Purdue's reformulated OxyContin gets US panel backing on second try
This article was originally published in Scrip
Purdue Pharma's reformulated OxyContin (oxycodone extended-release) may be less susceptible to abuse and manipulation than the currently marketed version, but risk management plans and postmarketing studies will be critical to determining whether the formulation is actually safer, the US FDA's outside experts have said.
The anaesthetic and life support drugs and drug safety/risk management advisory panels voted 14 to four, with one abstention, that reformulated OxyContin should be approved.
However, even those panellists voting in favour expressed hesitation and reservations, saying they recommended approval only because the new formulation appeared no more susceptible to abuse and manipulation than the old one, and the new version may provide a small, incremental advance in safety. They feared their votes would be seen as endorsing a "safer" version of the powerful, long-acting opioid in the absence of actual clinical evidence, and they had deep concerns that Purdue's messaging and promotional activities would directly or indirectly suggest the new formulation was safer.
Those voting in the minority said they could not recommend approval in the absence of a proposed risk evaluation and mitigation strategy (REMS). OxyContin will be covered under the class-wide REMS being developed for long-acting opioids and immediate-release methadone. It remains unclear when the class-wide plan will be in place, and the new OxyContin formulation could be approved with an interim REMS.
The panel's acting chairman, Dr Jeffrey Kirsch of Oregon Health and Science University, said that although Purdue presented higher quality data than at a May 2008 meeting on the same product, "I think it's unconscionable to move forward without a well-defined REMS".
Many panellists said Purdue should be required to conduct postmarketing studies evaluating whether the new formulation results in improved clinical safety and fewer cases of abuse, misuse and diversion.
"We will continue to work with the FDA to seek approval of our NDA," Purdue's president and CEO John Stewart said in a statement after the meeting. "We will also continue our ongoing discussions with the agency on the development and implementation of a REMS, as well as a carefully designed surveillance programme to assess the impact of the new formulation in the market, should it be approved."
second panel review
Purdue maintains that the controlled-release properties of the reformulation are less easily defeated through crushing, chewing, dissolution or vaporising than the original product, which has been the subject of widespread abuse in areas of the US.
This is the second advisory panel review for the proposed reformulation. In May 2008, the agency's experts said the new product was unlikely to reduce abuse or diversion, and may even increase misuse.
At the time, panellists said in vitro dissolution tests submitted to support approval were of questionable quality, not validated by a third party and did not go far enough in exploring ways to exploit the drug's controlled-release mechanisms. In addition to calling for more pre-approval clinical data on safety and efficacy, the panel criticised Purdue's plans to market the lowest doses in the new formulation while retaining currently approved versions of the two highest doses (60 and 80mg) pending agency approval at a later date.
The FDA issued a complete response letter last October seeking additional physicochemical testing of the reformulated tablets. The NDA was resubmitted in March seeking simultaneous approval for all seven doses ranging from 10-80mg, which would replace the currently marketed formulations. In another change from the previous submission, Purdue dropped its request that labelling reflect information about the reformulated tablets' physical properties and results of in vitro testing that would have allowed the company to market the product as being more tamper-resistant.
Purdue's chief medical officer and vice-president of clinical, medical and regulatory affairs, Dr Craig Landau, said the reformulation is bioequivalent and therapeutically equivalent to the current product. However, it should be more difficult to prepare the new formulation for abuse by multiple routes of administration and is less likely to be inadvertently crushed by patients or caregivers, he said.
The company presented results from a series of in vitro tests that simulated approaches to crushing or breaking of tablets for swallowing, or extracting the active ingredient through use of a solvent. Purdue also tested the ability to inject or smoke the reformulated product.
The in vitro data showed that reformulated OxyContin tablets are difficult to crush and release active ingredient slower than the current tablets in a range of solvents, even when reduced to particles. There is no evidence of "dose dumping" in the presence of alcohol. Reformulated tablets are difficult to draw up into a syringe or inject with an insulin syringe, and active drug is not efficiently released when a user attempts to smoke it.
marketing
Purdue's history of marketing violations weighed heavily on the committee.
The company's marketing tactics have been blamed for surges in OxyContin prescribing and abuse. In 2007 the firm pleaded guilty to a felony count of drug misbranding and paid $600 million to settle criminal and civil claims that it misrepresented the risk of addiction and euphoric properties in its marketing to doctors. Company executives paid $34 million and pleaded guilty to a misdemeanour violation of misbranding.
Panellists repeatedly questioned Purdue's marketing plans for the new formulation and whether promotional and detailing activities would create the impression that the formulation is safer than what is currently available.
Purdue's Dr Landau said the company has no plans to promote the characteristics in the new formulation that may make it less vulnerable to manipulation and abuse. "Until postmarketing data support it, we can't assume there's any reduction in abuse liability," he said. Company representatives said they decided to keep the OxyContin name because adopting a new brand would lead to inappropriate discussions with physicians and patients about differences between the two formulations.
generics
Panellists also questioned whether the new formulation would offer only a fleeting safety improvement because generic versions of original OxyContin will be eligible to enter the market upon patent expiry in April 2013.
Dr John Jenkins, director of the FDA's new drugs office, said that even if reformulated OxyContin is approved and the old version taken off the market, ANDAs may still reference the old product unless the agency has determined it was withdrawn for safety reasons. It would be hypothetical to speculate whether, in four years time, the FDA will have made such a determination, he said, meaning that generics of the old formulation could potentially compete against the reformulated brand.