The Food, Drug and Cosmetics Act of 1938 and the 1962 amendments to that law charged the Food and Drug Administration (FDA) with approving drugs that are safe and effective. Colchicine is one of many medications that was unapproved and was widely available before the act took effect. In June of 2006, the FDA and its Center for Drug Evaluation and Research (CDER) undertook the Unapproved Drugs Initiative to bring more of these older drugs into compliance.
“Our mission is to ensure that safe and effective drugs are available,” writes Michael Levy, Esq., director of CDER’s Division of New Drugs and Labeling Compliance, in an e-mail response to questions. “Since the initiative began, marketers of unapproved drugs are on notice that addressing risks from unapproved drugs is a high priority, and that the agency plans to ensure all products on the prescription drug market comply with current requirements for safety and efficacy.”
The approval pathways a pharmaceutical company takes to gain approval to market existing unapproved drugs are the same as for new drugs. Generally, all new prescription drugs must go through the New Drug Approval (NDA) process before being legally marketed. Since the initiative started, over 500 unapproved products have been removed from the market and more than 70 older, unapproved drugs have earned approval.
URL Pharma and the Rheumatology Market
URL Pharma, based in Philadelphia, decided to focus on colchicine, among other products. “We looked at the universe of unapproved drugs, searching for medications presenting safety risks or where we had a chance to improve efficacy,” says Richard Roberts, MD, president, chair, and CEO of URL Pharma. “As a physician, I was shocked that colchicine, with all of the toxicities taught [to] every doctor since medical school, was not an approved medication.”
In July 2009, the FDA granted URL Pharma approval to market a form of colchicine for acute gout and familial Mediterranean fever (FMF). An indication for gout flare prophylaxis followed in October. They were given three-year marketing exclusivity for gout and a seven-year term for FMF as an orphan drug. The branded medication called Colcrys sells for about $5.00 a tablet, or roughly 50 times the cost of the unapproved version.
The ACR, responding to member concerns about the new pricing, acted quickly, first consulting with the FDA to discuss its concerns, and then contacting URL Pharma. (A summary of the ACR’s discussion with the FDA is available online at www.rheumatology.org/advocacy/colchicine_ fda.pdf.) The ACR worked closely with URL Pharma on changes to its Colcrys patient assistance program (PAP), resulting in wider coverage. The ACR has also obtained a list of other colchicine makers and has encouraged them to go through the approval process for other indications.
The information URL gathered to file their NDA is a source of debate, with many rheumatologists suggesting that URL had not performed enough research to justify the price increase. These rheumatologists point to the limited information coming from a small dosing study showing that low-dose colchicine was a better treatment for acute gout than dosing to toxicity. These data were part of the NDA.
The study, published in Arthritis & Rheumatism (A&R), was a double-blind, placebo-controlled trial in acute gout comparing low dose (1.8 mg total over one hour) and high dose (4.8 mg over six hours) colchicine versus placebo. The researchers found the low-dose colchicine had comparable pharmacodynamics and efficacy as to high-dose administration and was comparable to placebo in side effects.1
“No one treats acute gout with that much colchicine anymore,” notes Edward Fudman, MD, a rheumatologist in private practice in Austin, Texas. “[URL Pharma] set up a straw man to knock it down.”
Colcrys Patient Assistance Program
One question that keeps being asked regarding the approval of Colcrys and the rise in price that followed is, What will the impact on patients be? URL Pharma is offering certain patients coverage assistance under their PAP.
For Patients on Government Programs
The program provides a Colcrys prescription with a co-pay of $5 per month to those who are uninsured or Medicare Part D patients with household incomes of up to four times the federal poverty level ($88,000 for a family of four). The plan has a co-pay of $25 per month for similar patients with household incomes between four and six times the poverty level ($132,000 for a family of four).
A patient’s physician must have recommended Colcrys and the patient must have a diagnosis of gout, acute gout, or familial Mediterranean fever (FMF). Patients can visit needymeds.org for links to the Colcrys PAP application or apply via phone at 1-888-811-8423.
Because of federal regulations, patients will be required to verify that they will not claim co-pay payments on Medicare, Medicaid, or other state or federal programs. This lets Medicare patients get their medications without having to worry about entering the “donut hole” in Part D. The patient only has to apply once each year, and the initial approval process takes up to two weeks. Both the patient and physician must sign the application. For refills, the patient calls the phone number above. The refilled prescription will generally be sent within 48 hours directly to the prescribing physician.
Private Insurance Assistance
Patients with private insurance who do not qualify for the PAP may benefit from co-pay assistance coupons. Many patients can have their co-pay reduced to $25. More information on coupons is available by calling 1-800-657-7613.
“We are in contact with many patient groups and the American College of Rheumatology on structuring the program to best meet the needs of our patients,” says Dr. Roberts. “We are proud of our program, which is among the most generous of its kind offered by any pharmaceutical company.”
Depth of NDA Research Questioned
There was also concern among rheumatologists when the price of Colcrys was announced.
“There are over 16,000 articles on Pub Med for colchicine, with 254 indexed as clinical trials,” says Dr. Fudman. “Doing one trial in patients and a few drug interaction studies doesn’t justify marketing exclusivity and a 50-fold increase in price.”
Others pointed to URL Pharma’s use of previously published trials to support the effectiveness of Colcrys in submissions to the FDA. “These studies were not done with the current formulation of Colcrys,” says Chris Morris, MD, a rheumatologist in private practice in Kingsport, Tenn. “They used information that, by their own definition, was gained using unapproved and illegal medications.”
In response to these issues, URL Pharma noted that only one earlier study was double-blinded and placebo-controlled, and only URL conducted a blinded/controlled dose ranging study. Previous trials were the only available alternative for the FMF indication because it would be unethical to place patients needing colchicine on a placebo.
Dr. Morris notes that Colcrys is one of two new medications for gout approved last year. The company making febuxostat (Uloric) paid for the initial development of the molecule, as well as doing phase 1, 2, and 3 trials. In addition, their phase 3 trial included two three-year extensions. Yet Uloric costs around $120 a month and Colcrys, taken twice a day for FMF or chronic gout, costs nearly $300.
Acute Gout Focus
The research focus on acute gout only was another concern expressed by the rheumatologists interviewed here. “While the company tried to focus on acute gout, the money is in gout prophylaxis and other chronic uses of colchicine that aren’t on the FDA label,” says Dr. Fudman. “There is no way they would recoup the expense of their trials selling three tablets for a gout attack. The money is in one to two tablets daily for a long time.”
Susan Hoch, MD, a rheumatologist at the University of Pennsylvania in Philadelphia, supports this view. “Even though few rheumatologists use colchicine for acute gout, URL was able to get the [other] makers of colchicine to leave the market. As a result, patients taking colchicine chronically for gout, pseudogout, and FMF will have only the expensive Colcrys available, even though it was not studied in those conditions.”
Matthew W. Davis, MD, RPh, chief medical officer and vice president of clinical development and medical affairs at URL Pharma counters that much more work went into their NDA than the study published in A&R. URL filed the results of 17 clinical studies, including 12 phase 1 drug interaction trials and another four phase 1 trials looking at Colcrys’ pharmacokinetics. These included a large, 54-center phase 3 study.
That research led to new label warning of interactions with statin drugs, among others. URL Pharma also showed that, contrary to the labeling of unapproved colchicine, dialysis was not an appropriate treatment for overdose.
Outdated Treatment Used in NDA?
Dr. Richards disputes the contention that the use of colchicine for the treatment of acute gout is outdated. “Newer rheumatology texts, such as Current Rheumatology Diagnosis and Treatment (2nd edition) released in 2007, advocate dosing to toxicity,” he stresses.2
“There are no guidelines from the ACR or others on using colchicine in gout,” he says. “We are working on educational outreach to healthcare professionals to bring these to their attention.”
Since Colcrys was approved, URL Pharma has produced it under FDA guidelines that unapproved medications are not required to follow. This includes rigorous standards for impurities and making the medication in a facility under yellow lights. Their raw material costs are three to four times that of other colchicine manufacturers because of these requirements.
Healthcare Costs
The potential implications for the patient and healthcare costs in general are another concern of the rheumatologists interviewed. Non-approved colchicine sold for around 10 cents a tablet, while Colcrys is currently being sold for around $5.00.
URL Pharma has established a PAP to address some of the payment issues, especially as they apply to patients with limited financial resources (see “Colcrys Patient Assistance Program,” p. 27). But the rheumatologists interviewed here also raised questions about the impact on healthcare costs overall.
“The function of the PAP may be to lessen the patient complaints about costs while still keeping the prices high for insurance purposes,” says Dr. Fudman. “The system may still pay tens of millions of dollars, if not hundreds of millions, but the individual patient won’t see it.”
The spokesmen for URL Pharma both say that the company has done more to address the patient concerns than most other similar programs.
There has been tension between the company and rheumatologists. In March, URL Pharma’s general counsel sent a letter to many rheumatologists who had discussed this on the ACR Advocacy list serve, suggesting they “clarify the record” by writing to the FDA to say that they do not support the continued availability of unapproved colchicine products, and that they send URL Pharma a copy of the letter. The URL letter says that physicians have created unnecessary exposure for themselves by advocating that “illegal” colchicine remain on the market.
Some of those of who received the letter described it variously as “intimidating,” “threatening,” and “offensive.” Dr. Hoch initially withdrew her participation in this article after receiving the letter, saying that she “felt intimidated from commenting on this at all, and that I feel my freedom of speech has been violated.”
Kurt Ullman is a freelance medical journalist based in Indiana.
References
- Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High-vs low-dosing of oral colchicine for early acute gout flare: Twenty-four hour outcome results of the first randomized, placebo-controlled, dose comparison colchicine trial. Arthritis Rheum. 2010;62:1060-1068.
- Imboden J, Hellmann D, Stone J, eds. Current Rheumatology Diagnosis & Treatment. 2nd ed. New York: McGraw-Hill (Lange Medical Publications); 2007.
Unapproved Drugs Drawing FDA Attention
The Food, Drug, and Cosmetics Act of 1938 and its 1962 amendments charged the FDA with approving medications based on safety and efficacy. At the time, there were a number of drugs already available.
“In both laws there were grandfathered medications,” says Kurt Karst, JD, a partner in Hyman, Phelps, and McNamara in Washington, DC. “The law said that only medications retaining the formulation and labeling from pre-1938 were grandfathered. The FDA doesn’t believe any drug qualifies.”
The laws required the FDA to review and approve medications already being marketed—and colchicine is one such unapproved product.
Colchicine Awaiting Approval Since 1938
“Colchicine has been out there waiting for someone to seek approval since 1938,” says Karst. “Prior to the appearance of URL Pharma, it was officially an unapproved drug. [URL Pharma has] satisfied the requirements for approval and has been given market exclusivity for a period of time.” An this is not the first time in recent memory that a company has obtained approval for an unapproved, pre-1938 drug. He points to guaifenesin and quinine as examples.
Karst says URL Pharma may be successful in getting other versions of colchicine off the market. The FDA is sending out warning letters to other makers telling them to stop making colchicine.
“Unapproved” Not Same As “Generic”
Legally, other versions of colchicine remain unapproved. This is very different from generic medications, which have gone through their own approval process at the FDA.
“It is important to note that there are no ‘generic’ colchicine products,” writes Levy in an e-mail response to questions. “By definition, generic drugs are those evaluated and approved by the FDA to demonstrate to a brand name reference product. These colchicine products have not been evaluated and approved by the FDA. They are therefore unapproved drugs, not generic medications, and neither their safety nor their efficacy can be ensured.”
Karst notes that, “even though [URL Pharma has] been given seven years of marketing exclusivity for the familial Mediterranean fever indication, they only were given three years on the gout indication. After that, the FDA could approve a generic colchicine for gout if someone comes forward and applies.”
