This is the text of Howard Scher M.D.'s letter to FDA about the March 29th advisory committee hearing on Dendreon's vaccine Sipuleucel-T (Provenge):
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. The final manuscript is currently under review at the NCI, FDA and the Group of established Prostate Cancer Clinical Trial experts who together, formulated the recommendations. I am also the Principal Investigator of a Multicenter Prostate Cancer Clinical Trials Consortium funded by the Department of Defense that focuses on phase 1 and 2 trials in this disease.
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, the results 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.
There were also methodologic concerns. Trial 9901 was designed to show an increase in time to disease progression from 16 weeks for placebo treated to 31 weeks for Sipleucel-T treated patients (HR = 1.92, alpha =0.05, two sided, with 80% power). A total of 127 patients were enrolled using a 2:1 randomization in favor of the experimental therapy. The study was double blind and included an independent review of all imaging results. The estimated time to progression on which the trial was powered proved to an overestimate, as the actual observed median time to progression was 9 to 11 weeks for both arms: a difference that was not statistically significant. A summary of the progression events showed that 90% (97/114) were by imaging, 10 were clinical, and 7 were for the new onset of disease related pain. Unrecognized at the time of the design of the trial, was that 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 led to trial entry, and not a failure of the treatment.(CCR 13:1488, 2007) This is similar to what was observed in the trial with the endothelin antagonist, atrasentan, in which a 12 week disease assessment interval was used and a large proportion of patients were withdrawn at the time of scheduled scans in the absence of clinical worsening of disease (ODAC, September 13, 2005). Recognizing this, the Prostate Cancer Working Group 2 was 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, (Abstract #221) February 22-24, 2007, Orlando, FL, 2007). Although the Sponsor suggested that the effect of the product was delayed, this hypothesis could not be explored because serial imaging to assess disease at defined intervals were not performed once a patient was considered to have "progressed" and taken off study. As a result, individual sites of disease were no longer being monitored, so that no statements could be made regarding a possible "delayed effect"of the product on disease status.
At 3-years, a prespecified survival analysis was performed which showed a 4.5 month difference in median survival favoring Sipuleucel-T, and while a significant p-value for the difference was determined, the type 1 error rate is surely inflated by this additional analysis. 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. The 2:1 randomization increased the power of the experimental arm, but it may have inadvertently made the small 43 patient control group more heterogeneous and less representative of the global population of men for whom the indication was proposed. The potential impact of heterogeneity in small patient cohorts was shown when a post-study change in the progression times of two patients (a change not accepted by the Agency), resulted in a change in the significance estimates.
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. This concern was based on the finding that 4.9% (17/345) of the Sipuleucel-T and 1.7% (3/172) of "placebo" treated patients who were enrolled on randomized trials for the indication, experienced a cerebrovascular event (p=0.092). The odds ratio for developing a cerebrovascular event was 2.92, with wide confidence intervals (0.82 to as high as 10 fold). Deaths due to CVA's were recorded in 1.5% of Sipuleucel-T patients and 0.9% of those receiving "placebo." Unclear is why there is no mention of CVA's in the published report of the study in the Journal of Clinical Oncology (JCO 24:3089, 2006). Given that the product is released for administration based on the increase in the proportion of CD54+ cells and not the absolute number of any particular cell type and that CD54+ cells actually represent only 20% of the final product, the contribution of the other cell populations and cytokines that may be present in the administered product on the development of a cerebrovascular event is not known. 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. 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). Neurologic events that were not detailed further were observed in 7% of the 338 patients who received estramustine which is known to be thrombogenic, in combination with docetaxel on the SWOG 99-16 trial (NEJM 351:1513, 2004).
Another concern is that the requirements for regulatory approval appear to differ between the ODAC and CBER Advisory Committee. As an example, ASCENT1 was a prospective randomized phase 2 trial of weekly docetaxel with or without high dose calcitriol (DN-101). The trial was powered to detect a 20% difference in the PSA response rate at six months between the two groups as the primary endpoint, but also included a pre-specified survival analysis, similar to that included in the Sipuleucel-T 9901 trial as one of the secondary endpoints. PSA response was defined as a 50% or greater decline from baseline according to Consensus Criteria (JCO 17:3461, 1999). 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< .16), yet here too, the pre-specified survival analysis showed a difference for docetaxel plus DN-101 vs. docetaxel plus placebo: median not reached but estimated to be 24.5 months vs. 16.4 months respectively with a hazard ratio for death of 0.67 (p=0.04)(JCO 25:669-74, 2007). The safety of the combination was no worse and perhaps better than docetaxel alone. Appropriately in my view, the results were not considered definitive by ODAC, no approval filing was made, and a new 900 patient phase 3 trial powered to test the hypothesis whether the combination of docetaxel in combination with DN-101 conferred a survival advantage relative to docetaxel alone was designed, initiated and continues to accrue. I am the International Principal Investigator on this trial. Contrast this with the regulatory filing history of Sipuleucel-T where the primary endpoint of the registration trial was also not met, yet, it is being considered for approval based on a similar post-hoc analysis with roughly half the total number of patients, and a control arm that is roughly one third the size. Why do the Sipuleucel-T results establish efficacy, while the DN-101 results do not? An approval recommendation has far reaching implications beyond making the product available that the data simply do not support or justify. For one, it provides the Agency's endorsement of Sipuleucel-T as a "standard of care" treatment for an asymptomatic population of men with androgen independent (castration resistant) disease that represents upwards of 45,000 men in the U.S. The second is that by extension, it 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. 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.
The above letter is reprinted from The Cancer Letter, Vol. 33 No. 14 April 13, 2007.