Purdue Pharma is looking for assistance from FDA to help protect the company’s OxyContin franchise from both branded and generic competitors.

The company recently petitioned FDA to require that King Pharmaceuticals and Pain Therapeutics’ pending NDA for Remoxy include certifications against OxyContin patents. Separately, Purdue is seeking an agency determination that its original OxyContin formulation was discontinued last year due to safety reasons.

The former move is aimed at heading off potential near-term competition from another branded product which, like the currently available version of OxyContin, has abuse-resistant properties. The latter action, if successful, would close the door to future generic versions of the old OxyContin formulation and require ANDA filers to prove bioequivalence to the new version, a more difficult hurdle.

Going After Remoxy, Again

In a Jan. 14 citizen petition, Purdue requests FDA refuse to approve Remoxy unless King’s recently resubmitted 505(b)(2) application specifically references the new OxyContin formulation and includes certifications to all “Orange Book”-listed patents for the opioid.

Remoxy is a long-acting oral formulation of oxycodone. It uses Durect Corporation’s Oradur technology to produce a tamper-resistant, high-viscosity liquid formulation in a hard gelatin capsule.

The Remoxy NDA was the subject of a December 2008 “complete response” letter requesting additional stability data (Also see "Now Who Needs a Painkiller? King and Pain Therapeutics Face a Remoxy Setback" - Pink Sheet, 7 July, 2009.). The development partners announced in December 2010 that they had resubmitted the NDA, which is undergoing a six-month review.

If approved later this year, Remoxy would compete with Purdue’s reformulated OxyContin (oxycodone controlled-release), approved in April 2010 (Also see "FDA Okays Purdue's Newer OxyContin; Payors And Physicians Chew On Drug's Benefit" - Pink Sheet, 6 April, 2010.). The new product is designed to make breaking, crushing or chewing more difficult, and to form a viscous gel that impedes injection of the dissolved drug.

Purdue stopped shipping the original OxyContin, which was subject of widespread abuse and misuse, in August 2010, the same month it began distributing the reformulated product.

Both Remoxy and the new OxyContin are among a handful of opioid drugs with purported abuse-resistant properties that have gone before FDA’s Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees in the last several years. The others are King’s Embeda (morphine sulfate extended release with naltrexone) and Acurox (oxycodone/niacin).

Purdue says publicly available information indicates the Remoxy NDA was supported by bioequivalence, in vitro and abuse studies that used the original OxyContin formulation as an active comparator.

Purdue filed a similar petition after the Remoxy NDA was first submitted in 2008. In comments on that petition, King said it need not certify against Purdue’s patents because its NDA did not rely on data from OxyContin but, instead, on the findings of safety and efficacy from a different approved product, which it did not identify. FDA subsequently denied the petition, saying the issues raised were not ripe for review.

Purdue argues anew that the Remoxy NDA must reference the approved product to which it is “most similar” and include certifications to the patents listed for that product.

“There can be no question that Remoxy is more similar to OxyContin than to any other approved oxycodone product listed in the Orange Book,” Purdue says. “It is clear that, from the inception of the development program for Remoxy, the goal was to create an ‘improved’ version of OxyContin, providing equally effective pain relief in a formulation that is not as easily manipulated by abusers.”

Inadvertent Reliance

The 505(b)(2) pathway is used by sponsors who wish to rely on FDA’s previous findings of safety and efficacy for another approved product. Purdue’s petition suggests the element of reliance applies even when it is unintentional.

Saying that FDA reviewers do not conduct their reviews in a vacuum, the petition continues: “The fact that Remoxy has been shown to be bioequivalent to OxyContin, a drug product already found to be safe and effective, will necessarily influence their reviews of the Remoxy product. In this way, the reviewers will necessarily rely on the OxyContin NDA, even if no reliance is intended by either the reviewers or by King.”

FDA has long required that 505(b)(2) applicants certify to patents for a reference drug, Purdue says. Furthermore, it argues that King is statutorily prohibited from amending or supplementing its current application to reference OxyContin if the NDA does not already do so.

“Thus, FDA should require the application for Remoxy to be withdrawn and resubmitted with the appropriate reference to OxyContin, appropriate certifications to the patents listed … and, if Paragraph IV certifications are made, appropriate notice to the holder of those listed patents.”

FDA’s “Orange Book” lists six OxyContin patents with expiration dates ranging from 2013 to 2025.

King has not yet filed comments on the citizen petition. A spokesman for King, which is in the process of being acquired by Pfizer, said he is no longer authorized to speak on behalf of the company. Pfizer said the firm had no comment on the petition.

Shutting Out ANDAs

As it seeks to delay near-term competition from Remoxy, Purdue is also trying to head off generic competition further down the road by barring the filing and approval of ANDAs that reference the old OxyContin. The company recently filed comments on two citizen petitions that request an FDA determination as to whether the original formulation was withdrawn from the market for safety or effectiveness reasons.

Since the original OxyContin is now listed as discontinued in the “Orange Book,” ANDAs that reference it cannot be approved unless FDA determines it was not withdrawn for safety or effectiveness reasons.

In separate citizen petitions, Lachman Consultant Services Inc. and the law firm Sheppard Mullin Richter & Hampton ask FDA to declare that Purdue’s voluntary withdrawal of the original formulation was for reasons other than safety or effectiveness. “It is believed the innovator has discontinued the sale of this product for commercial reasons due to the approval of a new formulation of OxyContin,” the Lachman petition states.

“Hypothetical” Matter No Longer

Questions surrounding what impact the approval of a new OxyContin formulation would have on ANDAs referencing the old product have been hanging in the air for several years.

In the second advisory committee review of the new OxyContin formulation in September 2009, panel members questioned whether the new formulation would have a real-world impact in reducing abuse if generics of the original product were allowed to come to market after Purdue’s method-of-use patent expires in 2013 (Also see "FDA Advisors Question Impact of OxyContin Improvements Due To Generics" - Pink Sheet, 5 October, 2009.).

At the time, Office of New Drugs Director John Jenkins said it was difficult to speculate on what may happen four years down the road. "Whether four years from now, with new accumulating data, we will consider it was withdrawn for safety reasons is hypothetical at this point," Jenkins said.

OxyContin has a long, complex history of patent litigation which includes three generic companies – Teva Pharmaceutical Industries, Endo Pharmaceuticals and Impax Laboratories – that launched after a federal judge declared Purdue’s patents unenforceable due to inequitable conduct. The court ruling was subsequently reversed on appeal and the generics came off the market by 2008 (Also see "Anatomy Of A Patent Dispute: Purdue Pharma’s OxyContin Battle" - Pink Sheet, 10 March, 2008.).

FDA’s decision on OxyContin will have ramifications for generic companies eyeing other opioids that are reformulated to include abuse-resistant technologies.

FDA’s decision will affect not only companies interested in marketing OxyContin generics but also those eyeing other opioid products, the Lachman petition points out.

“The decision on this issue is also important for the generic pharmaceutical industry, in general, since this raises questions as to the agency’s position relative to an applicant receiving approval of a pharmaceutical equivalent in a different formulation of a product claiming to have abuse resistant technology and how the agency will deal with other approved ANDAs for the older version and whether FDA will continue to receive and approve ANDAs for the older version,” the petition states.

In separate comments, two law firms support the view that Purdue voluntarily removed original OxyContin from the market for commercial reasons.

The firms of Rakoczy Molino Mazzochi Siwik and Olsson Frank Weeda Terman Bode Matz note that the new product’s label contains no statements indicating it is safer than the original version, and FDA reviewers acknowledged the lack of a significant safety advantage for the reformulated product.

FDA and Purdue never indicated that the original product, when used in accordance with labeling, was unsafe or ineffective, the firms say, and Purdue waited until four months after approval to introduce the reformulated product without recalling the existing product.

In its comments on the Lachman and Sheppard Mullin petitions, Purdue says the new formulation was designed with the intent to mitigate the risk of abuse, diversion and misuse associated with the original product. The company stopped shipping the original drug once the reformulated product was available in sufficient quantities so as to avoid disrupting patient access.

Although it has not completed required post-marketing epidemiology studies to assess the new formulation’s impact on misuse and abuse, “such data are not necessary to determine that the original formulation was withdrawn for safety reasons,” Purdue says.

By Sue Sutter

Purdue Moves To Stave Off Branded, Generic Competitors To New OxyContin

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