Last Thursday, March 29, 2007, I had the opportunity to participate as a patient advocate in the FDA’s Tissue, and Gene Therapies Advisory Committee. The purpose of the committee meeting was to evaluate the application of Dendreon Corp for approval of their new drug, Sipuleucel-T (Provenge).
I want to clarify the facts and dispel some of the rumors about Provenge. I also will share my experience and feelings as an active patient advocate at the committee meeting.
WHAT IS PROVENGE
Provenge has been receiving a huge amount of attention from the general press, the scientific community and from the prostate cancer community. This extraordinary interest is due to the fact that, if approved, Provenge would be the first and only therapeutic immunological vaccine approved by the FDA.
First and most important, I want to clarify that Provenge is NOT a cure for prostate cancer (PC) as some people believe. It is a treatment that has shown the possibility of providing advanced prostate cancer (APC) survivors the ability to extend their life with minimal side effects while maintaining their quality of life (QOL).
Currently, once an advanced prostate cancer (APC) survivor becomes hormone refractory (HR) there remains only one additional nonpalliative therapy approved by the FDA. Chemotherapy with docetaxel, also called Taxotere, brings with it major negative side effects, but does provide life extension of an average of 2.5 months. However, many men elect to completely forgo Taxotere in order to preserve their QOL, or fail to complete the full course of treatment because of the significant negative side effects.
Provenge, if approved, could be used at the point that Taxotere is currently prescribed. If it works, it could extend life for an average of 4.5 months with a minimum of side effects. There has been some additional research which demonstrates that Provenge combined with Taxotere can extend life for an average of fifteen months.
WHAT ARE THE SIDE EFFECTS
The side effects of Provenge seemed to be limited to flu like symptoms, which are experienced by patients after the infusion, have duration of one to two days and are grade 1 or 2 (not requiring hospitalization). These side effects include chills, fever, headache, weakness, nausea, vomiting and shortness of breath. About 98.6% of the subjects who received Provenge during the clinical trials experienced some of the side effects.
There is also some evidence that there is a small, but not statistically significant, increase in the risk for a cardiovascular event.
WHAT MAKES PROVENGE DIFFERENT
Cancer vaccines are designed to treat existing cancers (therapeutic vaccines) or to prevent cancers form developing (prophylactic vaccines).
Provenge is an example of a therapeutic vaccine, as it is administered to people who are already fighting advanced prostate cancer. Prior to treatment, the prostate cancer tumor is not recognized as being a foreign body, and so the immune system fails to mount an attack on the tumor. The vaccine is designed to stimulate the person’s own immune system so that it identifies a prostate cancer tumor as being a foreign body and launches an attack on the cancer.
The administration of Provenge requires three separate infusions, each about two weeks apart. Two to three days prior to each infusion the patient must go through a process called apheresis in which white blood cells are harvested. The apheresis process takes several hours to complete and some people report it to be unpleasant. The cells are then shipped to a laboratory where they undergo a manufacturing process that places an antigen on to the surface of the white blood cells. This antigen is designed to identify and target PAP (prostatic acid phosphatase), an enzyme that is expressed on 90% of all prostate cancer tumors, as a foreign body, causing the immune system to launch an attack against the tumors.
Currently, there are only two prophylactic cancer vaccines approved by the FDA. These vaccines are designed to prevent virus infections that can cause cancers — the hepatitis B vaccine (liver cancer) and the human papilloma virus (cervical cancer) vaccine.
There are no approved therapeutic vaccines, so if the FDA approves Provenge, it will be the first one licensed. However, several other therapeutic vaccines are in large scale clinical trials for many different cancers.
STATISTICAL PROBLEMS WITH THE CLINICAL TRIALS
There were a number of statistical issues with the clinical trials of Provenge. There were two separate trials involving men with hormone refractory but asymptomatic recurrent PC. Both trials had very small sample sizes (trial 1, n=127 subjects, and trial 2, n=98 subjects) and both used as a primary endpoint the time to disease progression. Neither trial reached a statistical significance as to this end point.
However, a retrospective analysis of the data did show that there was in the first study a statistically significant difference for survival time (4.5 month) between the treatment group and the placebo group. The second clinical trial was terminated early, had an even smaller sample size, and did not show a significant difference between the two groups as to the primary endpoint of time to disease progression or to the overall survival time (3.3 month overall survival difference).
As already indicated, in the first trial the overall survival time was statistically significant. However, since the sample size was small (n=127), a number of the committee members expressed concern that a different outcome of just one or two patients would have yielded entirely different statistical results.
In addition, I was bothered by the fact that the placebo group in study 2 had a longer survival time then did the treatment group in trial 1.
The racial composition of the first trial was about 90% Caucasian and in the second trial the Caucasian population was slightly higher. This raises the question of whether inferences drawn from the trials can be generalized to the broad population. This is a particularly significant issue as a higher percentage of African-Americans get prostate cancer as compared to the Caucasian population, and prostate cancer in African-American men tends to be more virulent.
THE ROLE OF PATIENT ADVOCATES
After I decided to go to the committee meeting and provide testimony, I spent some time writing what I wished to share with the committee. A few days prior to the committee meeting I thought about not testifying. Going there would require that I lose a day and a half of work, cost the price of a hotel room and four meals and require that I drive for six hours to get to the meeting and six hours to return home. Why would I want to do this? I assumed that the committee really couldn’t care what I had to say. The decision would be based on the science and on the statistics. Public comment was to appease the public and nothing more. So why waste the time and money?
I soon found out that I was very wrong. About fifteen patient advocates took advantage of the opportunity and spoke to the committee. Each of the presentations told a story about the speakerâ€™s personal journey or that of a husband, father or grandfather. They were all moving, and reflected the desperation that so many of us with advanced prostate cancer feel. As each advocate spoke, the committee members paid great attention, many of them leaning forward in their seats as they listened to each individual’s presentation. In one instance I thought I saw a tear wiped from someone’s eye.
The proof of the pudding came as the meeting was drawing to a close and the final voting began. All committee members voted without much comment that Provenge is reasonably safe for the intended population. Many committee members did expressed concern about the potential for a cardiovascular event and urged continued monitoring of this problem.
When they came to the final question, “Does the submitted data establish the efficacy of Sipuleucel-T (Provenge)?” the result was different. The first three committee members all voted no, but all of them went on to qualify their votes. The members struggled, as it was very clear they wanted very much to vote yes. Their explanations for how they voted more like an apology to those of us who had testified and as an expression of their feelings of concern that there isn’t any good alternatives to treat patients with advanced prostate cancer. Many of their comments reflected the concerns and thoughts that had been raised by the patient advocates. In some cases, we actually heard parts of our stories repeated back to us.
After the third committee member went through his very uncomfortable explanation, the committee chair, Dr. James J. Mule, stopped the voting process and addressed the members of the FDA who were present. He requested that they reconsider the wording of the question, as all of the committee members who had spoken indicated they did feel that there was a strong suggestion that Provenge did in fact extend life.
The FDA responded that they could not change the question, as this was a standard in all evaluations.
The next committee member again voted no, but with all the twists and turns that had already been expressed by the prior members. After this vote, the FDA stopped the process and changed the question for the committee to evaluate. The question was modified to whether or not the data submitted demonstrated substantial evidence that Provenge contributed to the extension of life (as opposed to establish the efficacy of the treatment).
The voting recommenced with the final vote of 13 to 4 in support of affirming the changed question! This was a historic vote that took a tremendous amount of courage from the individual committee members. I salute those members who voted in the positive, as they understood the nature and ramifications of the vote.
This vote not only offers hope to advanced prostate cancer survivors, but it will encourage the many biotech and drug companies that were in attendance observing the committee procedures. These companies are involved in developing additional vaccine treatments not only for prostate cancer, but also for other cancers. Since I also have kidney cancer, I have already been invited by one biotech group to meet with them and discuss advocacy issues.
The Cellular, Tissue and Gene Committee is only an advisory committee to the FDA, which has agreed to fast track their final decision. They will make their decision whether or not to approve and license Provenge by May 15. Most of the time, the FDA goes along with the advisory committee’s recommendation; however, they are not required to agree with the committee recommendation. Only time will determine what their ultimate decision will be.
Not everyone is in agreement that Provenge should be approved. The committee members who voted in the negative expressed the concern that the clinical trials did not establish that Provenge actually provided any real survival benefit. They may be correct, but with the FDA’s approval, a patient and his doctor can make the decision themselves, weigh the risks and benefits, and decide whether to use the Provenge. Men in this position are a desperate group with no other options. It should be up them to make the decision as they are in end stage disease and are looking at their own imminent death.
The following is from the google group alt.support.cancer.prostate
” I was in the clinical trial, and Provenge did nothing to help my condition. It probably hurt in the long run. My PSA prior to the trial was 550.58. After the trial it was 1399.7 They cracked the code and found that I had gotten the vaccine, not a placebo. They have not been able to bring the PSA down. My latest number was 3174 and I am now on Hospiceâ€¦â€¦.
â€¦â€¦.Even if it is eventually approved, I don’t believe that it will be a commercial success due to its delivery procedure. I had to go to a lab where my white blood cells and plasma were extracted. That was an unpleasant 2-3 hour procedureâ€¦â€¦. The side effects (of the treatment â€“ my addition) were very unpleasant. I was incapacitated for 2 days following the treatment.”
Dendreon, the manufactors of Provenge, are still running a third study with a much larger sample. Their goal is to run 500 subjects; they have already enlisted 400 people. (For further information, or to join the study, you can contact Dendreon at 1-866-477-6783.) The primary end point of this study is survival time, not progression to disease, as it was in the prior two trials.
This trial should be definitive and would determine if Provenge actually provides an increase in survival time. At the earliest, this study would not be completed before 2010. Given the lack of treatments currently available and that in every 24 hours 74 men die of advanced prostate cancer, many of us believe that this is too long to wait.
It has been suggested that Provenge should be provisionally approved with a complete review at the conclusion of this additional trial. However, it will become next to impossible to complete this trial as the recruitment of men into this study will become very difficult. How many of us would be willing to participate in a clinical trial and possibly receive a placebo when our doctors could just write a prescription?
The other issue is the economics of Provenge. Clearly, the development cost and economic risks to Dendreon have been high. No agency, including the FDA, can control what would be the cost to the patient for the treatment. The treatment is complex and is individually manufactured for each patient. Would private insurance carriers, the VA, or Medicare pick up the treatment cost? I don’t know.
I don’t know what the treatments would actually cost. I have even heard that the cost could be as high as $20,000 per person. These kinds of costs, what ever they actually become, will surely be out of the reach of many people.
Provenge is not a miracle cure, but it does hold the potential of providing a personal miracle for some of us. According to current Seer Relative Survival Rates from the National Cancer Institute, the expected mortality rate for advanced prostate cancer is over 50% in three years from diagnosis. An additional 4.5 months would increase by 12.5% the life expectancy of the average advanced prostate cancer survivor.
Those of us living with advanced prostate cancer have already gone through the mill of barbaric treatments. We have had our prostates removed, frozen or radiated; often leaving them with various degrees of incontinence and impotence. Then, 30% of us had initial treatment failures, so we will try salvage surgery or radiation. Many of us will also start hormone therapy, which makes us into physical and chemical eunuchs. We lose the little sexual ability we may have managed to cobbled back together after the primary treatment and trade it in for hot flashes, loss of muscle mass and bone density, peripheral neuropathy, mood swings and a host of other ailments.
Despite the terrible suffering we have endured our cancer marches on. We then become hormone refractory, develop painful soft tissue and bone metastases, and then we die.
Why shouldn’t we have the opportunity to make our own decisions, weigh the risks and suffer the consequences? Maybe we will be around a little longer. Wouldn’t that be a nice little personal miracle?
Joel T. Nowak MA, MSW