New Approaches to Opioids: Conundrum or Opportunity?

To paraphrase Peter Drucker, the information revolution will shift from the generation of data to figuring out the meaning and purpose of the data with the patient’s perspective in mind. Nowhere is this more pertinent than in the discussion of the future of opioid pain medicine and the role of the FDA – and advancing both the science and regulatory approaches to abuse deterrent formulations (ADF) are important steps in the right direction.

It’s important to remember that there is no such thing as an opioid that is 100 percent abuse-proof. The only abuse-proof medicine is one that is never prescribed – and for the hundreds of millions of Americans suffering from chronic pain that isn’t a viable option.

But cutting the Gordian Knot of abuse means more than advancing the science and regulation of abuse deterrence. It means working with the providers of continuing medical education to develop better curricula. It means validated risk evaluation and mitigation strategies.  And better REMS designs with more thoughtful purpose, using the tools of the 21st century century such as patient and physician apps. It means enhanced and validated reporting tools for post-marketing surveillance. And it means using real world data to provide real world advice.

It means using outcomes data for better social science tools that can assist prescribers in determining which patients are likely to abuse – and those for whom abuse is unlikely. The FDA can play an important role in working to develop and share (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.

At last month’s meeting of the FDA Science Board, more than a few FDA presenters discussed the importance of real world evidence.

What about the issues surrounding opioid misuse – at present the poor public health stepchild of abuse? And how can better physician education defer or deter the prevalent “opioids first” prescribing philosophy of many practitioners?

In the U.S., the use of opioids as first-line treatment for chronic pain conditions follows neither label indications nor guideline recommendations. 52 percent of patients diagnosed with osteoarthritis receive an opioid pain medicine as first line treatment as do 43 percent of patients diagnosed with fibromyalgia and 42 percent of patients with diabetic peripheral neuropathy.

Payers often implement barriers to the use of branded, on-label non-opioid medicines, relegating these treatments to second line options – along with new abuse-deterrent opioid formulations. The result is a gateway to abuse and addiction.

Does this mean that opioid products without abuse deterrent properties should be taken off the market? That’s a simplistic solution to a complex problem. The recent decision by Health Canada not to remove non-ADF opioids puts this issue into the proper perspective:

“… proposed regulations would have required therapeutic products containing controlled‑release oxycodone to have tamper-resistant properties before they could be sold in Canada. Following the consultation, and a review of the latest scientific evidence, the department has concluded that this specific regulatory approach, requiring tamper-resistance, would not have had the intended health and safety impact. Specifically, requiring tamper-resistant properties on all legitimate preparations of controlled-release oxycodone would have served to eliminate certain lower cost drugs from the market, increasing costs for patients and the health system, while having little to no effect in the fight against problematic opioid use. While the proposed regulations will not move ahead at this time, Health Canada supports efforts to develop strategies that can address problematic opioid use including industry efforts to develop tamper-resistant formulations of drugs.”

It’s important to remember, through the haze of political bullets, that the vast majority of Americans who use opioids do so legally and safely. A subset of approximately four percent abuse. Four percent. In fact, government statistics show that 78.5 percent of those who abuse prescription pain medication did not obtain the drugs from a physician in the first place.

“Abuse deterrence” isn’t just a formulation question – it’s a systems question.

The FDA has announced labeling changes and post-market study requirements for opioids, and the agency has signaled interest in using real world outcomes data to amend and update labeling.

That’s not regulatory mission creep; it’s the appropriate application of the agency’s Safe Use of Drugs initiative. The way you make a drug “safer” is to ensure that it is prescribed to the right patient and used in the proper manner.

A logical next step is to utilize that real world data to amend product-specific abuse-deterrent labeling to indicate lessons learned outside of the rarified world of the randomized clinical trial environment to assist physicians in using the right product for the right patient.

Real world evidence doesn’t just mean recognizing new risks, but also communicating new benefits learned through patient outcomes. And such evidence is both available and exciting.

According to the Journal of Pain, in a real-world study, abuse by snorting, smoking, and injecting prescription opioids declined by 66 percent after the reformulation of a drug with abuse deterrent properties. And the New England Journal of Medicine reported that a new formulation decreased abuse from 35.6 percent of respondents to 12.8 percent in 21 months.

Such changes mark important steps in highlighting the value of individualized patient pain-management programs.

To better understand the real-world impact of ADF therapies and continue to support innovation in this space, the FDA has required all sponsors of brand name products with approved abuse-deterrent labeling to conduct long-term epidemiological studies to assess their effectiveness in reducing abuse in practice.

And then there’s the thorny question of FDA labeling. Product labeling is the basis for articulating the value proposition of a product. And, in the case of categories 3 and 4 opioids, that value is likely or proven abuse deterrence. It’s harder than it sounds and resides at the eye of the opioids policy hurricane.

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 FDA recognizes that the ADFs are not failsafe and more data are needed.

One crucial question that deserves more conversation is the nature of the evidence that should be used to decide whether or not a given ADF product “works” to reduce abuse in the “real world.” Given the data challenges, it may be almost impossible to ever demonstrate a causal link between a new formulation and an impact on patient abuse – but is that because the product didn’t have an effect or our current measurement methodologies and data systems are inadequate to detect it? Are there other ways to conclude that a category 4 level has been achieved? That’s the problem that should be keeping the FDA and industry up at night.

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 percent of branded opioids contain ADF properties, only 2 percent 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.

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. The FDA’s recent draft guidance on the development of generic ADF opioids will significantly expedite both the development programs and approval timelines of these products.

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.”

Abuse-deterrent technologies are an important step in the right direction. They are part of the solution, but they’re not the whole solution. 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.

Abuse deterrence is a worthy goal and will only evolve when all the players work together in a more regular and synchronistic fashion. As the Japanese proverb goes, “Don’t fix the blame, fix the problem.”

Peter J. Pitts, a former FDA Associate Commissioner, is President of the Center for Medicine in the Public Interest.