ODAC Member Raises Concerns About Dendreon's Provenge

The Cancer Letter, a weekly oncology paper (these are the guys who broke the ImClone (IMCL) story all those years ago, back when Inmate Waksal was spinning his lies), published an article on Dendreon (DNDN) and the Advisory Panel review of Provenge. They also published a letter to the FDA from Howard Sher, a major urological oncologist from Sloan-Kettering and a member of the Oncology Drugs Advisory Committee. Dr. Scher sat on the Provenge review panel and voted against Provenge on the question of substantial efficacy.

Below are excerpts from his letter - but there's a lot more in the Cancer Letter worth reading. I think the likelihood that the FDA will not ask DNDN for additional data from the ongoing survival trial is small - though I'm confident that the trial will fail; if you are long, you might want to ask yourself if it's really worth waiting a couple of years to find out? While the CEO is selling shares? And don't forget the capital raise that is certain to be coming. May 15th we'll see a Complete Response letter from the FDA, with a request for an additional trial, and I believe the DNDN bubble will burst.

One thing is sure, from the panel vote and from this letter - even if it were to get approved, it sure doesn't look like oncologists want any part of this treatment. Maybe DNDN will have better luck selling it to the lab jockeys, PhDs and veterinarians on the advisory panel who voted for approval.

Onto Dr. Scher's words to the FDA; he's a lot more articulate and authoritative than I am:

I am writing to express concerns about the recent review of Sipuleucel-T at the FDA Advisory Meeting on March 29, 2007. These concerns are: a recommendation for approval based on data that fall short of the regulatory requirements; an inadequate statistical construct to determine definitive benefit; incomplete data on product safety; and what appear to be different criteria for approval by two Advisory Committees to the Agency. All but the latter were discussed in the open meeting, but warrant further consideration given the outcome. The concerns are based on my experience as a voting member on several ODACs representing the Agency, and separately, as a Presenter to ODAC for Industry Sponsors. I have been one of the Academic Leaders of the Prostate Cancer Clinical Trial Endpoints initiative begun under the joint Sponsorship of the FDA, AACR, ASCO and PCF in 2004, which were presented at the February 2007, Prostate ASCO Meeting in Orlando.

. . . .

Let me state at the outset that I was one of the four Committee Members who voted “no” to the question whether the trials presented by the Sponsor established the efficacy or demonstrated substantial evidence of benefit to justify an approval recommendation to the FDA. My vote was based on the fact that neither of the two trials presented met their primary endpoint, which renders the significance of results from any subsequent analyses as “exploratory” and “hypothesis generating.” As such, theresults do not constitute “proof” of benefit or justify a conclusion that they are “reasonably likely” to predict benefit. The trial data were not consistent. Even if one accepts the posthoc survival analysis results of the larger 127 patient trial (82 men treated with Sipuleucel-T and 45 men treated with a “placebo”), the second trial of 98 patients (65 treated with Sipuleucel-T and 33 with placebo) was not confirmatory. Consequently, the only conclusion that can be reached is that the survival difference observed may have occurred by chance alone, and that the results do not support an approval recommendation. This, and the Sponsor’s recognition that an additional prospective study was needed, mandates deferring any decision on whether an approval should be granted until the results of the ongoing 500 patient phase 3 trial that is powered on a primary endpoint of survival, is accrued and analyzed.

Concerns about the validity of the findings were reinforced by the absence of other signals of an antitumor effect. Specifically there were no data provided of a favorable effect on PSA, regression or stabilization of soft-tissue or boney disease radiographically, health related quality of life, or that administration of the product delayed the development of pain. Even the time to the administration of chemotherapy, an indication to the treating Physicians that the clinical course had worsened, was similar between the two groups. Reinforcing the uncertainty was the fact that in response to a direct question at the meeting, none of the Physicians representing the Sponsor could articulate how treatment with the product had “helped” any individual patient.

. . . .

Finally, the original question posed by the Agency to the Advisory Committee at the meeting was: “Does the submitted data establish the efficacy of Sipuleucel-T (APC-8015) in the intended population?” The first 4 respondees on the Committee voted “no.” The question was then changed to: Do the data show “substantial evidence.” A series of “yes” votes followed. Consider the conclusion in the manuscript describing the results of trial 9901, published in the Journal of Clinical Oncology in Volume 24, page 3093, in 2006.(JCO 24:3089, 2006) In it, the Investigators state “that while sipuleucel-T fell short of demonstrating a statistically significant difference in TTP, it MAY provide a survival advantage to asymptomatic HRPC patients. Supportive studies are underway to confirm this effect.” All of the difficulties cited, and the Investigator’s own conclusions, show how there are simply too many alternative explanations for the observed survival difference beyond treatment with Sipuleucel-T. Couple this with that fact that were no secondary signals of an antitumor effect and no confirmatory trial however flawed, mandates that any decision for approval be deferred until the phase 3 study, currently underway, has been completed and analyzed.

Disclosure: Author has a short position in DNDN

Comments

[Wall Diver:]

In Dr. Scher’s letter, there were a number of questionable, or debatable, assertions, and a number of seeming logical flaws and contradictions, to the extent that it seems possible that he was not the actual author of this letter. However, for the sake of discussion, the authorship attribution by The Cancer Letter is considered to be factual. This response to Dr. Scher’s letter is an attempt to address some of those items, both to clarify the issues, and to encourage debate about them.

In addressing his efficacy concerns, Dr. Scher reportedly stated:
“My vote was based on the fact that neither of the two trials presented met their primary endpoint, which renders the significance of results from any subsequent analyses as “exploratory” and “hypothesis generating.” As such, the results do not constitute “proof” of benefit or justify a conclusion that they are “reasonably likely” to predict benefit.”

This is, of course, in reference to the time to disease progression (TTP) (11.7 weeks Provenge vs. 10.0 weeks placebo) endpoint pre-specified in the primary trial (D9901). Depending on the 2002 unblinding or the 2003 unblinding of the TTP data, the p value was either 0.085 (91.5% chance that the 1.7-week benefit was due to Provenge), or it is 0.052 (94.8% chance that the benefit was due to Provenge). In other words, Dr. Scher's argument is that because the probability of the 1.7-week benefit being due to Provenge treatment was not 95.0% (p=0.050), then the reported survival benefit of p=0.01 (99.0% probability that survival benefit was due to Provenge) must be disregarded as an "exploratory" statistic. Provenge supporters contend that the correlation between time to progression (91.5%-94.8%) and survival (99.0%) is so strong that the FDA should approve Provenge as soon as possible, especially considering its much milder side effect profile when compared to the treatment alternatives.

It should be noted that the TTP endpoint is only a surrogate endpoint for survival, often used because it could be measured faster than survival. It is somewhat disheartening to see Dr. Scher make the above argument. He is undoubtedly familiar with "A Clinical Development Paradigm for Cancer Vaccines and Related Biologics", to which the reader is referred, www.sabin.org/files/PD... Dr. Scher is surely aware of the new guideline on "Other Time-to-event Endpoints" on page 6 of the Clinical Development Paradigm (“Therapeutic cancer vaccines pose the possibility of a delayed onset of activity….based on the time required to mount an effective immune response and the time for that response to be translated into an observable clinical effect”, with discussion of TTP measurement issues) developed after extensive debate among the FDA, the NCI and outside experts, including Paul B. Chapman, M.D. and James Allison, M.D. from his own institution, Sloan-Kettering. There were no objections to the presentation of this paradigm during the second day of the FDA/NCI Workshop on Bringing Therapeutic Cancer Vaccines and Immunotherapies through Development to Licensure (February, 2007) and during the panel discussion on the second day, at which the FDA was represented by two physicians. A videocast may be seen at: videocast.nih.gov/Past...

Also, see Slide 7 of the following link, a copy of which was also shown at the Advisory Meeting, investor.dendreon.com/...
A cursory view of Slide 7 of Dr. Small's presentation of Provenge data would indicate that, using this new experience driven change in the way immunotherapies impact TTP and allowing for a three-month ramp up of the immune response, TTP would clearly achieve statistical significance. Of course, if TTP is accepted as significant, it would provide support to the survival benefit finding which, as noted, achieved p-value of .01, highly statistically significant.

Dr. Scher stated, “Another concern is that the requirements for regulatory approval appear to differ between the ODAC and CBER Advisory Committee.”

His discussion of the work at ODAC on clinical trial endpoints is somewhat stunning in regard to omission, especially with respect to the ODAC meeting on the afternoon of March 3, 2005 which he attended, when that Committee unanimously recommended that survival should be the only endpoint in AIPC / HRPC trials. It is incongruous that Dr. Scher now dismisses the survival finding in the D9901 trial just because the trial slightly missed the TTP endpoint which the FDA, NCI, and experts from around the world decided was inapplicable to immunotherapies.

As an aside, regarding Provenge survival data, the reader is referred to the presentation of Dr. Daniel Petrylak at the Chemotherapy Foundation in New York in November 2006, neglected by Dr. Scher, but accessible at: chemotherapyfoundation...
Although this presentation was indeed a retrospective analysis of 9901/9902a Provenge data, Dr. Petrylak reported that patients who received Taxotere 4 to 6 months after Provenge, when compared to that predicted by the Halabi nomogram (with which Dr. Scher is familiar), showed an astonishing increase in median survival of some 14 months (as compared to the 2.4 month increase demonstrated in the Taxotere TAX327 pivotal trial and the 4.5 months increase of Provenge as a standalone therapy). Dr. Petrylak’s presentation anticipated follow-up clinical trials in which the sequencing of Provenge, followed by some Taxotere, followed by a Provenge booster can be explored to further extend survival, perhaps in the absence of any prolonged chemotherapy. Surely, Dr. Scher and every oncologist hope that this will be the beginning of unprecedented management of this deadly disease. This further supports the comments of NCI’s Dr. Niederhuber at the outset of the second day of the FDA / NCI Workshop, that chemotherapies may be the first combinations used and approved to further improve cancer vaccines. The FDA will look forward to receiving the confirmatory data and analysis from Provenge’s third 9902b trial in 2010. Until then, Dr. Petrylak’s future Provenge sequencing trials of Provenge followed by a taxane and perhaps followed by a Provenge booster present reason for real, enduring hope by prostate cancer patients. Such additional studies will, of course, be greatly facilitated by FDA approval of Provenge.

Among his efficacy objections, Dr. Scher found, “Imbalances in disease aggressiveness and disease extent were noted between the Sipuleucel-T and “control” groups including a higher proportion with Gleason 6 disease or less at diagnosis (26.8% vs. 15.6%), and a lower proportion with both bone and soft tissue disease (52% vs. 69%) at the time therapy was started. Both factors favored the Sipuleucel-T arm, predicting a longer survival for the “treated” patients independent of therapy.”

None of the cited imbalances was statistically significant. However, Dr. Scher did not mention the most important imbalance, the number of bone metastases (BM) > 10, which heavily favored the placebo arm: 40.2% treatment with #BM>10 compared to 26.7% placebo. This prognostic factor was highly predictive of survival in both D9901 and D9902a trials. It also makes clinical sense, as advanced prostate cancer has a tendency to metastasize to bone, the higher the number of bone metastases, the more severe the disease. AC members thoroughly reviewed issues of imbalances between experimental and control arms.

Dr. Scher also stated, “Specifically there were no data provided of a favorable effect on PSA…”
However, this observation seems disingenuous, and surprising in light of Dr. Scher’s own Slide Presentation at the 3/3/05 ODAC meeting, where a slide was entitled: "Post Therapy Based Outcomes and Survival" states at item 3, “May not apply to non-cytotoxic agents or drugs directed at different aspects of the metastatic process." Later, under "The Association Between Time Dependent PSA Levels and Relative Risk of Death is Modest", he indicated that "A large part of the treatment effect is not explained by PSA" www.fda.gov/ohrms/dock... At page 285 of the Transcript of that meeting, Dr. Scher is quoted as, "So, where does this leave us in terms of PSA change and survival? Trial 9916 showed that there was an association of PSA decline and the treatment effect was eliminated when adjusting for the intermediate, did not see the same effect in both arms of the TAX-327 study. The Q3 week arm was the only arm to show a survival difference.” And, at page 289, "The regulations for accelerated approval are very clear. They require substantial evidence from well-controlled trials regarding a surrogate endpoint."

It is perhaps only slightly gratuitous to note Dr. Scher’s 3/3/05 reference to the term, "substantial evidence", as opposed to the term, "establish.” This has been the subject of some controversy both during and after the 3/29/07 Advisory Committee meeting. In his letter, Dr. Scher complained,

“Finally, the original question posed by the Agency to the Advisory Committee at the meeting was: “Does the submitted data establish the efficacy of Sipuleucel- T (APC-8015) in the intended population?” The first 4 respondees on the Committee voted “no.” The question was then changed to: Do the data show “substantial evidence?” A series of “yes” votes followed.”

Apart from the irony of his own previous statement suggesting general endorsement of the term “substantial evidence” (albeit in regard to accelerated approval), as an Advisory Committee member, Dr. Scher should well understand that this term is specifically cited in the May 1998 FDA Guidance for Industry publication regarding evidence for effectiveness of drugs and biological products, regulation, www.fda.gov/CDER/GUIDA... The regulatory requirement is that the treatment must find “substantial evidence of efficacy”. There is no deviation between Advisory Committees as long as they conform to clearly articulated regulatory requirements. It is not known why the original wording of the question to AC members was altered from the standard regulatory language, but this alteration created conceptual difficulty, and it was properly corrected.

Despite himself having voted in favor of the Provenge AC safety question, Dr. Scher averred in his letter, “The first question the Agency posed to the Committee was whether the product was “reasonably safe” for the intended population. While the vote was yes, the issue of cerebrovascular events as a potential safety signal was raised….Deaths due to CVA’s were recorded in 1.5% of Sipuleucel-T patients and 0.9% of those receiving “placebo.”

Readers may recall that the subjects in this trial were elderly men, who, independently of prostate cancer, had an age-associated, elevated risk of cerebrovascular accidents (CVAs). The risk of CVAs of U.S. men older than 65 is anecdotally estimated to be 2-3% per year. For the 147 patients in the 9901/9902A treated group, there were 8 CVAs. If one estimates that the average survival of this group for the three-year study period was ~26 months (median was 23.2 months), this data would be consistent with the expected risk of CVAs.

Dr. Scher further stated, “To place the frequency of the neurologic events in perspective, no cerebrovascular events were observed in TAX-327, a 997 patient three arm randomized trial that evaluated two different dose schedules of docetaxel in comparison to mitoxantrone,(NEJM 351:1052, 2004) or ASCENT1, a 251 patient randomized comparison of docetaxel weekly with or without high dose calcitriol (DN-101)(JCO 25:669, 2007).”

If true, this absence of CVAs in the TAX-327 trial group would be rather amazing, as these 997, primarily older patients were followed for some 18 months! Instead, it may be that specific CVAs were not reported; e.g. the FDA documents on the trial report only TEAE (Treatment Emergent Adverse Events). How Dr. Scher could confuse the absence of a specific item report with non-occurrence, given generally known incidence, is not readily apparent. Despite being the lead investigator for the ASCENT trial, he seems to not have recalled that, in the 125-patient Taxotere arm, there were 10 (8%) thromboembolic events, of which 2 were CVAs, 1 Myocardial infarction, and 1 arterial thrombosis. The first link below is the table from the JCO article on the ASCENT trial, the second is the abstract.
meeting.jco.org/cgi/co...
meeting.jco.org/cgi/co...

In addition, from five earlier Taxotere studies, 15/149 patients experienced thromboembolic events, including 3 CVAs and 2 arterial embolisms. For example, in this 2003 Docetaxel citation, www.pubmedcentral.nih...., it is stated,

“In the Columbia Presbyterian Phase II trial of docetaxel and estramustine, the occurrence of vascular events, including grade 4 and 5 cerebrovascular accidents (6%) and grade 3 deep vein thrombosis (5%), prompted the initiation of prophylactic anticoagulation.”

The above phase II trial tested Taxotere+Estramustine, the same regime tested in the Southwest Oncology Group's phase III counterpart to the TAX-327 phase III trial that Dr. Scher quoted, and 6% of treated patients had CVAs. This data suggests that TAX-327, for whatever reason, simply did not report CVAs. Dr. Scher’s suggestion that this proves their absence, and that, in contrast, Provenge is unsafe, seems to represent remarkably flawed reasoning.

The Provenge AC voted unanimously positive on the safety question, a vote which occurred after AC discussion of the CVA issue and members being informed that the FDA and Dendreon have planned to subsequently monitor 3000 Provenge patients for CVAs and any other identified safety issues. Provenge is generally considered to have very minimal side effects, in stark contrast to chemotherapy treatments.

Dr. Scher also suggested that the frozen version of Provenge given to placebo crossovers may have harmed them, “More important, and perhaps underappreciated during the discussion, is the recognition that the “placebo” used in this trial, a portion of the leukopheresis product that is cultured without the immunizing antigen and reinfused, may not be inert and in itself contributed to a relative worsening of survival for the control group in this trial.”

However, he did not identify any physiological process to support the assertion, and failed to represent the Dendreon clinical trial evidence that contradicts this assertion. According to the briefing documents posted by Dendreon and FDA, each subject in the Provenge trial underwent aphresis to collect peripheral blood mononuclear cells (PBMC) in certified hemodialysis centers. Subjects in the APC placebo arm underwent the same apheresis procedure as those in APC 8015 arm to harvest PBMCs. One-third of the total PBMCs were freshly administered to subjects and the other two third were frozen. If a subject in the placebo arm had disease progression, these frozen cells would be thawed and loaded with the therapeutic vaccine- PA2024 (APC8015F) and infused.

Transfusion of leukopheresis product is a safe and widely used clinical option; therefore there is no reason to believe that fresh PBMCs from patients’ body would be harmful. On the contrary, data supports that some placebo patients may have benefited from receiving the frozen vaccine. In study 9901, the median overall survival was 21.4 months, contrasted to 19.9 months as predicted by the widely used and validated Halabi nomogram. The 1.5-month benefit showed a trend of some benefit due to frozen Provenge. In addition, placebo patients that received frozen vaccine survived longer than those who did not. Furthermore, among the placebo patients who received second-line docetaxel therapy, the median survival was 25.7 and 20.2 months for those who received frozen vaccine and those who did, respectively. In addition, preliminary survival data from the D9901 from an interim unblinding in September 2003, two years after the last patient enrolled, showed a laddered improvement in median survival (MS) from the placebo patients who did not receive salvage Provenge (19.3 months), to the placebo patients who crossed over to receive salvage Provenge after their cancer progressed (23.9 months), to the Provenge trial arm itself (26.3 months). This two-year data strongly indicates that the exact opposite of Dr. Scher’s suggestion occurred.

In addition to expressing reservation on efficacy and safety despite votes of majority and unanimity, Dr. Scher was concerned “that the requirements for regulatory approval appear to differ between the ODAC and CBER Advisory Committees. As an example, ASCENT1 was a prospective randomized phase 2 trial of weekly docetaxel with or without high dose calcitriol (DN-101)... A total of 250 patients, 125 per arm were enrolled and followed. The 9% difference in the PSA response rate observed at six months was not statistically significant (P

2007 Apr 16 06:52 AM

[Echo To All:]

When I first heard this letter was out I got pretty angry. The reason I got angry is because this person has dedicated their life (or current chapter of life) to save people's lives (or at least I am assuming that is the case), and yet is turning away a treatment that the AC panel deems EXTREMELY safe and has substantial efficacy.

This person is a leader in the field (at least to someone outside the cancer community), and has the responsibility to NOT be overwhelmed by one side vs the other. Why is it so difficult to see the middle of the road here? I just do not get it.

Where is the risk to which drives the inability to adapt at least in a half way point?!? WHERE?!?

Provenge shows NO risk to the patient, NONE. On top of that, after the infusions, chemo can be applied (if the patient desires it). Also, the point is not about Provenge VS Chemo, but about choice to the patient.

If there was a risk to taking Provenge the letter like this would be justified and I would agree completely, but we can not just close our eyes to the most beneficial path (for PC patients) because someone's opinion does not agree with the facts. The PC patients do not deserve such ignorance.

(The most beneficial path may very well be a combo of Provenge w/Tax... why deny this option to the patients by denying Provenge when Tax obviously holds the greater risk... WHY?)

2007 Apr 16 08:22 AM

[iamahoo:]

Shame, Shame, Shame! You must be desperately short DNDN. Also you must be on the payolla list of certain desperate heggies that are sweating bullets. It is not abnormal for one or more panalists to take an opposition view, particularly with new science that they are unfamiliar with. Even the Supremes issue minority opinions. It is most noteworthy that the good doctor voted in uniminity with the other 16 that the drug is safe. That fact alone would make DNDN a winnning bet in Vegas, which is the type of circus the various market manipulators (look in a mirror) have turned this saga into.

By the way, I believe it is not factual that Dr. Gold sold ALL his shares. Maybe he just needed some cash to cover his obligations, in the same manner you and your fellow nay sayers will need to do on May 15.

For the record, I am very long DNDN with a counter hedge position in put options.

2007 Apr 16 09:19 AM

[wahl44:]

This stock/company should be trading on the potential science that underlies Provenge. Whether it trades up or down is not the issue. The blatant attempts to manipulate this stock downwards (irrespective of the science) are despicable if not criminal. A widely circulated report that is on Fidelity and disseminated by M2 PRESSWIRE via COMTEX has a clearly false statement regarding FDA approval of Provenge. The quote from the article that was posted as of 10:53am is: "Shares were down 4% as FDA denies drug approval." The FDA has NOT denied approval of Provenge. Investors tend to trade on seemingly substantial news such as this. This "report" has been posted all day. Is the market determining fair value of this stock or is it being massively manipulated??

2007 Apr 16 03:47 PM

[dorotie97:]

From: 10 MD's, 4 Phd's and a research advisor

As a group of medical doctors and scientists we are writing to express our concern with the contents of a letter reportedly sent by Howard Scher, M.D. of the Memorial Sloan-Kettering Cancer Center, to the FDA, and published in Volume 33, No. 14 of The Cancer Letter, on April 13, 2007. Dr. Scher reportedly warned the FDA about flaws in the Provenge (Sipuleucel-T) trial data (Sponsor, Dendreon Corporation). The FDA decision about Provenge approval is presently pending. As Dr. Scher acknowledged, he served as a member of the Cellular, Tissue and Gene Therapy Advisory Committee on March 29, 2007, which voted positively on the FDA questions placed before it. The Advisory Committee efficacy vote was 13-4 in favor of Sipuleucel-T; Dr. Scher was among the four Committee members who voted in disapproval on that point though the transcript reveals that he voted Yes to the question of “substantial evidence” and No to “established efficacy” but changed his vote in an unclear manner (EXHIBIT-1).

The Advisory Committee safety vote was a unanimous 17-0.
In Dr. Scher’ s letter, there were a number of questionable, or debatable,
assertions, and a number of seeming logical flaws. This response to his
letter is an attempt to address some of those items.

Dr. Scher opens by stating his concerns on a Committee recommendation for approval based on: (a) data that fall far short of regulatory requirements; (b) “an inadequate statistical construct to determine definitive benefit”; (c)
incomplete data on product safety; and, (d) “what appears to be different
criteria for approval by two Advisory Committees to the Agency” Dr. Scher
acknowledges that all but the latter were discussed at the open meeting, but
warrant further consideration given the outcome”.

To begin with, one must ask why an expert invited by the FDA as a “special Federal employee” with expert knowledge in the given field, given a waiver of Conflict of Interest requirements (we are delighted that the outdated conflict of interest waiver guidelines under which Dr. Scher’s waiver was issued are currently being revised by the FDA) to participate in an Advisory Committee (EXHIBIT-2) with respect to “a particular matter”, and given access to Briefing Materials, the opportunity to comment, question and vote, chooses to question the outcome of the Committee’s recommendation, including his own vote on Safety, after the fact. Absent new material information, Committee members, if no one else, should respect the fairness of the process and the final vote of the Committee.

In addressing his efficacy concerns, Dr. Scher stated: “My vote was based on the fact that neither of the two trials presented met their primary endpoint, which renders the significance of results from any subsequent analyses as “exploratory” and “hypothesis generating. “As such, the results do not constitute “proof” of benefit or justify a conclusion that they are “reasonably likely” to predict benefit.”

The FDA has allowed increases in overall survival to be statistically tested for significance where it was not a primary endpoint and has approved a supplementary NDA, where the primary endpoint of survival was not statistically significant. The pre-specified primary endpoints in both the 9901 and the supporting 9902a trial were the time to disease progression (TTP). While not reaching statistical significance, a probability of 0.052 was undeniably close. It is understood that the positive Advisory Committee (AC) vote was primarily on the basis of the survival benefit subsequently discovered (and agreed by the FDA for the proper endpoint for filing of the Provenge BLA). The FDA has, in the past, considered an increase in overall survival in a life threatening disease, as a “gold standard” worthy of its own “alpha” of 0.05. See: www.ncbi.nlm.nih.gov/e...;db=PubMed&lis... In addition, the FDA has given Accelerated Approval to a supplementary NDA in NSCLC to Alimta, which failed to reach its primary endpoint of survival with a p value=0.93.: The Oncologist, Vol. 10, No. 6, 363-368, June 2005: FDA Drug Approval Summary: Pemetrexed for Injection (Alimta®) for the Treatment of Non-Small Cell Lung Cancer. theoncologist.alphamed...


The FDA, NCI and academic experts from around the world have agreed on a new Clinical Trial Paradigm for cancer vaccines which, if applied to the Provenge 9901 clinical trial would have made the increase in Time to Progression (TTP) statistically significant. See: “A Clinical Development Paradigm for Cancer Vaccines and Related Biologics”
www.sabin.org/files/PD...
T.2007.pdf.
Specifically, “Other Time-to-event End Points” on page 6 of the Clinical Development Paradigm stated: “Therapeutic cancer vaccines pose the possibility of a delayed onset of activity based on the time required to mount an effective immune response and the time for that response to be translated into an observable clinical effect, Drs. Paul B. Chapman, M.D. and James Allison, M.D. Memorial Sloan- Kettering, where Dr. Scher also practices medicine, participated in this development effort. There was further discussion of this Paradigm during the second day of the FDA / NCI Workshop on “Bringing Therapeutic Cancer Vaccines and Immunotherapies through Development to Licensure”
The agenda for the Workshop is accessible at: https://cms.palladianp... and a video webcast of the Conference is accessible at:
videocast.nih.gov/Past...


Dr. Scher debates whether there was a “Delayed Effect” observed in the Provenge 9901 trial, but strangely goes on to implicitly suggest that more modern methods of measuring progression could have made Provenge’s TTP statistically significant without the need for a “Delayed Effect” adjustment. Dr. Scher disputes the existence of a Delayed Effect in the 9901 trial since: “serial imaging to assess disease were not performed once a patient was considered to have “progressed” and taken off study. As a result, individual sites were no longer being monitored so that no statements could be made regarding a possible “delayed effect” of the product on disease status”. Please refer to the Provenge 9901 plot (Slide 7) and the ITT and control group separation of curves at approximately 12 weeks accessible at: investor.dendreon.com/...
Dr. Scher comments that: “the Prostate Cancer Working Group 2 has advised that an apparent progression on bone scan at a three month assessment, be confirmed by documenting further progression on a subsequent scan six or
more weeks later before considering a patient to have failed the treatment.” (ASCO Multidisciplinary Prostate Cancer Symposium, (ASCO Abstract #221) February 22-24, 2007, Orlando FL, 2007). With respect to the Provenge trial : “the eight week interval between disease assessments was too short to observe clinically significant changes by bone scan, and that in many cases apparent progressions eight weeks after the start of a therapy are more a reflection of disease worsening that lead to trial entry, and not a failure of the treatment (CCR1 3: 1488, 2007)”. Thus, the Provenge Phase 3 protocol adopted in 2001 used a method of measuring progression that needlessly penalized treatment effects during the early months by actually documenting as progression, metastases that existed at randomization. So long as the measurement protocol was consistent between ITT and control groups during the entire time that Time to Progression was assessed, this logic suggests that eventual separation of curves could be expected and the actual Provenge TTP p value was much better than the p value of 0.052 reported. Thus, consideration of the recommended Delayed Effect for immunotherapies would have been unnecessary.

If Provenge’s 9901 trial’s TTP, its pre-specified primary end point, was statistically significant due either to a “Delayed Effect” or a methodology that, in effect censured early progression events due to metastases present at the time of randomization, then statistical analysis of overall survival to confirm that TTP is a surrogate for a meaningful clinical benefit is required.
The Kaplan-Meir log rank p value for increased overall survival was 0.01 for the 127 patient 9901 trial and 0.011 for the integrated 225 patient database of the 990l/9902a trials. Dr. Scher should be particularly sensitive to the desired use of overall survival in AIPC/ HRPC since he participated in the Oncology Drugs Advisory Committee (ODAC) meeting on March 3, 2004 when ODAC unanimously recommended that overall survival should be the primary endpoint in all AIPC / HRPC clinical trials. The 3/3/05 ODAC afternoon transcript discussing endpoints in ADPC and AIPC, and mentioning the importance of control crossover in the FDA approval of Mitoxantrone is accessible (starting at page 204) www.fda.gov/ohrms/dock... The Power Point Slides prepared for the meeting are available at: www.fda.gov/ohrms/dock...

The transcript and slides of the March 3, 2005 ODAC meeting further reveal conflicting inconsistencies with Dr. Scher’s letter. Dr. Scher writes; “Concerns about the validity of the findings were reinforced by the absence of other signals of an antitumor effect. Specifically there were no data provided of a favorable effect on PSA, regression or stabilization of soft-tissue or boney disease radiographically, health related quality of life, or that administration of the product delayed the development of pain. Even the time to the administration of chemotherapy, an indication to the treating Physicians that the clinical course had worsened, was similar between the two groups. Reinforcing the uncertainty was the fact that in response to a direct question at the meeting, none of the Physicians representing the Sponsor could articulate how treatment with the product had “helped” any individual patient.” Is it really necessary for one physician to tell another physician that increased survival “helps” a patient? Slide 15 of Dr. Small’s presentation at 2005 ASCO shows that, although not statistically significant, there was a positive trend in the delay of onset of Time To Disease Related Pain (TTDP) in the Provenge 9901 Phase 3 trial: www.asco.org/portal/si...;vmview=abst_detail_vi...


Consider Dr. Scher’s issue of “ a favorable effect on PSA”. Dr. Scher’s Slide Presentation at the same 3/3/05 ODAC meeting included a slide titled: "Post Therapy Based Outcomes and Survival", which states at item " 3. May not apply to non-cytotoxic agents or drugs directed at different aspects of the metastatic process". Later under "The Association Between Time Dependent PSA Levels and Relative Risk of Death is Modest" Dr. Scher shows that "A large part of the treatment effect is not explained by PSA" At page 285 of the Transcript: "So, where does this leave us in terms of PSA change and survival? Trial 9916 showed that there was an association of PSA decline and the treatment effect was eliminated when adjusting for the intermediate, did not see the same effect in both arms of the TAX-327 study. The Q3 week arm was the only arm to show a survival difference."

Dr. Scher’s letter states: “Finally, the original question posed by the Agency
to the Advisory Committee at the meeting was: “Does the submitted data establish the efficacy of Sipuleucel-T (APC-8015) in the intended population?” The first 4 respondees on the Committee voted “no.” The question was then changed to: Do the data show “substantial evidence.” A series of “yes” votes followed.” Dr. Scher fails to point out that the question was changed by the FDA to conform with Federal law and FDA published guidelines. The FDA Guidance points out that: “ Congress adopted the 1962 Drug Amendments, which included a provision requiring manufacturers of drug products to establish a drug’s effectiveness by "substantial evidence." Substantial evidence was defined in section 505(d) of the Act as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.” See: www.fda.gov/cber/gdlns...
More surprising is the fact that Dr. Scher clearly knew what the proper standard was and not only failed to suggest clarification at the meeting but now objects to its use. Dr. Scher noted at page 289 of the Transcript of the 3/3/05 ODAC meeting: "The regulations for accelerated approval are very clear. They require substantial evidence from well-controlled trials regarding a surrogate endpoint." Thus, "Substantial evidence", not "establish" were the correct operative words. Dr. Scher went on the say at that same ODAC meeting at page 294: " One could certainly consider an accelerated approval based on an interim evaluation assuming the trial endpoint was met, with the proviso that the trial accrual and monitoring continue until accrual was complete, the analysis complete, to assess the primary endpoint, which in this case would be survival." Thus, if the 9901 Provenge trial TTP was corrected for a Delayed Effect or realizing that early progression is often misleading and followed by a delayed increase in time to progression, the 9901 TTP would have been significant, and FDA approval could have been granted in 2002, with trial accrual, monitoring, and analysis for survival to follow in a confirmatory trial. This is exactly what the Committee recommended on March 29, that the accrual, monitoring and analysis of the 500-patient Provenge 9902b trial be continued, but that FDA Approval be given now. It is also in accord with the FDA’s comments of November 11, 2005 that the FDA has the authority to require that Sponsor conduct a Phase 4, post Regular Marketing Approval Phase 4 confirmatory trial, and to withdraw or modify its Regular Approval should such trial fail to confirm the efficacy or safety of the therapy. See: (pages 59 to 65) at www.fda.gov/ohrms/dock...

Dr. Scher raises questions about trial size, but a prior FDA approval of Mitoxantrone in AIPC /HRPC and the use of the “Halabi nomogram” as a check on the heterogeneity of the control group suggests that this concern is not justified. : Dr. Scher states: “The 2: 1 randomization increased the power of the experimental arm, but it may have inadvertently made the small 43 patient control group more heterogenous and less representative of the global population for whom the indication was proposed”. At that same March 3, 2005 ODAC meeting, much was made of the few – four – number of FDA approvals in AIPC /HRPC. One of these was a 1996 FDA approval of Mitoxantrone for quality of life (QOL) / palliation of pain; The Mitoxantrone pivotal Phase 3 trial enrolled 160 patients. That trial had a high crossover rate (approximately 62%) which negatively impacted a potentially more significant p value by effectively making the treatment given to the Intent to Treat (ITT) group ultimately be measured against itself when the control group receives the treatment upon crossover. Mitoxantrone’s p value for palliation of pain was 0.01. The crossover rate in the Provenge trials was higher ( over 70%) than the crossover rate in the Mitoxantrone trial, the number of enrollees in the integrated 9901/9902a trials (225) higher in the Provenge trial, and the Provenge p value for overall survival of 0.011 remarkably similar to the Mitoxantrone’s p value for palliation of pain of 0.01. See: www.jco.org/cgi/reprin...

Dr. Scher coauthored and published in 2002 a study based on a 409 patient reference group of AIPC / HRPC patients detailing a nomogram which predicted survival based on certain diagnostic and functional patient characteristics. . See: jco.ascopubs.org/cgi/c... A year later, Dr. Susan Halabi and several distinguished coauthors, including Dr. Eric Small, the lead investigator of the Provenge 9901 clinical trial, published a similar study and nomogram. See: jco.ascopubs.org/cgi/c... The “Halabi nomogram” has since become a standard reference tool in comparing the survival it predicts for any group of AIPC / HRPC patients with the actual survival of the same group of patients treated with a new therapy. Since none of the Halabi reference group of 1100 patients benefited from any therapy extending survival in the period from 1991 to 2001, when no such therapies were available, the nomogram is based on a truly untreated group of patients where the confounding effects of a crossover trial protocol would not be a factor and the large number would assure heterogeneity. Dr. Small tested the Provenge 9901 ITT group against the Halabi nomogram and reported that median survival increased from 4.5 months to 5.8 months. See Slide 14 accessible at: investor.dendreon.com/...

While the FDA does not accept a nomogram in place of a control group in a randomized clinical trial there is no question that an appropriate nomogram serves as an invaluable check on the heterogeneity of both the intent to treat and control groups in a clinical trial.

Dr. Scher makes no reference to, or indication that he is aware of, a November 2006 presentation by Dr. Daniel Petrylak, a lead investigator of the Taxotere SWOG 9916 Phase 3 trial, at the Chemotherapy Foundation in New York that reported a remarkable increase in survival of AIPC /HRPC patients who received Taxotere after Provenge when compared to their survival predicted by the Halabi nomogram. See: (a) Dendreon’s November Press Release at investor.dendreon.com/...;Header=News
and (b) Dr. Petrylak’s presentation at: chemotherapyfoundation...

Although this presentation was indeed a retrospective analysis of 9901/ 9902a Provenge data, it was also supported by some very strong immunology
data reported by Dendreon in November, 2006 regarding the potential
efficacy of a Provenge booster infusion with a follow-up presentation at the annual AACR meeting on March 16, 2007, See: investor.dendreon.com/...;Header=News and www.abstractsonline.co...={34D88016-D025-4791-B...
Dr. Petrylak reported that 81 AIPC /HRPC patients in the 9901 and 9902a Provenge trials who received Taxotere 4 to 6 months after Provenge, showed an astonishing increase in median survival of some 14 months as compared to the 2.4 month increase in median survival reported in the Taxotere TAX327 pivotal trial, and the 4.5 month increase in median survival reported in the Provenge 9901 trial when compared to that predicted by the Halabi nomogram. This analysis was per the 9901 and 9902a trial protocols, which did not allow any booster dose of Provenge after the initial three dose therapy. The Dendreon P11 immunology trial data, where a single booster is given per its protocol in Androgen Dependent Prostate Cancer (ADPC), reported that Provenge primed long lasting, highly avid T cells against the PAP antigen (strongly supporting the conclusion that these are “memory” T cells), but also that the avidity of these T cells could be substantially increased with a single booster. Dr. Petrylak’s presentation anticipated follow-up clinical trials in which the sequencing of Provenge, followed by some Taxotere, followed by a Provenge booster may be explored to further increase patient survival, perhaps in the absence of any prolonged chemotherapy. These findings further supports the NCI’s Dr. Niederhuber’s comments at the outset of the second day of the February FDA / NCI Workshop that chemotherapies may be the first combinations used and approved to further improve cancer vaccines.

Provenge is an active immunotherapy, not a cytotoxic drug. Dr. Scher should look to reported successes in immnotherapy to inform the proper analysis of its likely method of action. Dr. Steven Rosenberg and his NCI colleagues are making startling advances with immunotherapy in end stage melanoma. See his presentation during the first day of the FDA.NCI Workshop at : videocast.nih.gov/Past... To briefly summarize the method that Dr. Rosenberg uses in his adoptive immunotherapy, it is the infusion of (a) large numbers of (b) long lasting T cells, (c) primed against a single melanoma antigen, into (d) patients who have been preconditioned with chemotherapies to deplete regulatory T cells. Provenge can be described as an active immunotherpy, which infuses (a)large numbers of dendritic antigen presenting cells, which in vivo prime even larger numbers of (b) long lived memory T cells against (c) an AIPC/HRPC antigen, Prostatic Acid Phosphatase (PAP). Instead of preconditioning patients to deplete regulatory T cells, which could also deplete the available pool of naïve T cells for Provenge’s dendritic antigen presenting cells to prime, the Taxotere (docetaxel) post Provenge analysis suggests that docetaxel, which preferentially targets rapidly proliferating regulatory T cells and cancer cells expressing bcl-2, (d) “post-conditions” and depletes the regulatory T cells in an established tumor and its microenvironment, potentiating a patient’s powerful immune response against cancer. See, for example, the fundamental research coming out of the laboratories of Professor Hans Schreiber at the University of Chicago at: www.jem.org/cgi/conten... and the presentation at the NIH of Professor Ulrich non Andrian of Harvard explaining how the ex vivo maturation of dendritic antigen presenting cells leads to the priming of long lived memory T cells upon their infusion. See: Migratory Properties and Immunological Consequences of Dendritic Cell Migration Wednesday, October 25, 2006 Uli Von Andrian Total Running Time: 01:03:39 videocast.nih.gov/Past...;s=11 The Provenge trials excluded men who had known metastases to visceral organs. It is just such metastases, frequently undetected, that ultimately cause death in AIPC/HRPC. Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases Lessons from a Rapid Autopsy Program Cancer Research 64, 9209-9216, December 15, 2004 cancerres.aacrjournals... A logical hypothesis to explain how an immunotherapy such as Provenge, can fail to cause the regression of an established tumor, and yet increase overall survival is that it may slow or stop cancer metastases by destroying targeted cancer cells in the bloodstream that are shed by an established tumor and are relatively unprotected by regulatory T cells. When Taxotere or some other post-conditioning agent depletes regulatory T cells, some tumor regression should result until and unless too much or too long administration of Taxotere also depletes attacking CD8 effectors T cells. At that point a Provenge booster may be given to initiate a further sequence of tumor destruction. While only a logical hypothesis, this would explain Provenge’s method of action far more plausibly than proposed methods of action, or absence thereof, for many drugs on the market today.

Dr. Scher raises question concerning the safety of Provenge and of his own Committee meeting vote on safety by making irrelevant and somewhat absurd comparisons to the cardiovascular side effects of chemotherapies while not addressing Dendreon’s direct statements regarding Provenge safety. The safety issue is not the cardiovascular side effects of Taxotere or of DN-101, which Dr, Scher discusses, but the safety of Provenge. At the Committee meeting, Dendreon’s Dr. Frohlich responded to the safety question by pointing out that there were no CVA’s in the ADPC Provenge treated patients (P16, 9906 and P11), there were no CVA’s in the 3 months following Provenge dosing for men who experienced CVA’s, and that reference to a large database of men with similar advanced cancer indicated that there was nothing extraordinary about the Provenge CVA rate. Dr. Frohlich then described the proposed FDA / DNDN 3,000 patient monitoring plan for CVA’s in men treated with Provenge. That obviously satisfied the Committee on the safety issue leading to a 17 to 0 vote, If Dr. Scher has problems with any of the Sponsor’s comments, he should discuss those comments as they deal with Provenge safety and not digress to safety issues in two unrelated chemotherapy trials.

Scher’s letter concludes with a warning regarding the far reaching implications of any FDA approval of Provengen: “For one, it provides the Agency’s endorsement of Sipuleucel-T as a “standard of care” treatment for asymptomatic androgen independent (castration resistant) disease that represents upwards of 45,000 men in the US. The second is that by extension its elevates Sipuleucel-T 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. It also opens the door to the premature approval of drugs based on inconclusive data”.
“The “standard of care” designation comes with ethical and possible legal implications for doctors. Marketing data makes it clear that far fewer AIPC / HRPC patients choose to take the only standard of care presently FDA approved that extends survival, Taxotere, than its is indicated for, reportedly due to the side effects patients experience over its 7 month course of therapy. Taxotere’s pivotal Phase 3 TAX327 trial showed only a 2.4-month increase in median survival. If the FDA approves Provenge doctors would be expected to fully discuss treatment options to this dying AIPC/HRPC patient population with explanations of what clinical trials for various FDA approved therapies demonstrated, may have demonstrated, and did not demonstrate, and even, perhaps, to ask for signed acknowledgments that they were given this information before making a therapy choice. What a revolutionary idea! Doctors would actually give a dying man the best available information about his disease, and allow him to make his own informed decision after consulting, if he chooses, with one or more doctors. How would most asymptomatic AIPC / HRPC patients respond to a question as to whether or not they would consider a three dose course of Provenge, if: (a) the side effects were much like 3 flu shots and were generally resolved within a couple of days; (b) the chances of being alive three years hence would double or triple, (c) there was a possibility, however, that the risk of stroke might increase by about 1% over that period of time, and, (d) if Provenge is chosen, a later choice to take some Taxotere, or other taxane, and a possible Provenge booster might further increase survival substantially?

The FDA can make decisions with sponsors of new trials of experimental drugs or therapies in AIPC / HRPC, as to whether the use of Provenge treated patients in a control arm would be appropriate pending completion and analysis of the 9902b Provenge Phase 3 confirmatory trial. Sponsors of future trials may have reason to be concerned and potentially have a high bar to overcome if, when, and subsequent to, Dr. Petrylak introducing the sequencing of Provenge, then limited Taxotere or other taxane, then a Provenge booster into a FDA Phase 3 pivotal trial. AIPC / HRPC patients and their families may benefit enormously, but competitive therapies may indeed suffer.

The March 3, 2005 ODAC meeting dealt with the issue of clinical trial endpoints in prostate cancer, in part, because there have been so few that have received FDA approval in a cancer where there is a significant unmet need. A slide presentation to ODAC listed four therapies approved by the FDA: (a) Taxotere (docetaxel) approved in 2004 for increased survival; (b) Zoledronic Acid approved in 2003 for QOL; (c) Mitoxantrone approved in 1996 for QOL; and (d) Estramustine approved in 1981 under the “Old Rules”. It is disheartening to think that so few therapies have been tested in clinical trials and approved by the FDA for such a large population of critically ill men. ODAC gave a recommendation to the FDA during its March 3, 2005 meeting that survival should be the primary end point in all AIPC /HRPC trials. It is disheartening to see an oncologist, as distinguished as Dr. Scher, use a scientifically outdated analysis of Time to Progression, a proposed surrogate for survival to argue against an intelligent analysis of survival, and then failing that, to criticize the Provenge trials as too small, when comparison of the Provenge trials to the FDA approval of Mitoxantrone in AIPC /and HRPC, and the actual survival of Provenge treated patients compared to that predicted by an 1100 patient reference control group in the Halabi study strongly support the finding of substantial evidence of efficacy.

In retrospect, with what we now know about the measurement and analysis of increased Time to Progression in therapeutic cancer vaccines, Provenge theoretically could have filed its BLA and received FDA Accelerated Approval in 2002, and continued with the data collection and analysis of 36 month survival data to receive Regular Approval. Time has long since passed when this valuable new tool in the treatment of prostate cancer should be made available to all AIPC/ HRPC patients.

For all of the above reasons, but most of all for the benefit of all present and future prostate cancer patients and their families, we urge the FDA to approve the Biologics License Application submitted by Dendreon Corporation for Provenge (Sipuleucel-T).

Very truly yours,




Exhibit 1.—Text of Dr. Scher’s vote on efficacy

The following discussion took place after a round of voting on safety of Provenge (unanimous Yes) took place. The discussion below and reference to two questions are regarding efficacy, the original question was regarding the efficacy was established. The question was revised into a second question of “substantial evidence”. Due to quality of audio transmission the text below is deemed “complete and accurate to better than 95% of the transcript” by the transcriber.

Dr. Mulé - Dr. Scher?

Dr. Scher -
I think is complete and accurate to better than 95% of the transcript of Scher's vote on efficacy.

I think we are really poised at the beginning of what will be hopefully an outstanding era of immunotherapy. I think there is sufficient evidence demonstrated which justifies the definitive study, and I would say there are investors in that who concur. But I think it does not meet the … umm … as the question was phrased, to establish the efficacy, I think this is still an open question.

M - So I take I you’re saying “yes” with these provisos?

S. You have two questions, I would say yes to one, no to the second.

Pausing, murmuring laughter and confusion in the room.

S - If the question is posed as “establish”, I say “no”.

M - No, its, uh, “substantial evidence”.

S - No.

M - No.



Exhibit 2.—Extract from Dr. Scher’s Conflict of Interest Waver

DATE: February 7, 2007

FROM: William Freas, Ph.D., Director, Division of Scientific Advisors and Consultants, CBER

SUBJECT: 208(b)(3) Conflict of Interest Waiver for Howard I. Scher, M.D.

TO: Randall Lutter, Ph.D., Associate Commissioner for Policy and Planning

Through: Vince Tolino, Director, Ethics and Integrity Staff, Division of Management Programs, OM




Dr. Scher advised the GDA that he has a financial interest related to the above topic that could potentially be affected by his participation in the matter at issue. Dr. Scher reported that he has joint stock in (DELETED) at a current value of (DELETED). Additionally he reported that his institution has a grant from (DELETED) (competing firm). The grant is current and his institution receives (DELETED) per year from 2006-07. Dr. Scher receives no salary from the grant. The grant is to study a licensed, approved drug (DELETED) in prostate cancer trials. (DELETED) is a licensed drug currently used in other cancer therapies. Dr. Scher also reported that his institution has a grant from (DELETED) (competing firm). The grant is current and his institution receives (DELETED) per year from 2006-2008. Dr. Scher receives no salary from the grant. The grant is to study an investigational drug (DELETED) that is also being studied in several types of cancer. It is unlikely that Dr. Scher's participation in the discussions on March 29 of a cellular therapy for prostate cancer will have a direct and predictable effect on his financial interest.

2007 Apr 19 04:33 PM

[hpski:]

I have previously posted a comment to PharmaTracker's presentation of Dr. Scher's letter, which, I believe dovetails with Dorotie97's collaborative discussion. I would like to build upon Dorotie97's fourth paragraph, "To begin with, one must ask why an expert invited by the FDA as a “special Federal employee” with expert knowledge in the given field....chooses to question the outcome of the Committee’s recommendation, including his own vote on Safety, after the fact. Absent new material information, Committee members, if no one else, should respect the fairness of the process and the final vote of the Committee", with an historical perspective, the words of a forward looking 14th century surgeon, John of Arderne:

Born circa 1308, John of Arderne practiced as a surgeon in Nottinghamshire and London. He is said to have developed his skills as a military surgeon during the 100 Years War. The evidence suggests that he traveled abroad, and his writings indicate that he was man of wide experiences. He wrote in Latin, and had read many of the scholastic authors closely, quoting extensively Galen, Guy of Chauliac, Avicenna, and Dioscorides. Having lived & practiced medicine through the great plague epidemic of 1347-51, his fame rests on a number of medical works that he produced towards the end of his life in the 1370s. His great advance at the time was to avoid the corrosive after-care treatment used by other practitioners; a great believer in cleanliness, Arderne counseled against overly meddling with wounds and dressings, thereby aiding the healing process. His thorough knowledge of the medical uses of herbs and plants is well documented, and he was fully aware of the effects of the mind on the body in sickness and health. Excerpted below from one of his many surviving manuscripts is his discussion of standards of deportment that all physicians should follow, as it CURRENTLY applies to the public display of antipathy by a high profile COI physician towards Provenge marketing approval:

“...And he be courteous at the Lord’s table, and he be not displeasing in words or deeds to the guests sitting nearby, hear he many things but let him speak but few…And when he shall speak let the words be short, and as far as possible, fair and reasonable…Beware that there never be found double words in his mouth, for if he be found true in his words few or none shall doubt his deeds”.

Arderne was way ahead of his time, maybe even ours, as evidenced by a tiny minority of contemporary physician(s) who make the mistake of thinking their titles and standings make them beyond reproach and outside Government agency S.O.P. More to the point, even during the middle ages, Arderne and a few other exquisitely learned, multilingual physicians, writing in Latin, were attempting to describe standards of professional behavior amongst their peers. Perhaps if Dr. Scher had reviewed and/or revered Arderne’s treatise for his professional progeny, he might have thought twice about having his dissent published in a non-peer reviewed throwaway publication.

2007 May 04 06:33 PM

[donny:]

Doesn't this contribution constitute plagiarism? The exact same words were disseminated a few days ago. I am glad to see that Seeking Alpha had the contributor's blatantly misleading statement about Gold selling all his shares corrected. I am disappointed that someone who is supposed to be able to write as intelligently as PharmaTracker would fail to do the math to determine that Gold exercised options and sold some shares. Then again, maybe this is just a copy/paste job from someone else's work earlier.

After all, today is options expiration day. Anyone short this stock likely is using options at this point since DNDN is on the Regulation SHO list.

2007 Apr 20 08:23 AM

[mdnacb:]

In reply to PharmaTracker's Blog:
Since an advisory committee voted strongly in favor of Provenge, Dendreon’s (DNDN) shares have increased to almost 300% from its lows of late. Sending Shorts into an all out War on Dendreon. Posting and placing false news reports which later were forced to be retracted.
Based on the Advisory Commitee's positive decisions for Provenge: Safety a 17-0 "Yes Vote" and on Efficacy a "Yes Vote" of 13-4 ,the FDA rarely goes against its advisory committee’s opinion, I am looking forward to seeing an Approval from the FDA on Provenge.
The key for cancer patients is survival and quality of life. Provenge is being tested in very sick cancer patients with positive results and for these cancer patients survival is as important as efficacy. There are many doubters who will twist and tweek the truth of Provenge saying it failed to meet its primary endpoints , a point of which will be used in an attempt to continue to short the stock.
I have had to stand on the sidelines and watch many of my family die from cancer and be tortured by Chemo. My elder Brother passed just over a year ago, Two Aunts less than a year ago(one resided with me and refused chemo having seen what it had done to other family members), My Sisters, Identical Twins died from similar cancers, one at the age of thirty and the other at Forty, Another Aunt, Three Uncles and my father to cancer related complications.
Now science is moving toward a New revolutionary way of Treating and Fighting cancer. Some of The Old Guards of Chemo-Mentality will have great difficulty moving away from their safety blanket(Chemo) and towards the New Immunotherapies coming into Mainstream Medicine. I can only assume based on Dr. Schers letter that he is holding on to his "Safety Blanket".

Disclosure: Author has a long position in DNDN and CELG

2007 Apr 20 09:28 AM

[hpski:]

Thank you, PharmaTracker, for posting this letter. There are a few aspects of its content I would like to address. Specific sections of Dr. Scher’s correspondence are pasted below, followed by my comments. I have not taken the time to access the actual publication for verification of the doctor’s remarks, trusting the poster to have presented it in its entirety. My comments are not intended to personalize these issues and certainly not intended to challenge Dr. Scher’s exquisite record of accomplishment and valued contributions to this process.


“I have been one of the Academic Leaders of the Prostate Cancer Clinical Trial Endpoints initiative begun under the joint Sponsorship of the FDA, AACR, ASCO and PCF in 2004, which were presented at the February 2007, Prostate ASCO Meeting in Orlando”. Tell FDA something they don’t know. Why does Dr. Scher go out of his way to build himself up to an agency that is well acquainted with his academic status?


“This, and the Sponsor’s recognition that an additional prospective study was needed, mandates deferring any decision on whether an approval should be granted until the results of the ongoing 500 patient phase 3 trial that is powered on a primary endpoint of survival, is accrued and analyzed”. Mandates? Should FDA, in consideration of his minority opinion, merged with his status as chief of genitourinary at MSKCC, make Dr. Scher their defacto reviewer of all immunotherapy BLA’s for prostate cancer?


“Concerns about the validity of the findings were reinforced by the absence of other signals of an antitumor effect. Specifically there were no data provided of a favorable effect on PSA, regression or stabilization of soft-tissue or boney disease radiographically, health related quality of life, or that administration of the product delayed the development of pain”. Dr. Scher recently reported, in December 2006, on, “ Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials”. The abstract he co-authored, below, suggests that PSA is not a reliable representation of treatment success or failure;

Fleming MT, Morris MJ, Heller G, Scher HI.
Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancer, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
To the investigator and clinician, prostate-specific antigen (PSA) level is a seemingly perfect outcome measure because it is easily assessable, quantitative, reproducible, and inexpensive. Whether post-therapy decline in PSA reflects true clinical benefit, and whether post-therapy declines can be used, as an intermediate endpoint for accelerated drug approval is still open to question. At present, no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Post-therapy PSA changes have been associated with improved survival in patients with castrate metastatic disease. The role of PSA changes as potential surrogates of clinical benefit have only been explored to a limited degree because to date, only two prospective randomized trials showing a survival benefit have been reported. Such trials are necessary, but not a sufficient pre-requisite to explore the potential role of any outcome measure as an intermediate endpoint. The clear demonstration that a post-therapy PSA change can account for all of the treatment effects seen is not yet available. A cytotoxic drug that does not produce any PSA decline is unlikely to be effective, but the converse is not always true because not all PSA rises represent a treatment failure. It is important to recognize that there are a range of clinical benefits to patients that can improve the quality and possibly the duration of survival, independent of PSA.


Boney disease? How realistic is it to expect any treatment approach, other than palliation, usually in the form of biophosphomates, to arrest bone infiltrates? For example, oncologists are certainly aware that, “in patients with hormone-refractory prostate cancer and bone metastases, zoledronic acid is the only bisphosphonate indicated for the prevention of skeletal complications. In conclusion, patients with prostate cancer are at high risk for skeletal morbidity”. (Clin Genitourin Cancer. 2006 Mar;4(4):257-62). When metastatic prostate cells are already present in the bone microenvironment, researchers have shown that transactivation of the alpha-platelet-derived growth factor receptor may provide select prostate phenotypes with a growth advantage. I submit that being disappointed in Sipuleucel T’s impact on radiographically proven boney disease is akin to being disappointed that the Sorceror’s Apprentice couldn’t keep up with his rapidly flooding basement.

Again, I’m sure Dr. Scher will agree that, “quality of life” in this studied population is another, “Sorcerer’s Apprentice” issue, since medical castration and/or radiotherapy reeks havoc with libido, bowel function, etc. So, IMO, a patient’s already dismal quality of life is iatrogenic (graviora quaedam sunt remedia periculis ). Thus at this stage, it is not realistic to expect a specific immune system boost to provide an objective improvement in this parameter, in my opinion.


“Consequently, the only conclusion that can be reached is that the survival difference observed may have occurred by chance alone, and that the results do not support an approval recommendation”. While Dr. Scher’s interpretation of the data, which by definition is solicited, respected and a welcomed part of the approval process, venturing it as the final word, a reverse, “fait d’accompli”, if you will, most likely is not welcomed by FDA in such a high profile format. Hopefully most of us in this industry are aware of the dangers of, “circulus in probando”. Certainly no one is “immune” to this time honored disease, which appears to be transfecting many researchers and investors these days.

Finally, it’s been my experience that the drug development process is more than about the science, more than about saving & improving lives – it’s often about alliances of interest, and by necessity, politics, internecine rivalries, about competition for research grants, unrestricted educational grants. There’s that magical time of year when all department chairmen/women are in, “grant Hell”, initiating and assessing requests, working with budgets, egos, etc. I have seen firsthand what happens when a relationship between an individual/group within medical academia falls out of bed with a biopharmaceutical company, or never gets off the ground in the first place. Everyone reacts differently, but some take a more proactive stance. I submit that there are life saving oncology products not on the market, as well as glorified placebos currently marketed; the, “no love lost”, offspring of the above intangibles.

I am long DNDN, CELG, and OMRI

2007 Apr 21 12:12 PM