老藥off label use, 但要藥廠申請認證，藥變得貴鬆鬆，誰得利?
Spotlight on Colchicine: The Colcrys Controversy
A very old drug gets new marketing exclusivity — at what cost?
On April 16, 2010, we summarized an article on an industry-sponsored randomized trial of colchicine for acute gout flares (JW Gen Med Apr 16 2010). But why did a drug company choose to perform this study? The answer to that question sheds light on a new controversy surrounding an old drug.
In 2006, the FDA launched the "Unapproved Drugs Initiative," which targeted old drugs that had never been approved by the FDA. The rationale was that older unapproved drugs, including colchicine, deserve as much scrutiny for efficacy and safety as do newer drugs. In response to this initiative, the drug company URL Pharma decided to conduct pharmacokinetic and clinical research on colchicine with the intention of bringing it to market as a brand-name product. The clinical trial covered by Journal Watch General Medicine was sponsored by URL Pharma and was a key factor in the FDA's approval of brand-name colchicine (Colcrys) in 2009.
In that trial, patients with acute gout were randomized to receive an oral "low-dose" colchicine regimen (1.2-mg dose initially, followed by a single 0.6-mg dose 1 hour later), a "high-dose" colchicine regimen (1.2-mg dose initially, followed by 0.6 mg hourly for 6 hours), or placebo. At 24 hours, patients in the low-dose group were significantly more likely than placebo recipients to report a ≥50% reduction in pain (38% vs. 16% of patients), and side effects were similar in those two groups. In contrast, patients who received hourly dosing for 6 hours had substantial gastrointestinal toxicity but no additional benefit compared with low-dose patients.
The controversy enters the picture here: URL Pharma has been given market exclusivity for 3 years, and companies that produce "nonapproved" colchicine — the products that we've prescribed for decades — are required to phase out production in 2010. Patients will experience this transition as an extraordinary increase in the cost of the drug: Colcrys sells for US$5 per pill, whereas nonapproved colchicine costs pennies per pill.
URL Pharma, the FDA, and healthcare professionals (notably the physician leadership of the American College of Rheumatology) have been engaged in a rather testy debate about these developments. The drug company and the FDA defend their position that efficacy and safety are enhanced because Colcrys is manufactured with FDA oversight and because the prescribing information provides guidance on indications, dosing, and drug interactions. In contrast, the American College of Rheumatology contends that, with responsible prescribing, nonapproved colchicine is safe and effective and that patients who cannot afford Colcrys will suffer. URL Pharma has countered with a program to assist low-income patients.
Practical clinical issues have been overlooked in this debate. The FDA-approved prescribing regimen for Colcrys in patients with acute gout flares is the low-dose regimen from the randomized trial — 1.2 mg initially, followed by 0.6 mg at 1 hour — and nothing else. In the clinical trial, assessment of efficacy ended at 24 hours, because providing ongoing placebo for a painful condition was considered to be unethical. However, most colchicine-treated patients still had substantial pain at 24 hours. How should we manage those patients, who will need further treatment? Switching to a nonsteroidal anti-inflammatory drug (NSAID) or prednisone makes no sense: Most clinicians consider using colchicine for acute gout precisely in patients with contraindications to NSAIDs or prednisone, which are the usual first-line oral treatments. Stated another way, why would we pick an initial treatment regimen that likely will require "rescue" therapy within 24 hours? A 1-week comparison between a low-dose colchicine regimen and a standard NSAID regimen would have been far more clinically relevant than the comparison in the published study.
In the end, I doubt whether the marketing of Colcrys will change the way most of us manage acute gout flares. Indeed, clinicians generally prescribe colchicine not for acute gout but rather for long-term prophylaxis. In fact, the FDA has approved Colcrys for prophylaxis at a dose of 0.6 mg once or twice daily. It's the cost of long-term prophylaxis — $1800 to $3600 per year at full price — that will likely have patients and clinicians scrambling during the next few years. For more on this topic, we invite you to listen to our interview with Aaron S. Kesselheim, MD, JD, MPH (Brigham and Women's Hospital, Boston, MA)
A very old drug gets new marketing exclusivity — at what cost?
On April 16, 2010, we summarized an article on an industry-sponsored randomized trial of colchicine for acute gout flares (JW Gen Med Apr 16 2010). But why did a drug company choose to perform this study? The answer to that question sheds light on a new controversy surrounding an old drug.
In 2006, the FDA launched the "Unapproved Drugs Initiative," which targeted old drugs that had never been approved by the FDA. The rationale was that older unapproved drugs, including colchicine, deserve as much scrutiny for efficacy and safety as do newer drugs. In response to this initiative, the drug company URL Pharma decided to conduct pharmacokinetic and clinical research on colchicine with the intention of bringing it to market as a brand-name product. The clinical trial covered by Journal Watch General Medicine was sponsored by URL Pharma and was a key factor in the FDA's approval of brand-name colchicine (Colcrys) in 2009.
In that trial, patients with acute gout were randomized to receive an oral "low-dose" colchicine regimen (1.2-mg dose initially, followed by a single 0.6-mg dose 1 hour later), a "high-dose" colchicine regimen (1.2-mg dose initially, followed by 0.6 mg hourly for 6 hours), or placebo. At 24 hours, patients in the low-dose group were significantly more likely than placebo recipients to report a ≥50% reduction in pain (38% vs. 16% of patients), and side effects were similar in those two groups. In contrast, patients who received hourly dosing for 6 hours had substantial gastrointestinal toxicity but no additional benefit compared with low-dose patients.
The controversy enters the picture here: URL Pharma has been given market exclusivity for 3 years, and companies that produce "nonapproved" colchicine — the products that we've prescribed for decades — are required to phase out production in 2010. Patients will experience this transition as an extraordinary increase in the cost of the drug: Colcrys sells for US$5 per pill, whereas nonapproved colchicine costs pennies per pill.
URL Pharma, the FDA, and healthcare professionals (notably the physician leadership of the American College of Rheumatology) have been engaged in a rather testy debate about these developments. The drug company and the FDA defend their position that efficacy and safety are enhanced because Colcrys is manufactured with FDA oversight and because the prescribing information provides guidance on indications, dosing, and drug interactions. In contrast, the American College of Rheumatology contends that, with responsible prescribing, nonapproved colchicine is safe and effective and that patients who cannot afford Colcrys will suffer. URL Pharma has countered with a program to assist low-income patients.
Practical clinical issues have been overlooked in this debate. The FDA-approved prescribing regimen for Colcrys in patients with acute gout flares is the low-dose regimen from the randomized trial — 1.2 mg initially, followed by 0.6 mg at 1 hour — and nothing else. In the clinical trial, assessment of efficacy ended at 24 hours, because providing ongoing placebo for a painful condition was considered to be unethical. However, most colchicine-treated patients still had substantial pain at 24 hours. How should we manage those patients, who will need further treatment? Switching to a nonsteroidal anti-inflammatory drug (NSAID) or prednisone makes no sense: Most clinicians consider using colchicine for acute gout precisely in patients with contraindications to NSAIDs or prednisone, which are the usual first-line oral treatments. Stated another way, why would we pick an initial treatment regimen that likely will require "rescue" therapy within 24 hours? A 1-week comparison between a low-dose colchicine regimen and a standard NSAID regimen would have been far more clinically relevant than the comparison in the published study.
In the end, I doubt whether the marketing of Colcrys will change the way most of us manage acute gout flares. Indeed, clinicians generally prescribe colchicine not for acute gout but rather for long-term prophylaxis. In fact, the FDA has approved Colcrys for prophylaxis at a dose of 0.6 mg once or twice daily. It's the cost of long-term prophylaxis — $1800 to $3600 per year at full price — that will likely have patients and clinicians scrambling during the next few years. For more on this topic, we invite you to listen to our interview with Aaron S. Kesselheim, MD, JD, MPH (Brigham and Women's Hospital, Boston, MA)
Colchicine 用在gout, 居然也是off label use->有個藥廠花錢幫FDA做了trial，買下了gout的indication, 一顆colchicine就賣成5美元，比原來貴了百倍。2010 年之後，全美國只要是gout的適應症，colchicine就一定要用它們家的………
回覆刪除賣礦泉水的公司要不要幫FDA做個trial? 看喝水的BA/BE, adverse effect, 以後只要喝水就一定只能喝他家的水?
這和carbamazepine一樣，本來就可以用在neuralgia，就因為是老藥沒利潤，沒人申請indication，搞得藥害沒人承擔，大家現在只敢用沒有用的NSAID，不然就用貴鬆鬆的garbapentin
⋯⋯
官僚介入專業的荒謬，就是如此……我沒說哪個署長