Comments of National Center for Health Research 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Thank you for the opportunity to comment on the draft guidance, “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products: Guidance for Industry.” This draft guidance is the first step toward the development of affordable pain medications that are more difficult to abuse, helping stem the tide of inappropriate and unsafe opioid use.
The National Center for Health Research scrutinizes research to determine the safety and effectiveness of medical products, and explains complicated research information to patients, providers, opinion leaders, policy makers, and the media. It is critical that safe and effective pain medications are available and accessible to patients who need them, and that FDA be part of the solution for the current opioid crisis. Our recommendations are as follows:
- Instead of the term “abuse-deterrent,” use language that more accurately describes the product’s abuse-deterrent properties.
We strongly urge FDA to avoid use of the term “abuse-deterrent,” which is often misinterpreted to mean “addiction-deterrent.” Unfortunately, a recent study found that nearly half (46%) of physicians think that abuse-deterrent formulations make these medications less addictive than others.[1] Instead, labelling language should more accurately capture the product’s abuse-deterrent properties. 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 to industry on a variety of abuse-deterrent technologies
The draft guidance recommends studies that would show that a generic opioid is no less abuse-deterrent than the brand-name (or reference) drug, with respect to all potential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. This field is continually evolving, so 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 comparison to the reference product for all potential routes of abuse
We strongly agree with FDA that a generic manufacturer should 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.
- Require comparison to a control product in tampering studies
It is essential to have a good understanding of the type of manipulation or tampering that could render an opioid non-abuse-deterrent. 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.
- Ensure statistical integrity of the tier-based approach
FDA recommended 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 requirements for real-world post-marketing studies for reference products
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, the FDA should 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.
Conclusions
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 strongly 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.
Sincerely,
National Center for Health Research
Reference
- 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.