The US Food and Drug Administration (FDA) has denied a petition submitted by Endo Pharmaceuticals that sought to require manufacturers seeking to market generic versions of its Opana ER (oxymorphone hydrochloride) product to show evidence of similar crush-resistant qualities, saying it needs more time to determine appropriate testing standards-a potential indication that it may be leaning toward such requirements in the future.
Endo's drug had received approval in two stages. In June 2006, it won approval for an extended release (ER) version that did not contain crush-resistant qualities. In response to public health concerns-namely, that the products were too easy to abuse and were contributing to an epidemic of overdoses-the company reformulated the drug, and released the crush-resistant version of Opana ER in December 2011. Endo then subsequently withdrew all stock of the original drug, though its new drug application (NDA) for Opana ER (NDA 201-655) is still active.
The question now is whether the original product was withdrawn for reasons of safety (as Endo has repeatedly stated, including in its August 2012 505(q) citizen petition), and whether that reason should compel FDA to require subsequent products to require crush-resistant qualities as well.
In December 2012, Endo lost a lawsuit against FDA seeking to establish that it had done so. A victory in that suit would likely have forced subsequent ANDAs to reference the new, crush-resistant formulation which is subject to additional patent and market exclusivity protections. Endo did not mention if it planned to appeal the lawsuit, which was dismissed.
Endo and other pain pill manufacturers have argued that their products' new formulations were done to enhance its safety. Before these changes came into effect, opioid analgesics were-and to some extent remain-"at the center of a major public health crisis of addiction, misuse, abuse, overdose, and death," Endo wrote, quoting FDA's own Risk Evaluation and Mitigation Strategies (REMS) document on opioid drugs. Endo further quoted abuse statistics showing that opioid abuse had increase nationwide from approximately 628,000 in 1990 to nearly 2.4 million in 2004-a trend that has only continued to rise, it said.
The company also pointed to a legislative directive passed by Congress, which encouraged the development of drugs with abuse-resistant characteristics by companies, as well as the expedited filing and review of these drugs by FDA.
The problem for Endo is thus: Before it had received FDA approval for its crush-resistant formulation or discontinued the same, FDA received two abbreviated new drug applications (ANDAs) for generic versions of Opana ER from Actavis and Impax Laboratories. These drugs do not have crush-resistant qualities.
In an unusual turn of events, however, FDA did not comment on whether it agrees with Endo's rationale. By some accounts, it does. The problem, it said, is that it needs more time in which to make a decision.
By law, all citizen petitions (505(q) petitions) require a response within 150 days. FDA explained that because of this statutory limitation, it "must take action on the Petition at this time."
"We deny the Petition's requests without comment on the approvability of any ANDA for a product citing reformulated Opana ER as the Reference Listed Drug because it would be premature and inappropriate to do so at this time," FDA continued. "Such an action could, in effect, render a decision on a specific aspect of an ANDA before the Agency has had an opportunity either to fully consider specific data and information in such an application or to provide the procedural rights that accompany FDA actions on applications."
Just a Matter of Time?
Among the unsolved issues cited by FDA are specific testing standards for crush-resistance, which the agency said it was still developing.
The insistence on developing standards may, itself, be an indication that the agency is planning to implement such requirements.
FDA also said there was "no evidence that in enacting section 505(q) of the Federal Food Drug and Cosmetic Act, Congress intended to short-circuit the application review process or to vitiate an ANDA applicant's procedural rights by requiring that the Agency make decision on scientific issues specific to pending applications."
"For the reasons described in this response, the petition is denied," FDA concluded.
Endo's December 2012 lawsuit saw a response from FDA indicating that it will issue a determination on the larger issues related to crush-resistance and whether generics may enter the market without them by May 2013.
In a letter sent to US legislators in early January 2013, Margaret Hamburg indicated that the agency is leaning toward requiring generic opioids to possess crush-resistant and other abuse-deterrent qualities, writing that FDA "shares those concerns" held by legislators that generic versions of the drug would be dangerous without resistance qualities.