US FDA guides on abuse-deterrent opioids; generics direction pending
This article was originally published in SRA
The US Food and Drug Administration has unveiled its final guidance on what makers of brand-name opioids need to do to obtain abuse-deterrent language in the labeling of their products1-3.
The document, Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling, describes the FDA's expectations on the types of studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties and how the results should be evaluated. It also discusses what claims of abuse deterrence the FDA may allow in labeling based on the results of a firm's studies.
US regulators have long urged manufacturers of opioids to include abuse deterrent mechanisms in their products to prevent abusers from cutting, breaking, chewing, crushing or dissolving the narcotics to attain an immediate euphoric high.
"Cooperation is essential for us to address [the] difficult challenge of opioids abuse," Douglas Throckmorton, deputy director of regulatory programs at the FDA's Center for Drug Evaluation and Research, said at a 1 April press briefing on the guidance.
Currently, four opioids have the coveted language, with three of those belonging to Purdue Pharma: reformulated OxyContin (oxycodone); Targiniq ER (oxycodone/naloxone) and Hysingla ER (hydrocodone). The fourth product belongs to Pfizer – Embeda ER (morphine/naltrexone), which initially was approved in 2009 but did not gain the abuse-deterrent language until this past October.
Zogenix had been pursuing getting abuse-deterrent language into the labeling of its new formulation of its pure hydrocodone medicine Zohydro ER. But the company recently sold the franchise to Pernix Therapeutics.
During a conference call with investors and analysts last month, Zogenix CEO Roger Hawley said his firm would provide assistance to Pernix in the development and regulatory approval of future abuse-deterrent formulations of Zohydro ER, including amending the current labeling with abuse-deterrent claims, and seeking approval of a new tablet abuse-deterrent formulation of single-entity extended-release hydrocodone, known as for ZX008, which is in development with Altus Formulation.
To combat opioid misuse and abuse, Dr Throckmorton said, the FDA is encouraging manufacturers to develop abuse-deterrent drugs "that work correctly when taken as prescribed, but are formulated in such a way that someone cannot easily modify for the purposes of abuse". "While abuse deterrence is not the same thing as abuse proof and there is much we still need to learn about the science of developing these formulations, we see this as an important action to help balance appropriate access to opioids for patients with pain and the need to reduce abuse and misuse," he told reporters.
Dr Throckmorton noted the FDA made some revisions to its recommendations from what was included in the draft document4 released in January 2013 based on the "numerous" comments the agency received, including those made at a two-day meeting this past October. That meeting was preceded by a two-day gathering in January 2013 of the FDA's Drug Safety and Risk Management Advisory Committee, which was focused specifically on hydrocodone products.
Dr Throckmorton said the FDA was taking a "science-based approach" to its guidance to address the misuse, abuse and overuse of opioids. He emphasized that the agency wanted to ensure any actions it takes is "not at the expense of access to opioids for patients who need them."
Generics
Dr Throckmorton pointed out the FDA's final guidance is for makers of brand-name opioids and not generics. The FDA is still working out the details of guidelines for abuse-deterrent generic opioid formulations but, he pledged, the agency would have a draft document published soon.
At the public hearing last October, Robert Lionberger from the FDA's Office of Generic Drugs said the agency’s standard for abuse deterrence for generic opioids would not be lower than that used for brand-name drugs. "In order for abuse-deterrent technologies to be effective, they have to appear in the generic products. They have to spread through the whole of products in this space," Dr Lionberger said.
During the 1 April call with reporters, Sharon Hertz, acting director of the FDA's Division of Anesthesia, Analgesia and Addiction Products, emphasized the agency had determined it would not be suitable for any generics to be substituted currently for the opioids with abuse deterrent properties.
"There are regulations regarding the development of generics and the products they reference and that is part of what underlies what are appropriate substitutions between branded and generics," Dr Hertz explained.
Patrick Raulerson, senior regulatory counsel in the FDA's Office of Regulatory Policy, noted that states regulated the process of determining substitution of branded products with a generic.
Before generics can be automatically substituted for the brand medicine, state laws require generics to have an "A" rating in the FDA’s Orange Book – officially called the Approved Drug Products with Therapeutic Equivalence Evaluations, a large volume containing patent numbers and expiration dates, which generic makers consult when filing abbreviated new drug applications for their products.
For the four opioid products with FDA-approved abuse-deterrent language in their labeling, "there are no A rated generics," Mr Raulerson said. "If a product is prescribed by name, it won't be automatically substituted for a non-abuse-deterrent generic," he noted.
References
1. FDA press release, 1 April 2015, www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm440713.htm
2. Abuse-Deterrent Opioids — Evaluation and Labeling Guidance for Industry, 1 April 2015, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM334743.pdf
3. Federal Register, 2 April 2015, 80(63), 17765, www.gpo.gov/fdsys/pkg/FR-2015-04-02/pdf/2015-07562.pdf
4. US FDA issues draft opioids guidance in hope of spurring abuse-deterrent technologies, Scrip Regulatory Affairs, 10 January 2013