Wall Street Journal | URL Pharma

On April 12, 2010, the Wall Street Journal published an article on colchicine and COLCRYS® that contained some correct information but also communicated a number of inaccuracies. We have reprinted the article below and interposed our responses to correct and clarify these inaccuracies.

An Old Gout Drug Gets New Life and a New Price, Riling Patients

By JONATHAN D. ROCKOFF

Wall Street Journal (WSJ): “A centuries-old drug used to treat excruciating gout pain had cost just pennies a tablet—until last year. Now, the retail price has skyrocketed to more than $5 and some of the manufacturers have ceased production amid a battle over marketing rights.”

URL Pharma Response: Colcrys is not a “centuries-old drug.” It was first approved in July 2009. There is a lot more to a “drug” than the chemical — scientific and regulatory issues, purity, stability and drug-drug interactions, to name a few. There are also new discoveries that can enable millions of people to use a new formulation of a drug to get the full medical benefits without all of the toxicity associated with the “centuries-old” formulations. All of those aspects define why Colcrys is better and safer than old, unapproved, colchicine.

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),” also 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.”

WSJ: “The tale of how this common gout drug, colchicine, became the costlier branded drug Colcrys offers a window into the Byzantine world of drug pricing. The price rise is a consequence of a Food and Drug Administration effort to improve the safety of long-used but unapproved drugs, with a trade-off often made between drug affordability and safety.”

URL Pharma Response: This article implies that Colcrys is just a higher-priced version of the “common gout drug” but, in reality, Colcrys represents dramatic scientific advancements in the safe and appropriate use of colchicine for patients suffering from gout.

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.

WSJ: “In July 2009, a Philadelphia drug maker received FDA approval to exclusively market colchicine for gout attacks for three years. The company, URL Pharma Inc., was taking advantage of a push to bring medicines predating the FDA, like colchicine, under the agency’s regulatory umbrella. The FDA offers exclusive marketing rights if a drug maker conducts clinical trials.

URL Pharma had commissioned studies that confirmed its colchicine product’s safety and efficacy, while demonstrating it should be taken at a lower dose than typical and not used with certain other medicines.”

URL Pharma Response: The preceding sentence downplays our research efforts by stating that studies were “commissioned,” that we “confirmed” the “product’s safety and efficacy,” and demonstrated that “it should be taken at a lower dose than typical.” The following demonstrates our research efforts, that have significantly improved patient safety through our scientific discovery.

First, URL Pharma did not just “commission” studies. Scientists at URL Pharma studied the medical science around colchicine, developed new theories on how it might be used and what changes might work, and then designed 17 clinical studies that yielded critically important discoveries. URL Pharma was the only company to take the risk, make the investment, and help millions of patients. The manufacturers of unapproved colchicine 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 for patients. Our work on Colcrys encompassed far more than simply “commissioning” studies. Our discoveries and contributions to understanding how to use colchicine safely and appropriately were unprecedented.

Second, stating that our significant research efforts merely “confirmed” safety and efficacy implies that what we discovered was already known. But that is not the case at all here.

Our studies made new and dramatic discoveries about how our formulation of colchicine, in a new dosing pattern, significantly reduced side effects and improved safety while maintaining full efficacy. Our study showed a reduction of diarrhea from 77% of patients to statistically no different than placebo, and a reduction of “severe adverse events” from 19% of patients to zero. And when the article states that we demonstrated that colchicine should “not be used with certain other drugs,” it downplays the fact that we discovered serious interactions with other drugs, including antibiotics, antihypertensives (high blood pressure drugs), and drugs for HIV/AIDS, that can unintentionally increase blood levels of colchicine by 300%. In fact, drug-drug interactions account for 60 of the 169 colchicine-associated deaths that FDA has reported. Our discoveries should help avoid those deaths in future medical practice.

Our research efforts are significant, and our work to transform colchicine into a safe, effective FDA-approved product has been acknowledged by FDA itself. In a March 3, 2010 letter from FDA’s Center for Drug Evaluation and Research (CDER), the Agency states that only URL Pharma “has chosen to take the clinically responsible step of seeking approval for unapproved oral colchicine.”

Prior to our efforts, there was only one placebo-controlled study of colchicine 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). In that study, 100% of patients developed diarrhea and the average dosage of colchicine was 6.7 mg. In our study, known as AGREE, patients received only 1.8 mg. of colchicine in our formulation of Colcrys and the rate of diarrhea was not statistically different than placebo. Also, in our study, the rate of “severe adverse events” was reduced from 19% of patients to zero when the Colcrys dosage regimen was used. While unapproved colchicine labels recommend up to 16 tablets to treat a gout flare, we discovered that the Colcrys formulation 3-tablet regimen could be fully effective while avoiding most of the toxicity. Additionally, not only did we discover drug-drug interactions that the unapproved colchicine products do not warn against but we also developed revised dosing schedules to guide physicians in safely administering colchicine in the face of such drug-drug interactions. Furthermore, while the unapproved colchicine products advise physicians that there is evidence to support using dialysis to treat a patient with a colchicine overdose, we discovered that this is not correct.

WSJ: “The company is marketing its drug as Colcrys—and the retail cost averages $5 per pill, according to DestinationRx, a health-care data provider.

URL is also suing longtime manufacturers of unapproved colchicine, saying the companies are now illegally marketing their products. Some of the companies are fighting the lawsuits. Some themselves have raised prices—including one increase of just under a dollar per tablet to $1.17, according to DestinationRx. The higher price for Colcrys was first reported by Kaiser Health News.

There were 3.5 million prescriptions and $6.4 million in sales in 2008, according to the most recent data available from IMS Health, a drug-data firm.

“It’s not a new product. It’s been out for hundreds of years. To all of a sudden have to pay $125 or $150 a month, after it only cost $5 or $10 a month, is a real problem,” said Stanley Cohen, a Dallas doctor who is the president of the American College of Rheumatology. He met with the FDA to express concern about the price increase.”

URL Pharma Response: There are several inaccuracies in this quote from Dr. Cohen.

Our Co-Pay Assistance and Patient Assistance Programs make Colcrys easily affordable to virtually all patients. The only patients not eligible for these programs are individuals whose income exceeds 600% of the Federal Poverty Level and who have chosen to not purchase health insurance. Additionally, the neediest patients can receive Colcrys free of charge.

By clicking on the following link, you will be able to read a sequence of documents that show our interactions with ACR regarding Colcrys.

WSJ: “The chief executive of URL Pharma, Richard Roberts, said that it priced Colcrys in line with other approved, branded drugs used to treat gout pain. To help patients afford Colcrys, Dr. Roberts said, the company is offering to pay a portion of co-pays, and it is providing a three-months’ supply to low-income patients for $15.

Eileen Wood, vice president of pharmacy and health-quality programs at CDPHP, an insurer in New York state, said insurers will have to absorb much of the added expense. URL’s contribution was “not any new therapeutic tool, not new science; they just added cost,” she said.”

URL Pharma Response: We believe that it is inappropriate to quote an insurance company executive offering a medical opinion about the therapeutic or scientific value of Colcrys.

We have already pointed out earlier in this article that our discoveries have added tremendous therapeutic value for patients, and we have cited the FDA’s own statements on the importance of our research. Prior to our work, guidance on colchicine dosing that was based on rigorous science was nearly non-existent. The major rheumatology society in the U.S., 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). Due to our discoveries, medical textbooks will need to be rewritten. If physicians follow the labels of the current unapproved colchicine products, they will be instructed to administer colchicine at more than 5 times the FDA-approved dosage of Colcrys and may be misled into thinking that the lack of drug-drug interactions on those labels means that there are no such dangers for patients.

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.”

WSJ: “Nancy Sparks Morrison, a retired schoolteacher who suffers from familial Mediterranean fever, an inflammatory disorder that’s treated with colchicine, said she is buying colchicine from Canada because she can’t afford Colcrys. Ms. Morrison said she plans to get help from URL Pharma to pay for Colcrys because the company has just expanded its assistance program. “I’m retired on Social Security, and I have a small pension,” said Ms. Morrison, 71 years old, who lives outside Charleston, W.Va’

URL Pharma Response: Fortunately, URL Pharma’s Patient Assistance Program (PAP) is comprehensive and generous. Our program covers patients without health insurance that have annual incomes up to $132,000 per year for a family of four. The program also covers Medicare Part D patients so that the cost of Colcrys does not affect the “doughnut hole.”

Under the program, uninsured and Medicare Part D patients with incomes up to $66,000 per year for a family of four can receive Colcrys free of charge. Patients with incomes up to $88,000 per year for a family of four will pay $5 per month for Colcrys. Those with incomes up to $132,000 per year for a family of four will pay $25 per month for Colcrys. Medicare Part D patients can participate in our PAP regardless of insurance coverage to protect them from the “doughnut hole.” Our PAP is possibly the most generous such program in the history of the pharmaceutical industry. We think that this deserves some mention by those who try to portray needy patients as being unable to afford Colcrys.

WSJ: “The price increase is an unintended consequence of the FDA’s nearly four-year-old initiative to regulate unapproved drugs. These medicines were sold before the FDA was established, and therefore weren’t required to undergo approval. After decades of use, the medicines are considered safe by doctors, but haven’t been proven to satisfy the agency’s standards. Colchicine’s use has been traced back to the sixth century, according to the FDA.”

URL Pharma Response: In reality, most doctors know that colchicine is toxic. What is true is that after decades of use, most doctors and pharmacists assumed that the colchicine they gave to their patients was approved by FDA. They did not know that they were giving an illegal product that does not have any of the FDA assurances of purity, stability, safety, and efficacy. We have an independently-commissioned study of 500 pharmacists showing that more than 90% believe that the unapproved colchicine they dispense is FDA-approved. Doctors didn’t know that they were unnecessarily overdosing patients, and that some patients were dying from drug-drug interactions, until URL Pharma made its discoveries, received FDA approval, and brought the product to market.

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 the 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.”

WSJ: “Seventy drugs that were grandfathered have been approved since the FDA began its initiative, most notably pain reliever Vicodin, from Amneal Pharmaceuticals LLC, the FDA said.

The FDA had hoped a significant price increase wouldn’t follow Colcrys’s approval and regrets the increase, said Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research. Dr. Woodcock encouraged more competition, saying another company could seek approval for colchicine’s regular use in gout, rather than the acute use that URL Pharma received approval for.

There had been no standard for dosage before FDA approval. Colchicine’s excessive use can cause side-effects, such as severe diarrhea that is potentially fatal. The FDA said it receives reports of five deaths a year, on average, involving patients who took colchicine tablets.”

URL Pharma Response: The “excessive use” that this author refers to is actually the way unapproved colchicine is commonly used. It wasn’t known to be excessive until URL Pharma took the initiative, conducted the scientific studies, and risked the financial resources to research this product. Our 17 studies revealed numerous new findings demonstrating that the conventional wisdom on colchicine use was wrong. Some of these discoveries have been cited earlier in this document.

WSJ: “‘We took bad guidance, even guesswork, and made this evidence-based medicine,’ Dr. Roberts said.

Closely held URL Pharma, which is owned by a hedge fund, a private investor and employees, is a longtime seller of generic drugs, including colchicine. When the FDA launched its push, the company began searching for those with safety risks whose patients could benefit from clinical testing, Dr. Roberts said.

URL Pharma said its 17 clinical trials of colchicine involved a total of 988 patients. The trials showed that gout patients need take two tablets after an attack and one more an hour later, the FDA said.”

URL Pharma Response: Our discoveries are specific to Colcrys. We did not test the unapproved colchicine products, because without FDA approval, there is no assurance of batch-to-batch consistency, purity, stability, and product performance.

WSJ: “Trials also demonstrated side-effects from use with certain other medicines, including some antibiotics and antihypertensive medicines. Those are now flagged on the label of Colcrys.”

URL Pharma Response: But they are not “flagged” on the labels of the unapproved drugs. Physicians who read the labels from unapproved colchicine, and who assume that these are FDA-approved drugs, will be misled into thinking that there is no danger for their patients who are exposed to drug-drug interactions that can increase colchicine blood levels by up to 300%.

WSJ: “After obtaining FDA approval of Colcrys, URL Pharma went to federal court to sue manufacturers of colchicine, including Excellium Pharmaceutical Inc., Vision Pharma LLC, Watson Pharmaceuticals Inc. and West-Ward Pharmaceutical Corp., saying they have been illegally marketing their colchicine products since Colcrys’s approval. A fifth company, Qualitest Pharmaceuticals, settled and stopped production. The four companies are fighting the lawsuits.

“You have this product out for at least a hundred years and all of a sudden it’s no good?” said Lou Dretchen, who oversees sales and marketing at Excellium of Fairfield, N.J. Mr. Dretchen said the small, closely held generic drug maker stopped colchicine production after URL Pharma sued. The other companies declined to comment.”

URL Pharma Response: It is not true that “all of a sudden” there are problems with unapproved colchicine. There have been at least 169 deaths associated with colchicine that FDA has reported. Doctors looking at the labels of unapproved products can incorrectly assume that there are no drug-drug interactions that might have caused illness or death in a patient, since the unapproved product does not have any such warnings and most doctors assume that the pharmaceuticals that they prescribe are FDA approved. This drug has been unnecessarily causing illness and death for “at least a hundred years” but this wasn’t known until URL Pharma made the significant investments, conducted the studies and made the discoveries that are now benefiting patients.

The person quoted is a financially motivated sales executive who has profited from the sale of illegal colchicine.