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The FDA’s Cancer Chief Speaks Out by Catherine Arnst
In a discussion with BusinessWeek, Dr. Richard Pazdur talks about clinical trials, small biotechs, and anxious patients
http://www.businessweek.com/bwdaily/dnflash/content/
may2008/db20080521_549448.htm

Steve Walker of Abigail Alliance writes a rebuttal:

May 23rd, 2008 at 10:32 am

With respect to the following:

We cannot approve drugs on the basis of emotion, says Pazdur. We cannot make drugs available at the expense of lowering standards of approval. difficult to argue with that logic. But it’s not likely to make cancer patients, or oncology-focused drug companies, feel any better.

To those of us who have been listening to and, much more importantly, following the actions of Dr. Pazdur over the last 7 years, his response regarding “lowering approval standards” is the kind of classic, disingenuous and condescending misdirection he is renowned for among those who have to deal with him on material matters, like approval decisions for safe and effective drugs.

Beginning in 2003, Dr. Pazdur unilaterally decided to raise the bar for Accelerated Approval of cancer drugs to the same height as the standards required for full approval. Accelerated Approval was created by Congress in 1997 because it had become obvious (through the FDA’s bureaucratic delays of drugs for HIV/AIDs a few years earlier) that thousands of people were dying waiting for the FDA to approve life-saving drugs.

The agency actually started moving toward faster approvals of drugs for HIV/AIDs and some compellingly promising cancer drugs between 1997 and 2003, and it was working well, bringing progress against these diseases to patients considerably faster than before, which meant they got to continue living.

But then, Dr. Pazdur brought that trend to an abrupt halt for cancer drugs with his announcement of what we call his “Decelerated Approval Initiative.” In an oncologic drugs advisory committee in the spring of 2003, Dr. Pazdur made clear that no matter how compelling the data that a cancer drug worked, he would require all drugs to be tested to statistical perfection (as measured by an arcane, scientifically-meaningless metric called a p-value) before he would consider even Accelerated Approval (conditional approve that requires continued testing to gain full approval) for the drug. The standard he announced, and that he has since rigidly and inflexibly imposed, is not even required by law for full approval, let alone the conditional Accelerated Approval, but is now required by Dr. Pazdur for virtually all cancer drugs.

The result has been the effective elimination of the Accelerated Approval pathway, and the delay of delivery of numerous, obviously safe and effective cancer drugs to the clinics. The effect is not an abstract policy one for people with terminal forms of cancer. Hundreds of thousands of them have died prematurely, waiting for progress to reach them. Pazdur’s logic? If he approves these drugs when he should, patients may not be desperate enough to enroll in randomized, double-blinded, placebo-only controlled (meaning one half of the patients enrolled get a sugar pill), no cross over (meaning they are not allowed to switch to the active therapy when their disease progresses toward killing them and they are taken off the study), and in many cases they are never told whether they got the active therapy, or not. The trials are necessary, Pazdur thinks, because it is the only way to get the (meaningless) p-value. The p-value he wants (rigidly) is 0.05, meaning that there only a 5 percent chance that the result measured by the statisticians is due to chance. Come in with a 0.055 (as has happened recently) meaning that it is only 94.5 percent certain that the result is not due to chance, and he won’t approve the drug.

None of this has happened with HIV/AIDs drugs. HIV/AIDs patients still gain access to drugs before they are approved if they need them, and those drugs still receive Accelerated Approval when they should, because Dr. Pazdur doesn’t review HIV/AIDs drugs. A lot of them remain alive as a direct result.

An example. Dr. Pazdur has held up drugs for lung cancer, a disease that kills more than 150,000 Americans a year, awaiting his p-value. A few hundred, at most, terminal lung cancer patients are needed to fill out the randomized trials he mandates through a binding negotiation between FDA and the sponsor called a Special Protocol Assessment. Half of those patients get nothing without being told they are getting nothing, and in some cases have been allowed to die getting nothing - this happening after the drug being tested had already shown compelling evidence of efficacy in earlier trials. In numerous cases under Pazdur’s control, that prior evidence met the legal standard, and the medical and written regulatory standard, for Accelerated Approval. Everyone else - the 150,000 plus who can’t get into the small trial - die waiting, so Pazdur can have his p-value. These trials take one and a half to two years (or longer) to complete, followed by 3 months to prepare an application based on the p-value, and 6 to 10 months for FDA to review the application.

The reason patients aren’t allowed to cross over to the active therapy when, as expected, the sugar pill does nothing for them and their cancer continues to spread and kill them, is because if they were given the drug, some of them would respond, live longer, better lives, and reduce the statistical difference between those who got the placebo, and those who got the drug that actually treats the cancer. The FDA refers to this as “confounding” the overall survival data. What Dr. Pazdur is requiring is that the placebo patents be forced to die on the schedule of an untreated patient. To get any physician to refer a patient into a trial like that, or to get any patient to agree to a 50-percent chance of being used up and thrown away, he has to deny the safe and effective drug by any other means to all patients who might benefit, so he can get the few he wants to enter the trial and risk the placebo. He would claim that the double-blinding is to prevent “bias,” but its really to prevent both the treating physician and the patient from knowing they are being “killed” prematurely in the name of a p-value, because if they knew the patient was getting nothing, common sense and the “do no harm” principal would cause them to go in a different direction for the patient.

These trial designs are perhaps morally acceptable for testing a toe fungus cream, where no one will die or even be significantly harmed by receiving a placebo, but doing this in terminal caner patients crosses the line. Under Pazdur, these types of trials for cancer drugs are common and increasing because there is no other way for the sponsors to give him his p-value, which means there is no other way for them to get their drug approved.

Barbaric? You bet. Unscientific and disastrous public policy? Absolutely. Criminal? By any normal moral standard yes, but FDA bureaucrats can violate those standards with impunity. The Supreme Court just affirmed that fact by denying cert in Constitutional rights case against the FDA. Archaic and obsolete given our exploding understanding of the biology of disease? Without question. Dr. Pazdur’s approval standards are reactionary and obstructionist in a time when we should have been moving rapidly forward to adopt new, more scientific and productive approaches to clinical testing that accommodate the new scientific understanding of genomics, proteomics, etc.

Provenge was rejected and delayed by the FDA’s Center for Biologics and Research after postive votes by an advisory committee not directly controlled by Pazdur, to which he appointed two members - the chairperson of his committee (whom he selects) and another oncologist with obvious financial conflicts of interest. They voted that Provenge is safe, but not that it was effective in a 13-4 vote in Provenge favor. Upset with the recommendations of their peers on the committee, the two members sent over by Pazdur then waged an aggressive letter writing campaign, which was leaked to the press, opposing approval of Provenge. Backed into a corner, a risk-averse FDA being beaten daily by Congress and the press over drug safety issues, delayed approval and required another (the third) double-blind, randomized, placebo-only controlled, no cross over trial in men with terminal prostate cancer. That was more than a year ago and more than 30,000 men have died waiting for Provenge since. The trial recruited its last patient several months ago, and some of them have already died. Given the data from earlier trials that already proved a robust survival advantage for men who got Provenge, the men getting placebos are at a severe disadvantage, dying on the scehdules of untreated patients. In the meantime, everyone waits. Dr. Pazdur might counter that Dendreon could give the drug away in an expanded access program and FDA might approve that, but Provenge is not a cheap, easily made pill. it is a cutting edge personalized therapy that requires harvetsing dendritic cells from each patient, treating them to create a vaccine (for that individual patient only) that fights the cancer, then reinjecting them with the vaccine. Dendreon is an innovative biotech startup financing itself with investor cash. It is not a big pharma company selling lots of approved products with a normal cash flow. This is typical of the small, nimble companies now making most of the exciting progress against cancer. It is simply not medically or economically feasible for them to provide this complex personalized therapy to the tens of thousands of men who need it for free, espevcially given that for all they know, even with positive data, Pazdur may delay approval again. Pazdur knows all of this, by the way. How could he not?

As for his comments that he is encouraging companies to bring him more scientific “personalized medicine” data, they have already done that more than once, and he has chosen to ignore its significance to approval decisions, rejecting and delaying drugs anyway because he did not get his perfect p-value.

Now you understand the “standards” Dr. Pazdur is unwilling to lower. His standard is a p-value of 0.05. He does not consider any other piece of information adequate to support an approval, no matter how compelling the case for safety and efficacy, or how dire the need of the patients waiting for progress to reach them. That.s it. A p-value. And if you think any of this is untrue, dig in to it yourself. Dr. Pazdur has explained his standards and the basis for them quite clearly. He also has demonstrated consistently that he means what he says. If a sponsor wants their drug approved, they must produce a perfect p-value, no matter the human cost of doing so.

The only truth in his “lowering standards” statement is that they are “his” approval standards, and they are the primary reason progress against cancer reaching the clinics is now almost completely stalled.

Dr. Pazdur is not entirely alone in his support of his standards. Some others in clinical research support what he is doing, but that support has long been waning in the face of emerging science that makes continued use of Pazdur’s archaic approaches ineffective, unscientific and simply wrong. Besides, the FDA does not exist to promote the best interests of doctors who conduct clinical research. It exists to protect and promote the public health, and I think most of us think that means getting progress to people who need it to live as fast as possible should be a higher priority than pleasing a few academic dinosaurs working to preserve their obsolete approaches to cionducting clinical research.

Important questions, and ones we have asked repeatedly, is how and why did his superiors at FDA let this happen, and what are they going to do to fix it. We have been asking these questions at the highest levels of the FDA for more than 5 years, and so far, we have not received an answer.

Steve Walker
Abigail Alliance

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Tags: AIPC, Allison Martin, Brachytherapy, Cancer Vaccine, Care To Live, CareToLive, commissioner Andrew Von Eschenbach, Dendreon, FDA, foia, Freedom of Information Act, hormone refractory, Howard Scher, Immunotherapy, Jesse Goodman flubs it, maha hussain, Michael Milken sadly remains silent, Mike Milken, oncologist, Prostate Cancer, Prostate Gland, Prostatectomy, provenge, Richard Pazdur, Rick Pazdur, Robotic Surgery, The Prostate Cancer Foundation stays silent, Thomas R Fleming

This entry was posted on Wednesday, May 28th, 2008 at 6:39 am and is filed under The Cause, The Dysfunctional FDA. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.