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How Will New FDA Guidance for Generic Abuse-Deterrent Opioids Pan Out? – an Update Based on the Final Guidance

With a recent update from the United States Food and Drug Administration (US FDA), the quest for abuse-deterrent opioids has taken another step. But will the new Guidance lead developers forward or backward?

We previously commented on the Draft Guidance for generic abuse-deterrent opioids in a post on August 2, 2016. To develop the final guidance, the FDA collected public commentary, including the input of both the generics producers and innovators. The FDA has now published the much-awaited Final Guidance for Industry: General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.

In this Final Guidance, the changes from the Draft version are glaring and reflect the continuously rising bar of requirements for development of opioids, and particularly abuse-deterrent opioids in the US. The question for the Generics industry is whether or not the economics at commercialization is worth the cost of developing a generic opioid.

The FDA states that the standard goal when evaluating a generic product is to determine whether or not the drug product is “therapeutically equivalent” to its Reference Listed Drug (RLD), adding that:

“When a potential ANDA applicant develops a generic solid oral opioid drug product, the applicant should review the approved labeling for the RLD, particularly the information presented in the DRUG ABUSE AND DEPENDENCE section under 9.2 Abuse. If the summary in section 9.2 indicates that FDA has concluded that the product has properties that are expected to (or have been shown through postmarketing studies or trials to) deter abuse, in addition to other testing that may be needed to support the ANDA, the potential ANDA applicant should evaluate its proposed generic drug to show that it is no less abuse deterrent than the RLD with respect to all of the potential routes of abuse. This will ensure the generic drug is no less abuse deterrent than the RLD with respect to all potential routes of abuse and minimize the risk of shifting abuse to other, potentially more dangerous, routes.”

Evaluation of ALL Routes of Abuse

The Agency places particular emphasis on the statement that ALL routes of abuse should be evaluated. This reflects a shift in thinking for both generics and new drugs that it is no longer acceptable to evaluate only those routes of abuse that the Sponsor wishes to make claims against; rather, all routes should be evaluated to inform the Agency on potential unidentified risks resulting from the abuse-deterrent technology used in each formulation.

Given the timing of this shift, it is reasonable to speculate that the well-publicized HIV epidemic and resulting discontinuation of Opana Extended Release (ER) due to the previously untested abuse-potential by injection has impacted the Agency’s thinking on the risk/benefit of approving new opioid drugs, including generics.

In Vitro and In Vivo Testing

The most obvious difference between the Draft version and Final Guidance, given the new focus on evaluation of all routes of abuse, is that the Agency has also clarified that this will require both in vitro (Category 1) and in vivo (Category 2 at minimum and possibly Category 3, depending on formulation) testing to support abuse-deterrence labeling claims and gain approval for generic opioids relying on abuse-deterrent RLDs. This is a departure from the initial Draft Guidance, which only mentioned in vitro studies as a requirement, with the potential for Category 2 on an as-needed basis and, only in rare cases, Category 3 in vivo studies. One minor allowance in the routes of abuse testing is that oral abuse only appears to require Category 2 (pharmacokinetics) testing under optimal conditions for abuse (generally crushed for a solid oral dosage form).

Market Impact

Based on the changes in requirements from the Draft to the Final Guidance, the question remains: will the market support the added development cost of generic abuse-deterrent opioids? We know that the abuse-deterrent opioid innovators have had a difficult enough time gaining market access, in part because of limitations in the reimbursement structure and formulary access. Generic developers don’t have the same reimbursement expectations, but generally their development costs are not as high as what is required for these formulations either.

Only time will tell how this pans out and whether or not generic abuse-deterrent formulations will succeed either in the market or in impacting opioid abuse. What we do know is that there is now a clear path forward for greater competition in the abuse-deterrent opioid marketplace.