Google “opioid abuse deterrence” and you’ll find a lot of hits from lawyers and elected officials. What you won’t find is a lot of expert thinking from the FDA. That needs to change.
FDA Commissioner Hamburg’s March 13, 2014 testimony in front of the Senate HELP Committee) hopefully represent a more aggressive stance by the agency. That’s good. But there needs to be more. The FDA must be the leading voice on the issue of abuse deterrence and the safe use of opioids.
The Commissioner got it right when she testified (per Zohydro), “We recognize that this is a powerful drug, but we also believe that if appropriately used, it serves an important and unique niche with respect to pain medication and it meets the standards for safety and efficacy.”
In short – not all opioids are the same and not all patients respond to all opioids in the same way. Further, it’s important to remember that “safe” doesn’t mean 100% safe. Never has. Never will. Not for any medicine. It’s always about the benefit/risk balance. Relative safety is an important conversation. It’s an opportunity for the FDA to help educate the public about the safe use of drugs.
(The foundational proposition of the FDA’s “Safe Use” initiative is that the way to make a drug “safer” is to better educate prescriber, dispenser, and user about the product.) And nowhere is “safe use” a more important issue than opioids.
The FDA must take the lead. And that means more than finessing the label. It means working with the providers of Continuing Medical Education (CME) to develop better curricula. It means more targeted Risk Evaluation and Mitigation Strategies (REMS). It means enhanced and validated reporting tools for post-marketing surveillance. It means using that data for better social science in developing tools that can assist prescribers in determining which patients are likely to abuse. “Abuse deterrence” isn’t just a formulation question – it’s a systems question. Unfortunately complex systems make for bad media coverage, while simplistic, dramatic demagoguing makes for sexier headlines.
As the saying goes, everything you read about in the news is true –except for those things you know personally. Case in point: coverage of the FDA’s advisory committee on Zohydro.
At an FDA advisory committee, the agency is asked to defend its scientific thinking in public, before a panel of experts who can dissect results, challenge conclusions, and ensure no clinical stone goes unturned. Seldom reported, however, is that advisory committee votes are recommendations. They aren’t binding on the FDA.
An analysis of advisory committee recommendations compared to agency actions shows FDA followed committee advice 74% of the time. Interestingly, the agency overruled “no” votes only three times: (Tarceva for maintenance therapy in lung cancer, Avastin for breast cancer, and Micardis to lower blood pressure.) Since their approval, these medicines have saved, extended, and improved hundreds of thousands of lives.
So, what about the Zohydro decision? The sound bite is that the vote was against approval of the drug. That’s true. But what the general public doesn’t know is that, by a vote of 11-2, the experts affirmed that there was no evidence to suggest Zohydro had greater abuse or addiction potential than any other opioid.
When the committee voted, the aforementioned Dr. Bob Rappaport (Director of the FDA’s Division of Anesthesia, Analgesia, and Addiction), asked members to explain their votes. All but two said that while Zohydro had met their requirements for approval, their votes were meant to call greater attention to the agency’s regulation of opioids in general – not Zohydro specifically.
The FDA decided to approve Zohydro based on the agency’s judgment (and the advisory committee’s concordance) that the medicine is safe and effective. But the FDA also heeded the expert panel’s advice for better post-approval regulation of opioids. Shortly before Zohydro’s approval, the agency strengthened opioid labeling and post marketing requirements to address the concerns raised by the advisory committee.
There’s an apt Japanese proverb that bears repeating, “Don’t fix the blame. Fix the problem.”Unfortunately, the recent bashing of opioids (and the FDA’s regulatory decision-making and oversight thereof) isn’t helping. It's time for the grown-ups to step forward and take charge of the debate on drug safety.
In the United States, the use of opioids as first-line treatment for chronic pain conditions doesn’t follow either label indications or guideline recommendations. 52% of patients diagnosed with Osteoarthritis receive an opioid pain medicine as first line treatment as do 43% of patients diagnosed with Fibromyalgia and 42% of patients with Diabetic Peripheral Neuropathy.
This places both education (of the CME variety) and best practices (developed not just by PDMPs but also by physicians, pharmacists, and patient organizations) front and center. What about REMS training? And what about more precise criteria for what “pain specialist” or “pain clinic” even mean? As the saying goes, “if you can’t measure it, then it doesn’t count.”
On April 3rd, 2014 the agency’s approved EVZIO™ (naloxone hydrochloride injection) for the emergency treatment of known or suspected opioid overdose. Smartly, the FDA used the approval to speak, more broadly, to the topic. In the immortal words of Don Draper, “If you don't like what is being said, then change the conversation.
During the stakeholder teleconference the Commissioner returned again and again to the role the FDA must play in facilitating physician education, not only through labeling language but physician education. She specifically mentioned CME and working to develop (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.
“It all comes back to provider education,” she said. Amen.
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 used by the right patient in the proper manner. Importantly, the Commissioner regularly referred not to “abuse” but to “misuse and abuse.” That’s more than a rhetorical flourish since it recognizes that misuse is a gateway to abuse.
Provider education – the Hamburg Manifesto.
Consider the program recently instituted by CVS (and detailed in a recent New England Journal of Medicine Perspective piece
What will the role of the 21st century pharmacist be in improving drug safety and medication adherence via more proactive (and remunerated) patient education?
How can pharmacists become better integrated (beyond Med Guides) into the FDA’s Safe Use of Medicines initiative?
When will pharmacy synchronization programs really kick into gear, and how will states help to jump-start these important initiatives?
To paraphrase the American political scientist Aaron Wildavsky, we need a strategy of resilience based on experience. We must learn from adverse consequences in order to develop a capacity to advance the public health. Variability is the key to survival.
A recent IOM report that was issued in June of 2011 found that 100 million American are living with chronic pain. That’s a third of the U.S. population. Ten million of those have pain so severe that the pain disables them. The report also said that pain costs the U.S. economy about 600 billion dollars a year in lost productivity and healthcare cost.
The vast majority of people who use opioids do so legally and safely. A subset, approximately four percent use these medications illegally. In fact, from 2010 to 2011, the number of Americans misusing and abusing opioid medications declined from 4.6% to 4.2%. And the FDA’s Zohydro decision was “controversial?” Really?
Was the FDA’a approval of Zohydro “controversial?” Well, it depends what you mean by “controversial.” It’s controversial because the issue of opioid abuse is controversial. And that’s an important difference. Nobody said the FDA’s job was easy.
Whatever your position on the issue of opioids, the proper venue for this decision is not the office of the Secretary of HHS or the halls of Congress or the courts -- but rather the office of the FDA Commissioner.
Rather than dealing with the problem of abuse with sledgehammer solutions, all parties concerned should focus on potential solutions such as:
* The role of the 21st century pharmacist in improving drug safety and medication adherence via more proactive and remunerated patient education? How can pharmacists become better integrated beyond Med Guides into the FDA’s Safe Use of Medicines initiative? When will pharmacy synchronization really kick into gear, and how will states help to jump-start these important initiatives?
* Government and legislative initiatives such as the Stop Act (H.R. 486), which focuses on tamper-deterrent formulations and the continued development of those. Also, Senate Bill 1277 (sponsored by Senator Barbara Boxer, D/CA) which would establish a commission to bring all of the stakeholders together to have discussions about how to approach this issue so that law enforcement, providers, patients, and pharma can debate the issues and reach common ground.
* The appropriate role of tamper-resistant technologies. They are part of the solution, but they’re not the whole solution. We need to develop policy options that focus on the prescriber/patient relationship, and a professional assessment of what’s the risk involving this patient. Is the patient is going to tamper with the medication and potentially expose themselves or others to some danger. We have to do a better job (via CME and other methods) of training physicians and other prescribers on how to do these kinds of assessments.
FDA must walk a difficult public health tightrope, balancing patient need, medication safety, and (in the case of opioids), the dangers of abuse. And, most importantly, we need to keep the needs of patients front and center.
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