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OK, I misinterpreted your statement. I thought you meant that there was no doubt that Provenge does have serious side effects.
re CEGE: A pivotal superiority trial such as the VITAL-1 trial pitting GVAX vs Taxotere means that GVAX needs to improve survival over the Taxotere arm with statistical significance. The asymptomatic patients in Taxotere's pivotal trial that got it approved had a median survival of 23.0 months. That figure will be extremely difficult, if not impossible, for GVAX to beat. If CEGE had been able to negotiate a noninferiority trial into the SPA instead, then roughly all GVAX would need to do is come within a certain percentage of Taxotere's median survival...perhaps 2%, or 5%, or even 10%. It appears that the FDA didn't let CEGE get a noninferiority design for this trial. Either that, or CEGE mgmt isn't very smart.
I would agree with the statements cited in your post after the colon, except this one:
<<There is no real argument that there are significant side effects with Provenge, certainly since the life expectancy of these patients is (currently) measured in months.>>
I believe that an argument can be made that the number of significant side effects caused by Provenge treatment is very low. The CVA event rate for the Provenge arm for all Phase III trials was 3.9%, compared to control arm rate of 2.6%. While it's possible that there are a few cases where Provenge did cause some CVA events, IMO much of the elevated rate of CVA events in the Provenge arm is simply the function of Provenge-treated patients living longer. I'll also point out that the panel voted 17-0 on the safety question, so they'd disagree with your statement on this issue, as well...although Scher and Hussain raised it again in their letters.
Black Wednesday at the FDA By MARK THORNTON
May 14, 2007
May 9, 2007, should be cited in the annals of cancer immunotherapy as Black Wednesday. Within an eight-hour period that day, the FDA succeeded in killing not one but two safe, promising therapies designed and developed to act by stimulating a patient's immune system against cancer. The FDA's hubris will affect the lives and possibly the life spans of cancer patients from nearly every demographic, from elderly men with prostate cancer to young children with the rarest of bone cancers.
The dream of stimulating a person's immune system to fight his cancer is older than the modern era of cancer chemotherapy. Over a hundred years ago, Dr. William Coley at Memorial Hospital in New York City experimented with bacterial agents that appeared to have properties in stimulating immune responses against sarcoma, a cancer of the muscles and bones. Advances ebbed during the era of chemotherapy in the mid-20th century, but over the last 25 years cancer immunotherapy has received much research focus and periodic support from the biotechnology industry.
Progress and investment, however, have been unsteady as tumor shrinkages following treatment never quite translated into "hard," clinically relevant outcomes such as prolongation of the survival of the patient. Still, this type of approach remains the Holy Grail of cancer treatment. One day current treatment approaches such as surgery, radiation and chemotherapy, which often kill most but not all of a cancer, could be made obsolete by a potent immune response that eradicates the cancer cells and provides subsequent protection against return and relapse.
Thus it was remarkable that in the last several months two different biotech companies, with products utilizing two completely different cancer immune approaches, came before the FDA's Advisory Committee Meeting for judgment. The first product, Provenge, made by the Dendreon company, is a cellular therapy that tackles prostate cancer. The results of the Provenge clinical trial in men with prostate cancer who had failed all other therapies appeared before the committee that advises on cell-based cancer products for the FDA Center for Biologics. This committee was comprised of immunology and oncology experts. The second product, Junovan, made by the IDM company, was tested in children with osteosarcoma, a rare bone cancer that affects just 900 children per year. The results of the Junovan clinical trial appeared before a different committee -- one that judges protein cancer agents and was comprised solely of oncologists with no immunology experts.
Both the Provenge and Junovan clinical trials provided evidence that patients lived longer compared to control groups. But according to the FDA, these "survival advantages" that statisticians talk about had "issues." When the issues were discussed in the Provenge public meeting the majority of the committee (in a 13-4 vote) thought the issues, while relevant and important, were superseded by the solid immunology science behind the product.
However, those voting in the minority, 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 immune-based products may be qualitatively different from, and may need to be judged by different criteria than, survival data from chemotherapy drugs.
But such intriguing academic discussions never had a chance to take root. Instead -- just a few weeks after the favorable ruling on Provenge -- the Junovan product came before the FDA's Advisory Committee for approval. Incredibly, the improvement in the survival rate of children with bone cancer who received Junovan was summarily dismissed as irrelevant by the committee. Why? The statistical data showing the odds of efficacy were 94% surety instead of the usual goal of 95% surety. This 1% difference was all the committee needed to justify a 12-2 "No" vote.
The Junovan meeting was chaired by the very physician who launched the PR campaign against Provenge. Unlike the meeting on Provenge, however, all discussion time on Junovan was spent kneeling before the altar of statistics -- not a single comment was made about the immunology science supporting the efficacy of Junovan. Remarkably, as the Junovan vote was taking place, the FDA folded under the pressure and announced that it would not abide by the favorable vote on Provenge. Instead, the FDA called for more testing that -- if the product is not killed outright by its maker Dendreon -- will take at least three years to complete.
In the span of eight hours, the dawn of a new era in cancer immunotherapy was driven back into the night. It will be years before we know the full impact of these decisions and how many cancer patients, young and old, have had their lives cut short as a result. For now, however, one thing is clear: While our lawmakers obsess over FDA "safety reforms," no one is holding this government agency accountable for its complicity in stalling therapies for life-threatening diseases.
Dr. Thornton, a former medical officer in the FDA Office of Oncology Products, volunteers as president of the Sarcoma Foundation of America.
http://www1.investorvillage.com/smbd.asp?mb=971&pt=msg&mn=112292
Patients in each arm have the option of getting a treatment that the FDA says is already proven to extend survival (Taxotere). So to the FDA, this satisfies the ethics question.
The Provenge given after crossover is frozen Provenge, with less than half the potency of the fresh Provenge given to the treatment arm. This trial design is the best that DNDN could negotiate in the SPA with the FDA. CEGE, on the other hand, was only able to negotiate a superiority trial with GVAX in one arm competing against Taxotere in the control arm. It's quite possible that if GVAX performs better in this trial than Taxotere in both median survival and landmark survival, but doesn't attain stat sig, it doesn't get approval. More details of CEGE's SPA haven't been released.
In placebo-controlled trials, there is a lot of pressure on the sponsor from the FDA and patient groups to have a crossover component worked into the protocol...and yes, there was a big difference in performance, at least in 9901, between the placebo crossovers and the placebo non-crossovers. The interim look taken in 9/03, two years after the last patient enrolled, had these median survival numbers:
Provenge arm: 26.3 months (n=82)
placebo crossovers: 23.9 months (n=34)
placebo non-crossovers: 19.3 months (n=11)
We never got to see the final MS breakdown of the placebo arm for 9901, nor any MS breakdown of the placebo arm at all for 9902A.
I believe that this was a mistake by Dendreon not to publicize this data. I'm sure the final 9901 numbers were similar to the two-year numbers, and based on the landmark survival analysis of the three-year survivors, I believe a similar laddered improvement would have been seen in 9902A. Perhaps it wouldn't have made a difference in the final FDA decision, but I imagine that the advisory panel and maybe some members of the financial press would have commented (and releasing the data certainly wouldn't have hurt).
Simple. Aschoff doesn't believe that Provenge works...and in his mind, even if there were some clinical benefit, it would be easier for stat sig to be achieved on the final look upon the 360th death.
Thanks for your post, Paula. TA is all Greek to me.
Don't know why the price rose...perhaps it's some technical reason, such as a Fibonacci number from where it opened on Wednesday in the low 8's to the low point late Thurs or early Friday around 5. As for the FDA changing its mind, they never have before without a formal appeal from the company. When they reversed themselves on Plan B, it was after a few years, and after the sponsor had submitted some additional data.
Wow...so Aschoff is saying that despite the existence of the SPA, stat sig survival results in 9902B won't get Provenge approved. One of the things that bugs me most about the Provenge nonapproval is that a liar like Aschoff came out smelling like a rose.
Dew, I'm assuming that when Aschoff says DNDN will need to do an additional trial other than 9902B, he means that 9902B will fail. He always says that 9902B will fail, because he believes Provenge has no clinical benefit.
To simplify things even further than what Dew wrote, they increased the number of patients in the trial, so that a smaller survival effect than was seen in 9901 could still achieve statistical significance.
OT-Have you ever tried a good acupuncturist? I'm talking about someone who has practiced for many years in Asia and is now in the US. Sometimes drugs have a rebound effect.
Personally, if they can't get a penalty-free look, then I would favor Dew's hypothesis, which is what I've posted about before. P value of 0.015 for 180 deaths. Cox regression analysis. DNDN said at the panel meeting that the two arms were stratified for # of bone metastases, which is by far the most important prognostic factor in HRPC patients. I think bisphosphanate use and Gleason score are other prognostic factors. I think 9902B would have a pretty good chance at the interim analysis. There could be a decent number of four and five-year survivors from the treatment arm by the time it's unblinded in 2H 2008. There were 99 enrolled patients as of 2/05, and 179 as of 2/06. There will be a lot of patients who enrolled in 2007 that would have to be censored, though...that will hurt the p value somewhat.
DNDN alpha for interim look..hmm...I've already speculated with those exact figures on more than one occasion. I think 180 deaths and 0.015 p value are what we will see.
I think there already is a DSMB that monitors 9902B. The question will be if they can take a penalty-free peek at 9902B this year. I don't think the FDA will let them...we're looking at 2H 2008.
There are only two possible ways that DNDN could get Provenge to market this year, but only if enrollment is completed in the next month:
-first step would be to persuade the FDA to give them a free look at 9902B
-next step would be to look at the overall survival curves, see if they are significant...pretty tough, because there will be many recently enrolled patients who would have to be censored...but maybe there will be some median survival benefit seen
-another option is to look at the ttp data...unblind it in late Aug, ten weeks after enrollment completion, hope it's stat sig, then try for Accelerated Approval on the ttp endpoint, send it to FDA before end of Oct, hope FDA grants Class 1 response, two-month review
re DNDN early unblinding:
http://www.investorshub.com/boards/read_msg.asp?message_id=19517017
The pain situation is completely out, because only the first 150-179 9902B patients who enrolled did so under the old protocol. The company could try to talk CBER into giving them a penalty-free early unblinding prior to the 180-death point, but (1) I think it's unlikely CBER would agree, and (2) it would be tough to hit stat sig with so many censored patients who have recently enrolled.
Convincing the agency to unblind and look at TTP data might have a different outcome, but the agency could argue that DNDN's point has been that Provenge has been all about survival, so forget about TTP. Pretty perverse, but that's life.
Well, thanks to all for the kind words. I was able to sell all of my April $10 calls for a huge return a few weeks ago. Today, I decided I had to sell my entire common stock position early this morning in premarket. I was on margin but not excessively so, the main cause of my going on margin was my exercise of a ton of April $7.5 calls. The cost basis of buying those calls, plus purchasing the stock at $7.50, caused me to break even on that trade when I sold today. I was able to make about a 75% profit on all of my other long shares. In hindsight, I should have sold about 20% of my long shares at the top of the short squeeze, which was roughly the same time I sold my $10 calls. I'm kicking myself over that...I wasn't expecting the FDA to make the unprecedented decision of overruling a positive advisory committee vote in a terminal disease indication. A lot of my holding on was the desire to not pay the 38% federal income tax (same rate as highest tax bracket, not the 30% short-term capital gains rate) and 9% California capital gains tax. All of these trades together, including my sale this morning, approximately quadrupled my DNDN investment from late March.
I had previously sold out of my position with the expectation of buying back in the day of the briefing document release (I expected to see negative briefing docs, not the neutral one that it ended up being), so all of my trades in the past month were of the short-term variety.
As a conference call has been scheduled very quickly, it appears to me that DNDN will take a conventional approach to resolving the Complete Response letter, and that will be to wait for interim survival data in 2H 2008. I don't think they will try to unblind sometime in the next few months, as I don't think CBER would grant them a statistical penalty-free look.
Again, as I said on the I-Village board, I think the biggest influence in CBER's overrule of the advisory panel was Dr. Fleming's letter. I think CBER was inclined to approve all the way up to that point, as I personally know of approximately 15 oncologists or urologists who emailed the FDA in support of approval, and almost every major prostate cancer advocacy group in the country also made their desire for approval known to the FDA. However, Fleming basically threatened Dr. Marincola with medical malpractice liability for wanting to use HRPC patients as guinea pigs for the greater God of wanting to open up venture capital funding for immunotherapeutics by approving Provenge. There were other statements that Dr. Marincola made during the advisory panel meeting that prove Dr. Fleming was taking his "funding" quote out of context, but nevertheless Fleming's words struck fear into the heart of CBER. I think they knew that if they approved Provenge and 9902B later missed the survival endpoint, their jobs would be toast. They would either be fired or transferred to CDER, under the auspices of Dr. Pazdur. The latter of course would be a worse fate than being fired...so they caved in. The ironic thing is that if 9902B comes out stat sig, CDER will probably look down its nose at CBER even more, because it didn't stand up to the political pressure. Dr. Von Eschenbach obviously caved in too, and all of his words at the February FDA/NCI immunotherapy conference now ring hollow.
I think it's obvious that the hedge funds used all of their oncologist and biostatistician contacts at their disposal, and probably were at the forefront of the organized effort to derail the Provenge BLA...no conspiracy, just the same lobbying effort that was a mirror image of the lobbying effort made by DNDN retail longs and PCa advocacy groups...except the hedge funds had bigger guns at their disposal (president of ASCO, Fleming, Scher, Hussain, and The Cancer Letter). Who cares about terminal patients, anyway?
Best of luck to all...I'll post a link to this post over on I-Village, which will probably be my last post over there for awhile. Too many posts to wade through over there.
Others I can think of are:
CYBX-Vagus Nerve Stimulator...implanted device for treatment resistant depression
SCIO-Natrecor
This is the first time that I can think of where the reversal of a positive panel occurred when it's for a terminal stage of disease.
The briefing docs for IDMI and DORB are the most critical I've ever seen...even worse than ABT's Xinlay in Sept 2005.
According to the Abigail Alliance, as of last year they had only advocated for access to a handful (five or six, can't remember) of experimental cancer treatments. All had either completed Phase II at the time when the AA advocated access to them (Gleevec, Erbitux), or had demonstrated clear clinical benefits in a Phase I (Gleevec). All have subsequently been approved by the FDA. I'm not sure what the other treatments were, but I could take a guess that Avastin would have been one. It's possible that Iressa was one, too, as I know that the AA has argued for it to remain on the CMS/Medicare reimbursement list for those still taking it.
I think a lot of what the AA advocates gets blown out of proportion by negative spin. They're not advocating that every experimental treatment be made available...only the handful of the most promising ones which have shown both evidence of efficacy in Phase II (and occasionally Phase I), and appear to be safe.
Definitely not true. I have no idea where he got that. Eleven are permanent members, Pazdur chose three, and CBER chose the other three.
re DORB OT: I would like to see how many gastro docs are added as temporary panel members (and how they vote) before I make that guess.
<<By the way, Provenge has been blessed since CBER got the football. Why some analysts and shorts insist on making fools of themselves since that happened is a question only they can answer.>>
Yep...it's amazing how far behind the curve they've been. We knew it was going to be CBER since Summer 2005. Then Von E and Gottlieb were named to the two top spots in the agency, making it tougher for Pazdur to wrest the BLA away from CBER. Then, Dickie only got to name three temporary voters to the panel...and CBER ALSO named three temporary voters, one of whom was an additional patient advocate! Almost unheard of. To compare and contrast, check out DORB's panel--two biostatisticians. Gee, I wonder how that vote's going to go.
re Hussain and Wolfowitz...holy crap!! Great find. eom
The Cancer Letter only interviewed biostatisticians for the rebuttal on that one point...I would imagine that many physicians would criticize the conclusion that "close but no cigar" on the 0.052 ttp p value argument is weak, when the survival p value of 0.01 is taken together with the ttp p value. These are actual patients we are talking about here, and the ttp endpoint has been subsequently discredited as an ideal surrogate for survival in HRPC. If the recent theory about cancer vaccines killing tumors from the inside, promulgated by Dr. Dranoff, is true, then the biostatisticians' argument goes out the window.
OT posts: I'm deleting any OT posts that don't have either OT or the company name in the very beginning of the post.
DNDN--Well, if it had indeed gone up before ODAC, I do believe we would be currently looking at sub-$4.50 prices. It also looks from today's filing that Edelman partially hedged his fund's huge short position with a little more than 60,000 call contracts.
OT-LOL...same website that advertised a "takeover offer" for DNDN last week, and just about every other smallcap that does well over any period of time in the past couple years.
OT-MEDI buyout was price was over 50% higher from when it announced it was up for sale a couple weeks ago.
OT-I was offered a ticket to last September's Dodgers-Padres game where the Dodgers hit four consecutive solo homers in the bottom of the 9th to send the game into extra innings. I had to decline....ouch!
OT quiz-What does Sunday's Red Sox feat have in common with the last time the same feat happened in the majors?
Ah...it appears I wasn't listening close enough. You guys caught that, I didn't.
It was the deal with Genentech on Trp-p8 that Gold negotiated which inspired Henney to name him CEO. My interpretation of the vaccine discussion was that Roche was referring to Transgene when they said "We didnt see an awful lot which is intriguing until quite recently." Since Roche and Genetech have been familiar with Dendreon's vaccine platform for years, I interpreted that paragraph as a positive reference to Transgene at the expense of Dendreon. They signed a deal with Transgene last week for Transgene's cancer immunotherapy platform, specifically those cancers caused by HPV. Of course, I'd love my interpretation to be wrong.
Roche doesn't sound like they're interested in any of the cancer immunotherapies in late-stage trials...no real surprise, as I've heard that Amgen wasn't much interested in Provenge either. I suspect that they've been looking at the PSA reduction measurement, and Provenge doesn't do much for that metric in HRPC.
<<If the above is correct, then DNDN could have easily made their case by taking scans every few months to demonstrate that effect for the people on Provenge Vs the placebo arm. I guess hindsight is always 20/20...>>
That theory has only started to gain acceptance in the past two or three years, so I don't know how you could possibly argue that this is what Dendreon should have done five to seven years ago...not to mention the extraordinary cost this would entail for a development-stage biotech.
Not much more to be said. CBER/FDA has the two compilations. The PCa advocacy groups have communicated their wishes already. For Von E to be able to alter the mindset inside the FDA about evaluating cancer treatments, the first necessary step has to be approval of Provenge. Going against approval would be counter to everything he's said publicly, would be counter to what the advisory panel voted, and would be counter to the tone of the CBER briefing documents.
One point to be noted: Dr. Dranoff was brought onto the Provenge advisory panel as a nonvoting member because of his expertise in cancer immunotherapy. The theory he posited in Business Week about measuring disease progression (the immune system kills the tumor from the inside, leaving a necrotic mess that nevertheless shows up on scans), isn't conjured up out of nothing. I would submit that the FDA reviewers take what he has said very seriously, and if so, the survival hit from 9901 and the mild toxicity profile would trump the narrow progression miss in their eyes.