Tuesday, August 2, 2011

How a Well-Intended FDA Policy on Colchicine is Harming Patients

The road to hell is paved with good intentions.

The FDA has reaffirmed the truth of this aphorism with its policy about Colchicine. Here's the story:

I recently spoke with a friend who has a family member suffering from Familial Mediterranean Fever (FMF), an auto-inflammatory disorder, most commonly seen in eastern Mediterranean populations. The condition is characterized by recurrent painful inflammation of the abdomen, chest and joints, accompanied by fever. FMF is associated with mutation of a gene on chromosome 16 involved with regulating Pyrin, a protein that is part of the inflammatory response. There is no specific test for the disease. Diagnosis is made on the basis of symptoms, family history, and ruling out other conditions.

Since the 1960s, Colchicine, a plant extract first used for treatment of gout two thousand years ago, has been used for treating FMF. As an ancient treatment widely used prior to formation of the FDA, Colchicine did not require FDA approval as a new drug.

In 2009, the FDA granted approval to URL Pharma for Colcrys, its version of Colchicine, based on randomized controlled trials the company conducted. Because Colchicine had never been subjected to the FDA approval process, Colcrys was, in a technical sense, a "new" drug approved for a "new" indication - treatment of gout and FMF - despite the centuries of prior use.

Here's where the well-intended harm comes in. The FDA is allowed to give market exclusivity to a new drug for new indications, as an incentive for pharmaceutical companies to conduct tests and seek FDA approval. In September 2010 the FDA did just that - it ordered all other manufacturers to cease production and marketing of their versions of Colchicine.

Generic Colchicine cost ten cents per dose. Colcrys costs close to five dollars. The company defends the price increase as (a) necessary to support its research and (b) offset for vulnerable patients by a support program for circumstances of hardship.

The FMF community, however, has documented that FMF patients respond differently to different preparations of Colchicine. Apart from the financial impact of a fifty-fold price increase, many who were stable on a previously available form of the drug relapsed on Colcrys.

That's what happened to my friend's family member - a series of severe fevers and inflammatory reactions, leading to emergency room visits and hospitalization.

An editorial in the New England Journal of Medicine argued that URL Pharma's research added no significant benefit to public health of the kind that would justify the reward of market exclusivity. (See here for a vigorous response from URL Pharma.) But apart from the financial hardship market exclusivity creates for patients and insurers, banning the alternative forms of Colchicine injures patients who respond to those forms and not to Colcrys.

My friend is resourceful, and was able to find "contraband" Colchicine. When it was administered, it did the job for his family member.

Encouraging research and true innovation is a social good. But so is preventing recurrences of FMF! A policy that does not allow exceptions to prevent avoidable harms is an unethical policy. Given that alternative forms of Colchicine are no longer manufactured and sold in the U.S., the FDA should make provision for importation from abroad for patients like my friend's family member.

(See here for an excellent article on FMF and the impact of the FDA policy by Dr. Janine Jagger, an epidemiologist who suffers from the condition.)


janine jagger said...

Thank you Dr. Sabin for bringing attention to the colchicine crisis that the FDA has caused for FMF patients (including me) in the US. We have been very effectively "stranded" by the FDA - leaving us with only one approved brand of colchicine that few of us can tolerate and providing no "plan B" when it cannot be tolerated. The distress calls are coming in at a tragic pace. Many of those who now living an FMF nightmare were effectively treated and were living normal lives just a few months ago. The FDA could change the situation for us in literally a heartbeat by franting approval to the West-Ward brand of colchicine - an application that is sitting on their desk. How can a small group of patients with a rare disease compel a huge lumbering federal bureaucracy to change course? Of more immediate importance - what does the FDA have to offer to suffering FMF patients TODAY who are trapped in the FDA's regulatory nightmare? Do our lives and health matter less because we are few?
Janine Jagger

Jim Sabin said...

Hello Janine -

Here are my thoughts about the crucial question you raise: "How can a small group of patients with a rare disease compel a huge lumbering federal bureaucracy to change course?"

1. I would encourage "FMF activists" like yourself and my friend to contact your representatives and senators about the issue. If even one legislator engages with the issue and contacts the FDA, that would pierce the bureaucracy.

2. Given that a number of FMF patients are experiencing potentially preventable flare ups right now, if it's possible to locate supplies of the "right kinds" of colchicine outside of the U.S., I would consider creating and publicizing a campaign of civil disobience centered on illegally importing the medication. Such a step would be clinically and ethically justifiable and could focus attention on the need for a Plan B.

3. I don't know if there are any research centers studying FMF, but if there are, the differential responsiveness to different forms of colchicine might be something the center would want to study. Having a reputable research site as an ally would be helpful.

4. If any of the FMF group you surveyed has contacts with a law firm, the issue could readily become the focus of a piece of pro bono legal advocacy.

5. Possibly some of the FMF sufferers are insured by one of the large, and powerful, insurers. It's worth exploring whether an insurer, or the pharmacy benefit management (PBM) company the insurer works with, has better access to the FDA than individuals have had.

The right outcome looks like an obvious "no brainer." Insofar as there are FMF sufferers who do not respond to Colcrys, access to the previously effective form MUST be made available.

Thank you for your comment and for the excellent article the post gives a link to.