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The basis of the filing to the FDA and the basis of the argument to the public will be two different things. You're not going to want to show a graph of the Phase 3 survival curves in your ad, but that was the main thrust of the BLA with the FDA.
In your ad, you'll want to discuss the 4.5-month median survival benefit vs the control arm (don't refer to it as the placebo arm), the 34% vs 11% three-year survival for 9901, the 32% vs 21% three-yr survival for 9902A, and the 33% vs 15% combined three-yr survival.
I think you should also cite the p value for overall survival in parentheses, immediately after the mention of the 4.5-month median survival in the main trial 9901 (p=0.01). Then continue with 34% vs 11% three-yr survival (p=0.0046). Then give a simple definition of p value and what it means (p=0.01 means that the results have 1% odds of being random chance).
re CEGE: I can't see GVAX surviving the first interim look of VITAL-1, but stranger things have happened. As it appears to be a superiority trial (with no crossover allowed in either arm), the median survival target to beat is Taxotere's 23.0 months (no bone pain subgroup of TAX-327 Phase III). Even Provenge would have a tough time in trying to beat 23 months MS in a stat sig manner. Anyway, FWIW, I think VITAL-1 will be stopped for futility at the first interim look. For the sake of future HRPC patients, I hope I'm wrong.
re DEPO-ouch...bye bye to my August calls. I'll tell you one thing, I need to get my hands on some of these placebos in pain trials. I could make a fortune selling them to Hollywood celebs...huge markup.
CEGE completes enrollment in VITAL-1 Phase III
#msg-21089642
Cell Genesys Completes Patient Recruitment for First Phase 3 Clinical Trial of GVAX Immunotherapy for Prostate Cancer
Tuesday July 10, 8:30 am ET
SOUTH SAN FRANCISCO, Calif., July 10 /PRNewswire-FirstCall/ -- Cell Genesys, Inc. (Nasdaq: CEGE - News) today announced that it has completed recruitment of over 600 patients into VITAL-1, the first of two ongoing Phase 3 clinical trials of GVAX immunotherapy for prostate cancer.
The multi-center, randomized, controlled Phase 3 study in advanced prostate cancer will compare GVAX cancer immunotherapy to Taxotere® (docetaxel) chemotherapy plus prednisone in hormone refractory prostate cancer (HRPC) patients with metastatic disease. The primary endpoint of the trial is an improvement in survival.
"Entering this final stage of patient recruitment for the first of our two Phase 3 clinical trials of GVAX immunotherapy for prostate cancer is an important milestone for the program, and we are very grateful to the men with prostate cancer and their physicians involved in this trial as well as the Cell Genesys employees who have made this possible," stated Stephen A. Sherwin, M.D., chairman and chief executive officer of Cell Genesys. "With the completion of patient recruitment behind us, we can now estimate the timing of the pre-planned interim analysis for the VITAL-1 trial to be in 2008, probably during the first half of the year, and that we will have a sufficient number of events required for the final analysis to follow sometime later in 2009."
Cell Genesys received Fast Track designation from the U.S. Food and Drug Administration for GVAX immunotherapy for prostate cancer and Special Protocol Assessments for VITAL-1 and VITAL-2, the second ongoing Phase 3 study currently under way at approximately 90 sites in the United States, Canada and Europe. VITAL-2 is enrolling metastatic HRPC patients who are symptomatic with cancer-related pain. The study will compare GVAX cancer immunotherapy plus Taxotere chemotherapy to Taxotere plus prednisone. The primary endpoint of the study is an improvement in survival. The company expects to recruit approximately 600 patients into VITAL-2 and plans to update the timeline for the completion of recruitment by the end of 2007.
Cell Genesys' ongoing Phase 3 GVAX immunotherapy for prostate cancer program is supported by the median survival results from two, independent, multi-center Phase 2 clinical trials in approximately 115 patients. The subset of patients in these two trials who received the doses comparable to the Phase 3 dose showed median survival of 34.9 months and 35.0 months, respectively. These results also exceeded the predicted survival of 22.5 months and 22.0 months, respectively, as determined by a seven point patient disease characteristic nomogram. The results of the first trial were published in the July 1 issue of Clinical Cancer Research. Results from both studies compare favorably to the previously published median survival of 18.9 months for metastatic HRPC patients treated with Taxotere chemotherapy plus prednisone, the current standard of care. Moreover, as previously reported, the safety profile observed in Phase 2 trials of GVAX immunotherapy for prostate cancer compares favorably with that reported for chemotherapy. The Phase 3 program is designed to confirm a potential survival benefit and safety profile for GVAX immunotherapy for prostate cancer.
About GVAX Immunotherapy for Prostate Cancer
Cell Genesys' GVAX cancer immunotherapies are whole-cell products that are designed to present the immune system with a broad spectrum of tumor antigens and stimulate an immune response against the patient's tumor. GVAX immunotherapy for prostate cancer is comprised of two prostate tumor cell lines that have been modified to secrete GM-CSF (granulocyte-macrophage colony stimulating factor), an immune stimulatory hormone which plays a key role in stimulating the body's immune response, and then are irradiated for safety. GVAX cancer immunotherapy for prostate cancer is being developed as a non patient-specific, "off-the-shelf" pharmaceutical product. The company is currently manufacturing GVAX immunotherapy for prostate cancer in its bioreactor manufacturing facility in Hayward, California, a facility that is also capable of producing the product during its initial commercialization.
About Cell Genesys
Cell Genesys is focused on the development and commercialization of novel biological therapies for patients with cancer. The company is currently pursuing two clinical stage product platforms - GVAX(TM) cancer immunotherapies and oncolytic virus therapies. Ongoing clinical trials include Phase 3 trials of GVAX immunotherapy for prostate cancer, Phase 2 trials of GVAX immunotherapies for pancreatic cancer and for leukemia, and a Phase 1 trial of CG0070 oncolytic virus therapy for bladder cancer. Cell Genesys continues to hold an equity interest in its former subsidiary, Ceregene, Inc., which is developing gene therapies for neurodegenerative disorders. Cell Genesys is headquartered in South San Francisco, CA and has its principal manufacturing operation in Hayward, CA. For additional information, please visit the company's website at www.cellgenesys.com.
http://biz.yahoo.com/prnews/070710/aqtu141.html?.v=7
I don't believe NWBT's results are from a randomized trial, as it's an orphan indication. Their results are therefore being compared to historical data. The Provenge non-randomized Phase II results were extremely impressive for progression in AIPC when also compared to historical data. One of my biggest beefs re DNDN mgmt is that they have yet to run a Neuvenge trial in HER2/neu+ ovarian cancer, which would be an orphan indication and could theoretically gain approval via a single-arm trial.
Probably so...but the stock price would probably have been a lot higher prior to the AC meeting...and I bet that would have been a gamble you would have taken.
9902A's 0.33 p value was my biggest worry heading into the briefing doc release/advisory panel meeting. But the negative aspects of both the briefing docs and the advisory panel focused on the TTP primary endpoint miss in 9901, and to a lesser extent, the TTP primary endpoint miss in 9902A. The letters that Pazdur ordered Scher and Hussain to write also focused primarily on the TTP miss, as did the Fleming letter. Even if 9902A was 0.10-0.15 for survival, I highly doubt Provenge would have been approved.
This is all a moot point anyway, as in many people's opinion (mine included), the CR letter was a political decision by CBER, who was inclined to approve, but caved in to CDER/OOD's threats during a crucial period for FDA/Congressional politics.
That Phase 2 was held at either one trial site (Johns Hopkins) or the JH site and one other. There are also have been rumors circulated that JH cherry-picked the enrollees, which is a frequent occurrence in earlier-stage trials. CEGE admitted last year that they were expanding VITAL-1 beyond Western Europe because of slow enrollment. It may be true that the goal for the injections is to limit them to two per visit, but it's been mentioned by more than one source that most patients need 16 injections per visit. There is also strict prohibition of crossovers from one arm to the other. This non-crossover component has played a large part in the slow enrollment. Some people don't want to be prevented from receiving Taxotere if they wind up in the experimental arm, so they don't enroll. Others don't want to take the chance of not being able to receive the vaccine, so they don't enroll.
I would tend to disagree...the negatives in the briefing docs focused primarily on the missed primary endpoint of the main trial, be it 0.085 or 0.052. I was very surprised by the extent to which the FDA de-emphasized 9902A. The agency seemed to agree with DNDN's position that 9902A was an incomplete trial.
Good points about the general lack of preparation regarding plausible MOA of Provenge on the part of DNDN's team. Probably wouldn't have made a difference, though, considering the internal politics between the OOD and CBER.
However, I would have to disagree regarding CEGE's chances of GVAX hitting stat sig in VITAL-1. I think the odds are well under 10%. The trial is only 80% powered to hit stat sig if the median survival of GVAX beats Tax's MS by 33%. There is no way that GVAX will come even close to besting Tax's MS by that much, for reasons outlined below. CEGE designed and powered the study at a time when they thought that Tax's MS was only 18.9 months. We now know that Tax's MS for asymptomatic patients was 23.0 months. I highly doubt that GVAX will even beat 23.0 months, let alone beat it in a stat sig manner. There is no crossover component in VITAL-1, there is going to be a large number of Central and Eastern European patients in the trial, and I think there will be a fairly large number of dropouts in the trial, who will still have to be counted as being in the intent to treat group. Administration of GVAX (the benign treatment of the two in the trial) means 16 injections per weekly visit for seven months. Ouch.
Edit: As for VITAL-2, rumor has it that enrollment has been all but halted at the expense of VITAL-1, due to CEGE's limited resources. Once VITAL-1 fails (and for CEGE's sake, they should hope it gets stopped for futility at the interim look), it will be years before VITAL-2 can get restarted, get completely enrolled, and then take time for the survival data to mature. Unfortunately for CEGE, they chose the longshot trial as the one to concentrate their resources on. The combo trial would have had a better shot at success.
OK, just listened to the Aaron Task/Adam Feuerstein interview. For the most part, Adam's overall message was accurate, IMO. The stock has become a trading vehicle, and has been spiking due to a positive feedback loop in the financial press.
However, one incorrect statement he made was regarding the journal article this week and how it relates to the FDA's May decision. Yes, the article in the cancer research journal merely theorized that the efficacy of cancer vaccines should be evaluated in terms of overall survival instead of tumor shrinkage. However, Adam stated incorrectly that this is why the FDA issued the CR letter, when in fact the FDA likely centered on the missed primary endpoint of TTP as the reason it couldn't approve Provenge. I'm not sure why Adam would make such a wildly incorrect statement. The journal article's conclusion and DNDN's rationale for filing its BLA on the 9901 data were one and the same: that survival should be the metric used to evaluate the efficacy of cancer vaccines. The FDA's decision was likely based on reasoning that comes to the opposite conclusion than that of the article.
One more thing to add would be that for current DNDN longs, what has been going on with the stock price lately is just the opposite of what used to happen prior to 3/29...the stock used to drop because of a negative feedback loop in the financial press. So the longtime current longs are getting some well-deserved payback.
I don't have a subscription to Real Money anymore, so I can't read his comments there. I would assume that he thinks the recent price spikes are irrational exuberance. I don't think anything is going to happen on the clinical/FDA front or the partnership/buyout front until 2008, so I'm not sure why the price keeps spiking. Probably a combination of rumors and the size of the short position.
I wonder if that nurse was including advertising costs in her overhead calculation.
Agree that the latest BSR writeup on the FDA saga is a fascinating read...while the story about the overall political climate re biopharma is depressing but also interesting.
Back in town after three weeks overseas. There is an SPA in place for 9902B, so Provenge won't get approved unless 9902B survival data comes out stat sig...and even if it does, and DNDN/Provenge appear to have satisfied the terms of the SPA, the 9902B data still has to get past the FDA biostatistician slice and dice. After seeing how the FDA raised the bar on Thelin after the SPA was signed with ENCY, you just can't discount some bit of potential bad info that only the FDA can see.
On the other hand, there could be enough cumulative pressure on the agency by that time that they could be more lenient than expected at the first interim look. Perhaps DNDN/FDA/DSMB will have some kind of understanding in place that lets the company see all of the survival data if the interim look is not stat sig. This would be done in case the alpha allocated for the interim look is in the 0.01-0.015 range, but 9902B's interim p value comes back between 0.015 and 0.05. The FDA would have to bend its Pazdurian standards somewhat to grant approval in this example, but the debacle of the past couple months has shined something of a flashlight in the mainstream press on the agency's cancer drug approval process, and this could work in DNDN's favor.
DSCO, Feb 2005 eom
<<The point is - how much does it matter if they were minor points that would have gotten signed off in less than 3 or 4 months? I believe that you would have considered an approvable (or approval with a lien? - not clear to me how they would have worded it) with the only lien being something worked off within 90 days to have been a home run. I certainly would have. I understood the 'might as well give them an approvable if they have a manufacturing issue' argument but I think this is a very weak argument if the 483 is something that could be worked off in 60-90 days.>>
Yes, it would be a weak argument if the delay was only 60-90 days...but if it was minor or routine but still required a reinspection, then we are possibly talking toward the end of the year for the FDA to schedule it. That's when the "wait a few more months for 9902B scenario" could come into play.
I'll be out of the country for a few weeks starting tonight. You kids be good while I'm gone. I will stop in here occasionally as time permits, so don't think you can go all hog wild...and no bouncing up and down on the bed!
Those are valid points raised by Toos...the question remains, though, did DNDN respond to the FDA prior to PDUFA with the necessary corrections to the issues outlined in the 483?
<<I accept this makes it a little different - but it is a nuanced scenario that even very smart people didn't predict - e.g. BSR's prediction of approvable for cmc issues was clearly separated from approvable for efficacy data issues. Not sure I could hold Dendreon mgt accountable for not predicting this nuance.>>
It also explains the company not negotiating, or not being able to negotiate, a free, unpenalized, interim unblinding to look at TTP data in Q2/Q3 2008. You would probably have almost the entire 500-person TTP dataset by that time. If 9902B were to be stat sig, you could either (1) try to persuade the FDA to go for Accelerated Approval on 9902B TTP data (and don't do interim unblinding for survival), or (2) if the FDA doesn't agree to granting AA on the stat sig full dataset for TTP, then the co ONLY THEN goes ahead and does the interim 9902B survival unblinding, thus accepting the alpha statistical penalty. Using up the alpha penalty in this scenario would be more acceptable, as final TTP data would already have been shown to be stat sig, meaning interim survival data would have a better chance of also achieving statistical significance.
<<Q: Do all approvable letters for CMC issues always result in a 483 well before the approvable letter?
I've believe I've seen multiple companies get approvable letters for relatively minor cmc issues (1 to 6 months to fix and get full approval without resubmission) where they did not notify the investors ahead of time about a 483.>>
Not doubting that. Where DNDN's situation is unique, is that in this case, the Provenge clinical data as interpreted by both the FDA reviewers and the advisory committee voters was not clear-cut, and there is an ongoing, more definitive trial. It's not out of the question that interim data from this ongoing trial could be ready as early as late Q1/early Q2 2008. If the resolution process of the Form 483 were to take several months beyond 5/15/07, then the subsequent waiting period after Q4 2007 to the possible Q1/Q2 interim unblinding for 9902B would probably be less unreasonable in the eyes of CBER...so why not wait for the definitive trial, especially when they are already taking so much political heat from the "stict constructionist" wing?
<<Was the company so naïve as to believe that an APPROVAL letter show up in the mail and it’s business as usual?
I think the answer is yes. It continued to hire a sales force and spend money.>>
I absolutely HATE to take the opposite point of view on this, but I think to interpret DNDN's actions between the positive panel vote and the 5/9 CR letter, it is necessary to be cynical if one believes the 483 scenario has merit. Basically, if the 483 scenario as outlined in the latest lawsuit is true, then the actions that upper mgmt took all point to deliberately giving the appearance of a company that expects approval, even though the execs know they won't get it. This way, they cover up the tracks left by the 483 evidence, and can act "surprised" by the CR letter.
I'm not referring at all to direct discussions over the question of approval, but rather label negotiations and post-approval trials, which typically occur toward the end of the review process.
The point I was trying to make is that it's quite possible that if it weren't for the 483, Provenge would have gotten approved by May 15th.
So let's say hypothetically that DNDN completed a detailed response to the FDA mfg inspectors for everything the inspectors detailed in the Form 483...let's say DNDN did this in early May 2007. The question then would be if anything in that Form 483 requires a reinspection of the NJ plant by FDA mfg inspectors. If so, then the FDA needs time to look over DNDN's responses to Form 483, and then schedule a reinspection. Let's say that FDA finishes looking over the company's responses by June 1st. If so, then would the new PDUFA date be 12/1/07? FDA could reinspect in 9/07 or 10/07, in order to allow some time for the back and forth discussions between the DNDN mfg team and the FDA mfg inspectors.
But as of 12/07 we would be getting closer to the 9902B interim unblinding, which will probably take place somewhere between 160-200 events. Maybe the agency was thinking after the positive advisory panel vote that since it might be another six to eight months after the 5/15/07 PDUFA date for DNDN to satisfy the mfg inspectors, then why not wait just a few more months for the 9902B interim survival data to be unblinded?
It's all water under the bridge now...but for Dr. No to succeed, he needs some willing tools. There also may have been more than meets the eye on the company's side of things. Not having any discussions with the FDA after the positive advisory panel vote strikes me as odd (no labeling discussions, no post-approval 9902B discussions?), and perhaps it means that CBER never was going to approve Provenge on this go-round. What other issues were going on behind the scenes that we'll never know about?
Thanks for posting that...even if there had been some hint at efficacy, weekly docetaxel is not the approved regimen for HRPC anyway, so it's not a proper control arm. That's why NOVC is having to run a Phase 3 that's using a different (Tax every 3 wks) regimen than their Phase 2 (weekly Tax).
Nope...wasn't me eom
Thanks Biowatch...I was pretty shocked at the time, and I'm glad that you weren't lumping all DNDN longs together.
Yes, io_io, the sheer frequency of your comments about Dew added to the percentage of your total posts containing negative comments about Dew probably led to your being banned from the BV board. While each one of these particular posts of yours wouldn't necessarily cross the line, the sheer number of them makes me weary. Yes, Dew makes frequent snide comments, but many of them are generalized and not singling out one particular poster. When a comment of his IS personal, it's usually included within a larger debate/discussion. Because that discussion is usually worthy otherwise, it doesn't warrant my censorship, as then I would have to pick and choose which posts/responses to delete and which to keep, and I'd probably make some mistakes. Anyway, Dew hasn't replied to one of your posts in a year, more or less, or if he did once or twice, then I missed it...so why don't you give it a rest? Besides, there is a decent chance (30-70%, IMO) that he and PGS were correct and we were not about DNDN gaming the Cox regression model for 9901 and 9902A after the interim 9902A unblinding in January 2005. I for one am enjoying the back and forth on the 9902B Halabi.
As for Ocyan, he's a big boy, and a smart one. All DNDN longs have benefited from his valuable contributions to the discussion. He's brought up a lot of excellent points about DNDN and Provenge on message boards and in emails. And, he certainly seems to be able to take any negative commentary and be able to dish it back out in kind, WITHOUT ESCALATION.
This is a more insidious matter than the bioscams of BPUR, INGN, and HEB. All indications point to some downright evil behavior on the part of TELK mgmt, starting with the decision to "unblind" all three of their important trials at once, with one of those three being unblinded virtually one year after the final data came in.
Jeez, would everyone just chill? eom
Sloan Kettering reported that Scher was threatened. I would imagine that for security to be provided, the emails in question would have had to be shown to the organization(s).
<<ps - it is unfortunate that there are a few that would put DNDN shareholders, in particular those who organized and participated in the Chicago rally in a bad light by making threats to Scher, etc., however, it is a greater shame that the media focuses on those few, rather than provide a balanced reporting that devotes proportional time to the imo greater misdeeds of the other side of this debate...>>
I have to agree with all the points mentioned in your paragraph, and also would add that the media seems to be wrongly focusing on the threats made to Hussain and Scher for their negative VOTES at the panel meeting, instead of their rather extraordinary step of writing negative LETTERS to the FDA urging the agency to turn down Provenge after the panel vote went against them, knowing all the while that the letters were going to be leaked to the public. Whatever the case, anyone who threatened the two is a complete moron and probably shouldn't be investing in biotech stocks.
Biowatch, I'm replying to your comment #msg-20151385 here because I also agree with some of the BV posters that DNDN is taking up too much discussion on the BV board. Anyway, I'm not sure why you lumped Aiming and me in together with the dumba*ses who threatened Scher and Hussain, but so be it. IMO, it's probably only a handful of DNDN longs at most who sent the threatening letters, not the large number implied in your post. It wouldn't surprise me if some of the same idiots who sent the asinine emails to Feuerstein (he posted some examples in his columns) also sent threatening letters to Scher and Hussain. Having subscribed to TheStreet.com for many years, I remember Herb Greenberg getting the same kind of email. The internet definitely brings out the worst in SOME otherwise decent people.
re DNDN: I'd have to disagree with your post about Dr. Mule's conflict of interest. His COI was related to the second day of the panel meeting (Topic #3), and not to the Provenge presentation, which was Topic #1.
As to urche's post, most of us longs did trim some of our shares or calls in the high teens or 20's before May 9th, myself included. I only know of a couple people who specifically mentioned that they didn't, but there were undoubtedly many more. Obviously, I wish I'd sold more of my long position than I did, but I was going with the odds of past thumbs-up advisory committee meetings translating into full approvals, plus all of CBER's actions up to that point regarding Provenge.
Obviously, the threats against Scher and Hussain are appalling, but not surprising considering the tone of some of the previous emails to Feuerstein on which he's commented.
LOL! Now I remember what HEB's lead drug is called! I swear I posted my previous reply before I read yours.
TB? I predict that Hemispherix's lead drug probably treats it, or at least that's what the company will say...lol
Actually, at least 1/3 of the patients (the earliest enrollees) have Gleason scores <8 AND no pain. I think the trial population overall at baseline will fall between the overall 9901 and 9902A populations in terms of health.