Dendreon has just announced some data from an interim analysis of a Phase III, randomized, double-blind, placebo-controlled clinical trial (the so-called IMPACT or D9902B trial) designed to assess the safety and efficacy of the investigational agent Provenge (sipuleucel-T) compared to placebo in men with metastatic, androgen-independent prostate cancer.
The independent data monitoring committee has informed Dendreon that there is a 20 percent reduction in risk of death in the Provenge arm relative to placebo. Apparently the data monitoring committee also reported no safety concerns and recommended that the study continue to its final analysis, which is anticipated in the middle of 2009. If this “reduction in risk of death” translates to a 20 percent increase in overall survival based on a so-called “intent to treat” analysis, then these data are important. However, readers should understand that the Dendreon release is primarily for the benefit of the investor community; the information provided is required by law because Dendreon is a publicly traded company, but it includes minimal clinical data and should be interpreted with caution.
The “New” Prostate Cancer InfoLink would remind readers that when this study was started in June 2003, eligible patients were limited to men with a Gleason score ≤ 7. The protocol for the study was amended in late 2005 to include men with any Gleason score and minor levels of symptomatic pain. This change in the protocol will affect the analysis of the final results of the study. We do not (currently) know how many patients were enrolled in the trial before and after the change in the protocol or how many patients only met the revised protocol eligibility standards.
Filed under: Drugs in development, Management, Treatment | Tagged: Provenge, immunotherapy
For another comment on why the Provenge data may not be as promising as the Dendreon press release suggests, please see Matthew Herper’s article on Forbes.com.
[Editorial comment: The "New" Prostate Cancer InfoLink respects the rights of individuals to present their opinions through this web site. The following post has been published without any editorial modification. We sincerely believe that the current systems available to terminally ill patients to seek treatment with investigational agents in the USA need significant modification and simplification. However, we do not believe that sipleucel-T (Provenge) has clearly demonstrated a survival benefit in any properly conducted, randomized clinical trial that has been completed to date, and we were not at all surprised that the FDA refused to approve this product in 2007. We believe that this was the correct decision based on the available data. Many who attended the FDA advisory committee meeting at which approval of this product was discussed understand that decisions taken at that meeting were improper based on the data presented. We further believe that the personal attacks made on some individual members of that advisory committee were and are utterly inappropriate and uncalled for.]
The Unreachable Availability of Provenge
Terminal patients are those who are not expected to live due to usually illness such as advanced cancer. If the patient has 6 months or less to live, those patients are considered terminally ill. Regardless, if a patient is terminal, they are without a cure or a tolerable treatment for their illness. Since such patients will likely die in a short period of time, treatment options, even if unproven, are often desired by such patients. This is understandable, because at such a severe stage of illness, such as prostate cancer, possible extension of their lives with comfort is worth it to them, regardless of lack of evidence of proof of whatever treatment that may be advantageous to them regarding these issues. The FDA, however, claims authority on the treatment options of such patients, although that administration has proven itself over the years to be rather inadequate with its frequent drug recalls and black box warnings, and they do these things only under pressure from the public, usually. So, the FDA may not be an ideal judge regarding such issues as treatment options for very sick patients.
Prostate cancer is rather frequent, with between 10 to 20 percent of men predicted to acquire the disease during their lifespan, resulting in about 30,000 deaths a year from this disease. It is the third most common cancer one can acquire, and the United States has the most cases diagnosed n the world, which usually strikes men past the age of fifty. One million do have prostate cancer in the United States, and about thirty thousand will die from the disease each year. Furthermore, there are different stages of prostate cancer, and the more severe the prostate cancer cases are, the higher of what are called Gleason Scores will be, and the severe cases are the most difficult to treat, of course.
Yet innovation still exists in medicine. A few years ago, a small Biotechnology company called Dendreon was working on a conceptually new treatment for the worst prostate cancer patients, and this treatment therapy created by Dendreon was named Provenge. Provenge is the first immunotherapy biologic treatment for the progressed prostate cancer patients. Usually, these patients are unresponsive to usual treatment methods for prostate cancer, and are left with chemotherapy, specifically a hazardous drug called Taxotere, as their only treatment option at such a traumatic stage of prostate cancer. Understandably, most patients at this stage refuse treatment entirely, largely due to the brutal side effects of such chemotherapy treatments as Taxodere, which include cytotoxic side effects and haematological adverse events. The immunotherapy method developed by Dendreon requires the removal of white blood cells of the diseased patient and, after altered, are re-injected into this patient now designed to attack within the diseased body what is called PAP, which is on prostate cancer cells only. This treatment requires only three such injections in a period of six weeks. This results in life extension twice that of Taxodere, and Provenge is free of the discomfort of the only other treatment of Taxotere. The medical community and survivors of prostate cancer were elated and waited with great anticipation for access to this treatment method.
Fortunately, as the years passed, Provenge, by 2007, had convinced others of its safety and efficacy in its benefit for severe prostate cancer patients. This caused great joy to such patients and their families. Perhaps greater elation was experienced by the caregivers and specialists of such a disease, such as Urologists and other caregivers who treat such patients. While Provenge was on fast track status at this time at the FDA, as they at the time agreed with the benefits of this new therapy, the FDA panel recommended with clarity the approval of Provenge based on its proven and superior efficacy and safety that was demonstrated in its trials, as they announced in March of 2007. Lifespan extension of severe prostate cancer patients was twice as long with Provenge versus Taxotere, which is the only other treatment indicated for this stage of prostate cancer that had only superficial efficacy, and is free of the toxic effects of this chemotherapy agent.
Now for the bad news: With great shock and surprise, the FDA agency rejected the approval of this great treatment for very sick patients due to, they said, ‘lack of data’ in May of 2007. This contradicts their favorable opinion of Provenge weeks before delivering this terrible news. Especially when one considers the FDA Commissioner is a prostate cancer survival himself! Many found this ruling completely unbelievable.
Soon after this judgment was passed by the FDA, conflicts of interest were discovered by others. For example, a member of the FDA agency who was evaluating Provenge, Dr. Scher, was found to have a financial commitment to a future competitor of Provenge that was being produced by a company called Novacea, and this company had signed a co-promotion agreement with Schering to provide support for this similar prostate cancer drug treatment being developed by this company. Dr. Scher never disclosed this conflict during the approval process of Provenge. As it turns out, this anticipated prostate cancer drug made by Novacea was discovered to have serious flaws, and Schering pulled out of the agreement with Novacea. In addition to this incident and before May of 2007, baseless letters were anonymously delivered to the FDA stating negative qualities about Provenge that were without Merit and speculative claims about the treatment were fabricated in these letters, it is believed Oncologists were speculated to lobby and pressure the FDA not to approve Provenge due to anticipated revenue loss. Yet overall, the disapproval by the FDA of Provenge angered and saddened many, and a newly formed advocacy group called Care to Live filed a lawsuit against the FDA for their clear lack of etiology for not approving Provenge, as they should have, according to the data about the therapy last year.
Terminal patients, I surmise, desire comfort during their progressive disease that has placed them in the last chapter of their lives, and certainly should have a right to choose any treatment that possibly could benefit them. Clearly, because of their lack of desirable and beneficial treatment options, most are willing to assume any risks of unapproved, yet potentially and likely beneficial treatments such as Provenge. Because they have a terminal illness, these benefits provided by Provenge take priority over any possible safety issues of unapproved treatments for them. The controversy could be concluded by a terminal patient signing a waiver of some sort, perhaps, stating that they are responsible for the consequences of an unapproved treatment regimen such as Provenge. Yet the FDA, with reckless disregard and with deliberate intent, denied what likely was a great treatment therapy for these very ill patients. Several have concluded that the FDA ultimately harmed others more by not approving Provenge, or offering any valid explanations explaining their action. Thier action was irrational, as one considers the agreement of the FDA and others regarding the need of the benefits provided by Provenge for the sickest of the sick with advanced prostate cancer.
The FDA does in fact presently have the ability to grant what is called conditional approval for such treatment methods as Provenge at this time, and why they have not remains completely unknown. What is known is that they are accelerating and worsening the illness, an illness the FDA pledged to protect so long ago. So now the FDA appears to be a bought, corrupt, and incompetent administration without loyalty and dedication to the public and its health, but with what appears to be overt collusion with venture capitalists and corporations. This needs to be corrected in any way possible for the lives of others- regardless of their own present health state today. Because of the FDA’s flaws in the past regarding drugs taken off the market along with increasing black box warnings of other drugs, which happens often with both, the individual should be the deciding factor in such matters of deciding thier treatment course presently, along with their health care provider, due to this unreliable administration called the FDA.
“Facts do not cease to exist because they are ignored.” — Aldous Huxley
Dan Abshear
Mike,
Maybe part of the problem has nothing to do with Provenge but rather Provenge highlighted the problem. Unfortunately I was not at the Provenge meeting because I had to be in Chicago. I guess I am a little confused because the words given to the committee to define an approving level were changed during the process. Which is the correct definition? Why wasn’t this resolved prior to the meeting? Based on the first definition, Provenge was not approvable. Based on the second definition, Provenge was approvable. Shouldn’t there be a standard that is consistent? Is there need for potential reform of the FDA system? Like the current financial crisis, is there need to transparency? Has there been politicization of the process? Should vaccines like Provenge be evaluated differently than chemotherapy agents? Did the FDA handle this appropriately? If there is any truth to what Dan is saying, then shouldn’t advocates like us be asking for explanations or answers to his questions? As advocates should we just accept, “Trust us we will do everything correctly”? I will go back to transparency because if there was more transparency in the process then I do not think we would be in the situation we are in today.
Kathy:
In my opinion you have hit the nail on the head. Provenge was simply the unfortunate trigger of an issue that should never have happened. The problem was exactly what you describe: the key question was changed during the meeting. As far as I am aware, this has never happened before, and I will make a bet that it never happens again.
The consequence of changing the question was that the Center for Biologics Evaluation and Research (CBER), which had never held an advisory committee meeting for a product of this type before, caused a furore within the FDA and among the academic oncology community. I have to say that I sat there in shock when it happened, as did almost everyone in the room with any understanding of the regulatory process.
If the second question (the one that received a positive response) was the one the FDA wanted answered, there was never any need for an advisory committee meeting because the answer to that question was very obviously, “Yes!” However, that wasn’t the question that had been approved by the FDA, and I do not believe that the FDA representative in question had the power to change the question in the middle of the meeting like that. Worst of all (and this is what caused all of the subsequent chaos), the question was changed after it became clear that the advisory committee was (very properly) going to say “No” to the first question!
I don’t think for one moment that advocates should simply roll over when some “authority” says, “Trust me/us, we will do everything properly.” I do, however, believe that there should be a consistent standard for the approval of drugs for marketing. The first rule for that consistent standard is that every drug should meet the criteria outlined in the clinical trials that the manufacturer agreed to up front. Provenge didn’t, largely because they didn’t invest in large enough clinical trials from day 1.
Having said all of that, I will repeat that the system for access to investigational therapies for people who are either terminal or have exhausted all other therapeutic opportunities still needs major simplification. You may want to look at a separate article addressing what has happened recently in the UK regarding access to investigational cancer therapeutics. So that I can be absolutely clear about this, I believe that Provenge should be available under some form of compassionate use protocol to any patient with metastatic prostate cancer who has failed docetaxel (Taxotere) therapy and who is not eligible to participate in a suitable clinical trial.