The US Food and Drug Administration (FDA) has finalized a decision made earlier this year granting generic pharmaceutical companies the right to introduce generic variants of Endo Health Solution's Opana ER, saying that it found that the products had not been removed from the market for reasons of safety or efficacy.
Background: A Long and Complicated History
Opana ER (oxymorphone hydrochloride) is an opioid painkiller that first obtained approval from FDA in June 2006 for a non-crush-resistant version of the drug.
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 (new drug application 201-655) in December 2011. Endo then subsequently withdrew all stock of the original formulation of the drug, NDA number 021610 (the '610 NDA).
On 10 August 2012, Endo filed a Citizen Petition with FDA asking it not to approve any abbreviated new drug applications-the type of application used to approve generic drugs-for its Opana ER drug, and to further determine that its original, non-crush-resistant formulation had been withdrawn for reasons of safety.
Under the Hatch-Waxman Act, FDA if a company withdraws a product, FDA is permitted to determine if it was done to remove a potentially dangerous or ineffective product. If it was not done for either reason, it may then clear the way for a generic competitor to submit an abbreviated new drug application (ANDA) referencing the now-withdrawn NDA as the basis of obtaining approval.
As a result, FDA was essentially faced with a conundrum, one balancing fair access to generic products with the safety of consumers. On one hand, if FDA accepted Endo's petition not to approve generic equivalents of the '610 NDA, consumers might be safer, but would have less access to cheaper generic equivalents. On the other hand, if the agency denied Endo's petition, it risked re-igniting an epidemic of abuse predicated on non-abuse-resistant versions of painkillers.
Endo's petition made ample note of the latter, arguing that prescription opioid abuse is, in FDA's own words, "at the center of a major public health crisis of addiction, misuse, abuse, overdose and death." And while opioids in general are subject to a class-wide protection program known as a Risk Evaluation and Mitigation Strategies (REMS) program, Endo argued that such programs only address part of the problem-access-while still leaving open the potential for abuse once a consumer is able to access the drug.
Faced with a difficult decision, FDA requested more time to review Endo's Citizen Petition in a 31 January 2013 response.
Despite the delay in FDA's response, the prospect for success for Endo's petition seemed high on account of other actions by the agency. On 16 April 2013, FDA issued a decision finding that generic equivalents of Purdue Pharma's OxyContin (oxycodone hydrochloride) could not be marketed without abuse-deterrent qualities equivalent to the ones now present in the drug's formulation. That case was markedly similar to Endo's: An opioid painkiller, having once been marketed without abuse-deterrent qualities, was facing generic competition and argued that the new qualities were essential to its safety profile, further rendering the old version unsafe.
FDA seemed to buy that argument in its entirety, saying that: "Because original OxyContin provides the same therapeutic benefits as reformulated OxyContin, but poses an increased potential for certain types of abuse, the FDA has determined that the benefits of original OxyContin no longer outweigh its risks and that original OxyContin was withdrawn from sale for reasons of safety or effectiveness."
FDA's Surprising Decision
But in a surprising decision on 10 May 2013, FDA came to the opposite conclusion for Endo's drug, saying that the original '610 NDA had not been taken off the market for reasons of either safety or efficacy, and could thus be properly subjected to generic competition.
The difference between the two decisions is likely attributed to the abuse-deterrent data submitted by both companies. In the case of Endo, FDA said it was unable to find any proof that the 201655 NDA was, in fact, more abuse-deterrent than the original '610 NDA.
"To date, the 'abuse potential' subsection of the 'Warnings and Precautions' section and 'Drug Abuse and Dependence' section of both products' labeling are virtually identical," FDA wrote. The agency added that it disagreed with Endo's interpretation of its postmarketing safety data, which the company argued showed a "significant reduction" in abuse potential. FDA said that while the data did show crush resistance, the same data show that the drug's features could be "compromised" and otherwise manipulated by physical methods like cutting, grinding or simply chewing. While FDA later conceded that these properties could slow down the time it takes to abuse a drug, the qualities were not sufficient to stop the abuse of the drug.
FDA Slams Endo's Petition
FDA also chided Endo for relying on what the agency called "inconclusive" and "preliminary" data that "suffer from significant additional deficiencies" such as a small sample size, misclassification of drug exposure, and "possibly artificially elevated baseline abuse rates."
"It is not possible to draw meaningful conclusions based on [the data," FDA wrote. "While FDA considers the development of abuse-deterrent formulations a high public health priority, such properties must be supported by adequate data," it added.
"In sum, while there were sufficient data to conclude that the 610 NDA posed an increased potential for abuse by certain routes of administration compared to the 655 NDA, there currently are not sufficient data to conclude that the 610 NDA poses an increased potential for abuse compared to the 655 NDA," FDA concluded.
The agency further explained that it plans to address these types of issues on a case-by-case basis, and use "the totality of evidence," including data obtained by the agency itself to support its findings.
In a statement, Endo was it was "extremely disappointed and disagrees with today's decision, and believes that the approval of non-abuse deterrent formulations of long acting opioids will contribute to a significant increase in prescription drug abuse."
"With the approval and expected launch of additional non-abuse-deterrent generic versions of OPANA ER, we will carefully assess Endo's position in the competitive landscape and explore all options, including those intended to mitigate the effect of this decision," added Rajiv De Silva, CEO of Endo. "Endo remains committed to patient safety, including appropriate use of our products, as a top priority."
Another key difference, though one not cited by FDA, was that Endo is already subject to generic competition for its original formulation, while Purdue's OxyContin was still under patent protection, though that expired the day FDA rendered its ruling. That factor could hypothetically have led to FDA considering a higher bar for Endo's petition, as it would have required the removal of several products from the market.
FDA has now finalized its decision by way of a Federal Register notice, confirming that "Opana ER tablet products approved under NDA 021-610 were not withdrawn from sale for reasons of safety or effectiveness."
"This determination means that FDA will not begin procedures to withdraw approval of abbreviated new drug applications (ANDAs) that refer to these drug products, and it will allow FDA to continue to approve ANDAs for oxymorphone HCl extended-release tablets if all other legal and regulatory requirements are met," FDA explained.
The announcement comes just as Congress is in the midst of determining FDA's budget for the 2014 fiscal year. In recent months, several legislators have threatened FDA with "consequences" if Opana ER was not taken off the market.
In a letter to FDA in May 2013, Rep. Hal Rogers, chairman of the House Appropriations Committee said he - and Congress - were "prepared to act" if FDA was unwilling or unable to.
"These powerful drugs have caused far too many overdoses and deaths around the country when misused, and in Kentucky, they have proved to be a gateway drug for heroin abuse," Rogers said. "The bottom line is that we need better technology to deter tampering and abuse of prescription meds to fix our country's pain pill addiction, and the sooner we can incentivize the development and approval of safer, tamper-resistant pills, the better we all will be."
Federal Register: Opana ER Decision