting did not boost the confidence level for the evidence to A (5). IT was only B-, (3.6). What a joke! The death threats and vilifications others experienced made it difficult for people with different views or different interpreations of the data to be found or included in the panel or to speak publically. In that regard, some of you did a great “job”. Nevertheless, feel free to use the product yourself if you believe it or love it. But remember there are always someone who stand strong for patient’s interest. Cheating patients with a flawed product is shameful. History will tell who are scientific liers.
ocyan
Pseudo -
The median is a noisy statistics when sample is small. As an extreme example to make a point, what is the significance of the median if the sample was something like this 1, 5, 11.6, 24, 36?
In the same way that the proponents of Provenge cannot use the 11.6 month median of the pure placebos to tout how much better Provenge is, you cannot use that number to say that Dan was wrong. That subgroup of patients was small. More importantly, the subgroup had an inherent bias in that those patients might not have got on the cross-over protocol because they died too early.
In any case, reread my answer to Hancock to see why the immuno-depletion argument made little sense. It was also mentioned at the meeting that a far more thorough analysis of the cross-over to Frozen Provenge data done by researchers at Duke University was submitted to be presented at a conference (ASCO?) next year. That data strongly supported that Frozen Provenge was beneficial to patients.
But you are right, “history will tell who are scientific liers” or at least scientifically uninformed. Bye and GLTA.
asco reviewer
duke’s “frovenge abstract” seems to me no more credible than the “immunothreapy paper”. for one of them we know the content but not the author. for the other we know the author but not the content. apparently it was submitted to asco, but that means nothing—will be accepted? probably not.
david mark summed up frovenge pretty well at the panel by likening it to a “red shirt”. anything given after the therapeutic intervention and after unblinding and given only to patients who were alive will “create” a survival benefit. as such, even handing out a red shirt to placebo patients who were still alive instead of giving them frovenge would have resulted in a survival benefit for the red shirt.
Scientific Rigor
Frozen Provenge was good for patients because they got their frozen T cells back that they had previouisly had taken away. The cells with which their body had replaced these cells were not of the same type as those removed, hence getting some of the originals back was most probably beneficial to survival (Frovenge administered on average ~4-5 months into a ~2 year survival, so plenty of time for those extracted T cells to confer survival benefit after re-infusion).
Any analysis of post-progression, post-unblinding, non-randomized, given-only-to-people-who-aren’t-dead-yet interventions is a totally unscientific nonsense, however. Dr Daniel George should be ashamed of himself.
Chris Chance 2.0
akw - because you all use the same, super-specific talking points that are so far off base and wrong that there is no way you arent all working together (probably on a nice short that’s going against you…) pathetic
rorschach
1. provenge does not work.
2. dendreon did hurt people in clinical trials.
3. by mid 2011 there will be shareholder lawsuits against dendreon, and you my dear CK 2.0 will pile on along with the other plaintiffs.
are those points specific enough for you, CK 2.0?
you twist and turn and offend and assault others on this message board; you should try to save some for when you turn against dendreon next year. trust me, you will. hessians like you always do.
Chris Chance 2.0
rorschach - hahahaha. you are going off a report that was drafted by a short research shop. care to prove any of those points? im talking with real data, not just your made up crap that you guys all spout. hows that short working for you?
ps i hear your shaky, awkward boy got destroyed by all the stat geeks after the meeting yesterday. hhahahah. pathetic.
Chris Chance 2.0
and i attack people? those are some serious allegations you have leveled against a company
Pseudoscience investigator
To OCyAN and By-Chance 2:
what was the most common feature in that subgroup with a median survival of 11.6 months in patients with early stage mCRPC? Be logic! They all had only 1/3 of their own cells infused back and they appeared sensitive to the withholding and became too deteriorated to have an opportunity to receive the other 2/3 of their own cells or even chemotherapy.
Subgroup analysis restuls are not useless but rather reveal improtant signals and tell where problems are or where further scientific invetigation should be conducted. How many subgroup analysis results in favor of the prodcut were used or presented by the company or people like you? Regardless of what you guys do, the emerging internal data or results inconsistency continues to be there. Scientific lies do not vanish with campaigning tactics. Think about the destiny of the high dose chemo plus stem cell transplatation treatment for breast cancer.
Be fair and be responsible for patients. Stop lying to the public and to patients. Immunotherpay is promising, but does not have to solely rely on provenge to boost the field. Hard work is the only way to find an answer. The provenge or frovenge diaster is a great lesson to all of us if you truely believe in science. One cannot receive blood from others without typing and cross-matching. But many years ago, people did it without doing what we do routinely today and patients died from incompatabile blood.
By-Chance, could you make some analytical scientific arguments? or going back to school to get some basic training.
Scientific Rigor
CC 2.0 …. I suspect that Varun Nanda (ex-head of oncology at Genentech/Roche, dude that launched Avastin) didn’t quit after 7 months on the job because he thought this was a great drug with great potential….. there’s more there, and the truth has a way of coming out….
And yes, there is REAL DATA behind the 27-page report….. the AGE STRATIFICATION, which makes NO SENSE and DEMANDS explanation…. the “placebo” treatment CLEARLY caused the older patients to die 11 months sooner than the younger patients. that’s REAL DATA. RIGHT THERE. DATA THE COMPANY HAS NEVER PRESENTED OR DISCUSSED. p=0.0004… making it THE MOST STATISTICALLY SIGNIFICANT result in the entire trial. whatever “placebo” was doing to those poor elderly patients was much more profound than the difference between the two arms of the trial.
Chris Chance 2.0
hahahaha all these short sellers getting burned… classic. your shaky, awkward “public speaker” got shut down by all the stat geeks. what a joke. how pathetic you guys are just to make a few bucks.
Chris chance 2.0
Haha first the bogus 27 page garbage gets destroyed by anyone with half a phd. Now i see the new short talking point will be a vp. leaving. Nice work guys. (grasp meet straw)