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Not formally...but both Mule and Dubinett emphasized that they believed the panel members should be flexible and vote Yes with 9902B stipulation. Witten on Marketwatch just said that FDA was looking for guidance on the survival benefit, and also expects results of 9902B in 2010. To me, this indicates there is no way the FDA will wait for 9902B survival to approve.
IMO, Hussain purposely failed to mention that the asymptomatic patients in the TAX327 trial showed a 3.2-month median survival benefit. In other words, DNDN's "failed" 9902a trial still beat TAX327 in median survival.
Check out Witten's statements on Marketwatch today....the FDA will likely approve and stipulate that 9902B be followed.
DNDN -- from my post on the DNDN I-Hub board...IMO, the keys today were:
(1) the inexperience of several panel members on the concept of
voting yes or no to approve a treatment for a terminal condition. As a pretty good reader of people, it was apparent to me that these less experienced panel members would be more likely to be swayed by the public testimonials...
(2) and of course, Dr. Mule the chairman of the panel asking the FDA to clarify the efficacy question, and then holding a re-vote after the first three panel members voted extremely reluctantly NO. The three said that there was substantial evidence of efficacy, but not 100% conclusive. Dr. Mule got FDA's Dr. Witten to state that "substantial evidence of efficacy" means thumbs up. Game over!! Re-vote, and first guy still hems and haws but says yes, next five or six all say yes, and eventually we get 13-4.
(3) Also, the nonvoting industry representative did a MUCH better job of clarifying some of the stats data for the others. DNDN had NO REAL WORLD presenters behind the microphone, or at least nobody who could explain things in layman's terms to some of the advisory panel members. The nonvoting industry representative Dr. Gunter did a better job of explaining Provenge's big picture than the DNDN personnel did, probably because the discussion got bogged down with the immunologists worried about irrelevant MOA data.
(4) The guy from UCLA Dr. Dubinett emphasized to the rest of the
panel that it was OK to vote thumbs up to let Provenge on the market AND stipulate that DNDN continue with the ongoing trial 9902B. It seemed to me that many members of the panel WEREN'T EVEN AWARE that DNDN was ALREADY going to follow up and finish 9902B. I wanted to scream at the DNDN personnel to get up and emphasize that DNDN was already going to fully enroll and track 9902B, and the company would be receptive to the option of approval with stipulation on 9902B.
#msg-18330144
Witten is either the head of CBER or the head of CBER's Office of Cellular, Tissue, and Gene Therapy. A person who I respect very much and is intimately familiar with DNDN (not David or BSR) said several months ago in a private conversation that he believed CBER/CTGT wanted Provenge to be a feather in its cap. It is obvious to me from the panel meeting viewing that there has been a turf battle going on between Pazdur/OOD and CBER/CTGT. Hussain was without a doubt Pazdur's proxy today. She was openly hostile to Dr. Witten during a couple points in the meeting. She also was SLEEPING with her back turned to the public testimonial speakers almost the entire time they were speaking their emotional testimonials.
She even raised the ridiculous point that Provenge should not only NOT be approved, but instead complete enrollment in 9902B AND run an expanded access program at no financial cost to patients for several years until 9902B survival results mature.
Scher was patently dishonest. Before he voted Yes on reasonable safety, he raised the point that Provenge might be toxic and dangerous and used the recent Epogen data as an example. Well, Dr. Scher, what about Taxotere'e side effect profile? How could he even imply that Provenge was in Taxotere's toxicity ballpark?
That is outdated short interest data. As of mid-March, # of short shares was 26.2 million. It's probably well over 30 million as of this afternoon.
Thanks everyone...words cannot express how giddy I am right now.
IMO, the keys today were:
(1) the inexperience of several panel members on the concept of
voting yes or no to approve a treatment for a terminal condition. As a pretty good reader of people, it was apparent to me that these less experienced panel members would be more likely to be swayed by the public testimonials...
(2) and of course, Dr. Mule the chairman of the panel asking the FDA to clarify the efficacy question, and then holding a re-vote after the first three panel members voted extremely reluctantly NO. The three said that there was substantial evidence of efficacy, but not 100% conclusive. Dr. Mule got FDA's Dr. Witten to state that "substantial evidence of efficacy" means thumbs up. Game over!! Re-vote, and first guy still hems and haws but says yes, next five or six all say yes, and eventually we get 13-4.
(3) Also, the nonvoting industry representative did a MUCH better job of clarifying some of the stats data for the others. DNDN had NO REAL WORLD presenters behind the microphone, or at least nobody who could explain things in layman's terms to some of the advisory panel members. The nonvoting industry representative Dr. Gunter did a better job of explaining Provenge's big picture than the DNDN personnel did, probably because the discussion got bogged down with the immunologists worried about irrelevant MOA data.
(4) The guy from UCLA Dr. Dubinett emphasized to the rest of the
panel that it was OK to vote thumbs up to let Provenge on the market AND stipulate that DNDN continue with the ongoing trial 9902B. It seemed to me that many members of the panel WEREN'T EVEN AWARE that DNDN was ALREADY going to follow up and finish 9902B. I wanted to scream at the DNDN personnel to get up and emphasize that DNDN was already going to fully enroll and track 9902B, and the company would be receptive to the option of approval with stipulation on 9902B.
>>Provenge arm 26.3 months
placebo crossovers 23.9 months
placebo noncrossovers 19.3 months<<
"Not sure in this case, but don't noncrossovers often do worse than crossovers in trials because at the time they were allowed to crossover they were ... (i) dead or (ii) in very bad shape or (iii) simply not fighting as hard as the crossovers for a few extra months of life?"
The patients prior to being randomized into the placebo or treatment arm had to choose whether to cross over or not. I believe that for most patients in the trials, progression occurred within three to six months after randomization. So whenever it was deemed that an individual had progressed, the blind was subsequently broken and the placebo pts who had opted for crossover were then administered the frozen Provenge soon afterward.
Why didn't the Provenge patients die sooner, once they found out they had progressed? Was it because they went to chemo faster? Nope. The FDA stated in the briefing docs that overall, the patients in the Provenge arm did not receive earlier chemo than the patients in the placebo arm. So how else can the laddered improvement from Provenge-naive, to salvage Provenge, to Provenge treatment arm be explained?
I'm going to guess either Herceptin or Avastin.
DNDN crossovers-We do have the two-year median survival for the 9901 trial from Sept 2003:
Provenge arm 26.3 months
placebo crossovers 23.9 months
placebo noncrossovers 19.3 months
I would imagine that the final data was fairly similar...and I would also imagine that the 9902A median survival breakdown would have had a similar, laddered improvement from placebo noncrossovers-->placebo crossovers-->Provenge arm
Well, in the four Phase III trials, we know that 18/461 (3.9%) patients in the Provenge arms had CVAs, compared to 6/231 (2.6%) in the placebo arms. However, some 200+ patients took Provenge in the Phase I/II trials, and the briefing doc release indicates that zero had CVAs...but I'm not sure how long those patients were followed. Possibly for a year or so...but if the CVA data from the Phase I/II trials holds up, I think that this "strawest" of straw man arguments of the bears will blow over and vanish into the wind.
<<I don’t like that because PBTA is also the Pensacola Beach Transit Authority.>>
sigh
Quantumdot, I completely agree. After Aschoff's previous argument of "Provenge patients got earlier Taxotere than placebo patients" got shot down by the biostatisticians this morning, he needed to come up with another false straw man argument. I even predicted early this AM that it would be the CVA issue. Sure enough, he did so, and cited the erroneous data of 8/147 Provenge arm CVAs in 9901/9902A vs 0/78 placebo CVAs. He either didn't read or he completely ignored the FDA's errata section, where the placebo CVAs were in fact 2/78. In addition, it appears that only 4 out of the 8 CVAs in the Provenge arm occurred within the first 16 weeks after Provenge treatment.
Well, in DNDN's PROTECT trial, there 0 out of approx 120 pts in the Provenge plus Lupron arm had CVAs, while several out of approx 60 in the Lupron alone arm had CVAs.
Perhaps there will be something on the label to monitor for hypertension for the first year after Provenge, but I highly doubt there will be anything like a black-box warning. After all, a number of Taxotere pts had CVAs as well.
Here is the text of the DJ story
(Updates with new information starting in fourth paragraph.)
By Jennifer Corbett Dooren
Of DOW JONES NEWSWIRES
WASHINGTON -(Dow Jones)- The Food and Drug Administration Tuesday questioned the effectiveness of a proposed prostate-cancer treatment from Dendreon Corp. (DNDN).
The agency said two studies of the proposed drug, Provenge, failed to meet both primary and secondary endpoints in documents posted to its Web site. The drug faces a review on Thursday by an outside panel of medical experts who are being asked to make recommendations about whether the agency should approve Provenge.
However, the FDA also said, "It appears that the two studies provide some evidence in support of using Provenge for the treatment of men with...(advanced) prostate cancer." One type of analysis conducted in one of the studies showed that patients receiving Provenge lived on average about four months longer than cancer patients not receiving the drug.
The Seattle-based company is asking the FDA to approve Provenge to treat men with advanced prostate cancer who stopped responding to hormone therapy. If approved, Provenge would be a first-of-a-kind treatment for cancer because the drug is designed to stimulate a person's immune system to fight the cancer.
In its briefing document, also posted to the FDA's Web site, Dendreon noted Provenge is "very well tolerated" and "has well characterized and manageable known risks."
The only other treatment for advanced prostate cancer that's been shown to improve overall survival is Taxotere, a chemotherapy drug from Sanofi-Aventis (SNY). Chemotherapy drugs often have significant side-effects including nausea, vomiting, anemia and infection that can make them hard for patients to tolerate.
The FDA agreed with Dendreon that Provenge was "generally well tolerated," with the most prominent side-effects being fever, chills and fatigue. However, the FDA said it was concerned about an increased number of strokes among patients treated with Provenge compared with patients who didn't get the drug.
The FDA said it would ask the panel whether a 3.9% stroke rate seen among Provenge patients - compared with a 2.6% rate among patients in the placebo groups - was a "potential safety signal" for Provenge.
The panel is being asked to vote on questions about whether it thinks Provenge is safe and effective. The FDA usually follows its panel's advice but is not bound by it. The FDA is scheduled to make a final decision on Provenge by mid-May.
Dendreon shares recently traded at $4.78, up 24 cents, or 5.3%. Volume stood at almost three times its daily average.
- By Jennifer Corbett Dooren, Dow Jones Newswires; 202-862-9294; Jennifer.Corbett@dowjones.com
(END) Dow Jones Newswires
03-27-07 1210ET
It's recent info. Remember that most of these cerebrovascular events took place many months after Provenge infusion, in a population cohort averaging ~72 years of age. What if some of these CVA events took place after the patients in question had passed the median survival point? Perhaps one can't definitively attribute these CVA events to the Provenge.
Edit: In addition, it appears that this CVA analysis might not take into account the fact that most in the placebo arms got Provenge as well. Were the two CVA events in the placebo arms crossover patients?
Yep, fairly neutral, but a lot better than what I expected. The market expected a lot worse as well, judging from this morning's price action.
Highly unlikely that the briefing docs have leaked, IMO. They will probably be negative... or at best neutral. So, the price probably would have dropped if there were a leak.
The briefing docs are almost never interpreted as positive...
OT-Here is the hilarious video of the same beach during a 747 takeoff.
DNDN Read Me First
Edit: Full presentation with slides of Dr. Petrylak's presentation of Provenge plus Taxotere patients, directions to presentation courtesy of stuck_holder
http://www.investorshub.com/boards/read_msg.asp?message_id=18179649
--------------------------------------------------------------------------------------
From I-Village, a good summary of DNDN/Provenge story to date, with an opinion at the end
http://tinyurl.com/2kv2t4
and a DNDN links page from froggmister
http://tinyurl.com/2q4gqe
---------------------------------------------------------------------------------------
All-cause mortality from 9901 Phase III trial presented by Dr. Eric Small at Prostate Cancer Foundation Scientific Retreat 10/20/06 (compilation of several I-Hub posts)
#msg-14152660
Notes from DNDN presentation at UBS Conference, 9/27/06, Dr. Gold presenting, courtesy of yarbonero on I-Village board
http://tinyurl.com/ftn75
Rancherho's 7/17/06 post on CD54 upgregulation, memory T-cells, and long-term survival
http://tinyurl.com/k24et
Dr. Scott Gottlieb's Feb 2005 Forbes column on Provenge; in 2/05 he was editor of a biotech newsletter, in 8/05 he became #2 at the FDA
http://tinyurl.com/43cvh
PubMed entry regarding Provenge, courtesy of thenewthinker on the Yahoo msg board
http://tinyurl.com/oavgx
PR regarding publication of the P-16 trial (Provenge+Avastin) in AIPC
http://biz.yahoo.com/prnews/060607/sfw079.html?.v=56
Several webcast presentations, including Provenge/JMP Securities/trial doctors conference call from 5/11/06
http://investor.dendreon.com/medialist.cfm
http://tinyurl.com/j9k4g
Go to: Transcript for Feb. 9, 2006
Potency Testing for Autologous Cellular Therapy
Nicole Provost PhD.
P. 131
Go to: Slides February 9,2006
From DNDN yahoo MB posted by zurdoc1...link below
http://tinyurl.com/gjnbv
spartex points out that Nicole Provost's presentation and panel questions start on page 135 in the link below.
http://tinyurl.com/fdgg8
P-11, or PROTECT Phase III for androgen-dependent prostate cancer
http://tinyurl.com/dmshb
Dr. Gold's presentation and Q&A notes at Bio-CEO conf in NYC 2/24/06
http://tinyurl.com/5hkvt
http://tinyurl.com/7w8gx
http://tinyurl.com/b6xug
9901 and 9902a Kaplan-Meier survival curves:
#msg-8677219
ECCO/Higano/9902a presentation:
http://www.sessions2view.com/ecco05c1/index.php
[Directions:
1.Click on acceptance box on bottom of screen.
2.Click on ENTER button at bottom of screen.
3. Click on Speakers link at bottom of screen.
4. Click on the letter “H” for Dr. Higano.
5. Click on one of the three icons for the slides, audio, and transcript, respectively. (The presentation audio can be cued from any individual slide.)
6. Slide #16 has the 9902a Kaplan-Meier survival curves.]
Dr. Sternberg’s 5-minute reply to Dr. Higano’s presentation:
#msg-8567652
Three most recent webcasts (10/31 conf call on Provenge 9902A trial results at ECCO, 11/4 conf call on Q3 financial results, 11/7 webcast at Rodman & Renshaw conference)
http://investor.dendreon.com/medialist.cfm
UBS 9/27/05 Conference Call Transcript and Breakout Session Notes
#msg-7922336
Dr. Eric Small presentation of 9901 trial results at May 2005 ASCO Conference
http://tinyurl.com/e2ceu
DNDN newsroom for investors
http://investor.dendreon.com/newsroom/
Discussion thread of some clinical trial summations on competitive hormone-refractory prostate cancer treatments (courtesy of rancherho)...thread continues with surrogate endpoint discussion and links
http://tinyurl.com/8syxr
http://tinyurl.com/99kfb
http://tinyurl.com/armgl
http://tinyurl.com/bnscm
http://tinyurl.com/7ozey
http://tinyurl.com/89h5p
http://tinyurl.com/ey5tf
http://tinyurl.com/99bdm
DNDN’s 9901 data-release CC (2/22/05):
http://investor.dendreon.com/medialist.cfm
ASCO Prostate Cancer presentation Dr. Eric Small 2/19/05:
http://tinyurl.com/4b7to
Provenge potential market:
http://tinyurl.com/7dwm6
http://tinyurl.com/3k857 (“Duh, yes”)
FDA Prostate Cancer Workshop 6/04 (change to Transcript2.pdf and 3.pdf for continuation)
http://www.fda.gov/cder/drug/cancer_endpoints/ProstateTranscript1.pdf
9901 trial Gleason score breakdown (we now know that 4 out of 5 surviving placebo arm patients crossed over to receive salvage Provenge after progression)
http://tinyurl.com/5v6xy
ASCO Prostate message-board musings by walldiver (2/05)
http://tinyurl.com/5hykx
http://tinyurl.com/4ssxf
The ever-changing short-seller arguments (inspired by David Miller)
#msg-5875436
DNDN Insider Transactions
http://finance.yahoo.com/q/it?s=DNDN
Basic facts about prostate cancer
http://www.cancer.gov/cancertopics/types/prostate
http://www.acor.org/cnet/glossary/45696.html
OT-That section of LA is almost right on top of the Newport-Inglewood Fault, which runs about five miles SW of downtown. An earthquake of maximum capacity on this fault would probably be in the 7.5 range, making it potentially more dangerous to the city than an 8.5 on the San Andreas, which is approx 50 miles NE of downtown.
You may want to edit that post. It looks a little confusing between 02B and 02A.
Cingular is by far the most conservative of the major wireless carriers when it comes to environmental reports. Their environmental attorneys scrutinize every report to the extent that they might as well have written it themselves. If we so much as included 10 site photos instead of the required 12, they would send us an email requesting two more photos. We're supposed to photograph the proposed wireless site looking at the site from all four directions plus looking away from the site towards all four directions, plus take four additional photos. It's hard to think of more photos to take if your site is an existing telephone pole. When we tried cutting down on the number of photos to save bandwidth by standing 40 feet from the site and captioning our photo "Looking North at and Beyond Site," it was a no go. We had to stand 50 ft away and take one photo looking north, then stand at the site and take another photo looking north. As if those photos would determine whether there was contaminated soil at that site.
None of the other carriers come even remotely close to scrutinizing reports written by their enviromental vendors. Just throwing this tidbit out there, as it's possible their conservatism could be company-wide, and extend into their licensing/business practices.
Correct, that's how we see it. Oncologists who prefer chemo don't. Many will still recommend Tax to asymptomatic patients because they distrust immunotherapy...even though Provenge will have been approved.
I honestly don't know if this action would be productive or counterproductive. Perhaps a note beforehand that his vote should be scrutinized because of his heavy involvement with Sanofi's Taxotere, which would be in direct competition with Provenge, might be appropriate...at least let them know that in your opinion, perhaps he should be a nonvoting member?
The reason it could potentially be counterproductive would be that some panel members might think that complaints came from the company.
<<Sanofi threatened short term because pts will take Provenge first who would otherwise have done Taxotere first. But maybe long term Prov is not so bad for Tax - given the apparent synergy between Provenge and Taxotere, or Provenge's survival effect that keeps more men around for Taxotere?>>
Agreed.
<<Or do you see better ways than Tax to get the T-cell effect that Prov looks to need?>>
Sure....a Provenge booster ...seriously, I think there is a very good chance they are synergistic...we'll see.
Here is the link...
http://tinyurl.com/3a9leb
-----------------------------------------------------------------
Here are Dew's comments...
Posted by: DewDiligence
In reply to: quantumdot who wrote msg# 43420 Date:3/22/2007 3:32:20 PM
Post #of 43427
DNDN – Feuerstein is being a wimp, IMO. He should simply say he is bullish because it’s pretty obvious that he is.
What he really ought to do is assign a numeric probability to each of the FDA outcomes, as I did. (But maybe he’s not a backgammon player ) If he’s unwilling to do that, he should at least take a freaking stand on the outcome from a binary standpoint.
------------------------------------------------------------------------
and here are my comments...
Posted by: walldiver
In reply to: DewDiligence who wrote msg# 43424 Date: 3/22/2007 3:39:05 PM
Post #
I think the reason he is publically on the fence is because most or all of his Wall Street contacts are bearish on Provenge's chances at the advisory panel, but Adam himself can't get around the apparent efficacy combined with the mild side effect profile, and part of him believes the panel will think the same way...which leads to a wishy-washy position.
Which could mean that he is probably the most favorably inclined of the Sloan Kettering docs toward immunotherapy, which isn't saying much...in the land of the blind, the one-eyed man is king.
I think the reason he is publically on the fence is because most or all of his Wall Street contacts are bearish on Provenge's chances at the advisory panel, but Adam himself can't get around the apparent efficacy combined with the mild side effect profile, and part of him believes the panel will think the same way...which leads to a wishy-washy position.
Yep...interesting that Scher gets to be a voting member while the guy with a lot of immunotherapy experience can't vote because of a conflict of interest with CEGE. It's Sanofi who could be threatened by Provenge approval--not Cell Genesys. CEGE doesn't have an approved product yet for PCa. This just goes to show how much differently bureaucrats see things than the rest of us.
You know me. I believe the CTGT members will overall be more favorably inclined to Provenge than the voting members named by Pazdur.
Interesting....as for Dr. Calos, I believe she will be busy in Maryland next week on 3/29.
Yes I'm almost sure it's Sanofi. I've heard from multiple sources (not just one or two) that he is not a fan of Provenge. Perhaps Dr. Petrylak can convince him....we will see.
Just goes to show....a little bit of knowledge is a dangerous thing...I wonder if this guy has ever heard of FDA briefing documents
I'm pretty sure that Provenge is also indicated for patients whose primary therapy was radiation.
OK, I grok what you mean on that first part. As for the second part of your post...
<<Agreed that while weight and LDH were stat sig in 9901 they were nowhere near stat sig in 9902a. But FWIW Location was also stat sig in 9901, but not in 9902a (although it was close). Strictly speaking they went from 5 stat sig covariates in 9901 to two in 9902a.>>
...actually, an argument could be made that p<0.10 could be considered stat sig in a Cox analysis (especially in a trial with only 98 pts), and disease localization was p=0.07. I could have sworn that they have designated PSA, bone mets, and disease localization as the three covariates to be used in 9902B's Cox.
<<Weight was a stat sig predictor in the Cox Regression for 9901. For 9902a it was not a predictor - in fact it was trended the wrong way. I assume this is what you are referring to - and the same thing I am referring to. One of the important things that the FDA will look at is whether the things found as predictors are accepted predictors - or whether they are just a random thing to put into the CR as a way of improving the p value of treatment.
BTW - None of the nomograms I have even looked at weight as a potential predictor.>>
Hmmm...I thought weight was one of the original factors of the 20 to be considered in the Halabi nomogram used in 9901. In addition, I swear that I heard something about only three covariates will be used in the 9902B Cox regression, these three being the ones that were stat sig for both 9901 and 9902A.
But weight was used in the nomograms for 9901 and 9902A, and I believe it was a stat sig predictor in one of them.
As discussed on I-Village, these are only the Provenge panel members with potential conflicts of interest....we may have as many as 17 or 18 voters on the panel if all CTGTAC members take part and vote.
GROAN...eom