May 24, 2016
Comments of members of the Patient, Consumer, and Public Health Coalition on “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products: Guidance for Industry”
Docket No. FDA-2016-D-0785
Thank you for the opportunity to comment on the draft guidance, “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products: Guidance for Industry.” Development of such products is of great public health importance as a strategy to help make pain medications more affordable to those who truly need them while also reducing opioid abuse.
The Patient, Consumer, and Public Health Coalition is an informal coalition of nonprofit organizations representing the interests of millions of patients, consumers, health-care professionals, scientists, and public health experts. The comments and recommendations of the members of the Coalition follow:
- Avoid use of the misleading term “abuse-deterrent”
While the guidance does not specifically address labelling, we urge FDA to avoid use of the term “abuse-deterrent” since it is often misinterpreted to mean “addiction-deterrent.” In fact, a recent study found that nearly half (46%) of physicians think that abuse-deterrent formulations make these medications less addictive than others. Instead, labelling language that more accurately captures the product’s abuse-deterrent properties should be used. For example, if a pill has been made difficult to crush, it should be labeled “crush-resistant.” It is important to use precise language because “abuse” and “addiction” are often used interchangeably.
- Provide guidance for all types of abuse-deterrent technologies
The draft guidance includes recommendations to industry on the studies needed to show that a generic opioid is no less abuse-deterrent than the brand-name (or reference) drug, with respect to all potential routes of abuse. It provides testing recommendations for four of the seven categories of abuse-deterrent technologies described in FDA’s “Abuse-Deterrent Opioids: Evaluation and Labeling” guidance: solid oral opioid drug products formulated to incorporate physical or chemical barriers, agonist/antagonists, aversive agents, and combinations of two or more of these technologies. Since this field is continually evolving, we urge the FDA to also develop guidance for products in the remaining three categories so that patients have access to a variety innovative pain management therapies that are also safe and effective.
- Require the generic product to show it is not less abuse-deterrent than the reference product with respect to all potential routes of abuse
We agree with FDA that it is necessary for a generic manufacturer to provide studies that show that their product is not less abuse-deterrent than the reference product with respect to all potential routes of abuse. This will help minimize the risk of shifting abuse to another potentially more dangerous route of abuse (e.g. oral abuse to intravenous abuse). It will also prevent the approval of a generic opioid product that is less abuse-deterrent than the reference drug, which could lead opioid abusers to preferentially seek out and abuse generics. It is critical that, in attempting to solve one problem, we avoid creating a new one.
- Include a control product in tampering studies
Since the abuse-deterrent properties of currently approved drug products can eventually be compromised, it is important to have a good understanding of the type of manipulation or tampering that renders the opioid non-abuse-deterrent. Therefore, we agree with FDA’s recommendation to include a control product (i.e. a non-abuse-deterrent version of the reference product) in studies of abuse-deterrence. This will help provide a more accurate understanding of the product’s ability to deter abuse.
- Apply extra scrutiny to Tier 1 studies
As stated in the draft guidance, FDA recommends that applicants follow a tier-based approach when comparing a generic product to a reference product. This tier-based approach allows for hierarchical testing, starting with simple and gentle manipulations of the product (Tier 1) and progressing to more destructive mechanical and chemical manipulations (Tiers 2, 3, 4, etc.). Using this method, all of the null hypotheses in Tier 1 must be rejected before testing the null hypotheses in higher tiers. For that reason, it is essential that Tier 1 studies are rigorously conducted and documented. We urge FDA to apply extra scrutiny to these Tier 1 studies to ensure the statistical integrity of the tier-based approach.
- Enforce post-marketing real-world epidemiological study requirements for reference opioids
While not specifically addressed in this guidance, we strongly urge the FDA to enforce post-market study requirements for reference drugs. Since generic abuse-deterrent opioid formulations use the branded product as the reference for actual ability to deter abuse, it is critical that FDA follow through on its requirement for real-world post-marketing studies. An unsafe and ineffective reference product will result in unsafe and ineffective generic products. Sponsors of brand name products with approved abuse-deterrent labeling must complete the required long-term epidemiological studies to assess their effectiveness in reducing abuse in practice or risk having their approval revoked.
In summary, we applaud the FDA for providing guidance to industry to advance the regulatory science behind abuse-deterrent oral opioid formulations. We agree with many of the recommendations in the guidance and urge the FDA to consider our recommendations regarding the use of the term “abuse-deterrent”, the development of guidance addressing additional abuse-deterrent technologies, the scrutiny applied to Tier 1 studies, and the enforcement of post-marketing study requirements for reference products.
American Medical Women’s Association
Cancer Prevention and Treatment Fund
Connecticut Center for Patient Safety
National Consumers League
The TMJ Association
Washington Advocates for Patient Safety
 Hwang CS, Turner LW, Kruszewski SP, et al. Primary Care Physicians’ Knowledge And Attitudes Regarding Prescription Opioid Abuse and Diversion. Clin J Pain. 2016 Apr;32(4):279-84.