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March Leads Off With a Bang




Since last May, the ODAC panel (Oncologic Drugs Advisory Committee) under the direction of the FDA's Richard Pazdur has become a point of worry for biotech investors. It seems every time this once-independent panel meets, new shockwaves are sent through the sector. With recent rumors that current interim head Dr. Lester Crawford might be nominated to as the FDA Commissioner, some expect ODAC to be a sore spot.

This is important in the biotech space because one of the few sub-sectors that could escape any increased regulatory vigor from the Vioxx fallout is oncology. Side effects are not so much a problem when the patient's alternative is death. That's not to say side effects are unimportant. It's an acknowledgement of the fact when life expectancies are measured in weeks, the only unexpected side effect anyone cares about is a few more sunrises.

ODAC's next meeting occurs on March 3rd and 4th.

On March 3rd, the ODAC panel will take up Advanced Magnetics' (AMEX:AVM) Combidex, a contrast agent designed to preferentially highlight cancerous cells on certain types of radiographic scans. This is the second time around for this drug.

But that's not the important part of this meeting (all apologies to those interested in AVM). In the second half of the day, ODAC will take up the question of surrogate endpoints for prostate cancer trials. As this is a high-value target disease, most of the industry and more than a few people on Wall Street will be tuned in.

Prostate cancer endpoints

Prostate cancer has few decent treatment options despite being the single biggest non-skin cancer. Initial treatment options are removal or degradation of the prostate gland and hormone therapy. Both have significant side effects in a significant portion of men. Once these treatments fail, there are no good treatments for men who want to preserve their quality of life. Once it's clear something has to be done (usually because of fatigue or bone pain), Taxotere has been shown to be effective - though it is somewhat of a devil's bargain as 7 months of chemo gets you a median survival advantage of 2.4 months.

The problem with developing better early-stage prostate cancer treatments is the length of time necessary to generate hard clinical endpoints like survival. Most men see their cancer go away for 5-10 years or more after surgery and/or hormone therapy. Most men with this stage of the disease die of something else before their prostate cancer progresses to the next stage. So, not only do you have to wait forever (in drug development terms) to get your data, it's confounded by the patients dying of something other than what your new drug can solve.

There is great pressure on the FDA, therefore, to come up with effective surrogate endpoints. A surrogate endpoint is a measureable patient event thought (validated) to predict a hard endpoint like survival. For example, the FDA will approve a cholesterol drug that drops LDL (bad) cholesterol by a certain percentage, knowing the drop will translate into reduced death and illness. Therefore, a drop in LDL is a "surrogate" endpoint for survival.

The FDA was supposed to take up this debate in its December 2004 meeting, but that was cancelled. They are leaving it for the afternoon of March 3rd. It is expected in the industry the FDA will choose a surrogate endpoint combining PSA velocity (not the net gain/loss in PSA but how fast it moves over time) and radiographic bone scans as an approved surrogate endpoint for survival. PSA is, as most of you readers should know, a blood protein used as a marker for detecting prostate cancer. While it is inappropriate to use PSA levels as a marker because of individual differences, a growing body of research shows that how fast PSA doubles (PSA Doubling Time or PSADT) is an effective surrogate for survival in all men.

This discussion will be complicated somewhat, we expect, by data to be published in mid-February by Dendreon (DNDN) showing their immunotherapy drug Provenge conferred a survival advantage among stage two prostate cancer patients without showing any benefit on traditional surrogate endpoints like time to progression. This is way too complex a story to go into here (but one we cover in a high degree of detail in my firm's research since Dendreon is one of the companies we cover), but suffice it to say any comments about the Dendreon trial will be followed not only by Dendreon shareholders but by the overall community.

A refusal to specify surrogate endpoints would be a bad thing for the sector and specifically for companies developing treatment for early-stage prostate cancer. It would be another signal ODAC continues to be biased towards biostatistical perfection instead of patient welfare.


As I Buzzed yesterday, the FDA will take up Astra-Zeneca's (AZN) Iressa at the March 4th ODAC session. The FDA has clearly signaled they will be considering pulling Iressa off the market at this meeting given the failure of the drug's confirmatory trial.

A bit of back story here is needed...

Iressa was granted accelerated approval in 2003 in an ODAC panel meeting that rather shocked the industry. The company clearly did not make their case as to the hard endpoints except to note there were some exceptionally durable remissions in some of the patients treated. Their case for approval really hinged upon emotional testimony from Iressa patients and quality of life data that even we (who tend to be forgiving of statistical variation) thought was bogus. In addition, the first of several confirmatory Phase III trials failed just a couple of weeks before the ODAC panel meeting. In a big surprise, the ODAC panel voted to approve the drug.

Sources tell us this enraged Richard Pazdur, the head of the oncology division and a confirmed biostatistical wonk. He was ready to override the ODAC panel's recommendation and deny approval until then-FDA head Dr. Mark McClellan said to pass the drug through.

It has since been determined that Iressa benefits 10-30% of the patients. Not only does it benefit them, the benefit is nearly instant and rather miraculous. If you've ever talked to a doc who has had a terminal patient respond to Iressa, you can see the wonder in their face. We are privileged, really, to have a front seat as dueling scientific presentations and papers race to determine how to tell in advance if Iressa will work on a certain patient.

In this month's Journal of Clinical Oncology, the debate rages on. I want to share a pair of quotes I found particularly interesting.

"Is the activity rate of [Iressa] disappointing? Medical oncologists do not have the luxury of being disappointed in the presence of exciting responses and symptom improvements, even if in a small number of patients." - Dr. Cristina Noberasco, European Institute of Oncology, Milan, Italy.

"The inescapable conclusion is that our current attempt to use EGFR [Iressa's target] IHC for patient selection for EGFR antagonist therapy has thus far been a total failure. We should acknowledge this and move forward. Use of currently available routine IHC measurement of EGFR status should not be regarded as part of routine patient management, as the assays available have no demonstrated predictive value. It is incorrect to select a patient or a tumor type for treatment with [Iressa] on the basis of high EGFR IHC expression. It is equally illogical and wrong to withhold [Iressa] solely because a tumor is negative for EFGR by IHC staining." - Dr. Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY.

I believe that Iressa shines as a success of the accelerated approval program, not a failure. A reasonably safe drug, approved for use only when other treatments have failed, is now broadly available. Hundreds of doctors and scientists are attempting to discover how to best use the drug, resulting in perhaps thousands of lives being positively affected each year.

Contrast this to what would happen if Iressa was pulled off the market. Assuming AZN even bothers to put it back in clinical trials given the dramatically reduced revenue potential, only a few dozen docs at a limited number of cancer centers would be participating in a clinical trial. A few hundred patients would have a chance to get Iressa, but only half would so the rest of the patients can be used as a control group comparison. A few dozen lives would be positively affected each year.

The proper course seems clear when placed in those terms, yes?

I'm not sure pulling Iressa off the market will hurt biotech valuations, mostly because Wall Street has already written off the drug. It will be important to carefully examine the transcript, however, to see if this decision has broader implications.

If Iressa is yanked, by the way, it will be the first time the FDA has withdrawn approval for a drug in the Subpart-H accelerated approval program because of non-confirmation of clinical trials.

My guess as to the outcome? If Mr. Pazdur does not stack the panel like he did in the Genta (GNTA) and Allos Therapeutics (ALTH) ODAC meeting, the vote will closely favor keeping Iressa on the market. Mr. Pazdur will then recommend pulling Iressa or placing significant restrictions on its distribution.

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