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TTP isn't the primary endpoint, and it seems that the company doesn't want to jeopardize the integrity of the survival data in the FDA's eyes by unblinding 9902B early to look at TTP. DNDN keeps talking about the survival data in 2H 2008, so I'd take them at their word.
Correct, but will the company announce the TTP data? I would hope so, but also remember that TTP is sort of a crapshoot...and do we know the measurement intervals this time? Because it's possible that its importance will be de-emphasized by the investigators due to it not being the primary endpoint.
<<Opinions as to likely reaction of share price if interim is not "successful"? What is "success" for the interim? Minimum p value for interim that would still suggest final p value may be stat sig?>>
Typically, companies and DSMBs do not announce the p value of the interim data if the trial continues. You're extremely lucky if the company says that there is a "trend" toward significance. Not sure what DNDN will say if the p value is worse than 0.05 (50% odds, IMO). I don't have a great idea what would happen to the stock price in this case. I imagine there would be a significant drop...just don't know how big it would be, and whether or not there would be somewhat of a recovery after the initial drop.
There is a strong possibility that DNDN files for approval if the p value is between the 0.01 interim alpha guesstimate and the 0.05 typical threshold. I think the price will go up in this case, but IMO the same ilk (Scher, Hussain, Pazdur, Fleming, ASCO, Sendek, Aschoff, Shenouda) who opposed approval before will oppose it again.
If the p value is better than the interim alpha, IMO there will be less opposition to approval (perhaps only Sendek, Aschoff, Shenouda, and one of the other examples above). However, a lot is going to depend on the relationship between the log rank and Cox regression p values. If log rank is >0.05 and Cox is >0.01 but <0.05, IMO there will be significant opposition to approval from all of the elements in the previous paragraph. If log rank is better than 0.05 and Cox is still worse than 0.01, there will be less opposition. If log rank is better than 0.05 and Cox is better than 0.01, the opposition will be lesser still. The price should increase proportionately with better p value. However, we still don't know how much info the company will announce, even if they do announce they are re-filing.
I think we will see a lot of FUD being stirred up by the negative analysts no matter what, especially Aschoff and Shenouda. There will probably be insinuations of faked data, or improper Cox regression calculations. DNDN mgmt has not helped this at all with their secretive policy over the Cox regression methodology for 9902B. We don't know for sure if they will use all 20 covariates in the Halabi nomogram and gradually eliminate the non stat sig factors, or if they will just use the three covariates that were stat sig in both 9901 and 9902A and do a straight calculation with those three.
I don't know if HR will be as relevant as the p value. As I recall, the HR for 9902A wasn't bad, something like 0.77-0.79 if calculated the same way that every biopharma company in the world except DNDN does it. Taxotere's pivotal Phase III that got it approval in AIPC had a similar HR, but Tax's p value was <0.01 while the Provenge p value in 9902A was 0.33.
Considering MyVax needed a p value of 0.0002 to get stopped for efficacy on the first interim look and 0.0026 for the second interim look, it's not surprising that the trial would be continued to the end, even if it were efficacious. What's interesting is that the stat sig p value for the final look isn't
0.05 minus 0.0026 minus 0.0002 = 0.0472.
The final p value needed for stat sig is supposedly 0.019, which means that the total allocated over the three unblindings is 0.0218. I guess the reason it's not 0.05 is the fact that the primary endpoint is not overall survival, but some sort of progression measurement like PFS or TTP.
Saul, it's going to be a tough call. We don't know the percentages in each arm who will have taken Tax. It's actually the recent enrollees who are survivors that will have the biggest effect on the interim data. They will have to be censored at the moment of unblinding for the interim data calculations. That will cloud up the p value. If the unblinding occurs sometime in October 2008, there will be anywhere from 225 to 240 patients who will have been enrolled for less than 24 months. The biggest positive factor, if Provenge does impact survival, will probably be the long-term survival of the earliest enrollees. They won't have to be censored at 36 months as the long-term survivors were in the 9901 and 9902A trials.
I'm sure that there are plenty of DNDN investors who will respond that while survival wasn't an official endpoint, it was prespecified, and the FDA's briefing document reviewer stated that survival is the one metric that is valued highly enough that even if it isn't an official endpoint in a trial, the FDA always treats it seriously.
Good points too. I personally believe that P-11 will come back stat sig, but I also think that the FDA still will not have made up its mind about a proper endpoint in this indication, rendering P-11 incapable of becoming a registration trial. Obviously, if Provenge has been approved for the androgen independent indication by this time, it will see considerable off-label use.
<<In this double blinded randomly controlled pivotal study of zoledronic acid (Novartis), the authors find that at two years time, when the study was discontinued for lack of efficacy, 33% of patients had experienced the primary endpoint of time to distant metastases. P-11 is now going on 2.5 years. It is very reasonable therefore to expect that it will or has reached the median time to distant metastases.>>
Yes, but if Provenge is working well in this population, and with 2/3 of the patients in the trial being in the Provenge arm, wouldn't you expect the trial to take longer than 2.5 years to reach the median time to distant mets?
If you're asking how exactly to calculate it, that's a question for the stats folks. But for simplification purposes, the recent enrollees are considered to have survived for however many months they have been randomized. For an extreme example, let's say that 99 patients were randomized on September 30, 2007, and the interim look occurs on Sept 30, 2008. Assume all of the Sept 07 pts are still alive on 9/30/08. So 66 pts in the treatment arm have 12 months survival and 33 pts in the control arm have 12 months. That's going to mess up the p value for the treatment arm, because there is no separation vs the control arm. It's obviously not as bad as if it would be the 33 control pts all surviving on 9/30/08 and all 66 treatment pts dying one month earlier. But it's still going to hurt the p value.
I'd have to take issue with your point #3. I don't see the stock hitting sub 2 bucks if the trial is continued after the interim look. I just don't believe that the majority of long shares invested in DNDN are expecting the interim results to trigger a renewed filing for approval. Sure, there will be a lot of retail and mo-mo shares sold on this type of news, but not IMO enough to drop it that low. I can see it hitting the low side of the pre-advisory panel meeting trading range.
Because there will be so many censored patients (and so many more total patients in the trial), I don't see the Cox exercise improving the p value as much as it did in 9901. In fact, I've heard that many IMPACT patients were also stratified at randomization for # of bone mets, and that's probably half of the Cox improvement right there. Of course, that should make the log rank better than it otherwise would be.
The concern for the interim look is the large percentage (20%) of patients who enrolled in the final 18 months of the enrollment period. These patients, if still alive, will have to be censored at the time of the interim trigger in Sep/Oct 2008. If IMPACT goes like the other Phase III trials, there won't be much separation between the two arms for the first 18 months. The censored patients cloud up the p value.
DNDN has said that if they get better than 0.05 but worse than the interim alpha (probably around 0.01) using the primary analysis of Cox regression, they will submit to the FDA for approval again, but this submittal would be outside of the SPA. I can see the same elements who fought approval this spring fighting it again next year, especially if log rank is worse than 0.05 and Cox analysis drops it below 0.05. Of course, they are within the guidelines of the SPA if the Cox p value is better than the allocated alpha. Even so, longs will breathe easier if both log rank and Cox are better than the interim alpha. The best thing 9902B has going for it is that patients who live longer than 36 months get credit for those extra months. That's one of the factors that hurt the 9901 and 9902A p values. They had to stop at 36 months for the long-term survivors, and ~25% of the Provenge arm in 9901 probably lived for 65 to 84 months after randomization.
I'm not sure how they are going to run the Cox regression exercise. I had heard that they were only going to use the three stat sig prognostic factors that were common to both 9901 and 9902A (I believe bone mets, LDH, and PSA)...but I could be wrong. DNDN isn't saying anything.
OT-I don't have any doubts that orBec improves the clinical benefit over prednisone. Pazdur's comments left the door open, and one could have taken advantage by buying soon after the negative panel vote and selling before PDUFA date. I don't remember if they extended right at the first PDUFA date or a few days before. Anyway, it's too bad for the patients that neither orBec nor Provenge is on the market.
OT-In retrospect, DORB was a great trading opportunity right after ODAC.
Because of the comments Pazdur made toward the end of the ODAC meeting after orBec received the thumbs down...something like "Wow, I hadn't seen this piece of data, we are really going to take a look at this...very intriguing." Pazdur doesn't normally say positive things like that about a drug they've rejected. I'm paraphrasing, but his comments caused the stock to go from 20 cents per share when trading opened after the meeting to over 50 cents a few days ago. In addition, 90 days ago, the FDA extended the PDUFA date by 90 days. Again, extending the review date doesn't normally happen after ODAC votes thumbs down. So, OOD was behaving in an unusual manner regarding a thumbs down drug.
Anyway, I stayed away from DORB because Pazdur is an LSOS, so I didn't get burned.
OT-DORB gets Pazdurized
Sorry to all longs
re TELK:
<<Someone please tell me what OOD is thinking?>>
Dr. P: "All chemo, all the time! Hooray!!!"
OT-DORB: I was just going on the briefing documents. Those briefing docs were among the harshest I had ever seen for a drug at ODAC.
Is this particular vaccine autologous?
The article that Feuerstein wrote a few months ago about INGN pretty much summed up what a number of posters on this board have been saying for years. Microcapfun just gave an extremely succinct summary a few posts back. Its stock price will spike every so often on a PR, but the company's products won't ever amount to anything.
OT-Does her voice come through clear as a bell?
I'm not familiar with OPK, but I'd like to meet the Maxim analyst in that article because I'm curious to see if she rings when she walks.
Until something unexpectedly amazing happens, one should just assume that INGN and scam should always accompany each other in a sentence.
OT-I wonder if the same type of study will be done with Taxotere. The main difference between Taxol (Pacific yew) and Taxotere (European yew) is the species of tree each drug is derived from.
I would definitely agree with that last point, medchal. Net covering plus the anticipation of more future short covering is what's driving the stock price, IMO.
DORB is an FDA decision...odds are better than GTOP's Phase 3, IMO. Pazdur said they were really going to study it closely, so who knows?
OT-GTOP...I have little confidence the Phase III will succeed. Stat sig hurdle for the final data is approx 0.025. They already missed stat sig on both of the two interim looks. However, not much that has happened in 2007 in development-stage biotech has been true to form. So, I could very well be wrong, and all of those biotech hedge funds that make a ton of money by betting on negative Phase 3 results from development-stage biotechs (including GTOP) could wrong as well. Just remember that you're getting an opinion from someone who believed the SNUS Phase 3 would succeed based on stellar Phase 2 data, and thought the FDA would almost certainly approve Provenge after the thumbs up from CTGTAC.
OpEdNews.com: FDA Industry Insiders Derail Approval of New Cancer Treatments
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OpEdNews
Original Content at http://www.opednews.com/articles/genera_evelyn_p_071009_fda_industry_insider.htm
October 9, 2007
FDA Industry Insiders Derail Approval of New Cancer Treatments
By none
FDA Industry Insiders Derail Approval of New Cancer Treatments
George W Bush's FDA, stacked with insiders from the industry that literally carried him to Washington, has stooped to a new low to protect the obscene profits of the multi-billion dollar cancer industry by blocking the approval of a new class of immunotherapies that can extend the lives of dying cancer patients with minimal side effects.
In the May 14, 2007, Wall Street Journal, a former medical officer in the FDA Office of Oncology Products, Dr Mark Thornton, denounced the FDA's decisions, and stated, "May 9, 2007, should be cited in the annals of cancer immunotherapy as Black Wednesday."
"Within an eight-hour period that day," he wrote, "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."
Experts say, the new immunotherapies hold promise for many forms of cancer. "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," according to Dr Thornton.
With the approval of the new therapies, the profits, along with the horrendous side effects of the only treatments now available, could become a thing of the past. "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," Dr Thornton wrote.
As such, the new therapies pose a grave threat to the cancer industry as a whole, and the lost profits would not be limited to the sale of products. The pharmaceutical giants have spent a small fortune to gain control of every segment of the industry, from researchers to government regulators, and every year, billions of dollars flow through a nationwide network of research institutions and treatment providers under the guise of finding a cure for cancer.
However, the profits up for grabs have become so enormous that critics say the goal of industry-controlled research is no longer focused on finding a cure for cancer to save lives. Instead, the focus is on thwarting the development and approval of new therapies in order to protect the profits of the treatments already on the market.
The FDA's refusal to approve Provenge, a new immunotherapy vaccine manufactured by the Dendreon Corporation, has caused major outrage in the cancer community. Provenge supporters have sent thousands upon thousands of letters and other correspondence to the FDA, members of Congress, the Department of Justice and others.
In addition, the Ohio-based non-profit corporation, CareToLive, has filed a lawsuit on behalf of terminal cancer patients seeking a declaratory judgment that the FDA acted "arbitrarily" and "capriciously" by denying patients access to Provenge, in violation of their constitutional right to live.
Dendreon sought approval to treat late-stage androgen-independent prostate cancer (AIPC) patients who have no other options. A study presented to an FDA Advisory Committee at a March 29, 2007, meeting showed that, after 36 months, 34% of the men who received Provenge in a clinical trial were still alive, compared to only 11% of those who received a placebo.
Provenge is designed to stimulate the patient's own immune system to specifically attack only cancer cells, unlike chemo drugs that attack any fast-growing line of cells.
Patients who qualify for Provenge have already had their prostates removed or have undergone radiation and hormone therapy. Eligible patients receive a one-time round of treatment consisting of 3 visits to a urologist's or oncologist's office to give blood, and 3 visits for the blood enhanced with Provenge to be infused back into the body.
On September 10, 2007, CareToLive filed a motion asking the court to issue an order enjoining the FDA from denying the marketing and distribution of Provenge. The plaintiffs charge that within six months, another 15,000 patients will have died waiting for justice.
The memorandum filed with the motion points out that the only available treatment approved for terminal AIPC in the last 42 years is a chemo drug, Taxotere. "The effectiveness of Taxotere," it states, "is so superficial, and the side effects so severe, that most men decline the treatment, as the risks far outweigh the benefits."
According to the filing, between 300 and 600 patients per year die from the Taxotere treatment itself. "This is truly amazing," the memo states, "considering the cost of the treatment and the cost of hospitalization and that the average benefit is an increase in survival of only 2 ½ months."
In contrast, the Provenge safety profile is so good that nobody has died from it and less than one in four patients experience side effects consisting of mild flu-like symptoms lasting one or two days, the memo notes.
The defendants named in the lawsuit include Mike Leavitt, Secretary of the US Department of Health and Human Services; FDA Commissioner Andrew von Eschenbach; Dr Richard Pazdur, head of the FDA's Office of Oncologic Drug Division, and Dr Howard Scher, chosen by Dr Pazdur to serve on the advisory panel set up to review the approval of Provenge.
CareToLive is represented pro bono by Attorney Kerry Donahue, of the Dublin, Ohio law firm Bellinger & Donahue, while the FDA officials are represented by a legal team of 11 government attorneys, at last count, funded by tax dollars.
The plaintiffs allege that the defendants engaged in a conspiracy to prevent the approval of Provenge and that Dr Pazdur, "purposely located two conflicted oncologists who he was sure for a variety of reasons would be anti-Provenge and he instructed them to try to derail the approval of Provenge."
The plaintiffs charge that, by choosing Dr Scher, and also Dr Maha Hussain, to serve on the advisory panel, Dr Pazdur "likely found two of the most conflicted oncologists in the country to sit in judgment of Provenge, and who would both assuredly continue his plot to lobby others at the FDA to vote for non-approval."
At the behest of Dr Pazdur, and for their own future political and monetary gain, the plaintiffs claim, "these two oncologists did everything they could think of to obstruct and impede the approval of Provenge."
The waiver of conflicts of interest granted by the FDA to Dr Hussain, which allowed her sit on the panel, reveals that she is the lead investigator on a research contract awarded by a company that competes with Dendreon, and her husband owns stock in three competing companies valued at between $15,000 and $300,000.
The lawsuit alleges that, as part of the conspiracy, on May 9, 2007, the FDA denied terminally-ill patients access to Provenge, even though the FDA Advisory Committee recommended approval, found the vaccine safe by a 17-0 vote and found there was "substantial evidence" of efficacy with Provenge by a 13-4 vote.
In an attempt to derail an approval recommendation by the panel, the plaintiffs claim that, prior to the vote on efficacy, Dr Pazdur and "his co-conspirators changed the statutory question regarding efficacy from 'substantial evidence' to 'absolute certainty' of efficacy, in an effort to obtain a 'no' vote on Provenge."
However, during the voting, this manipulation was discovered and promptly corrected by the FDA's Dr Celia Witten and Dr Jesse Goodman, and by an overwhelming majority, the panel voted "yes" to the revised efficacy question.
"It is unprecedented for the FDA to overturn the Advisory Committee on such a positive vote when men are out of options, delaying approval and asking for more trials," according to CareToLive spokesman Mike Kearny in an August 2, 2007, press release.
"Men are dying now," he states. "They do not have years to wait."
In the case of Provenge's approval, the profits at stake could not be higher. Prostate cancer is the most common non-skin cancer in the US and the third most common cancer worldwide. More than one million men in the US have prostate cancer, with an estimated 232,000 new cases diagnosed each year and more than 30,000 men face death from the disease each year.
As an initial treatment, when diagnosed with prostate cancer, most men have their prostate removed, or undergo radiation, which can lead to various degrees of incontinence and impotence. After the initial treatments fails, hormone therapy is given to block the production of androgens such as testosterone, needed for cancer cells to grow, and some men undergo testicle removal in an attempt to stop the androgens from spreading the cancer.
With AIPC patients, prostate cancer has usually gone into remission and then returned, spreading to other parts of the body including the bones, lymph nodes, bladder, rectum, liver and lungs. All men who do not die of other causes progress to the final stage where the cells no longer respond to hormone therapy. Provenge is intended for use by patients who have already failed other types of therapy.
Because Taxotere is the only approved drug, Sanofi would have suffered the greatest immediate loss had Provenge been approved. According to firm's 2006 Annual Report, Taxotere was the company's 4th best-selling product in 2006, and the US is listed as the number one country contributing to sales.
As far as profits per dose, in the February 7, 2007, article, "What Does It Cost to Have Cancer?", a patient who received the chemo drug for breast cancer in 2006 reported that "each infusion of Taxotere cost over $16,000."
She also stated: "That's just for the drug, not administration or anything."
According to the lawsuit, defendant Dr Scher, Chief Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, is a scientific advisor and lead trial investigator for a competitor of Dendreon called Novacea. Under faculty disclosures at the University of Michigan, Dr Hussain is listed as an advisory board member of Novacea, and she receives research funding from Sanofi.
Dr Scher also has an interest in ProQuest Investments, which stood to reap windfall profits if Provenge was not approved. ProQuest is a venture capital fund established in 1998, in large part by Michael Milken, who was given the nickname "Junk Bond King," after being indicted on nearly 100 counts of insider trading and sentenced to 10 years in prison, in addition to being barred from the securities industry for life.
The ProQuest fund was established with a specific focus on prostate cancer, and SEC filings show that ProQuest and its principals are major shareholders of Novacea.
Citing documents from ProQuest, the plaintiffs allege that Dr Scher is a "ProQuest Executive" and "member of the Board of Directors", ProQuest reaps millions of dollars investing in prostate cancer companies based on advice from doctors such as Dr Scher, and ProQuest own stock in direct competitors including Novacea.
Dr Scher receives compensation from ProQuest as a scientific advisor recommending investments and for conducting clinical trials that result from the investments. He also holds an ownership interest in ProQuest.
The lawsuit also alleges that Dr Scher receives research support from the Prostate Cancer Foundation, as well as financial benefits, as one of a consortium of members who reviews new research on cancer drugs to determine which grants should be awarded by the Foundation.
The PCF, also founded by Mr Milken, is one of the largest sources of funding for the National Cancer Institute and government research programs. A following of the tangled web involved in the PCF reveals that Dr Jonathan Simons, President of the Foundation, Dr Stuart Holden, Medical Director, and Dr Howard Soule, an Executive Vice President of the Foundation, are all scientific advisors to ProQuest.
Another research arm found to be infested with several of the same insiders is the Prostrate Cancer Research Program, within the Department of Defense, which since 1997 has been appropriated a total of $730 million by Congress. According to a PCRP report, "Today, the PCRP is the second leading source of extramural prostate cancer research funding in the United States."
The PCRP funds a Clinical Consortium Award to support the creation of a major multi-institutional clinical trial resource, "to speed development of novel therapeutics that will ultimately decrease the impact of the disease."
Here, too, Dr Scher is listed as the leader of the consortium, and the list of participating clinical sites and lead investigators includes none other than Dr Hussain. Dr Simons is listed as developing new clinical therapeutics for late-stage prostate cancer, but a review of upcoming research listed in the report shows immunotherapies are not in the cards.
These consortium members are invaluable to the industry and investors due to their unique access to insider information about clinical trials and influence over the FDA approval process. Evidence of this claim came on May 30, 2007, less than 3 weeks after approval for Provenge was denied, when Novacea announced an agreement with Schering-Plough worth over $450 million, in which Schering agreed to jointly fund and develop Asentar, a competing prostate cancer drug, for which Dr Scher happens to be the lead investigator.
"The partnership leverages Novacea's existing capabilities with Schering-Plough's experienced development, regulatory and commercial teams and will provide Novacea with an opportunity to support the commercialization of Asentar in the United States," John Walker, company chairman and interim CEO, stated in a May 30, 2007 press release.
A May 2000 ProQuest document provides insight about the investment firm's interest in Asentar's success and states: "ProQuest Investments is a $100 million oncology-focused investment fund, partnered by Jeremy Goldberg and Jay Moorin."
Mr Moorin owned 1,910,988 shares of Novacea stock at the time of a May 15, 2006, SEC filing, and the ProQuest document mentions an investment from Domain Associates, "whose general partner, Jim Blair, has also worked with the fund to plot its strategy."
As it turns out, Mr Blair and Mr Moorin were both members of Novacea's board of directors when the Schering deal was set up. However, apparently their services are no longer needed, because on August 30, 2007, Novacea announced the resignation of James Blair and Jay Moorin, effective September 4, 2007, and September 19, 2007, respectively.
All that said, it does not take a financial genius to figure out that this whole deal could have gone up in smoke had Provenge been approved, because there would have been a drastic drop in the enrollment of late-stage cancer patients in clinical trials as soon as they learned that there was a new vaccine that could not only increase their survival rate but allow them to live out their final days without the agonizing side effects of chemotherapy.
Provenge's approval also would have caused many patients currently participating in trials to drop out. Novacea's 2006 Annual Report filed on April 2, 2007, less than 2 months before the Shering announcement, warned that the "clinical development and regulatory approval processes inherently contain significant risks and uncertainties."
The report shows Novacea was going broke trying to keep the Asentar trials running, with research and development expenses associated with the drug of $12.9 million for the year ended December 31, 2006, up from $7.3 million for the year ended December 31, 2005.
The $5.6 million increase was due primarily to the Phase 3 Asentar trial, and the filing warns that Novacea could experience many delays in getting its product to market due to problems in trials including, "patient enrollment may be slower than expected at trial sites due to factors including the limited number of, and substantial competition for, suitable patients with the particular types of cancer required for enrollment in our clinical trials".
It also notes that there "is a limited number of, and substantial competition for, suitable sites to conduct our clinical trials; clinical trial sites may terminate our clinical trials"; "patients and medical investigators may be unwilling or unable to follow our clinical trial protocols;" and "patients may fail to complete our clinical trials once enrolled."
In addition, another ongoing trial is evaluating Asentar as part of a combination therapy for AIPC patients with Sanofi's Taxotere. If safety or efficacy issues arise with Taxotere, the annual report warns, Novacea could experience significant regulatory delays, and the clinical trial may need to be terminated or redesigned.
Even if Asentar were to receive FDA approval, Novacea would continue to be subject to the risks that could arise with Taxotere or that Taxotere may be replaced as the standard of care for AIPC. "This could result in Asentar ™ being removed from the market or being less commercially successful," the report states.
Ironically, in one of 3 derogatory letters sent to the FDA urging the non-approval of Provenge leaked to the media following the failed efforts to rig the advisory panel vote, Dr Scher discussed the same fatal effects that the approval could have on the research industry. "An approval recommendation has far reaching implications beyond making the product available that the data simply do not support or justify," he wrote.
Approval would provide the Agency's endorsement of Provenge as a "standard of care" for men with AICP, he said, and by extension, elevate Provenge "to a position of being the new 'control' arm for future randomized phase 3 trials that are being designed for the regulatory approval of any new experimental agent or approach."
In other words, all the billions of dollars invested in the clinical trials now underway, or set to begin, conducted in hopes of gaining FDA approval for a new ACIP treatment, could go right down the drain if Provenge is approved as the first-line treatment for this patient population.
Dr Scher is probably more aware of this fact than anybody. On February 26, 2007, MedPage Today reported that in a satellite symposium titled, "Improving Upon Current Standards: The Integration of Novel Therapies in the Treatment of Androgen-Independent Prostate Cancer," sponsored by Novacea, Dr Scher said Taxotere-based combination therapy is being investigated in a dozen clinical trials for ACIP patients, and he reported receiving grants and research support from both Novacea and Sanofi.
Authors Bio: Evelyn Pringle is a columnist for OpEd News and investigative journalist focused on exposing corruption in government and corporate America.
Nothing is in the news pipeline, except for the upcoming announcement of 9902B's completion of enrollment, which everyone knows is coming soon. So, it's probably either short covering, or buying because of anticipated short covering.
OT-We'll know tomorrow and Friday. Sabathia and Carmona should get some confidence, starting at home. A-Rod has hammered CC in the past, but they haven't faced each other for a few years. I'll say one thing, though. The Sawx look scarrrrryyyy.
I would imagine that you understand my point. The more publicity NewsMax gives this article, the more men gullible enough to reject Lupron, Casodex, etc. at a time when they need these drugs the most. They do have their side effects, but they're not nearly as severe as the typical chemotherapy side effects, and they do keep men alive. Some men have been on them for over ten years, when otherwise they would have died in less than two.
It's a dangerous article that could end up killing people unnecessarily.
OT-The Angels also have two aces. Unfortunately, one of them (Lackey) always seems to implode at Fenway. My hope for this series is that all the crucial at-bats for the Sox always seem to happen with JD Drew at the plate with two strikes on him.
I think everyone is blowing my statements out of proportion. I've repeatedly said that I don't believe this scenario will happen...only that it can happen, but it's unlikely. It's even less likely now than it was a few months ago because of the publicity from the advocacy groups.
SPAs aren't completely legally binding. The FDA can do whatever it wants. I can see a Pazdurized CTGT taking apart the Cox regression analysis, i.e. using different stratification factors than the ones in the SPA in order to discredit the Cox. Then, even if the log rank p value is stat sig, the agency can claim that log rank is the secondary analysis in the SPA, and since the Cox regression primary analysis was flawed, DNDN needs to run another trial.
This is most likely unduly pessimistic, since I don't see CBER/CTGT losing purview of the BLA to CDER/OOD. However, this is how a negative scenario, even with stellar trial results, would play out if Pazdur were to succeed in wresting away the purview. Again, the more political pressure applied to the FDA by the advocacy groups, the less likely this scenario would happen, IMO.
I think the more likely it is that the CTGT Office in CBER remains quasi-independent from CDER/Pazdur/Office of Oncology, then the more likely Provenge gets approved, assuming a p value of 0.05 or better. Even if the p value is better than 0.01, which is the probable alpha allocated for the interim look, if the Office of Oncology somehow takes control of cancer vaccine purview, the SPA could just get thrown out, i.e. the "not invented/negotiated here" syndrome. Especially considering the person who will likely still be the head of the OOD, all bets are off.
Now, I don't believe that the cancer vaccines will be taken from CTGT's purview. I also believe that the more pressure can be applied to the OOD by the advocacy groups, the less likely CTGT will lose the purview. But I don't believe it's a total slam dunk, even if the results are stellar. If the Cox regression p value is a big improvement over the log rank, you can bet that the reviewing biostatisticians in either office will be all over it. I don't think we can call anything a slam dunk after what happened after the Provenge AC meeting.
SNUS-The PFS results won't be available until at least Q2/Q3 2008. The primary endpoint is ORR. I'm guessing that TOCp hit stat sig on noninferiority, with a trend toward superiority, and showed an improved side effect profile. From all of the Ph2 results, this scenario had the highest odds. We'll see.
Edit: the p value for both superiority and noninferiority is 0.025.
-9902A three-year survival: 32% Provenge arm, 21% control arm
-9902A median survival: 19.0 months Provenge arm, 15.7 months control arm
-Glad you don't think approval is a slam dunk, even with stat sig 9902B results on the interim
I wonder also about the timing of the SNUS pivotal results announcement, with the UBS conference going on. It starts Monday, right?
<<Which trial showed Provenge's 3 year survival advantage?>>
Both 9901 and 9902A...9901's metric was stat sig at 0.0046
<<What are Provenge's TTP results? Where were they published?>>
9901 = 0.052 published in JCO July 2006
9902A ~ 0.70 from FDA briefing docs
<<Provenge's effect on PSA doubling time?>>
Delays it, I believe significantly, but PSADT was not the primary endpoint of P-11 trial. Time to threshold PSA velocity was, and I believe Provenge showed a clinical benefit that was not stat sig. Check the archives on the DNDN website, I believe the PR is from Q3 or Q4 2006.
<<Which trial showed the Provenge 300% three year survival advantage?>>
9901, but the survival advantage vs control was only a triple, therefore it was only a 200% advantage (34% alive vs 11% alive)
<<When were the new FDA COI rules put into effect? Link?>>
If you're referring to the rules in the new PDUFA law, the Senate is currently working on it. Then it goes to our Chimp-in-Chief. There have been no other "new" COI rules, despite what some I-V posters believe. The announcement a few months ago wasn't new, they had always been in place.
<<Quotes from VE, Padzur, Scher, Hussain and others regarding delayed immunotherapy response...examples of VE's support of Provenge and other immunotherapies leading up to AC panel.>>
Check the ODAC archives on the FDA website and the 3/29 CTGTAC transcript. Anything Von E said might be at the February conference archives, I believe it was the NIH-NCI immunotherapy meeting.
<<Reasons why Provenge approval would be a slam dunk given the new CBER guidelines released on 5/15>>
Uh, no. No new CBER guidelines on 5/15, they had already been in place, it was just a clarification. In addition, Provenge approval is not a slam dunk, and you know it. We had a 13-4 efficacy vote go in our favor, and it was still turned down. CBER is probably the weakest division politically inside the FDA. Who's to say it won't cave again, even if DNDN files on 9902B interim results with a p value between 0.01 and 0.05? Pressure needs to be applied on the FDA by the advocacy groups prior to the decision, even if the p value is better than 0.01.