FDA is advising ANDA applicants to follow a tier-based approach in comparing the abuse deterrence of a generic product to the innovator product. Under this approach sponsors start in vitro testing with simple, gentle manipulations and "progress to complex and more destructive manipulations."

The agency's draft guidance on "General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products," says that generally, comparative in vitro and pharmacokinetic studies provide sufficient evidence to demonstrate that the generic product is no less abuse-deterrent than the reference listed drug product.

At a March 24 press briefing on the release of the guidance, FDA Commissioner Robert Califf described the document as "a work of art."

"This is like a textbook of how to think about abuse deterrence and how to translate the concepts into formulations that really have promise of working," he stated.

Califf said that in issuing the guidance FDA is helping to assure that generic abuse-deterrent formulations are no less abuse deterrent than their branded counterparts. And second, he said the agency hopes the availability of less costly generics will have the potential to accelerate prescribing away from older products without abuse deterrent properties.

FDA released guidance for brand-name sponsors of abuse-deterrent opioids in April 2015. The document advised sponsors to compare their formulations against an already approved abuse-deterrent product ([A#14150401006]).

The Generic Pharmaceutical Association expressed some concern about the new draft guidance.

"GPhA believes that FDA's determination of whether a generic prescription opioid receives the 'abuse-deterrent formulation' labeling should not be based on whether the generic has an identical ADF technology," the association said in a statement.

"GPhA believes that we should encourage innovation by drugmakers in developing abuse-deterrent formulation of prescription opioids, and that requiring a specific type of technology – rather than having the determination based on scientific results – would discourage that innovation," it added.

Post-Market Studies Are 'Really Hard To Do,' Califf Says

There are currently five branded opioid products with abuse deterrent claims on the market: Purdue Pharma LP's OxyContin ER (oxycodone extended-release), Targiniq ER (oxycodone/naloxone), and Hysingla ER (hydrocodone bitartrate); Pfizer Inc.'s Embeda ER (morphine/naltrexone); and Inspirion Delivery Technologies LLC's MorphaBond ER (morphine sulfate).

Douglas Throckmorton, deputy director for regulatory programs in the Center for Drug Evaluation and Research, noted that post-marketing studies are underway to assess the real-world evidence that these products actually deter abuse. He said he expects "it will be a little bit of time to get the data."

Throckmorton and Califf both commented that post-market studies are challenging to conduct and that the uptake of abuse-deterrent products has been relatively limited. Throckmorton noted that 90% of the total market share is for immediate release products.

"These are really hard studies to do just because it's a delicate subject and getting accurate information about this topic is extraordinarily difficult," Califf said. "There is a good interchange between experts at the FDA and the companies who are paying for the studies to be done. So I'm hopeful we really will get the answer. But I wouldn't underestimate the difficulty of really knowing whether someone is abusing an opioid. It's such a difficult topic to even talk about."

In a sign of how challenging these studies are, Purdue withdrew its supplemental NDA with information from its post-market studies in June 2015 and FDA canceled an advisory committee that had been scheduled to discuss the studies ([A#14150630005]).

Purdue is continuing to evaluate the data. "We continue to aggregate and analyze the epidemiological data on the real-world impact of OxyContin's abuse-deterrent properties," Richard Fanelli, Purdue's head of regulatory affairs, told "The Pink Sheet" DAILY. "This includes new assessments and continuing discussions with the FDA, to demonstrate the benefits of this critical technology."

Asked if FDA had a timeframe for removing non-abuse deterrent products from market, Throckmorton said "FDA looks forward to a time when the majority of opioids are in abuse-deterrent formulations." But he added, "We are not there yet."

Opioid Crisis Takes Center Stage At FDA

The guidance is part of FDA's overhaul of its policies on opioid drug products to deal with what Califf described as the "national epidemic of abuse, misuse, addiction and overdose." The media call, the second this week, underscored the agency's intense focus on the issue.

After members of Congress tried to derail Califf's nomination to head the agency on the grounds FDA's opioid policies were inadequate, FDA released an opioid action plan describing its new approach ([A#14160204003]).

One of its commitments is to convene an expert advisory committee before approving any NDA for an opioid that does not have abuse-deterrent properties and to consult an advisory committee about abuse-deterrent formulations when they raise novel issues.

As for what FDA plans to do vis-à-vis generics, Throckmorton said the agency is working through this question right now. He added that the law prevents FDA from keeping a generic off the market if it meets standards for approval.

The release of the draft guidance came two days after the agency announced the addition of several boxed warnings to the labels for immediate release opioid products, which was also accompanied with a press briefing ([A#14160322005]).

And it followed a March 1 meeting of FDA's Science Board, which focused on what actions FDA can take to deal with the opioid epidemic. One of the board's recommendations was to expand prescriber education about opioids to include information about alternative treatments ([A#14160302005]).

Control Product Needed For Some Studies

The draft guidance lists several general principles for evaluating the abuse deterrence of generic solid oral opioid drug products. In addition to following a tier-based approach to testing, the guidance says sponsors should evaluate the generic's performance relative to the brand-name product.

The ANDA applicant should identify the brand's abuse deterrence for all routes of abuse, the guidance says. And if the brand product does not have any abuse deterrence for a particular route of abuse the generic sponsor should summarize the studies conducted and the results to support its assessment that the brand has no abuse deterrence with respect to that route and explain why there is no need to test its product in comparative in vitro or other studies for that route.

The guidance also directs ANDA applicants to identify appropriate "discriminatory study conditions" to compare the generic and reference listed drug products. The guidance describes the study conditions for each of the potential routes of abuse: injection (extractability and syringeability); ingestion (extractability); ingestion (dissolution); and smoking (sublimation).

For certain comparative studies, such as extractability studies, such discriminatory conditions should be identified by including a control product and comparing it to the reference listed drug in order to identify the abuse deterrence of the reference listed drug, the guidance states. It says that when available, the control product should be a non-abuse-deterrent version of the reference listed drug that contains the same active pharmaceutical ingredient as the reference listed drug.

The guidance says the ANDA applicant should compare its product against the brand product for each of its strengths, or alternatively, provide supportive data to demonstrate compositional proportionality across different strengths of the generic and brand products as justification for not conducting studies to make comparisons of all strengths. Extrapolation problems between doses have led some generics to be pulled from the market Also see "Watson’s Bupropion XL Undone By Outlier Patient, Bankrupt CRO" - Pink Sheet, 21 October, 2013..

To evaluate abuse deterrence for each route of abuse using FDA's tier-based approach, the ANDA applicant must first demonstrate that the reference listed drug product is statistically more abuse-deterrent than the control. The guidance says the generic must be found non-inferior to the reference listed product, and superior to the control product, at each set of discriminatory study conditions for which it is evaluated in order to claim it is no less-abuse deterrent than the corresponding reference listed product.

FDA To Hold Public Meeting On Guidance

With regard to pharmacokinetic studies, the guidance says they should be conducted in cases where there are no reliable in vitro testing methodologies. As a general principle, FDA says they should be conducted in healthy volunteers, incorporating a naltrexone blockade to thwart the pharmacodynamic effects of the opioids.

Studies other than in vitro and PK studies are generally not recommended, the guidance states, except in certain circumstances, such as comparing the abuse deterrence potential of an excipient that functions as an aversive agent and is different or differs in amount in the generic and brand products.

FDA noted that additional studies beyond those described in the guidance may be required.

"There may be instances in which the tier-based approach to evaluation of abuse deterrence for various routes of abuse cannot adequately capture the complete profile" for a generic product "due to factors including, but not limited to, inclusion of novel inactive ingredients, use of new technology, and formulation design," the guidance states.

In such instances, based on the performance profile of the generic abuse deterrent opioid, FDA may request additional studies be conducted to evaluate the failure mode or modes of the generic product, the document says.

Public comments on the draft guidance are due in 60 days. FDA will also hold a public meeting later this year to discuss the guidance and a broad range of issues related to the use of abuse-deterrent technology. The date of the meeting has yet to be announced.

Generic Abuse Deterrent Opioids: FDA Offers Tier-Based Testing Approach

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