Nowhere is this more pertinent than in the discussion of the future of opioid pain medicine and the role of the FDA when it comes to Category 3 and 4 labeling opportunities for abuse deterrent formulations (ADF) Labeling is the basis for articulating the value proposition of a product. And, in the case of Categories 3 and 4 – that value is likely or proven abuse deterrence. It’s harder than it sounds.
Category 3 products, based on pre-approval clinical trials are “expected to reduce abuse.” A Category 4 product, based on real-world evidence “has been shown to reduce abuse” – the Holy Grail of ADF labeling language.
Data definition and generation for categories 3 and 4 are very much still a work-in-progress – as is their relationship to clinical relevance. No absolute magnitude of effect can be set for establishing ADF characteristics. And the FDA continues to talk about the ambiguous totality of evidence standard – which really means using their best regulatory judgment.
The path forward is unclear. Is real world data reliable and robust enough? Should the FDA define and then assign various statistical weights to ADF comparison and population studies? And what about REMS reporting? At the end of the day, the agency can’t only look to REMS for risk mitigation but must also seek out data that supports more aggressive abuse deterrent labeling language. Nobody said it was going to be easy.
The challenge is that, when it comes to categories 3 and 4 (and especially 4), there’s limited data and (at present) no numerical threshold to define “meaningful reduction” in abuse. Obviously, more work needs to be done in order to refine optimal data sources, study design, statistical methods, and epidemiologic outcomes of interest both developers, regulators, physicians, and patients – and payers.
Payers, at least to date, have been unwilling to aggressively tier existing approved ADF opioids on their formularies. While nearly 60% of branded opioids contain ADF properties, only 2% of generic products do. The numbers are staggering -- 240,120,330 non-ADF generic opioids were prescribed in 2015 (nearly a quarter of a billion tablets) versus 5,068,398 branded opioids with ADF properties.
Would more aggressive Category 3 and 4 labeling help to change this shortsighted, cost-driven criterion? Stay tuned.
And this raises another FDA question, how will the agency assess ADF generic formulations. Beyond traditional AUC bioequivalence, how will the agency measure “abuse equivalence?” FDA guidance has been promised and is anxiously awaited.
For ADF innovators, a predictable regulatory pathway towards Category 4 labeling will incentivize continued investment and comprehensive reimbursement strategies. For generic manufacturers, defining best practices for for “abuse equivalence” programs will allow the Hatch/Waxman paradigm to take effect, driving prices down while also incentivizing further branded innovations.
As Dr. Douglas Throckmorton, the FDA’s point man on opioids said at the recent meeting of the Agency’s Science Board, “FDA will act within its authorities in support of our public health mission to help defeat the epidemic of opioid abuse through a science-based and continuously evolving approach by improving the use of opioids through careful and appropriate regulatory activities, improving the use of opioids through careful and appropriate policy development, improving the treatment of pain through improved science, and improving the safe use of opioids through communication, partnership and collaboration.”
The public health goal is safe, effective, and affordable access to opioid pain relief. Active partnerships between academics, developers, payers, patients, and physicians are crucial. And, as is often the case, the FDA is at the center of the ecosystem.