Working Together to Reduce the Devastating Effects of Opioid Misuse

By Robert M. Califf, M.D.

The public health crisis of opioid misuse, addiction and overdose is one of the most challenging issues the U.S. Food and Drug Administration has faced during my time as FDA commissioner.  Solving this issue is critical to our future.

The issues cut across every socioeconomic level and geographic boundary. It would be difficult to identify any community in America that has not been touched by friends, family members or colleagues suffering from addiction, and far too often, losing their lives to it. As I leave the agency as part of the presidential transition, I have reflected on what I have seen, how far the nation has come, and the important work that remains for both the public and private sectors.

Robert CaliffI’ve made it a point to see affected communities, first-hand, because interventions and national policy solutions work best when they are well informed by what communities actually need. Just last week, I visited Baltimore to better understand how our cities are being affected – in this case, by an inflow of illicit fentanyl, a synthetic opioid that is about 100 times more potent than many other prescription opioids, and can be deadly on its first use. I have also visited the neonatal intensive care unit, or “NICU” of a Tennessee hospital where babies were screaming and shaking in the pain of withdrawal because they were born with Neonatal Opioid Withdrawal Syndrome. I have met people in West Virginia who did back-breaking work in power plants or in coal mines; after suffering on-the-job injuries they were first afflicted with pain, then by addiction. They got prescription pain relief but, too often, it wasn’t accompanied by the proper support and counseling. In Kentucky, I spoke to spouses and families whose lives have been forever changed by addiction, even as the community rallied together to fight it. And, much closer to home, I have heard personal stories from FDA employees and providers in local health care facilities, whose families and friends are not immune.

We have taken a number of actions at the FDA over the past several years to help reduce the number of people who become addicted, or who ultimately overdose from prescription opioids. We’ve improved product labeling, pushed for prescriber education, and encouraged the development of abuse-deterrent formulations. In addition, we have approved new intranasal and auto-injector forms of naloxone — products to reverse opioid overdoses, which can be administered by laypersons and are, therefore, better available able to save lives.

I’m also proud of the partnerships we have formed with other federal Agencies and the work that has resulted from them. But the latest data, including data from the Centers for Disease Control and Prevention (CDC) remind us that while some progress is being made, there is more to do. For example, it is promising to see that the nationally estimated number of outpatient prescriptions dispensed for Schedule II opioids decreased by 10 percent in 2015 compared to the previous year, according to IMS Health. However, the CDC reports that while the rate of overdose deaths associated with prescription opioid use increased by just 4 percent instead of by 9 percent the previous year, deaths associated with heroin use have skyrocketed. Clearly, more work needs to be done.

As I prepare to turn over the awesome responsibility of FDA commissioner to the next Administration, I feel compelled to point out that public and private sector efforts in this area must be continued and strengthened. In particular, I want to call on the pharmaceutical companies that manufacture and sell these drugs to dig deeper into their expertise and resources to prioritize finding solutions to this public health problem. I have consistently been impressed that the motivation to cure disease and improve quality of life for patients is shared across the spectrum of federal agencies, public health workers, health care providers and scientists within the pharmaceutical industry. However, the financial incentives in the industry can lead to a focus on short-term profits instead of patient well-being.This is the time for both branded and generic drug companies  to go beyond marketing and distribution plans and instead commit their expertise and resources to  confronting  the devastating negative consequences of a class of drugs that brings much needed pain relief, when used appropriately.

Specifically, I urge us all to focus on the following priorities:

  1. Encouraging appropriate prescribing by healthcare practitioners. Too many people become addicted from unnecessary prescriptions for minor pain or injury. And even appropriately prescribed opioids can lead to addiction, so careful monitoring of patients prescribed these powerful drugs is needed. While there are situations where opioids are appropriate, there are also situations where other alternatives can be effective. Therefore, conversations between provider and patient about the pain treatment plan are imperative. If an opioid is appropriate, CDC guidelines and FDA labeling emphasize the need to start on the lowest dose and minimum time necessary, and carefully monitoring patients for signs of addiction and inadequate pain control.
  1. Considering the family as well as the patient. Pain treatment, and use of opioid drugs, will be more successful when the family is involved. It will result in fewer drugs diverted from the medicine chest, fewer babies born addicted to opioids and better treatment of pain. Women who use or abuse opioids, or who are in treatment for opioid addiction, should talk to their health care provider before considering pregnancy.
  1. Finding better ways to treat pain with new medications and with more holistic pain management. It’s time to put more resources into the development of non-opioid, non-addictive medications to help people who are in serious, debilitating pain. We need more research to define the most effective non-medication approaches to pain and how to deliver them in a complex and financially constrained healthcare system.
  1. Improving how companies, professional societies and academics communicate about their activities in this area. I urge companies to commit to transparent and appropriate company communications and to work with government and others in the community to do a better job in educating the medical professionals responsible for treating our nation’s pain, as part of the overarching effort to do everything possible to help prevent addiction. Professional societies and academic medical centers also need to continue their efforts at educating their members and examining their practices to find ways to improve. For example, the education of the next generation of physicians about how best to manage pain is critical.
  1. Finding new ways to curb diversion and misuse of opioids. In addition to our continuing efforts to help support the development of abuse-deterrent formulations, the FDA is exploring potential packaging, storage, delivery, and disposal solutions that companies and other stakeholders might consider that would prevent opioids from being diverted to those without a legitimate prescription for these powerful drugs. I implore companies to conduct research and offer their creative ideas and resources to innovate in this area.
  1. Increasing pragmatic research to better understand how to implement appropriate pain therapy in general and use of opioids in particular. Post-market requirements from FDA that mandate industry-funded studies and recent pragmatic research efforts by the Patient-Centered Outcomes Research Institute and the NIH and Department of Defense are expected to provide important data, but we need more robust evidence to better guide practice. Pain is a vexing issue that seems to fall between the cracks in research funding; we need to keep the pressure on funding entities to move pain to the forefront as a research issue.
  1. Treating addiction as a disease, not as criminal behavior. We have the tools to treat addiction and reverse overdose from opioids and are working to develop more of them. But there’s a lot we don’t know about the drivers for drug abuse, and scientific knowledge will help us make better decisions. This is one reason why we need companies with products on the market to monitor the safety of those drugs and make their data public. We have mandated post-market studies to define major questions about chronic use of opioids, and it is essential that industry fulfills these requirements.

I am proud to have been part of the effort that’s changing the tide on this epidemic, but the nation has a long way to go.Government, companies, healthcare systems and healthcare providers all have important roles to play. The most recent data reminds us it’s time to double down on these efforts. While I won’t have the good fortune of leading this fight in an official capacity, I’m proud of the work the FDA and others have done so far. I leave FDA’s efforts to the many leaders at the agency who have been working tirelessly on this issue — and will continue doing so — and look forward to supporting public and private efforts to bring this epidemic to an end.

Robert M. Califf, M.D., is Commissioner of the U.S. Food and Drug Administration

FDA’s Opioids Action Plan: A Midyear Checkup

By: Robert M. Califf, M.D.

As FDA works to address the opioid epidemic of abuse, misuse and addiction, it’s valuable to see firsthand some of the ways the crisis is affecting our communities.

This summer, I toured areas hard-hit by the opioid crisis in Tennessee, West Virginia, and Kentucky, visiting  with survivors of opioid addiction and overdose as well as community activists, government officials, and health care providers, all of whom are working diligently and creatively to address and overcome this crisis.

Robert Califf

Robert Califf, M.D., is Commissioner of the U.S. Food and Drug Administration

My visit to the nationally-recognized neonatal intensive care unit at East Tennessee Children’s Hospital was deeply moving and set the stage for the rest of my tour and underscored the urgency of fighting this epidemic. More than a third of the babies admitted to the NICU have neonatal opioid withdrawal syndrome (NOWS), a condition which can be life-threatening if not recognized and treated

Watching a nurse treat a fretful baby suffering from NOWS underscored the complexity of the opioid problem.  Many women taking opioids haven’t planned their pregnancy, don’t immediately know they are pregnant and may not be aware of the risk that opioids pose to their unborn child. This includes those women who are taking medication as part of medication-assisted treatment (MAT) which also includes counseling and behavioral therapies. For women on MAT, the risk of NOWS must be balanced against the additional dangers of untreated opioid addiction during pregnancy.

How best to prevent NOWS and treat opioids use disorder was a continued theme of my trip, and among the issues we grappled with during a roundtable at the University of Tennessee’s Medical Center hosted by Surgeon General Vivek Murthy, who is traveling the country to discuss solutions to opioid abuse as part of his TurnTheTideRx campaign. I’m pleased that expanding access to and the use of evidence-based MAT is a key focus area for the Administration, is a part of the HHS-wide opioid initiative, and is an approach supported by a recent FDA advisory committee.

In Charleston, WV, I met with several patients who are reclaiming their lives with the use of MAT including “Dave.” Like so many others, Dave became addicted to opioid pain medication after being treated for an injury. As a result of his addiction, his marriage failed and he lost contact with his children. But with treatment, he has reunited with his family and next spring will graduate from college and hopes to taper off of his treatment.

Throughout my tour, I heard that opioid education – including training during medical school and residency and greater public awareness far and wide – is a key component in fighting the opioid epidemic. At a roundtable in Charleston, Gov. Earl Ray Tomblin and U.S. Sen. Joe Manchin singled out their state’s model mandatory education program for prescribers and they told me the state is leading an effort to implement the CDC’s Guideline for Prescribing Opioids for Chronic Pain as a best practice for their state-run Medicaid program.

At a firehouse in the town of Williamson, WV, I met with those on the frontlines of the opioid epidemic – the firefighters and first responders who carry life-saving naloxone to help reverse an overdose. They told me more education about naloxone was needed and told me that they appreciate our efforts to help make naloxone more available to the general public.

My last stop this summer was to Kentucky where I toured the emergency room at the Pikeville Medical Center and participated in a roundtable with physicians, pharmacists, and state policy and community leaders brought together with the help of the regional organization Operation UNITE. UNITE coordinates treatment for those with substance use disorder as well as support for their families and friends, and educates the public about the dangers of drug use. These measures, combined with a recent state law requiring prescribers to register with a prescription drug monitoring program are working, we were told.

Throughout my travels, I listened and learned more about how FDA can help end this crisis. I also had the chance to share what FDA has been doing this year to implement a multipart plan to address the opioid epidemic.

Our milestones so far include:

  • Developing warning and safety information for immediate release opioids and requiring that prescription opioid analgesics and opioid-containing cough product labels include strengthened warnings about the risk of using benzodiazepines at the same time.
  • Working to better understand the long-term safety of using extended release/long acting opioids. Sponsors must now conduct a number of studies to generate postmarket data on these products.
  • Issuing draft guidance for industry to support the development of generic versions of approved opioids with abuse-deterrent formulations.
  • Seeking advice from the National Academy of Science Engineering and Medicine on how to balance both the needs of patients with pain and the need to address opioid misuse and abuse.
  • Supporting increased access to naloxone; for instance, by awarding a contract to conduct consumer behavior studies based on model product labeling for a potential OTC version of the antidote and by launching a competition to create a mobile app that could help find the closest available naloxone treatment in an emergency.
  • Approving the first implantable treatment for the maintenance treatment of opioid dependence.

The community-based successes I observed on my three-state tour reinforced my view that we are making important progress in addressing this crisis.  But continued hard work, creative ideas, and collaboration — across government, with the medical profession, health care providers, industry, and, most importantly, patients and their families, is still required.

We at FDA will continue to work with all of these groups, using all the resources at our disposal, to improve the judicious and responsible use of opioids and to help bring an end to this epidemic.

Robert M. Califf, M.D., is Commissioner of the U.S. Food and Drug Administration

 

Changing course: A new approach to opioid pain medication at FDA

By: Robert M. Califf, M.D.

As a doctor, I have a first-hand understanding of the important and legitimate need for powerful medication to help people deal with chronic or severe pain. If you have had a family member or loved one touched by a serious illness or injury, you understand it too. You know how tough it can be to see them try to endure pain that can’t be touched by anything you can get over the counter.

Robert M. Califf, M.D., MACC, FDA's Commissioner of Food and Drugs

But as all of you know, more Americans now die every year from drug overdoses than they do in motor vehicle crashes. Opioids were involved in 28,648 deaths in 2014, according to the CDC.

The FDA is deeply concerned about this growing epidemic, and I am personally disturbed by the toll it has taken in communities across the country. It’s an issue I’ve been involved with for years as an academic, having overseen the NIH’s National Institute on Drug Abuse Clinical Trial Network, which was involved in some of the early medication assisted treatment studies.

After seeing the dependence and mortality numbers continue to rise and hearing from voices who care about this issue, I asked our folks to take a hard look at whether we’re doing everything we can to ensure that we’re appropriately taking into account the public health crisis that confronts us in the context of the role we play in ensuring the safety and efficacy of drugs.

The conclusion of that comprehensive assessment was that we can do more.

So we are announcing a change in course in how our agency approaches opioids – their approval, their labeling and their prescribing. We are going to fundamentally re-examine the risk-benefit paradigm for opioids and ensure that we consider their wider public health effects.

To that end, we have developed a comprehensive action plan to take concrete steps toward reducing the impact of opioid abuse on American families and communities.

There are four main pillars to the plan.

First, we’re going to be more transparent and open in the approval process for this category of drugs. Starting today, the FDA will convene an expert advisory committee before approving any new drug application for an opioid that is not in an abuse-deterrent formulation (ADF).

Additionally, we’re going to engage the Pediatric Advisory Committee to make recommendations on pediatric opioid labeling before any new labeling is approved.

Importantly, the advisory committee process is going to provide opportunity for public input, which is going to help us better understand and answer the concerns people have about these drugs.

We have also engaged the National Academies of Sciences, Engineering, and Medicine on how to take into account our evolving understanding of the risks of opioids, not only to the patient but also the risks of misuse by other persons who obtain them. The goal is to formally incorporate the broader public health impact of opioid abuse in approval decisions. And in March, we will seek advice from the Agency’s Science Board to reassess the risk-benefit approval framework for opioid use. The results of these efforts will be made public.

Second, we’re going to improve our communication with the medical community about these drugs. That starts with enhancing safety labeling. Our goal is to provide better information to doctors about the risks of these drugs and how to safely prescribe them. We’re developing changes to immediate release opioid labeling that will bring it more in line with the extended-release/long-acting labeling that occurred in 2013.

After reviewing the existing requirements and hearing recommendations from an advisory committee, we’re also going to update our Risk Evaluation and Mitigation Strategy (REMS) program requirements for opioids. We need to increase the number of prescribers who receive training on pain management and improve the safe prescribing of opioids to decrease inappropriate prescribing.

That effort will complement work being done at the Department level and at the CDC to help ensure that opioids are prescribed appropriately. We believe that this is a key component of ending this public health crisis. The more than 250 million prescriptions for these types of pain killers in 2012 – enough for every adult in the U.S. to have a bottle of pills – is clear evidence of the work ahead of us.

Third, we’re going to work to improve the information that’s available about opioid use. We’re going to require drugmakers to strengthen post-market analysis of these drugs. Today, that information, especially about long-term use, is lacking. We need more and better evidence on the risks of misuse and abuse associated with long-term opioid use and to better understand predictors of addiction, among other issues.

Finally, we’re going to focus efforts on approving drugs that have the potential to help mitigate the crisis. That means spurring the development of promising generics with abuse deterrent formulations. The FDA will issue draft guidance with its recommendations for the approval standards for generic abuse-deterrent formulations. We believe the availability of less costly generic products should accelerate prescribers’ update of abuse deterrent formulations.

And we’re going to work to improve access to naloxone, which is effective at treating overdoses. The FDA is reviewing options, including over-the-counter availability, to make naloxone more accessible. That work builds on FDA’s recent approval of intranasal naloxone.

What I’ve just described is a change in course – a framework for how FDA can better do its part to confront the opioids epidemic. In the coming weeks and months, we’re going to further develop these plans and continue to fill in the details for each initiative I’ve described.

But it’s time for us to act – to take the first steps toward changing how we do business and addressing this problem.

Robert M. Califf, M.D., previously FDA’s Deputy Commissioner for Medical Products and Tobacco, became FDA’s Commissioner of Food and Drugs on Feb. 25, 2016

Naloxone – FDA hosts meeting to discuss expanded use of overdose medicine

By: Peter Lurie, M.D., M.P.H.

At the FDA, we’re proud of our work supporting the development of important and innovative medical products that address the critical needs of patients. Sometimes this means wholly new molecules to treat previously untreatable diseases; other times it simply requires the combination of more user-friendly formulations and enhanced efforts to get the drug to patients. The potentially life-saving drug naloxone, which can reverse opioid overdoses, is a poster child for the latter situation. The drug, which literally dislodges opioid drugs such as heroin or oxycodone from their receptors, thus reversing overdoses in minutes, has increasingly been administered outside of conventional medical settings by community and family members, as well as by first responders such as police and fire departments.

Dr. Peter LurieA little over three years ago, FDA partnered with other HHS agencies and laid out the pathway for the development and marketing of naloxone. It was the first public meeting on naloxone sponsored by the Federal government. A key development since that first meeting was FDA’s approval of Evzio, a prescription naloxone hydrochloride injection that can be used by family members or caregivers to treat a person known or suspected to have had an opioid overdose. Evzio rapidly delivers a single dose of the drug via a hand-held auto-injector. Now work is underway to administer naloxone through the nose.

According to a survey just published in CDC’s medical journal, there also has been enormous growth in the number of programs in which naloxone kits, primarily for delivering naloxone through the nose, and the associated training have been provided to laypersons. That survey reveals that since 2010 there has been a 243% increase in the number of local sites providing naloxone, a 183% increase in the number of laypersons provided naloxone kits, and a 160% increase in the number of overdose reversals reported.

This week FDA is hosting a two-day public meeting, co-sponsored by the National Institutes of Health’s National Institute on Drug Abuse, the Centers for Disease Control and Prevention, the Substance Abuse and Mental Health Services Administration, and the Health Resources and Services Administration. It brings together members of the community-based organizations that first pioneered lay administration of naloxone, medical professionals, policy-makers, public health officials, first responders, product developers, researchers and, of course, patients and their families, to explore and discuss issues surrounding the use of naloxone. The group will address a wide range of topics from a review of current naloxone use in clinical and non-clinical settings to questions of access, state law, over-the-counter status, training and evaluation of effectiveness.

The meeting builds on the good work already done to examine “second generation” questions: growth and sustainability. Discussions will include ways to further involve police and fire departments, expand the range of new products, and address issues of cost, logistics, and supply.

Science doesn’t stand still. But, as this week’s meeting on Exploring Naloxone Uptake and Use demonstrates, neither does the FDA. We will continue to explore every opportunity to apply the best regulatory science to the technology of today in support of our work to protect and promote the health of all Americans.

Peter Lurie, M.D., M.P.H., is associate FDA commissioner for public health strategy and analysis.

Opioid Auto-Injector Can Help Prevent Overdose Deaths

By: Dr. Douglas C. Throckmorton

The Food and Drug Administration has today made an important advance in helping to save lives when overdoses from drugs known as opioids occur: the approval of a drug that can actually reverse that overdose.

Douglas C. Throckmorton, M.D.Opioids include legal prescription drugs, such as OxyContin (oxycodone) and Vicodin (hydrocodone with acetaminophen), used to treat pain, as well as illegal street drugs, such as heroin. In 2010, overdoses of prescription opioids were linked to 16,651 deaths and heroin was linked to 3,036 deaths in the United States.

Whether opioids are used by patients as prescribed by their health care professional or are misused or abused, these drugs have one important thing in common: They can all cause rapid and fatal overdose.

FDA, along with other organizations, has been working diligently on ways to address this major public health issue. That’s why FDA has approved a drug-device combination product that delivers the medication known as naloxone, which is the standard treatment for a drug overdose. This product is potentially easier to use than existing technology and thus could save lives.

Overcoming an Obstacle

Naloxone reverses the effects of opioids. Most significantly, it reverses the severely slowed breathing that can lead to death during an overdose. When naloxone works, the results can be dramatic: Comatose patients can wake up in minutes.

Over the years, emergency health care professionals and others with special training have saved thousands of lives by giving injections of naloxone to people suffering from opioid overdoses. Although effective, this requires expertise – to be able to draw the naloxone up from a vial and then inject it with a needle and syringe. In some cases, the injectable form is adapted so it can be administered through the nose, but there is currently no intranasal form of naloxone approved by FDA.

FDA has now approved  the first naloxone product that is given using an auto-injector, without having to use a separate needle and syringe.  Available via prescription, the product enables anyone – even the general public – to inject naloxone from a pre-filled, single-use device into a person who is overdosing. This is similar to devices used by laypeople to administer epinephrine in cases of severe allergy. In addition, the auto-injector gives recorded instructions to the user describing how to deliver the medication. The instructions also reinforce the need to seek emergency medical attention immediately because while naloxone works rapidly, it only temporarily reverses the effects of opioid overdose. The patient still needs immediate medical care.

The product’s brand name is Evzio, and information on its safe use is available by clicking this hyperlink.

This approval is the culmination of concerted efforts at FDA and throughout the Department of Health and Human Services (HHS) to spur research into alternative forms of naloxone and to expand its availability. On April 12, 2012, FDA co-sponsored a meeting that highlighted the impact of community-based naloxone distribution programs and explained to sponsors the path to FDA approval.

FDA Working on Other Fronts to Combat Opioid Misuse and Abuse

FDA has a responsibility to demand the best science and data to uphold its high standards to ensure a proper benefit/risk profile for drugs that treat pain. We also foster discussion and research that leads to a better understanding of pain and pain drugs. Because we are concerned about the public health issue, the agency has taken a number of actions to help reduce the devastating consequences of opioid misuse, abuse, and fatal overdoses. We are targeting key drivers of the problem with efforts that include:

  • Changing the labeling of certain opioids to help improve their safe use.
  • Requiring that manufacturers conduct studies of the safety of long-term use of certain prescription opioids.
  • Requiring that manufacturers  of certain opioids make training available to practitioners (physicians, dentists and others authorized to prescribe opioids) on responsible prescribing practices and assessing and addressing signs of abuse and/or dependence.
  • Strengthening our surveillance efforts to actively monitor the changing nature of prescription opioid abuse and identify emerging issues.
  • Working with the Drug Enforcement Administration on opioid controls.
  • Encouraging the development of new forms of opioids that are resistant to abuse.
  • Supporting the development of new pain treatments, especially non-addictive treatments.

While FDA plays an important role in mitigating the risks of addiction, abuse and misuse of prescription opioids, we cannot fix the problem alone. A comprehensive approach must be taken by federal and state governments, public health officials, opioid prescribers, addiction experts, researchers, industry, patient organizations, and others. That is why FDA is working closely with our HHS counterparts, including CDC, NIDA, SAMHSA, and throughout the US government.

There’s much work to be done, but today’s approval of the opioid auto-injector could save thousands of lives. FDA will continue to work to prevent the consequences of misuse and abuse of opioids, including preventing fatal overdoses.

Douglas C. Throckmorton, M.D., is Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research