New England Journal of Medicine

The New England Journal of Medicine (NEJM) published a Perspective on April 14, 2010 that contained numerous inaccuracies and misleading assertions about COLCRYS® and our substantial efforts to bring patients and physicians a better and safer colchicine. Listed below are the false statements from the NEJMPerspective, followed by our responses to correct those statements. To access the full text of the original NEJMPerspective, without our corrections.

Incentives for Drug Development — The Curious Case of Colchicine

Posted by NEJM • April 14th, 2010

Aaron S. Kesselheim, M.D., J.D., and Daniel H. Solomon, M.D., M.P.H.

NEJM: “In July 2009, the Food and Drug Administration (FDA) officially announced what physicians have long known — that the drug colchicine can effectively treat acute flares of gouty arthritis.”

URL Pharma Response: This Perspective begins with a misleading statement. The truth is that FDA announced a lot more “in July 2009” than just “what physicians have long known.”

In a July 2009 press release announcing the approval of Colcrys, the FDA stated, “During the drug application review, FDA identified two previously uncharacterized safety concerns associated with the use of colchicine (marketed as Colcrys). First, FDA analyzed safety data for colchicine from adverse events reported to the Agency, the published literature, and company-sponsored pharmacokinetic and drug interaction studies. This analysis revealed cases of fatal colchicine toxicity reported in certain patients taking standard therapeutic doses of colchicine and concomitant medications that interact with colchicine, such as clarithromycin. These reports suggest that drug interactions affecting the gastrointestinal absorption and/or hepatic metabolism of colchicine play a central role in the development of colchicine toxicity.”

“Second, data submitted supporting the safety and efficacy of Colcrys in acute gout flares demonstrated that a substantially lower dose of colchicine was as effective as the higher dose traditionally used. Moreover, patients receiving the lower dose experienced significantly fewer adverse events compared to the higher dose.”(See Colchicine (marketed as Colcrys) Information)

In “Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys),” again “in July 2009,” FDA stated that “oral colchicine has been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.” Under “Information for patients, family and caregivers” in the same document, FDA also stated, “Understand that life-threatening and fatal drug interactions can occur with Colcrys if it is given with certain medications. These interactions can occur even at prescribed Colcrys doses, and with medications that are given for a limited time, such as antibiotics.” The Agency also counseled patients to “Avoid consuming grapefruit and grapefruit juice while using colchicine.”

NEJM: “The plant from which colchicine is derived was first used as a therapeutic agent for gout more than 3000 years ago in ancient Greece, and the tablet form has been widely available as a generic prescription drug in the United States since the 19th century.”

URL Pharma Response: This statement is not true. There has never been a “generic” colchicine. The authors are calling marketed unapproved colchicine drug products “generics.” This statement by the authors demonstrates a lack of understanding of one of the most fundamental issues with unapproved colchicine in particular and unapproved drugs in general. Generic drugs have been reviewed and approved by the FDA. Unapproved drugs are illegal. Unapproved colchicine products lack FDA controls on potentially toxic impurities, sources of raw material, labeling to warn about drug-drug interactions, dosage adjustments to implement in the face of drug-drug interactions, and manufacturing and chemistry controls. An FDA Alert, issued upon the approval of Colcrys on July 30, 2009, states, “FDA has now approved the first single-ingredient oral colchicine product, Colcrys, for the treatment of familial Mediterranean fever (FMF) and acute gout flares.”

A March 3, 2010 letter from the Center for Drug Evaluation and Research (CDER) of the FDA states, “Of important note, the colchicine products you are referring to in your communication to FDA are not “generic” drugs. By definition, generic drugs are those evaluated and approved by FDA to demonstrate bioequivalence to a brand name reference product. Healthcare professionals and consumers can be assured that FDA-approved generic drug products have met the same quality, strength, purity and stability as brand-name drugs. Additionally, the generic manufacturing, packaging, and testing sites must meet the same quality standards as those of brand-name drugs. These colchicine products have not been evaluated and approved by FDA. They are unapproved drugs, not generic medications, and neither their safety nor their efficacy can be assured.”

NEJM: “On the basis of evidence that had built up over the years, numerous consensus guidelines recommended colchicine as an effective second-line treatment for gout — for example, in patients who had adverse effects from nonsteroidal antiinflammatory drugs.”

URL Pharma Response: This statement is not true. The reference cited is guidance from the European League Against Rheumatism (EULAR). The EULAR reference states, “Oral colchicine and/or NSAIDs are first line agents for systemic treatment of acute gout.” The reference that the authors cite does not relegate colchicine as a “second-line treatment for gout.” At a minimum, this demonstrates faulty research by the authors. Also, EULAR states, “In the absence of contraindications an NSAID is a convenient and well accepted option.” But that is a European recommendation. In the US, NSAIDs carry two Boxed Warnings for heart attack/stroke and for GI bleeding.

NEJM: “It came as a surprise to many patients and physicians that the FDA not only approved the new version of colchicine (Colcrys) but also granted the manufacturer, Philadelphia-based URL Pharma, 3 years of market exclusivity for this ancient drug.”

URL Pharma Response: Patients were getting sick or even dying from this “ancient drug” until URL Pharma decided to test the old beliefs, risk the resources, make the discoveries, and save millions of patients from adverse reactions. In our society, people are rewarded for making advancements.

NEJM: “The possibility of such an exclusivity period arose because colchicine, despite its longevity, had never been officially approved by the FDA for a particular indication.”

URL Pharma Response: “Longevity” implies trust earned through historical usage, but illegal, unapproved colchicine is not a benign drug by any definition. Most patients experience gastrointestinal toxicity resulting in diarrhea that is often severe (Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-304.). Additionally, 169 deaths have been associated with colchicine, as reported by FDA. Also, even if a particular physician or patient has not had an adverse reaction on unapproved colchicine, every physician should know from medical school that anecdotal evidence is not to be relied upon for making science-based decisions. Using “longevity” as a proof that advancements were not needed is an adoption of anecdotal evidence and purely non-scientific and faulty thinking. The March 3, 2010 letter from FDA states “the approval of Colcrys demonstrates that while a patient or prescriber may believe that a drug is safe or effective because of individual experience, such subjective experiences can be misleading and insufficient to establish safety and effectiveness. Instead, FDA relies on carefully designed clinical trials that weigh the risks and benefits of taking a drug compared with the risks and benefits of taking a placebo or another accepted therapy. Carefully designed clinical trials have repeatedly demonstrated that the safety and effectiveness of drugs cannot be adequately established from anecdotal evidence or consumer or prescriber preferences.”

Also, what do the authors mean when they say that colchicine has never been “officially approved by the FDA”? This implies that there was some “unofficial” approval by FDA but that is a false implication. The drug was never approved by FDA before Colcrys, so there were no FDA controls on any impurities, such as those resulting from the formation of lumi-colchicine, nor were there any FDA-approved controls on testing and manufacturing procedures or on dangerous, misleading labeling.

NEJM: “The 1938 Food, Drug, and Cosmetic Act required that all new drugs be approved by the FDA for safety before being introduced on the market, but it allowed drugs that were already on the market to remain available. Starting in the 1960s, the FDA began to evaluate the safety and efficacy of older drugs, looking first at drugs that might pose the greatest threat to public health or that appeared to lack effectiveness. Colchicine was one of a number of drugs that the FDA never formally evaluated, although the agency did review and approve a combination pill containing colchicine and probenecid (Col-Probenecid, Watson Laboratories) for use in gout.

In 2007, URL Pharma organized pharmacokinetic studies testing its version of colchicine in healthy volunteers and a randomized, controlled trial involving 185 patients with acute gout.”

URL Pharma Response: URL Pharma did not simply “organize” studies. This characterization, by the authors, unfairly minimizes our efforts and contributions. We designed and conducted 17 human clinical studies that required extensive scientific planning and analysis and millions of dollars of expense and risk. Our efforts resulted in many discoveries that have positively changed the safety profile of colchicine use. Those changes are reflected in our FDA-approved formulation of colchicine, called Colcrys. For example, FDA wrote in July 2009 (FDA Approves Colchicine for Acute Gout, Mediterranean Fever – Agency also provides new information to physicians regarding safe use of drug) “Physicians historically have given colchicine hourly for acute gout flares until the flare subsided or they had to stop treatment because the patient began experiencing gastrointestinal problems. A dosing study required as part of FDA approval demonstrated that one dose initially and a single additional dose after one hour was just as effective as continued hourly dosing for acute gout flares, but much less toxic. As a result, the drug is being approved for acute gout flares with the lower recommended dosing regimen.

The FDA is alerting healthcare professionals to this new dosing regimen and also warning about the potential for severe drug interactions when patients take colchicine.”

In October 2009, FDA published (FDA Patient Safety News: Show #91, October 2009 – New Colchicine Product and Dosing Regimen)

“Colchicine has historically been given every hour for acute gout flares, either until the flare subsided or treatment had to be stopped because the patient developed gastrointestinal problems. But a dosing study conducted as part of the approval of Colcrys demonstrated that one initial dose and a single additional dose after one hour was just as effective and much less toxic. Healthcare professionals should use this lower recommended dosing regimen to treat acute gout flares.”

This FDA publication continued with the following additional safety information that resulted from discoveries from our research at URL Pharma.

“Healthcare professionals should also be aware that colchicine interacts with other drugs, including P-glycoprotein and strong CYP3A4 inhibitors such as cyclosporine and clarithromycin. This can lead to serious or even fatal colchicine toxicity, particularly if a patient has renal or hepatic impairment. And so concomitant use of colchicine and P-glycoprotein or strong CYP3A4 inhibitors is contraindicated in these patients. For patients with normal renal and hepatic function, consider interrupting colchicine therapy or reducing the dose if the patient needs treatment with a P-glycoprotein or a strong CYP3A4 inhibitor.”

On April 27, 2010, FDA sent out emails titled “HIV/AIDS Update – New label information affecting all approved protease inhibitors for treatment of HIV” in which FDA notified people of the following dosage changes, for patients suffering from HIV/AIDS and gout, which again resulted from research conducted by URL Pharma. The FDA required protease inhibitor labeling to be amended as follows:

Colchicine:

Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Note: Lexiva (fosamprenavir) without ritonavir: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout-flares: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Note: Lexiva without ritonavir: if the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day

Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Note: Lexiva without ritonavir: maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).”

Clearly URL Pharma’s discoveries have made a positive impact for patients.

NEJM: “The combined findings of these studies confirmed the drug’s safety and efficacy.”

URL Pharma Response: Our studies did not simply “confirm” the drug’s safety and efficacy. Until our research, there was only one placebo-controlled colchicine trial in acute gout (Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-304). All of the patients in that trial who received colchicine developed toxicity. We discovered that millions of patients have been unnecessarily exposed to toxic dosages of this drug. We found many drug-drug interactions that have been responsible for deaths. We received approval for dosage adjustments that protect patients from these drug-drug interaction increases in blood levels. We discovered that dialysis does not treat overdosage, despite the continued recommendation on the label of unapproved colchicine to use dialysis for this purpose.

We did not just “confirm” as these authors state. We provided the evidence to rewrite the textbooks. In a July 30, 2009 press release to “Rheumatological healthcare professionals”, FDA stated “FDA analyzed safety data for colchicine from adverse events reported to the Agency, the published literature, and company-sponsored pharmacokinetic and drug interaction studies. This analysis revealed cases of fatal colchicine toxicity reported in certain patients taking standard therapeutic doses of colchicine and concomitant medications that interact with colchicine, such as clarithromycin. These reports suggest that drug interactions affecting the gastrointestinal absorption and/or hepatic metabolism of colchicine play a central role in the development of colchicine toxicity. Data submitted supporting the safety and efficacy of Colcrys in acute gout flares demonstrated that a substantially lower dose of colchicine was as effective as the higher dose traditionally used. Moreover, patients receiving the lower dose experienced significantly fewer adverse events compared to the higher dose.

Based on this information, FDA has included important safety considerations in the approved prescribing information to assure safe use of Colcrys and is providing background information, a data summary and recommendations in this alert.”

On July 30th, 2009, in a publication titled “Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys)”, FDA wrote “the manufacturer of Colcrys submitted data from a clinical trial to evaluate the safety and efficacy of a low-dose regimen of oral colchicine for treatment of acute gout flares compared to the traditional high-dose regimen”. Furthermore, that publication stated “These findings suggest that prior use of high-dose colchicine may have exposed patients to increased toxicity with no greater efficacy than the low-dose regimen. Based on this trial, FDA recommends that healthcare professionals prescribe the approved Colcrys dose”.
Our studies obviously did a lot more than just “confirm.”

NEJM: “The randomized, controlled trial, which followed patients for 1 week, showed that a shortened dosing regimen produced good symptom management in patients with gout while leading to fewer adverse events than a longer regimen.2 Its effect size (38% in the group receiving shortened dosing of colchicine vs. 16% in the placebo group) was similar in magnitude to that of a previous randomized, controlled trial of colchicine for the treatment of acute gout (73% vs. 36%).3 According to earlier reports, colchicine’s adverse-event profile included diarrhea and vomiting, and these effects were also reported in the new trial.”

URL Pharma Response: Our dosing regimen is not just “shortened” – it is vastly different. Two tablets followed by one tablet one hour later is very different than one tablet per hour for 8 hours or until diarrhea develops. The authors also ignore the fact that, prior to our trial, there had never been a clinical trial of low-dose colchicine. If the authors have evidence of any double blind, placebo controlled, low-dose colchicine trials other than our own, they should produce it. Regardless, the authors grossly mischaracterize our work. It is misleading to say that our trial had “colchicine’s adverse-event profile” of diarrhea and vomiting as in “earlier reports” without mentioning that our trial reduced the incidence of diarrhea from 77% of patients to statistically no different than placebo and “severe adverse reactions” from 19% of patients to zero.

NEJM: “The reduced rate of side effects in the group receiving the shortened regimen confirmed the usefulness of a dosing adjustment that had been recommended in guidelines from one of the major rheumatology professional societies.”¹

URL Pharma Response: This is another blatant misrepresentation of the facts and demonstrates a lack of understanding of basic pharmacology or review of the data. The cited reference states that “Low doses (for example, 0.5 mg three times daily) may be sufficient for some patients with acute gout.” Colcrys is 0.6 mg, not 0.5 mg. Anyone with a basic understanding of pharmacology knows that for an immediate release product, taking one tablet three times a day should not be expected to yield the peak blood levels (Cmax) as two tablets taken at one time followed by one tablet one hour later. Our novel dosing regimen achieved the same Cmax as one tablet per hour for eight hours, but had a much lower total body drug exposure (AUC). Also, taking one tablet three times a day, with no limit on the number of days (per the EULAR recommendation) is very different than three tablets in one hour then no more drug thereafter. The authors falsely state that the Colcrys dosing regimen “had been recommended in guidelines from one of the major rheumatology professional societies.”

Furthermore, the major rheumatology society in the US, the American College of Rheumatology (ACR), does not have any formal guidelines for the dosing of colchicine to treat gout flares. Leading rheumatology textbooks, which were written before the discoveries from our research, recommend high doses of colchicine (see Hellmann D. Chapter 67. In: Imboden J, Hellmann D, Stone J, editors. Current Rheumatology and Treatment, Second Edition. New York City: The McGraw-Hill Companies, Inc.; 2007).

NEJM: “On the basis of this new trial, combined with the previously published evidence, the FDA approved Colcrys for treatment of acute gout. Because this was technically a new indication for the drug, the Waxman–Hatch Act authorized the FDA to award the company 3 years of market exclusivity — an incentive that the agency believes could encourage voluntary compliance with the drug-approval process.

At the same time, under the Orphan Drug Act, the manufacturer also received 7 years of market exclusivity for the use of Colcrys in the treatment of familial Mediterranean fever (FMF), a genetic inflammatory disorder that affects only about 100,000 patients worldwide. The Orphan Drug Act provides federal grant funding and tax credits for clinical trial costs, as well as market exclusivity, to encourage research into rare diseases. The orphan-drug incentive is not restricted to new products: currently available drugs that are approved for a new orphan indication can also be granted exclusivity. For example, thalidomide, a drug designed as an antiemetic agent that fell out of favor in the 1960s after it was linked to birth defects, was approved in 1998 as an orphan product for the treatment of leprosy and in 2006 for the treatment of multiple myeloma. In the case of FMF, the usefulness of colchicine in helping to control debilitating attacks of fever and abdominal pain was already established, and the orphan indication for Colcrys was approved on the basis of a review of previously collected data, along with additional limited safety information from the pharmacokinetic trials.”

URL Pharma Response: There was nothing “limited” about the safety information we uncovered. Our safety discoveries, especially for drug-drug interactions, should be especially helpful to FMF patients who take high doses of colchicine. We were the ones to design and develop the studies, take the risks, make the investment, and now help FMF patients.

NEJM: “The implications of market exclusivity for the public health can be substantial.”

URL Pharma Response: Yes, market exclusivity is a powerful tool that congress has established to incentivize the development and approval of clinically proven safe and effective drugs. Even with the incentive of market exclusivity, URL Pharma was the only company to take the risk, make the investment, and help millions of patients. The manufacturers of unapproved colchicine just continue to illegally market and sell their products and yet have never conducted even a single study nor made any contribution to improving the safety of colchicine.

NEJM: “After the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market and raised the price by a factor of more than 50, from $0.09 per pill to $4.85 per pill.4 These increased prices directly affect the availability of the drug to patients with gout or FMF who have long been using colchicine safely in an evidence-based manner.”

URL Pharma Response: This statement is untrue. Our Patient Assistance Program protects virtually every patient and is one of the most generous programs ever offered by the pharmaceutical industry. It is only individuals with income greater than 600% of the Federal Poverty Level, who decide to not purchase health insurance, that are not covered for their Colcrys purchases. Also, it is false and misleading to state that we “raised the price” as there was no price for an approved colchicine product prior to Colcrys. The price of a safe, legal, FDA-approved drug, backed by research, discovery, and the financial risks and intellectual commitment to achieve such advancements, cannot be compared to that of an illegal, unapproved product. As shown above, anecdotal information cannot be relied upon as medical evidence, and doing so endangers patients. Additionally, 169 deaths, millions of cases of diarrhea, and other unnecessary toxic reactions do not constitute “using colchicine safely in an evidence-based manner.”

NEJM: “Exclusivity can also affect health care delivery more broadly. According to the Centers for Medicare and Medicaid Services, state Medicaid programs filled about 100,000 prescriptions of colchicine in 2007 and paid approximately $1 million for the drug. Use of the new brand-name colchicine could add as much as $50 million per year to these insurance programs’ budgets at a time when they are addressing the rising costs of health care by reducing some services or raising eligibility thresholds.

URL Pharma Response: “The colchicine case demonstrates some important limitations of our current system for rewarding innovation in the pharmaceutical market. Incentive programs like those enacted by the Waxman–Hatch Act and the Orphan Drug Act offer market exclusivity to encourage drug research, but these rewards are not calibrated to the quality or value of the information produced.”

This is unsubstantiated opinion and criticism and the authors should consider the perspective of patients taking colchicine before deciding on the quality and value of having a safer and better product available. FDA wrote on March 3, 2010, “The fatalities associated with unapproved oral colchicine products are among many other serious adverse events associated with unapproved drugs. These adverse events, in addition to being tragic and in many cases preventable, place a serious burden on the healthcare system. The Agency is particularly concerned because labeling of many unapproved drugs does not adequately convey the risks of the drugs and how to best use drugs safely, such as what kind of other medicines should be avoided at the same time to lower the chances of side effects. When a drug is not used properly because the labeling is inadequate, there is a cost to patients and the healthcare system because of the care required as a result of adverse events.”

NEJM: “Although the goals underlying the development of Colcrys were sound — few would argue against the need to comply with FDA requirements and the need to ensure the safety and efficacy of all prescription drugs — and the manufacturer seems to have followed FDA guidance, the reward appears to be out of proportion to the level of investment. More important, there is no evidence of any meaningful improvement to the public health.

URL Pharma Response: On the contrary, URL Pharma’s 17 clinical phase 1 trials were considered so important to public safety, that on April 27, 2010, the FDA mandated all approved protease inhibitors for the treatment of HIV-1 infection to include relevant URL Pharma drug-drug interaction information on their product labeling. (http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm209920.htm) Some of this information was also on the original FDA-approved Colcrys package insert.

NEJM: “We believe that when creating and implementing incentives for private investment in drug research, policymakers should seek to avoid policies that can lead to such outcomes. An alternative solution, probably much less expensive, would be for the FDA or the National Institutes of Health to fund trials that address outstanding questions related to widely available drugs such as colchicine.”

URL Pharma Response: The authors have made an interesting and bizarre contradiction to the major theme of this entire Perspective. Throughout this Perspective, the authors have claimed that nothing new was discovered by us for colchicine. But now the authors state that the government should “fund trials that address outstanding questions related to…drugs such as colchicine”. So which is it, did we not make new discoveries or are the authors just complaining that the government should have done the research instead of us to address “outstanding questions”?.

NEJM: “In addition, it is important to remember that the financial burden of market-exclusivity incentives in the United States falls primarily on the patients who are given prescriptions for the drug, or their insurers. Consequently, it seems reasonable to expect that costly new drugs or increases in drug prices would be accompanied by a substantial benefit in disease management to be enjoyed by these patients. This standard is not met by Colcrys; in this instance, the public may bear considerable costs for a poorly executed administrative goal.”

URL Pharma Response: The authors of this NEJM Perspective have made a severely distorted presentation of the facts, as demonstrated throughout this document, to support their arbitrary conclusion about the “standard” that they claim was not met. It seems very clear that they had this conclusion in mind when they started to write this Perspective and then they used misrepresentations of facts, and literary devices, to dismiss and distort the contributions that we have made. This could be related to the lack of disclosure on the “Disclosure forms” that are the subject of the next line in their publication.

NEJM: “Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

URL Pharma Response: The disclosure form is inaccurate for one of the authors and we wonder whether there has been an attempt to hide bias.
The disclosure form used at the NEJM⁵ states that “The goal of this [form] is to provide information for our reviewers and readers about your interactions with entities in the biomedical arena that could be perceived to influence, or that give the appearance of potentially influencing, what you wrote in the submitted work. You should disclose interactions with ANY entity that could be considered broadly relevant to the work.”
Dr. Daniel Solomon failed to disclose numerous important facts on his conflict disclosure form for this NEJM Perspective about gout. For example:

D Dr. Solomon did not disclose the financial support that he received from another company, Savient, which has a drug for gout that is awaiting FDA approval.
Dr. Solomon did not disclose the financial support that he has received from another company, Pfizer, which has a drug in Phase III trials for gout.

Each of these associations “could be perceived to influence” the work that Dr. Solomon submitted. His interest in, and association with, potential commercial competitors with other gout medications are potential conflicts that should have been disclosed. Moreover, in previous disclosure forms from Dr. Solomon, for unrelated published articles, Dr. Solomon did disclose his associations and various benefits, including salary support, from other sponsors of gout products. However, in this article in which Dr. Solomon has made numerous misrepresentations about our research for a gout product, Dr. Solomon did not disclose these conflicts.

NEJM Source Information
From the Division of Pharmacoepidemiology and Pharmacoeconomics (A.S.K.) and the Division of Rheumatology (D.H.S.), Brigham and Women’s Hospital, and Harvard Medical School — both in Boston.
This article (10.1056/NEJMp1003126) was published on April 14, 2010, at NEJM.org.
References
1. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. II. Management. Ann Rheum Dis 2006;65:1312-1324. [Free Full Text]
2. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-1068.
3. Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-304. [Web of Science][Medline]
4. Mutual Pharmaceutical Co. v. Watson Pharmaceuticals, 2009 WL 3401117 (C.D. Calif., Oct. 19, 2009).
5. http://content.nejm.org/cgi/data/NEJMp1003126/DC1/1