With last week's announcement by the FDA that it was ordering unapproved colchicine products off the market, the year-old debate over the agency's handling of the popular gout treatment has flared anew.

The wisdom of granting periods of marketing exclusivity to the maker of Colcrys, the sole approved form of colchicine, was debated in the letters section of the Oct. 7 issue of the New England Journal of Medicine by two top FDA officials and two physicians at Brigham and Women's Hospital in Boston.

And the American College of Rheumatology (ACR) reiterated concerns first expressed in 2009 about price hikes associated with the approval of Colcrys and the impending removal of much cheaper unbranded colchicine products.

The FDA's action against the unapproved products has been expected since URL Pharma received formal approval of Colcrys in July 2009.

At the time, the FDA indicated that makers of other, unapproved colchicine products would either have to submit marketing applications or take their products off the market. It cited a decades-old policy requiring that the safety and efficacy of drugs that were on the market in the 1950s, when the agency won full authority to regulate them, would eventually have to be proven. There were dozens of such drugs, including colchicine.

That requirement was largely ignored until 2006, when the FDA began to crack down on some of these "grandfathered" drugs, such as hydrocodone-containing cough syrups.

Under the stricter policy adopted in 2006 and backed up by legislation enacted by Congress, the agency indicated that it would provide incentives for companies to submit marketing applications for drugs in the targeted classes.

Specifically, the FDA would grant three years of marketing exclusivity to the first company to receive a formal approval, or seven years if the drug was for an orphan disease.

The agency also indicated in a guidance document that it would ordinarily wait one year after granting an approval before taking action against unapproved products. That, the FDA argued, would give their manufacturers a chance to submit their own applications or take steps to wind down production and inform customers in an orderly way.

In June, Aaron Kesselheim, MD, and Daniel H. Solomon, MD, published a letter in the NEJM berating the FDA for the negative impact that patients with gout and familial Mediterranean fever would suffer as a result of this policy as applied to colchicine.

Colcrys has three years of exclusivity in treatment of acute gout flares and seven years for familial Mediterranean fever, an orphan disease. The drug is also approved for preventing flares, with no exclusivity.

Whereas the unapproved products cost around 10 cents a pill, Colcrys comes with a sticker price of nearly $5 a pill, Kesselheim and Solomon wrote.

They also questioned whether URL Pharma's one-week, 185-patient trial in acute flares added significantly to scientific knowledge of the drug, which has been in clinical use for centuries.

In a response published this week, the director of the FDA's drugs unit, Janet Woodcock, MD, and colleague Sarah Okada, MD, argued that the agency had little latitude under federal law in this situation.

"Congress wrote these laws to encourage innovation, although such regulations sometimes have a broader sweep. The FDA is required to implement the laws as written and has no authority to regulate drug prices," they wrote.

Kesselheim and Solomon, in a response posted alongside the letter from Woodcock and Okada, countered that the agency should seek changes in the legislation if it believes a strict interpretation is affecting patients negatively.

Woodcock and Okada also noted that the marketing exclusivity applies only to the treatment of acute gout flares and familial Mediterranean fever, not to the larger market of gout prophylaxis where the price impact would hit hardest.

In the wake of complaints from patient and physician groups including the ACR, URL Pharma beefed up its patient assistance program to provide Colcyrs at reduced cost to patients with household incomes under $132,000. Depending on income, the monthly cost for these patients would range from $5 to $30. The program also sets a copay of $25 for patients not qualifying for the assistance program but who obtain the product through prescription drug insurance.

The company has also maintained that physicians should prefer Colcrys because, unlike the unapproved products, its purity and uniformity has been confirmed by the FDA.

"Illegal, unapproved colchicine has not undergone this FDA review. Even if one found that some tablets of illegal colchicine were consistent, there would be no assurance that the next batch would meet these standards since they are unapproved," said URL Pharma's CEO, Richard H. Roberts, MD, PhD, in a letter to ACR President Stanley Cohen, MD.

Cohen, in turn, informed ACR members last week that some of the concerns about Colcrys' price and the market exclusivity had been alleviated.

In an open letter posted on the ACR website, he acknowledged that the company's patient assistance program would soften the cost blow for at least some patients. But, he added, "the increased financial burden could possibly be reflected on the insured through increased insurance premiums."

Cohen indicated that a second company has now submitted a marketing application for colchicine as gout prophylaxis.

"We are hopeful FDA will conduct an expedited review process so that possible cost relief is available to our patients," Cohen wrote.

paul leber, md - Oct 07, 2010
I'm a 70+ yo physician who has had gout for over 15 years. My urate levels on allopurinol are about 5 mg/dL, but I still require 1.2 mg a day of colchicine to remain free of acute attacks. Over the past 5 years or so, my annual cost for colchicine has been about $ 35 dollars. If I have to switch to Colcrys, my estimated annual cost will rise to about $3650. I'm mindful that our Federal Drug regulatory law is intended to ensure the safety and efficacy of the drug supply, but how does a regulatory decision that creates a situation in which URL Pharma is free to charge an exorbitant price for a use of colchicine it didn't even evaluate serve the public interest? Makes no sense, but given the way things are going, I'm hardly surprised.