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I asked the company what statistical method was used to allocate the interim alpha. Answer: O'Brien-Fleming.
9902B used the O'Brien-Fleming method.
According to the company the interim data will only be unblinded if the P-value is hit. If the designated P-value is not hit the IDMC will only inform the company that the trial should continue to the final or stopped for futility.
In case you missed this on the IV board, some interesting comments from a discussion with Greg Schiffman.
In speaking yesterday about the New Jersey facility, Dr. Gold used two words that left unclear his exact meaning.
Those words were "ramp-up" and "validate"
I spoke this morning with Mr. Schiffman. When asked for clarification as to the intended meanings, he took time to explain. I received permission to share these explanations publicly.
1. Throughout 2007, the plant was quite busy attending needs imposed by the 9902b Trial. But in November, the plant went back into a "maintenance mode" as work levels dropped off dramatically as a consequence of the completion of enrollment on 8/31/07.
2. It had been "validated" (by FDA inspectors) for Production in January 2007 (or earlier). (You perhaps recall that in the Fall of 2006 Jersey and others monitored unusually heavy activity at the plant—which a guard told jersey had something to do with an FDA inspection, as I now recall.)
3. Processing of patient's blood cells had been shifted from the Mayo Clinic and Seattle (and maybe elsewhere) to New Jersey at that inspection time or shortly after. This was done soon after the plant had been "validated." Gold told us yesterday that the plant in 2007 achieved a high level of activity—the most processing in any given period that the company had ever done. The meaning of those words was simply that, with the plant available for use, the company had taken over all the processing just as the 9902b Trial was enrolling at its maximum rate. He was telling us that the plant performed very well and had demonstrated an ability to deal with volumes larger than the company ever had experienced before.
4. The now infamous CMC 483 inspection in January 2007 had nothing to do with this "validation." I understood him to say that those January 2007 additional inspections were something apart that in no way interfered with the production levels achieved throughout the year in 2007. Further, Dr, Gold was telling us that they also had in no way interfered with our existing prior "validation," IMO, when he stated that the plant is now (and has been) fully "validated" for Production. In other words, those words of his had nothing to do with the 483s.
5. But it is important here to discuss—and this is me speaking now—what is going on at the plant right now in March 2008. It has been minimally occupied and in most businesses, would have been "shuttered" for a few months to save money. This, of course, has not been done, and, in fact, could not be done without costing the company as much as a year or more to re-start and re-validate it. This is an important point. I have written before that it is like restarting an oil refinery once it has been mothballed. So Gold and Schiffman were telling us yesterday that the plant is being maintained "at the ready" despite that this is a costly proposition. It simply would be more costly in delay when the company could least afford delay, if they had retreated to the production elsewhere while the New Jersey plant lay fallow. So the plant remains fully "validated" to avoid re-validation.
Why are they telling us this? Because they wished to convey that we remain "at the ready" awaiting the Interim and, hopefully, an opportunity to swing into production a few mnonths later. It bespeaks confidence in the near-term outcomes in my opnion.
________
As to the reference to "ramp-up" of the plant later this year, it apparently was a reference to the work required on the new Provenge Trials to be launched this spring, and was not a reference to expanding plant capacity except for the additions of employees necessary to handle the new Trials.
Ranchero,
I actually asked that question directly to Gold. I was attending an investor conference in the Fall and during the break-out session I asked what is the interim P-value of 9902B. He said that the company is not disclosing that information. I then asked why the company would not provide that information because other companies do.
I forget the exact reply, but the response was because of competitive concerns.
For what it is worth, I have been to several DNDN presentations and they always stress that the interim is well-powered and has a reasonable chance of success.
Ocyanblue & Rancherho,
I would interested in your comments on Feuerstein's (pasted below) take on the quality of CEGE's Phase II results.
Feuerstein's Biotech-Stock Mailbag:
I received a ton of email about my bearish take on Cell Genesys(CEGE - Cramer's Take - Stockpickr) and its prostate cancer vaccine, GVAX Prostate, in last week's Mailbag. The column really set some of you off.
I'm accustomed to hearing from the bottom dwellers and the tin-foil-hat crowd, but oh boy, the curses and insults were flying! Too bad I can't share the best of these emails with you for laughs, but my editors are squeamish about such things.
Thankfully, some of you were a bit more genteel than the missile throwers. Which brings me to an email from Dilip S. He asks, "How can you say that GVAX is a dud? The phase II trials showed a median survival of over 35 months. If that's not an improvement over regular Taxotere, then what is? Am I missing something here?"
Dilip, you're missing something very important. Uncontrolled phase II studies in oncology are completely worthless. The data generated from such trials -- and that includes Cell Genesys' phase II study of GVAX Prostate -- are meaningless.
If you remember one rule about biotech investing, or more specifically, one rule about investing in biotech oncology stocks, it's that you should never (never!) trust phase II data from uncontrolled studies.
Print that out. Place next to your computer. Memorize.
Prostate cancer patients taking GVAX Prostate in the phase II trial had a median survival of 26.2 months. In a subset of patients at the higher GVAX dose (oh heavens, a subset?!) median survival was 35 months.
All patients in the phase II study received GVAX, so there was no control, and the study wasn't randomized so there was nothing to which GVAX patients' survival could be compared.
But what folks like Dilip and others do is compare these GVAX patients to historical data. In this case, Taxotere, approved for prostate cancer patients, produced a median survival of about 19 months in its own pivotal study.
Twenty-six or 35 months' survival from GVAX's phase II study is way better than what Taxotere produced in the past. Therefore, the ongoing phase III GVAX study, which tests the vaccine directly against Taxotere, is going to be a slam-dunk success. Right?
Wrong!!
The quality of treatment changes, patient characteristics are different, there is selection bias -- heck, everything is different from one study to another. When the phase III GVAX results are announced next year, patients on the vaccine will live far shorter than they did in the phase II study. Likewise, Taxotere patients in the study will live longer than expected. This is why the odds are strongly against GVAX Prostate and why I'm no fan of the stock.
I don't expect the dunderheads out there who insult me to take my advice, but for the reasonable folks like Dilip and others, do yourself a favor a read this article in Slate from January. Download these two papers from respected oncology journals, here and here.
They all deal with the shortcomings and unreliability of uncontrolled phase II oncology studies.
Mark Ratain, an oncologist and professor at the University of Chicago, has long been on a crusade against non-randomized phase II oncology studies. He was responsible for the randomized phase II study of Nexavar, the successful kidney and liver cancer drug from Onyx Pharmaceuticals(ONXX - Cramer's Take - Stockpickr). Ratain's phase II study was a revelation because it accurately predicted the later, positive results from Nexavar's phase III study.
I called him this week to discuss this topic (but not to specifically rip on, or criticize, Cell Genesys or GVAX, mind you.) He referred me to the articles above. Along with some very distinguished colleagues, he also co-wrote an editorial in the European Journal of Cancer earlier this year calling for randomized phase II oncology studies to become the norm, not the exception as they are today.
Sadly, Ratain explains, most small biotech companies don't bother to heed his advice because they're not interested in eliminating the uncertainty and better defining risk of their experimental cancer drug as it moves (hopefully) into phase III studies.
Instead, these companies see phase II studies as box checkers something they can do on the cheap to get a positive result -- no matter how meaningless -- that allows them to say they have a phase III drug in development.
"And for some reason, Wall Street rewards these companies by helping them raise money," he says, adding, "What should really happen is that the market should punish companies like this, making sure they can't raise money."
Amen! If that happened, maybe we'd see more successes and fewer failures in cancer drug development. Of course, savvy short sellers don't want that to happen, because they make a nice living off issues such as these.
Do any of you guys have concerns that this company only has 7 employees? It would appear that everything is outsourced, not necessarily bad, but quite different than most developmental biotechs.
Below is a link to a good review of DSMB's.
www.ncchta.org/fullmono/mon907.pdf
Read the answer to Question 17 (Page 38)
As per the SEC website, the test for material information is below:
"Regulation FD addresses the selective disclosure of "material nonpublic information." The Regulation does not define the term "material, " but instead relies on the same definition as is generally applicable under the federal securities laws: information is material if "there is a substantial likelihood that a reasonable shareholder would consider it important" in making an investment decision, or if it would have "significantly altered the 'total mix' of information made available."
The potential effect on the stock price is not relevant. The test is would a resonable shareholder consider it important. When you apply this test you must consider the industry and the company you are applying the test too. For instance, biotech companies are very news driven, so just about any type of information would be considered important. However, the same type of news from Genetech compared to Dendreon could be viewed differently.
IMO, a 483 issued in mid-February, two weeks before the AC meeting would be considered material by the majority of shareholders.
In addition, the CR letter would also be considered material by the majority of shareholders. Talking about the CR letter is not enough it should have been released. If the company truly disscussed on key components of the letter, then they should have no problem in releasing it to the public.
Update!
I told the IV board on Monday that I wrote numerous editors from the Philadelphia Inquirer in hopes of getting someone interested. I was contacted on Monday by the health editor and was interviewed by her on Monday. At that time she was planning on some type of coverage the next day. I thought it will be a minor ad in the back sections or in the online edition.
Today, to my surprise it got front page coverage. It was a long article and very well written. It covered all the key issues that I spoke to her about, including the AC panel letter writing.
The link is below:
http://www.philly.com/inquirer/home_top_stories/20070605_FDA_criticized_for_delay_in_prostate_cancer...
I would again like to stress that everybody write or email their local papers. The Provenge story is getting national visibility. The Provenge situation is a very viable article for any paper across the U.S.
I almost did not contact the Inquirer, because I mistakenly thought it would be a waste of time. Two days later it gets front page coverage!
Now, I believe getting any type of FDA reversal or alternative consideration is a long shot. But, I never thought that the Provenge story would ever get the level of attention it is getting now. I now know for sure that if you sit back and do nothing, nothing will happen.
Take the time and write!
Ed Gorkes
This is all very strange or very poor management control. News of layoffs and guidance on a future Provenge approval should not come from a newspaper reporter.
This information is clearly material and should be from a PR. Why would a corporate investor relations employee agree to an interview and disscuss these items??? Anybody with any common sense would not disscuss these items with a newspaper reporter prior to being announced in a PR!
Wall,
Can you explain this responce a little more. I am not sure what you mean.
Q: How might slow ramp up on enrollment of 9902B affect the results at the interim and final for an event given trial?
A: There will be a greater effect at the interim look. There will be a lot more censored patients who are more recent enrollees, and this will be a confounding factor.
Thanks.
Doc, My thoughts exactly. If this goes a little lower it turns into a good risk/reward investment.
Also, I forget when it was said but the comapny did say Frozen Provenge is less effective than fresh.
DNDN has been dealing with CBER since (I think) about 1993. It is a cancer drug now and was a cancer drug then. Why would they switch approval authority to CDER when the BLA was filed.
CBER was in control of this drug for over 10 years, they have all the expertise and knowledge to review the application.
It is a biologic drug and it is in the correct division. Just because the indication is cancer does not mean CDER is the proper authority to make the approval decision.
IMO, CDER is PO that the future of cancer treatments will gradually shift away from them. Rightly so and to the benefit of all cancer patients!
It is amazing how both of these letters (Scher & Hussain) got mysteriously published in the fine newsletter (Cancer). If they were actually sent to the FDA (Von E direct), they would have NEVER reached outside publications.
I also like these two paragraphs from Hussain's letter:
From the scienti.c and procedural aspects, in general, it would seem that at the end of the day what should determine a positive verdict in any therapeutic trial is the strength of the evidence as critically reviewed by an Advisory Committee with the proper expertise in the context at hand (ODAC in the case of a therapeutic cancer trial), with clear guidance on the questions posed to the committee within the framework of the regulatory guidelines and requirements of the FDA for approval. This needs to be coupled with an atmosphere that is conducive to an objective discussion and vote.
Another concern, based on this case, is the appearance of discordance in the burden of proof required for regulatory approval between CBER and CDER. In the meeting regarding endpoints in 2005, ODAC reaf.rmed the importance of powering trials for endpoints that measure true clinical bene.t. But fundamentally here this particular agent did not even meet criteria for its primary endpoint.
What an insult to CBER, it appears that Hussain only thinks that CDER is capable of approving a drug!
This latest letter reminds me of my two children having a temper tantrum because they did not get there way. It is comical and also pathetic for two professionals to act in this manner.
I get the impression that they are puppets on a string from another fine ethical professional!
Scher, by giving his opinion, is not risking his reputation at all.
However, IMO, if a person wants to express there position on an issue in this case to Von E. that is fine. Call him or send him a letter. I really have to ask why did this "Letter" find its way into the public's eye? It strongly appeares he wanted it to become public, not very professional, IMO.
Also, why did Scher & Hussain vote "Yes" to safety? Does not make sense to me!
Assuming Provenge gets officially approved by the FDA, What is everybodies opinion on what the CORRECT market cap should be upon that announcement.
I am looking for insight from others on the correct value only at that point in time and not factoring in potential future events.
Thanks!
It has been said before, but is important to remember that the original word "Establish" is not generally used in FDA documents or guidance to describe acceptable efficacy. The wording that was added "Substantial Evidence" is wording that is commonmly used in FDA guidance to describe efficacy. The wording change was proper and most likely the original question was improperly worded.
The first voting question on safety used the word establish, HOWEVER, later in the question it included the word "Reasonably" safe...If the word "reasonable" was ommitted from that question the same voting problem would have occured for that question.
If the word "reasonable" was included with the efficacy question then it would have read ...Establish Reasonable efficacy...then there would have not been any voting confusion.
IMO, establish means absolute and within the context of talking about drug safety and efficacy nothing is established, especially about drugs that have never been on the market.
IMO, the wording change was necessary and proper.
Wall Street Article, does anybody have access to the WSJ online article today on DNDN, if so please post. Thanks!
Interesting PR on a HER2/neu vaccine.
December 14, 2006 09:30 AM Eastern Time
HER2/neu Vaccine Results Spurs Phase III Planning by Apthera, Inc.
29th Annual San Antonio Breast Cancer Symposium
SCOTTSDALE, Ariz.--(BUSINESS WIRE)--Col. George E. Peoples, M.D., Chief of Surgical Oncology at Brooke Army Medical Center in San Antonio, TX will be presenting the results of a 200 patient Phase II study of a HER2/neu vaccine (E75) for the prevention of recurrence in high risk breast cancer patients at the 29th Annual San Antonio Breast Cancer Symposium, the premier breast cancer educational and scientific event. Dr. Peoples will present positive interim analysis of the Phase II study of E75 on Thursday, December 14th at 10:30am (CST) at the Georgia and Henry B. Gonzalez Convention Center in San Antonio, Texas.
Based on the advanced development stage of this product and the promising Phase I and Phase II results, Apthera, Inc. has exclusively licensed E75 from The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and another major academic institution.
About the Company
Apthera, Inc. is a private company established in July, 2005 to develop and commercialize advanced-stage clinical programs in cancer immunotherapy licensed from renowned academic institutions. Apthera’s initial focus is on funding and completing the final phases of development of E75 (NeuVax™). Apthera’s licensed technology is based on the use of single immunostimulatory peptides, such as E75, and peptide combinations to activate multiple “killer” T-cell clones against multiple tumor antigen epitopes. This new adjunct therapy, used in a clinical setting of minimal residual disease, will result in less disease recurrence and improved long-term cancer survival. Apthera has patents and strong proprietary protection on the naturally-presented human leukocyte antigen (HLA) peptides, methods of use, compositions, modifications, and processes. NeuVax™ is being readied for Phase III studies and indicated for the adjuvant treatment of breast and prostate cancers, and other HER2/neu-expressing tumors. Based upon the early success achieved in the clinic, the company now plans an end-of-Phase II meeting with FDA to discuss a Special Protocol Assessment (SPA) and the design and conduct of a large, randomized, pivotal Phase III registration study for the breast cancer indication.
This news release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements are not historical facts and are subject to risks and uncertainties which could cause actual results and the timing of certain events to differ materially from those set forth in or implied herein including, without limitation, risks associated with clinical development, regulatory approvals, product commercialization, intellectual property claims litigation and other risks associated with the Company’s proposed activities.
Bio Tech Boss, Excellent Post! Finally somebody explained why Gold had to do this financing now. To wait until the panel vote would have been foolish and like you said he had to avoid the going concern issue. I knew financing of some sort was coming soon. Now cash is available until the first look at 9902B data is ready, just in case. That is the extra runway he was referring to.
ADVR still headed up.
ADVR looks ready to run. Over .10 and it can really go, IMO
Anybody follow Oxford Media (OXMI.ob)?