Abuse-Deterrent Opioids: Generics Worry Comparator Standard Impedes Approvals

FDA's draft guidance could make it difficult for generics to show abuse deterrence, especially given 'moving target' of innovator labeling changes, generic firms say.

Generic firms could face hurdles in showing that their opioid products have abuse deterrence properties comparable to the innovator product, stakeholders suggest in response to FDA's draft guidance.

Edward Cone, principal scientist, drug delivery and abuse-deterrent drug products at PinneyAssociates, said the agency's call for generic companies to first evaluate the reference listed drug versus a control without an abuse deterrent feature (ADF) could make it difficult for generics to get an abuse deterrent claim.

FDA's draft guidance providing general principles for evaluating the abuse deterrence of generic solid oral opioid drug products lays out a tier-based approach for comparing the abuse deterrence of a generic product to the innovator product. In a press briefing announcing release of the guidance, FDA Commissioner Robert Califf described the document as "a work of art" (Also see "Generic Abuse Deterrent Opioids: FDA Offers Tier-Based Testing Approach" - Pink Sheet, 24 Mar, 2016.).

But in a May 25 webinar hosted by PinneyAssociates, DrugsScan and the clinical research organization INC Research, Cone noted that the approach could be problematic for generic sponsors.

The guidance says that for certain studies comparing the generic to the reference product, such as extractability studies, discriminatory study conditions should be identified by comparing a control product to the reference product to identify the abuse deterrence of the reference product. It says that when available, the control should be the non-abuse-deterrent version of the reference product.

Cone said the criteria for determining if a generic is abuse deterrent "is based on success or failure with a so-called delta that's derived from the comparison of the reference product to a non-ADF control." For example, if the reference product can be extracted at a specific time point and provides only 10% of the label in solution while the non-ADF product can be extracted to the extent of 90% under the same conditions that would demonstrate abuse deterrent features. The delta is derived from the difference between the two.

"The delta becomes the criteria for success or failure and that can be quite small," he stated. "And that's where I think some of the products are going to – even though they may have very rigorous abuse deterrent features – may fail."

What Does 'Overly Sensitive' Mean?

Cone said FDA recognized the delta dilemma and stated that if the test is overly sensitive there may be a need for additional clinical studies to support the ADF features of the generic product.

The guidance states that if an in vitro methodology is deemed to be overly sensitive or cannot adequately assess the abuse deterrence potential of the product and a pharmacokinetic evaluation is performed, ANDA applicants should only have to conduct the pharmacokinetic study under the chemical and/or mechanical manipulation. The Generic Pharmaceutical Association (GPhA) asks for clarity on what "overly sensitive" means.

GPhA is also seeking clarity on several other technical requirements for evaluating and analyzing abuse deterrence data.

For example, FDA said it intends to consider the totality of the evidence when evaluating the abuse deterrence of a generic solid oral opioid drug product. GPhA questioned if this means that all studies for all routes of abuse indicated in the guidance would be required to be done for all opioid products irrespective of technology of the dosage form, or whether this would be decided case by case based on rationale and justification.

Will Generic Labeling Differ From Innovator's?

During the webinar someone asked if the generic product would end up with the exact label as the reference product. INC Research's Beatrice Setnik, VP of clinical pharmacology early phase, cited the potential challenges with the delta. She said it is possible that if the generic does not fulfill some of the criteria it may have "more scaled back labeling compared to the reference." She added that this could depend on whether clinical studies are conducted and on their outcomes.

GPhA expressed concern about labeling in its comments to FDA. It asked the agency for guidance on how it plans to address innovator labeling changes regarding abuse deterrence.

"If a reference listed drug (RLD) is permitted to make sequential labeling updates to include new routes of abuse-deterrence, generic companies will face a moving target, lengthening the review time for generic products and impeding public access to critical, affordable generic products which treat chronic pain," GPhA stated.

The association also raised several questions about the comparison of the reference product to a control.

GPhA asked for greater clarity on the ranges of potential study conditions to assist in identifying differences between the reference product and the control. It requested FDA to elaborate on the rationale for providing large study condition ranges. For example, the guidance recommends extraction conditions of "100-300 mL" at a duration of "5 to 60 minutes."

GPhA also asked why the control product is required when the labeling for the reference listed drug is already approved based on the evaluation done by the RLD manufacturer to prove its abuse deterrence formulation. It asks whether testing can be limited to a comparison between the generic and the RLD.

With regard to the choice of the control product, GPhA asked if an immediate release product can be used, which may contain lesser quantity of the active ingredient, or only an extended release version may be used, and if a salt change of the active pharmaceutical ingredient could be used as a control.

Generics Should Look Different, Surveillance Firm Says

Inflexxion Inc., which conducts post-marketing surveillance and epidemiology studies for branded abuse-deterrent opioids, also submitted comments on the draft guidance. It questioned the lack of any reference to post-marketing surveillance and epidemiology studies for generic products in the guidance and said these studies should be required to validate findings from in vitro laboratory and in vivo pharmacokinetic studies.

In addition, Inflexxion called for generic opioids to have a distinctive size, shape, or other appearance from the RLD and preferably from other brand or generic opioids. The company acknowledged that this recommendation counters FDA's final guidance on size, shape and other physical attributes of generic tablets and capsules, which permits limited size differential (Also see "Generic Firms Fear 'New Lifecycle Management Tool' From FDA Pill Size Guidance" - Pink Sheet, 22 Jun, 2015.).

However, Inflexxion said that if generic ADF versions are made to look like the RLD, it will be impossible for self-report systems to differentiate what product abusers actually used. "Identical size, shape and color of tablets and capsules will likely also impact the ability of reports to poison control centers to differentiate exposure of specific products," the company stated.

Must Aversive Ingredients Be The Same?

In other comments on the guidance, Acura Pharmaceuticals Inc.criticized the document with respect to its handling of generic opioids with aversive agents. It said FDA should require generics to use all the same aversive ingredients and in the same amount and concentration as the reference drug to qualify for an exemption from clinical testing. The comments were submitted by Acura's attorney at DLA Piper.

The specialty pharmaceutical company said its abuse deterrent technology, which contains inactive ingredients to impart physical/chemical barriers to abuse, is included in Oxaydo, an immediate-release opioid formulation approved by FDA in 2011. Egalet Corp. markets the drug under license from Acura.

The company said its abuse deterrent properties are described in Oxaydo labeling. The labeling cites a double-blind, active-comparator, crossover study in 40 non-dependent recreational opioid users in which "drug liking" responses and single-dose safety of crushed Oxaydo tablets were compared with crushed immediate-release oxycodone tablets. It says 30% of subjects exposed to Oxaydo responded that they would not take the drug again compared to 5% of subjects exposed to immediate-release oxycodone.

However, the labeling states that "the clinical significance of the difference in drug liking and difference in response to taking the drug reported in this study has not yet been established" and "there is no evidence that Oxaydo has a reduced abuse liability compared to immediate- release oxycodone." The labeling also states that Oxaydo may be abused by crushing, chewing, snorting or injecting the product.

FDA has approved abuse-deterrent labeling for six opioids, all of which are extended-release/long-acting products (Also see "FDA Latest Opioid Dilemma: Can Apadaz Stop Snorting Abuse – And Does That Even Matter?" - Pink Sheet, 3 May, 2016.).