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Abuse Deterrence Labeling – Generic vs 505(b)(2) Drug Development

With the ongoing opioid epidemic, drug abuse, diversion, and misuse are significant concerns for the FDA. The current opioid abuse problems also present significant opportunities for companies willing to explore new formulation technologies to deter abuse. Premier Consulting has significant experience in opioid abuse and abuse-deterrent labeling.

Current Status of Abuse Deterrence Labeling

A number of formulations have been presented to the Agency to date and, in evaluating the different options for abuse-deterrent technologies, the Agency’s thinking has admittedly evolved on both data requirements to demonstrate abuse deterrence, as well as on allowable labeling claims regarding abuse deterrent technologies (as discussed by FDA officials during the recent Pfizer Advisory Committee meeting). Adding to the complication of gaining abuse deterrence labeling is the fact that the Division of Anesthetics, Analgesics, and Pain products has held an FDA Advisory Committee for each product claiming abuse deterrence properties in its proposed labeling following NDA review.

Abuse Deterrence and the FDA

Based on the 16 April 2013 notice that no new generics would be allowed to reference the old formulation of OxyContin, and the 02 July 2014 notice that the original non-abuse-deterrent OxyContin formulation was discontinued for reasons of safety concerns due to the abuse potential, it would appear the FDA is doing everything in its power to encourage the development of abuse-deterrent drug products to replace the non-abuse-deterrent formulations currently on the market.

Despite these efforts, groups interested in reducing the possibility of opioid abuse continue to pressure the Agency to do more faster (relevant news links: here, here, here, here, here, and here). Understanding that the removal of non-abuse-deterrent formulations from the market may be a long-term goal, it does provide a unique opportunity for drug developers with a novel formulation approach to enter a potentially lucrative market while providing a much-needed benefit to society.

In order to aid in the development and successful demonstration of abuse deterrence properties in new analgesics products, the FDA has finalized the Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling.

To date, all of the abuse-deterrent formulations approved by the Agency have utilized the 505(b)(2) pathway because of the significant differences in formulation required to confer abuse-deterrent properties compared with the available non-abuse-deterrent products currently marketed.

As more abuse-deterrent formulations have been approved, demand for a pathway for generic products with abuse-deterrence properties has been increasing. The Agency responded by releasing a Draft Guidance for Industry: General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.

This new Draft Guidance focuses primarily on development of products that use the same or very similar technologies to deter abuse as a currently marketed product while maintaining therapeutic equivalence (i.e., interchangeability with the Reference Listed Drug (RLD)). While, the guidelines for testing abuse-deterrence of a generic product are now clearly laid out, the requirements add a significant burden to what is generally a fairly straightforward generics pathway.

The initial in vitro testing methods required to demonstrate similar abuse-deterrence properties for a generic product align closely with the requirements for a novel formulation, except that all testing requires comparison against the abuse-deterrent product as opposed to comparison against a non-abuse-deterrent formulation for a novel formulation. The Agency was even kind enough to define an allowable margin of non-inferiority (10%) for abuse potential testing against the RLD for the new generic formulation.

The Difference in 505(b)(2) and Generic Pathway Requirements for Abuse-Deterrent Drugs

Where the generic and 505(b)(2) pathways differ is in the in vivo requirements. Generics are only required to conduct in vivo PK studies under certain circumstances because the goal is to establish similarity to and interchangeability with the RLD for abuse-deterrent properties. Whereas, a product developed under the 505(b)(2) pathway would likely require in vivo human abuse-liability studies for each route of administration for which abuse-deterrence labeling claims are sought.

The possibility for development of generic abuse-deterrence formulations necessarily requires an innovator product to exist to compare against.

Several approved products with abuse potential still lack an alternative approved abuse-deterrent formulation, meaning that new products in those areas still require a 505(b)(2) development approach. One example area where marketed abuse-deterrent formulations are lacking is the Immediate-release (IR) opioid space.

The U.S. Centers for Disease Control (CDC) recently released its Guidelines for Prescribing Opioids for Chronic Pain in which it recommends against prescribing extended-release (ER) or long-acting (LA) opioids in preference for IR prescriptions due to the potential safety risk associated with the ER/LA products.

Obviously, it is difficult to develop a product that releases its active ingredient immediately in the stomach and still provides abuse-deterrence properties. That said, a number of formulation options are in development that may provide incremental improvements in abuse-deterrence by other common routes of abuse. A number of similar opioid and non-opioid products still have no abuse-deterrent formulations in the works, so plenty of opportunities exist for Sponsors who wish to get into this market.

Advantages of the 505(b)(2) Pathway for Abuse-Deterrent Formulations

Another area in which the 505(b)(2) pathway may be advantageous over the generics route is that specific abuse-deterrence claims may be irrelevant or unjustified based on the formulation or abuse-deterrence technology. A Sponsor pursuing the 505(b)(2) route has the flexibility to pursue only those abuse-deterrence claims for which they wish to make a claim in their approved labeling.

To use the above example of an IR oxycodone product, if the product is intended to release oxycodone immediately when administered by the oral route, then oral abuse-deterrence claims would be irrelevant because an abuser could intentionally administer enough of the product orally to produce a euphoric “high” from the drug. In this case, it would be reasonable to pursue intranasal and possibly intravenous (depending on the abuse deterrence mechanism), but not oral abuse deterrence claims.

While some mechanisms may deter even oral abuse by so-called programmable release formulations, it is important to remember that the product must still accomplish its intended role of providing analgesia to patients who require significant pain relief. The 505(b)(2) pathway provides the flexibility to pursue only those claims that are reasonable and apply to the abuse-deterrent formulation.

While navigating the development requirements for an abuse-deterrent formulation are clearer now than ever before, it is also clear that this is a constantly evolving field that requires both experience and creative, agile thinking to achieve success.

The efficiencies and flexibility gained by the 505(b)(2) development pathway extend to the demonstration of abuse-deterrence properties for drugs with abuse potential. Even compared against generics, the 505(b)(2) pathway provides an efficient and flexible development path for those looking to enter this unique market.

With a multidisciplinary staff and extensive 505(b)(2) experience, Premier Consulting offers the expertise needed to navigate the complex regulatory matters involved with developing abuse-deterrent drugs via the 505(b)(2) pathway. Contact us to learn more.