There was ample of evidence of survival benefit conferred by Provenge as a treatment in contrast to Dr. Pazdur’s statement: “Believe me, if there were a clear survival effect, the drug would be approved,”. In fact, Dr. Pazdur’s focus on the statistical flaws showed that the main problem in the FDA drug approval process as practiced by Dr. Pazdur is a slavish following of rigid statistical rules without properly factoring in clinical knowledge required to give meaning to such numerical data.

The irony is that FDA has a process to incorporate clinical knowledge into drug evaluation. Advisory Committees made up of world-class experts are often convened to discuss clinical data and provide advices to the FDA  during the evaluation of drugs up for approval. The AC convened to consider Provenge voted 17-0 that the drug was safe and 13-4 that there was substantial evidence that it was effective. When Dr. Pazdur helped rejecting Provenge, he effectively ignored that body of knowledge. He showed himself to be not only a slave to simple statistical calculations but also one who cared little for the scientific process and the needs of desperate patients.

For Provenge, the clinical data were:

1. D9901, a phase 3 trial enrolling 127 patients, whose primary endpoint, Time To Progression, barely missed statistical significance with p-value .052 and Overall Survival was highly significant with p-value .01. The survival rates at three years were 1 in 3 for patients treated with Provenge compared to 1 in 9 for patients treated with placebo. Per several sensitivity analysis performed by the FDA statisticians themselves, this trial was well run, the data self-consistent and the survival benefit unlikely to be spurious.
2. D9902a, a smaller phase 3 trial enrolling 98 patients, missed statistical significance for both TTP and OS. Again, per analysis done by FDA statisticians, this trial unfortunately enrolled much sicker patients on the treatment arm than on the control arm. This imbalance meant that patients on the treatment arm died faster without any intervention and that stipulated the miss of statistical significance. However, after three years, even with such a disadvantage, Provenge stopped the disease in time to again save 1 in 3 patients on the treatment arm compared to 1 in 5 on the placebo arm.
3. The Hazard Ratio is a common measure of comparative risks of death between two treatments. The D9901 trial exhibited an HR of 0.58 meaning that patients on the treatment arm had 42% survival advantage over patients on the placebo arm. The D9902a trial exhibited an HR of 0.76 or a 24% survival advantage for treated patients.
4. Patients in D9902a were much sicker than D9901 and more similar to the patients enrolled in the TAX327 trial that led to the FDA’s approval of the chemotherapy Taxotere as the current Standard Of Care for prostate cancer. The HR for TAX327 was also 0.76 comparable to D9902a.
5. Another Taxotere phase 3 trial, SWOG99-16, showed a worse HR of 0.80. At three year, less than 1 in 5 treated patients were still alive. After four years, all passed away. There are patients treated with Provenge still living today after six to seven years.
6. Placebo patients in the Provenge trials were allowed to cross over to take a form of Provenge made from their cryo-preserved blood. Of the 12 out of 78 patients on the placebo arms of the Provenge trials D9901 and D9902a who survived past three years, only two did not cross over. The cross-over protocol was there for compassionate reason. But without it, the survival benefit of Provenge over non-treatment would have been much clearer in the statistical sense

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Provenge Science Overview provenge-science-overview.pdf

Scientific Publications http://www.dendreon.com/dndn/publications

Active Cellular Immunotherapy http://www.dendreon.com/dndn/pipaci

3/3/08 — Dendreon Publishes Manuscript on CD54 as a Surrogate Marker of Antigen Presenting Cell Activation

2/14/2008 — Dendreon Presents Data Correlating the Cumulative Potency of PROVENGE® to Overall Survival

1/2008 Nature Biotechnology 26, 1 (2008)Editorial: The regulator disapproves Abstract (click this link)
Pressure is mounting on the US Food and Drug Administration (FDA) to explain its decision to ignore an advisory committee’s positive recommendation for the cancer vaccine Provenge.

8/19/2007 — Dendreon Announces Publication of Phase 1 Study Highlighting Immunologic and Clinical Activity of Lapuleucel-T (Neuvenge(R)) in Advanced Breast Cancer Patients

7/1/2007 Dr. Jeffrey Schlom — http://clincancerres.aacrjournals.org/cgi/content/abstract/13/13/3776
Cancer Vaccines: Moving Beyond Current Paradigms
Jeffrey Schlom, Philip M. Arlen and James L. Gulley
Authors’ Affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
Requests for reprints: Jeffrey Schlom, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Room 8B09, 10 Center Drive, Bethesda, MD 20892. Phone: 301-496-4343; Fax: 301-496-2756; E-mail: js141c@nih.gov.
“In the randomized multicenter Sipuleucel study described above, patients in both the vaccine arm (n = 51) and placebo arm (n = 31) went on to receive docetaxel at progression. There was a striking and statistically significant (hazard ratio, 1.90; P = 0.023) increase in overall survival with docetaxel treatment in patients having had prior vaccine versus placebo (Fig. 4).”

A placebo-controlled randomized phase III trial in patients with metastatic asymptomatic androgen-independent prostate cancer using Sipuleucel-T has been reported recently (19). Patients were randomly assigned in a 2:1 ratio to receive vaccine (n = 82) or placebo (n = 45). The primary end point of this study, which was progression-free survival, did not achieve statistical significance (P = 0.052; Fig. 1A). Overall survival, however, was statistically significant (hazard ratio, 1.70; P = 0.01) between vaccine (25.9 months) versus placebo (21.4 months; Fig. 1B). A second randomized trial with Sipuleucel-T in this patient population showed a trend toward increased survival (19 months for vaccine versus 15.7 months for placebo) that did not reach statistical significance. Thirtysix- month survival was 32% for vaccine-treated patients versus 21% for placebo-treated patients. The integrated analysis of both of these randomized trials, vaccine (n = 147) versus placebo (n = 78), showed a statistically significant increase in overall survival (hazard ratio, 1.5; P = 0.011) in vaccine-treated patients. Thirty-six-month survival was 15% for placebo and 33% for vaccine.”

5/20/2007 — Dendreon Announces Presentation of Data at American Urological Association Annual Meeting — Data May Support Use of Provenge as Front-line Treatment in Advanced Prostate Cancer

The abstract, titled “Advanced prostate cancer Patients who Receive Sipuleucel-T followed by Docetaxel Have Prolonged Survival” (#605), authored by Daniel P. Petrylak, M.D., associate professor of medicine at New York- Presbyterian Hospital at the Medical Center, is based on an exploratory analysis conducted to assess the influence of the active cellular immunotherapy PROVENGE on the clinical outcome of patients who subsequently went on to receive docetaxel chemotherapy after primary treatment with PROVENGE. The analysis was conducted by evaluating data from two Phase 3 clinical trials of PROVENGE in patient with asymptomatic, metastatic, androgen-independent prostate cancer (AIPC).

“The results of this analysis suggest that the use of sipuleucel-T as a first-line treatment followed by the chemotherapy docetaxel upon disease progression may provide patients with a substantially prolonged survival benefit,” said Dr. Petrylak. “This analysis provides valuable clinical insight as to how the treatment of men with advanced prostate cancer will likely evolve with the potential introduction of new products like sipuleucel- T that complement the currently available treatment regimens for men with advanced prostate cancer.”

2/9/06 — Potency Testing for an Autologous Cellular Immunotherapy — Nicole Provost, PhD VP Product Development — Dendreon Corporation — Click here to Download FDA Powerpoint Presentation — www.fda.gov/OHRMS/DOCKETS/ac/06/slides/2006-4205S1_7.ppt

7/1/05 — Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3089-3094
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.04.5252

7/1/2005 — Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer

Eric J. Small, Paul F. Schellhammer, Celestia S. Higano, Charles H. Redfern, John J. Nemunaitis, Frank H. Valone, Suleman S. Verjee, Lori A. Jones, Robert M. Hershberg http://jco.ascopubs.org/cgi/content/full/24/19/3089

David Miller of Biotech Research Rebuttal to Dr. Howard Scher’s “Leaked” Cancer Letter (click this link)

Walldiver & Company’s Rebuttal To Scher’s “Leaked” Cancer Letter (click this link)

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