Are Congress and the FDA missing the big picture
Another day and another story breaks about a member of Congress asking the FDA for answers about how a drug with potentially significant safety issues has made it through the agency’s review process and been approved for full marketing and use. While it is to be applauded when Congress correctly invokes its oversight role in reviewing FDA decisions and processes, one must question if the bigger picture is being missed as Congress focuses on the issue of drugs that have been approved which perhaps should not have been, but fails to make any mention of the drugs or therapies that have NOT been approved that very likely should have been. The number of innocent human lives lost to cancer, for instance, while not being able to access potentially lifesaving new therapies that the agency had reviewed but delayed or denied based on an outdated and incorrect understanding of the law and congressional intent. It has also become increasingly clear that the ‘science’ the Agency claims drives all decision-making is a blind devotion to statistics and the FDA is doing anything but protecting the public good by denying patients access to potentially life-saving treatment options that have advanced to Phase II or III testing. For example, the FDA’s currently manifested ‘aggressive incompetence’ has led to the point where the average length of clinical trials of a new therapy from Phase I through Phase III, is now approximately seven to ten years, literally several lifetimes for terminal cancer patients and the cost estimates range from just under one BILLION dollars per drug to about $1.5 BILLION. Is it any wonder that approved drug costs are rising so rapidly?
An excellent case study of this aggressive incompetence recently surfaced in the FDA’s decision delivered on Wednesday, May 9th, to not approve Provenge, a first of its kind immunotherapy that combats prostate cancer in late-stage, hormone-resistant patients. The FDA’s choice contradicted its own Advisory Panel vote that three existing Phase III trials demonstrated Provenge’s safety (17-0 vote) and substantial evidence of efficacy (13-4 vote). Instead, the agency issued a Complete Response Letter (CRL) asking for additional clinical efficacy data. In its history, the FDA had never overturned a positive panel recommendation on a drug intended for a terminally ill patient population -- never mind one with a 17-0 vote affirming its safety. This same day, another FDA review panel rejected a promising new therapy for bone cancer in children because this therapy, during the trial that took TWELVE years to run and meet FDA muster, showed only a 94% certainty that the significant survival benefit was due to the drug instead of the FDA-preferred 95% certainty. The FDA has asked for another trial and apparently, another twelve year delay before delivering hope to these children in need.
Some 25,000 men die of prostate cancer each year. The average life expectancy of the men who could be treated by Provenge is less than two years. In two pivotal Phase III trials, 33% of the men who received Provenge were alive at three years compared to less than half that in those receiving placebo. The current standard of care, a chemotherapy drug called Taxotere (docetaxel), is less effective in a similar patient population at a much higher cost in terms of side effects – side effects that can be so severe that between 1-2% of patients receiving Taxotere die of these side effects.
This FDA-imposed delay has a direct adverse effect on public health. Without Provenge, thousands, if not tens of thousands of men will die earlier than they had to– some years earlier. The FDA approval process is designed to balance the risks and benefits of a drug before it is allowed on the market. The Advisory Committee of leading immunotherapy researchers, cancer doctors, and advocates met on March 29. This group of experts held lengthy deliberations that included presentations by the sponsoring company (Dendreon) and the FDA, as well as discussion of questions relating to safety, efficacy, and manufacturing before ultimately voting to affirm Provenge’s strong safety profile and positive evidence of efficacy. Both votes meet the letter of FDA regulations for immediate approval.
The FDA’s decision to ignore the Advisory Committee vote necessitates immediate public hearings and a detailed explanation by the office of Dr. Andrew von Eschenbach, Commissioner of the FDA to explain the following:
· Why did the FDA choose to overrule its own Advisory Committee?
· What role did internal FDA politics play in the decision?
· Why were panel members with potentially significant conflicts of interest allowed to participate in the committee vote and post-meeting decision-process?
· Who was responsible for the leaking of internal FDA documents about this decision to the media?
· How is it that this decision does not violate the due process rights of these prostate cancer victims, who have an average life expectancy of 18-20 months?
· How is it that this decision does not violate the basic, fundamental tenets of the Hippocratic Oath, to “do no harm”?
As Dr. Mark Thornton, President of the Sarcoma Foundation of America, has said, “It will be years before we know the full impact of these decisions and how many cancer patients, young and old, have had their lives cut short as a result.” Thomas Farrington, founder and president of the Prostate Health Education Network (PHEN) summarized “We believe that the FDA’s decision to delay approving a safe, effective treatment for prostate cancer patients is inhumane. Furthermore, we are saddened and concerned the FDA has blatantly ignored – not only its own advisory panel of experts – but the voices of the patients.” 73 of those voices are silenced every day this new therapy is delayed.
Some complain approval of Provenge would set a new precedent, implying that such a thing would be negative for patients. How dangerous a precedent would it be to approve a drug that received a unanimous vote that it was safe, demonstrated a significant survival advantage superior to all current treatments, and missed its primary endpoint by 0.2%? If indeed such a decision to help a terminally-ill patient population would set a new precedent, perhaps someone should look hard at how we approve drugs for cancer patients. Survival is a clinical endpoint that can not be faked, stroked, massaged, or open to interpretation. If a year or so from now interim results confirm earlier survival statistics about Provenge, what will we call the more than 6,000 American men who may have died prematurely due to the FDA delay in making Provenge available? Heroes? Victims? Collateral damage?
Dr. George Cooper, M.D. and distinguished Professor at the Medical University of South Carolina summarized the FDA’s decision this way:
“Denial of approval for Provenge is a classic example…where an agency that was established to protect the public from dangerous and/or useless substances is instead…dictating to dying patients and their families what they will and especially will not be given access to solely on the basis of cold statistical fine points, even when one is dealing with advanced malignancies wherein the lethal clinical outcome of placebo treatment in clinical trials or of standard therapy is known with near certainty. This is simply cruel, and as a physician I think that it is insupportable.”