Generic Oxy makers, too, must offer risk management


Two generic manufacturers—Endo Pharmaceuticals Holdings and TEVA Pharmaceutical Industries—recently filed risk management plans for generic versions of OxyContin (oxycodone, Purdue Pharma) with the Food & Drug Administration—a move that reflects an increasingly strict stance by the federal drug agency in monitoring painkillers.

"The FDA accepted our plan, which contains all the elements necessary for labeling, education, monitoring, and surveillance," said Bill Newbould, Endo's VP of corporate communications. "The plan is complete and allows us to begin marketing our product, which we will do as soon as Purdue's [federal court] appeal is denied, probably by next summer."

Newbould was referring to a decision in January in a Manhattan federal court that found that Purdue Pharma misled federal officials to gain patents protecting OxyContin—a $1.8 billion-a-year blockbuster that industry analysts say accounts for more than 70% of Purdue's income. The court's decision against Purdue allows Endo to begin selling a generic version of the medication, which the generic manufacturer is prepared to market in 10-, 20-, and 40-mg tablets, the dosages Purdue claims adequately reduce pain for 90% of patients.

It's that claim that got Purdue in trouble. The court did not rule based on the issue of patent infringement—the issue that Purdue brought to court. Instead it found that Purdue made false claims about OxyContin's effectiveness in small doses when the pharmaceutical giant filed its patents with the U.S. Patent & Trademark Office. According to Federal Judge Sidney Stein, "Purdue made a deliberate decision to misrepresent ... a theoretical argument and an expectation as a precisely quantified result or discovery."

Purdue announced that it was "surprised and disappointed" by the court decision and quickly filed an appeal. The court's decision paved the way for Endo and TEVA to receive final ANDA approval from the FDA in March 2004. Soon thereafter, the two companies filed and the agency approved risk management plans for their generic versions. Endo announced it would not market its drugs until the appeal is resolved. When the company does roll out its version of oxycodone hydrochloride, it will have marketing exclusivity for six months on the smaller doses, but then probably will be followed to market by TEVA and another manufacturer, according to FDA filings. TEVA did begin marketing an 80-mg, extended-release dose of the drug at the end of March.

In announcing approval of the company's risk management plan, TEVA spokesman Kevin Mannix said, "We've initiated a risk management plan as encouraged and guided by the FDA and DEA that's consistent with the brand product plan and reflects the strategy coordinated by the Office of National Drug Control Policy, DEA, and the FDA that deals with the four important areas of labeling, education, surveillance, and intervention."

Newbould said that the company would actively participate in efforts by DEA and local authorities to monitor the prescribing patterns of physicians who prescribe oxycodone and will report "unusual patterns" to authorities. Its oxycodone HCl education program is "comprehensive and our labeling clearly outlines the potential for abuse," he said.

The coordinated strategy Mannix is referring to was announced in March 2004 as part of the Bush Administration's National Drug Control Strategy. Its goal is to reduce prescription drug abuse by 10% within two years and 25% within five years through public awareness campaigns, physician education, and participation by states in criminal investigations and charges, according to the White House.

To that end, the National Drug Control Strategy requires that agencies mandated to monitor painkillers:

• carefully consider labeling and commercial promotion of opiate drug products

• ensure wider dissemination of education and training on appropriate pain management and opioid treatment procedures for physicians authorized to prescribe controlled substances

• increase the number of state Prescription Monitoring Programs, which detect suspicious prescriptions and individuals redeeming Rxs from multiple physicians (so-called doctor-shopping) to identify abusers

• use Web crawler and data-mining technology to identify, investigate, and prosecute "pill mills," i.e., Internet pharmacies that provide controlled substances illegally

Federal initiatives aside, it was Purdue that insisted Endo and TEVA be required to submit risk management plans with the FDA for final approval of generic OxyContin—perhaps because misery loves company. It made that demand right after the Manhattan court's ruling. Robert J. Meyer, M.D., who oversees the FDA's division of anesthetic, critical care, and addiction drug products at the Center for Drug Evaluation & Research, announced soon thereafter that Endo's and TEVA's plans must be consistent with the one used by Purdue. Officials of neither generic company would comment on the specific language of their risk management plans because they contain marketing strategy. They both said it meets Meyer's criteria (see sidebar "Purdue's Oxy risk management contains three key features").

Endo and TEVA have, no doubt, learned from Purdue's experience. The pharmacy giant has faced increasing federal scrutiny in its promotional and labeling practices since it received FDA approval for the Schedule II drug nine years ago. Criticism by federal officials of Purdue reached a crescendo in a Government Accountability Office (GAO) report issued in December 2003 that called the company to task for failing to adequately monitor its product and for conducting aggressive ad campaigns that promoted the drug without paying adequate attention to its potential for abuse.

"Purdue conducted an extensive campaign to market and promote OxyContin that focused on encouraging physicians ... to prescribe the drug for noncancer as well as cancer pain," stated the GAO report. "Purdue significantly increased its sales force and used multiple promotional approaches. OxyContin sales and prescriptions grew rapidly following its market introduction, with the growth in prescriptions for noncancer pain outpacing the growth in prescriptions for cancer pain. DEA has expressed concern that Purdue marketed OxyContin for a wide variety of conditions to physicians who may not have been adequately trained in pain management. Purdue has been cited twice by the FDA for OxyContin advertisements in medical journals that violated the Food, Drug & Cosmetic Act (accuracy requirements)."

Abusers of the product generally crush the tablets and snort the powder or dissolve the tablets in water and inject the solution, according to the Justice Department's National Drug Intelligence Center. GAO reported that 146 Americans died from illicit OxyContin use in 2000 and 2001. A black-box warning was added to the labeling of OxyContin in July 2001, stating that the tablets were to be swallowed whole and not broken, chewed, or crushed. In fiscal years 2001 and 2002, GAO's report noted, DEA initiated 257 OxyContin-related abuse and diversion cases, which resulted in 302 arrests and about $1 million in fines.

The GAO report said that there were a number of factors that may have contributed to the abuse and diversion of OxyContin. The fact that the drug is a controlled-release opioid twice as potent as morphine may have made it an attractive target for abuse and diversion.

In addition, said the report, "the original label's safety warning advising patients not to crush the tablets because of the possible rapid release of a potentially toxic amount of oxycodone may have inadvertently alerted abusers to possible methods for misuse. Further, the rapid growth in OxyContin sales increased the drug's availability in the marketplace and may have contributed to opportunities to obtain the drug illicitly. The history of abuse and diversion of prescription drugs in some geographic areas, such as those within the Appalachian region, may have predisposed some states to problems with OxyContin."

The GAO's harshest criticism of Purdue was this: "Although Purdue used specific information on physician-prescribing practices to market and promote OxyContin, it waited seven years—until October 2002—to use those data and other indicators to identify patterns of prescribing that could point to possible improper sales representative promotion or physician abuse and diversion of the painkiller."

As a result of GAO recommendations, FDA officials said they revised their controlled-substance risk management guidelines to reflect GAO concerns by September 2004. FDA's Anesthetic and Life Support Drugs Advisory Committee had come to the same conclusion in September 2003, Meyer said.

According to published reports, abuse of generic OxyContin has already started. A May 21 Associated Press report cited eastern Kentucky law enforcement officials as saying that undercover narcotics investigators have purchased the generic drug from street-level dealers, even though it wasn't available in area pharmacies. Investigators said they suspect a shipment of the drug was stolen from a storage building in eastern Kentucky. "When we first got the pills, we didn't know what they were," Dan Smoot, chief detective for an antidrug task force in eastern Kentucky, told AP. "They look nothing like the OxyContin we were familiar with."

Purdue's Oxy risk management contains three key features

Purdue Pharma LLP has issued public statements that describe parts of its OxyContin risk management program. Endo Pharmaceuticals Holdings and TEVA Pharmaceutical Industries, generic manufacturers of oxycodone hydrochloride, say their programs are very similar. According to Purdue officials, the three key elements of their program are:

• Extensive education of prescribers, pharmacists, and patients on proper pain management and the safe use of OxyContin in appropriate patients.

• Active surveillance to detect signals of abuse, diversion, addiction, and overdose. The company's RADARS System can detect signals down to the three-digit zip code in specific geographic areas. The system allows the company to gather information in a more timely manner than publicly available surveys of abuse, said Purdue officials.

• A wide range of interventions, including support and education of law enforcement, targeted education of healthcare professionals on combating diversion and abuse, and awareness and prevention programs to the public in affected communities about the dangers of prescription drug abuse.


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