Monday, March 07, 2005

Public Citizen vs. FDA and Iressa

Reuters reports on an interesting story that raises a number of issues.

In December of last year, AstraZeneca announced that its drug for treating advanced non-small cell lung cancer, Iressa (gefitinib) failed to increase life expectancy. This is despite the fact that Iressa was demonstrated to actually shrink tumor size. A similar drug, Tarceva (erlotinib) has been shown to prolong life (6.7 months vs. 4.7 months).

Iressa has been marketed in the U.S. under the FDA's "fast track program". It hasn't yet been granted full approval (as Tarceva, also initially fast tracked has). The Public Citizen, a nonprofit consumer advocacy organization, has asked the FDA to ban the drug last week. Their position is that since Tarceva already has a documented benefit, then the availability of Iressa, which does not, will only serve to divert patients from an efficacious therapy.

People with serious life-threatening illnesses (eg. late stage lung cancer) constitute an important lobby and a lot of emotionality surrounds policy regarding their care. One of the reasons for creating a fast track approval system was to increase the armamentarium for such diseases. Many AIDS drugs were initially evaluated on this basis.

That said, the Iressa experience is instructive. Patients and physicians alike (myself included) often don't understand how a drug that causes a clinical response (eg. tumor regression) doesn't prolong life. Unfortunately, this is a common pattern. I remember when Proscar (finasteride) came out for treating benign prostatic hypertrophy (enlarged prostate). The drug was shown to shrink the prostate and promote faster urinary flow rates. Unfortunately, when studied, patients were unable to perceive the improvement and essentially felt that their ability to urinate was unchanged.

It may be that in addition to its tumor shrinking effects, it may have other side-effects that shorten life expectancy. Interstitial lung disease is one possibility and a number of deaths have been attributed to ILD. AstraZeneca states that the incidence of ILD is low (they cite .22% in the U.S.) and that even those cases can't be proven to be due to Iressa. They also note that ILD occasionally can occur with lung cancer anyway.

If Iressa shrinks tumors but doesn't lengthen life (or can't be demonstrated to improve quality of life), then it should be taken off the market. On the other hand, it may be that the study failed to detect a true improvement because it either wasn't powerful enough (didn't have a large enough sample size) or that it was powerful enough but was the victim of an anomaly the statisticians call a type 2 error (another name for bad luck).

A more significant possibility was raised in this article published by the Journal of the National Cancer Institute. Iressa's efficacy appears to be dependent on a mutation in a protein found on some lung cancers. It may be that through statistical chance, the number of tumors studied in their trial didn't have enough of the mutations. If this were so, the Iressa arm wouldn't be expected to show much difference in life expectancy compared with the placebo arm.

An analogous situation would be to do a study testing an antibiotic for say pneumonia against a placebo and finding no benefit because instead of having pneumonia, most of the patients had emphysema instead (for which any antibiotic wouldn't be effective).

I don't have the original data so I can't say for sure. If this is so, then a very good argument can be made for testing tumors for one of the 20 some mutations that may respond to Iressa (assuming that such an assay is commercially available) and limiting treatment to only those that have it. It may be that Iressa is effective against mutations that are unresponsive to Tarceva and vice-versa. If this can be demonstrated then it is reasonable to make both drugs available.

To me the goal of the FDA shouldn't be to complicate the treatment of illness but to increase the availability of proven, efficacious therapies. We don't just need more and more drugs (and more "me too" drugs). We need confidence that the drugs we do have will work and that their benefits outweigh their downsides. We shouldn't simply rubber stamp drugs because they may work. At best this can be a waste of money and at worst, catastrophic.

This is why I believe that even drugs for "hot button" diseases such as breast cancer or any other life-threatening diseases should go through the same methodical, careful evaluation as other drugs. Patients in desperate situations need to be able to enroll in clinical trials designed to evaluate. Drugs without proven efficacy should not be on the market.

As an aside, I should say one thing about Public Citizen. This organization was formed in the 70's by Ralph Nader and is almost reactionary in their zeal to get drugs off the market. I don't know how much of this is true patient advocacy and how much is a general mistrust and dislike of the pharmaceutical industry. See their companion website They list 182 DO NOT USE drugs. Some of their indications for being on the list are "questionable" to say the least.



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