Full Summary — Medications Development for Opioid Use Disorders and Overdose Prevention and Reversal
Cutting Edge Science Meeting Series to End the Opioid Crisis
June 5, 2017
As part of a government-wide effort to address the opioid crisis, NIH is initiating a public-private collaborative research initiative on (1) new and innovative medications and biologics to treat opioid addiction and for overdose prevention and reversal; (2) safe, effective, and non-addictive strategies to manage chronic pain; and (3) neurobiology of chronic pain.
To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH is bringing together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. NIH seeks to pursue new approaches and recruit additional expertise with the aim of developing new safe and effective therapeutics for opioid abuse and chronic pain in half the time it currently takes.
The first of these meetings was held on June 5, entitled Medications Development for Opioid Use Disorders and Overdose Prevention and Reversal. This meeting will be followed by meetings on June 16th, entitled Development of Safe, Effective, Non-Addictive Pain Treatments, and July 7th, entitled Understanding the Neurobiological Mechanisms of Pain.
Welcome and Opening Remarks
Dr. Francis Collins, Director of the National Institutes of Health (NIH), highlighted the urgency of the opioid crisis, and the high priority agencies throughout the federal government have placed on ending this crisis. This meeting is the first of three that are being convened to identify areas for a public private partnership recently initiated by NIH to address the opioid crisis. Dr. Collins and Dr. Nora Volkow, Director, National Institute on Drug Abuse (NIDA), published a Special Report in the New England Journal of Medicine to describe the initiative which focuses on three scientific areas:
- developing better overdose-reversal and prevention interventions to reduce mortality, saving lives for future treatment and recovery;
- finding new, innovative medications and technologies to treat opioid addiction; and
- finding safe, effective, nonaddictive interventions to manage chronic pain.
The goal of this initiative is to develop public private partnerships to cut in half the time to develop new treatments. NIH has successfully used this model to address other scientific priority areas. For example, the Accelerating Medicine Partnership with NIH, FDA, Foundation for NIH, and 10 pharma companies aims to develop treatments for three disease areas, with 50/50 contributions from government and industry for a total of $230 million over 5 years.
While this meeting is focused on what can be accomplished with a partnership with the pharmaceutical industry, NIH is still committed to research on behavioral treatments, and NIDA has a robust portfolio in this area. NIH aims to identify areas of opportunity for partnerships that will accelerate development of therapeutics for OUD and overdose prevention and reversal.
Jessica Nickel: Patient and Family Perspective
Jessica Nickel, the president of the Addiction Policy Forum (APF), shared the perspective of patients and families affected by opioid use disorders and overdose. The APF represents nearly 5 million families, and launched the 144 a Day campaign to highlight the 144 people who die of an opioid overdose each day in the U.S. Ms. Nickel shared some of the many stories of families who have lost loved ones to this epidemic, some of which point to devastating failures of the treatment system in our nation. In one story, a family was told their child needed to be homeless before she would qualify for treatment services. Tragically, the young woman died that same night. Another family discovered after their son’s death that he had overdosed eight times prior, but the hospital had never followed up to engage him in addiction treatment.
Ms. Nickel conveyed that this NIH initiative is bringing hope to patients and families and that the advocacy community is committed to helping move this forward. She stressed that the families need and want the scientific and healthcare communities to have the same level of focus and urgency to address addiction as they would for any disease that is taking over 50,000 lives each year.
Ms. Nickel also expressed a need to communicate the scientific understanding of addiction to the broader addiction community to combat the many myths that hinder effective treatment. For example, making it clear that patients don’t need to hit rock bottom before treatment can be effective; early intervention is key, and effective medical treatments are available.
Nora Volkow: Research Update on OUD Treatment and Overdose Prevention/Reversal
Dr. Volkow provided an overview of the state of the science related to treatment OUD and overdose prevention. She challenged the participants to think boldly and creatively about what can be done to accelerate the development of cures.
- Currently three medications are available for OUD: methadone, buprenorphine, and naltrexone. However, they are highly underutilized, and are not ideal for all patients.
- OUD is a chronic illness, but most patients never receive treatment. Those that do are often not provided with evidence-based care, and/or care of a sufficient duration.
- We need new medications for patients who don’t respond well to currently available treatments, including new formulations that can improve adherence and retention in treatment.
Dr. Volkow highlighted recent research on improving engagement in treatment including studies demonstrating positive outcomes following:
- Emergency department initiated buprenorphine treatment;
- Provision of interim buprenorphine while patients were on waiting lists for comprehensive treatment;
- Use of naltrexone in criminal justice-involved populations with linkage to community-based care.
She also reviewed recent successes including FDA approval of Probuphine, a 6-month buprenorphine implant, and Nasal Narcan, the intranasal formulation of naloxone.
NIH infrastructure and programs that can be leveraged for this initiative include:
- NIDA’s Clinical Trials Network (CTN);
- NIH’s Clinical and Translation Science Award (CTSA) program;
- NIDA-VA medication development and subject recruitment;
- NIH blueprint for neuroscience research; neurotherapeutics network;
- The National Center for Advancing Translational Services (NCATS) molecular libraries and imaging program;
- Contracts and funding opportunity announcements (FOAs)
- Strategic alliance for medications development;
- Confidential pharmacology studies;
- Synthesis and dosage formulation (cGMP);
- Standard preclinical safety and toxicokinetic evaluations;
- Multi-site efficacy trials.
- Grand Opportunity in Medications Development for Substance-Use Disorders (SUD) (U01): accelerate development of SUD medications; funds up to 3 years; up to $5M/year.
- Strategic Alliances for Medications Development to Treat SUD(R01): advance compounds towards FDA approval in partnership with outside organizations; up to 3 years; up to $3M/year
- Translational Avant-Garde Award for Development of Medications for SUD(UG3/UH3): support outstanding basic and/or clinical researchers towards translation into medications for SUD: UG3: 2 years to achieve specific milestones: UH3: 3 years to complete project. Up to $1M/year
- Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Grant and Contract Solicitations
Dr. Ivan Montoya, Acting Director, Division of Therapeutics and Medical Consequences, NIDA: OUD Treatment Research Directions and Challenges
Dr. Montoya summarized participant feedback solicited prior to the meeting related to future research directions, challenges, and partnership opportunities for OUD treatment. See Appendix A.
Dr. David McCann, Acting Deputy Director, Division of Therapeutics and Medical Consequences, NIDA: Overdose Prevention/Treatment Research Directions and Challenges
Dr. McCann summarized participant feedback solicited prior to the meeting related to future research directions, challenges, and partnership opportunities for overdose prevention and treatment. See Appendix A.
He also highlighted the need to align pre-clinical studies with clinical objectives:
- Who is the patient population? How can we reliably identify patients at high risk for overdose? Will they be willing to use devices that prevent or detect overdose?
- Will payers provide reimbursement? For example, would payers reimburse for overdose prevention medications for patients using illegal drugs?
- Can we design adequate clinical trials with sufficient statistical power to evaluate endpoints that will be accepted by the FDA?
Group Discussion – OUD Treatment
- This is an urgent issue that needs collective action to have an impact on public health both in the short term and the long term;
- Researchers in this field need to be more in touch with needs of patients and families;
- Implementation issues present a significant challenge;
- Incentives are needed to encourage pharmaceutical and biotechnology companies to invest in research in this area.
- There are major ongoing challenges related to implementation of evidence based treatment strategies
- Stigma, workforce shortages, billing/reimbursement issues, poor integration between behavioral health and general health care, inadequate clinician training, and an inadequate infrastructure for OUD treatment all limit access to quality care.
- For example, emergency departments are interested in implementing interventions to initiate buprenorphine treatment, but they lack the infrastructure to link patients to behavioral health treatment providers for follow up care (workforce shortages, lack of sufficient billing models).
- These same barriers are likely to be faced by new medications and devices.
- A major research question that can be addressed by NIH: How can evidence based interventions be implemented to effectively address OUDs?
- Effective interventions could result in cost-savings across society -- economic modeling studies could estimate the return on investment, potential reductions in healthcare and criminal justice costs, and other benefits of increasing access to evidence-based OUD treatment.
- Pharmaceutical and biotechnology companies are reticent to invest in this space due to the:
- High cost of clinical trials with uncertain return on investment;
- Difficulty of conducting clinical trials in patients with OUD due to high rates of comorbidity and low rates of treatment adherence;
- The high bar for regulatory approval; there is a need for endpoints other than complete abstinence;
- Possible misalignment between what FDA will approve and what insurance companies will reimburse.
- Vaccines have significant promise but funding is not available for the necessary clinical trials.
- Vaccines targeted to heroin, prescription opioids, fentanyl, and fentanyl analogs have been developed and show promise in preclinical studies.
- Technology has tremendous potential to revolutionize the field, but funding and billing models to support medical device development are limited. Device-based approaches could:
- Provide medication implants (e.g. buprenorphine) or pumps (e.g. naloxone);
- Deliver behavioral interventions;
- Promote and monitor adherence and retention in treatment;
- Monitor treatment progress and outcomes;
- Provide recovery support;
- Predict relapse and support early intervention.
- A very large investment is needed. Participants suggested exploring ways to create economies of scale by industrializing the clinical trials process to bring down costs of screening, toxicology, etc.
- FDA recommended using standing protocols to speed clinical trials.
Group Discussion – Overdose Prevention and Reversal
- There is a need for better surveillance on overdoses and the use of naloxone to reverse them.
- How often is naloxone used? What is the success rate?
- How often are multiple doses required, for Nasal Narcan, for injectable, and for improvised devices?
- Rates of multiple overdoses.
- Patients are often alone when they overdose. Technology can play a significant role in identifying, preventing, and reversing overdoses, but there is minimal investment in this area.
- Implementation issues are also a concern related to overdose. Recommendations for naloxone co-prescription are rarely followed.
- Too few patients are engaged in OUD treatment following a non-fatal overdose.
- There is a need for methods to reliably identify patients at high risk of overdose:
- Biomarkers for determining risk for overdose and for detecting an overdose before respiratory depression reaches a dangerous level would be important tools; more research is needed in this area.
- Algorithms are in development based on the following factors, but further research is needed.
- Patients in recovery are at very high risk if they relapse;
- Patients coming out of criminal justice settings;
- Patients with previous overdoses;
- Patients prescribed more than 90 morphine milligram equivalents of opioids;
- People with sleep apnea;
- Those on benzodiazepines.
- Risk stratification is valuable, but all people who use opioids are at risk for overdose (especially if they obtain opioids illicitly, or if the opioids contain fentanyl or other high potency synthetic opioids).
- There is significant anecdotal evidence of overdoses in the community requiring multiple doses of naloxone to reverse. However, the data are not yet clear on whether this is related to Nasal Narcan or improvised nasal sprays. More research is needed on the scope of this problem and to identify the dose of naloxone that would be sufficient to reverse overdoses of fentanyl and other high potency opioids.
- Monoclonal antibodies can also potentially be used to reverse an overdose. This could be used in conjunction with naloxone, with naloxone having a faster but brief effect and the antibodies producing a more sustained response to prevent overdose recurrence when naloxone wears off.
- This would take less than 5 years to develop with adequate funding.
- There are ethical questions related to clinical trials – which patient population to test – but these can be overcome
- Other opioid antagonists with longer half-lives can be explored, as well as novel targets such as ampakines.
- For example, an existing analog of naloxone that is 20 times more potent with a half-life of 4-5 hours might have a clearer path to market in the current landscape (especially given the rise of fentanyl).
- Potential new technologies discussed include:
- Phrenic nerve stimulation;
- Alerts to track when naloxone is opened/used;
- Devices that monitor respiration;
- Implant/pumps that can auto-deliver naloxone in response to a drop in respiration;
- One concern raised is the high rates of infection among injection drug users that could cause complications;
- Using Uber or other forms of crowd sourcing to deliver naloxone in an emergency;
- Use of automatic defibrillators to stimulate respiration;
- Drones to deliver naloxone.
Possible Action Items
- Short Term Actions:
- Improve existing medications:
- Depot formulations of buprenorphine;
- Longer term formulations of naltrexone;
- Biodegradable polymer implants;
- Sustained release morphine;
- Longer acting naloxone formulations;
- FDA indicated that there are accelerated pathways to approval of new formulations of approved medications. In some cases, pharmacokinetic comparisons would be needed but clinical trials would not. However, if higher doses were used that would likely require clinical trials.
- Explore historical data on opioids and evaluate through new lens of understanding of the opioid system.
- There are many existing opioids that may be useful.
- Establish a clinical trials infrastructure with a standing protocol to bring down the cost and increase the speed of trials in this area.
- A new initiative/partnership could focus on implementation: Test treatment delivery models such as using hubs of behavioral health providers to coordinate care with primary care providers
- Develop and test standard treatment protocols for specific treatment settings (Emergency departments, primary care, etc.)
- Establish and test OUD healthcare infrastructure models:
- Potential partnership between NIDA’s Clinical Trials Network and CMS Innovations Center;
- Recommendation to explore the CDC emerging threat network, the NINDS SIREN network of emergency medicine doctors, and CTSAs.
- Organize an FDA meeting to think through the endpoints/study design for overdose prevention interventions;
- Research to develop a non-proprietary algorithm on overdose risk;
- Research to determine the extent of the issues with multiple doses of naloxone needed to reverse overdoses – is this related to Nasal Narcan or is it due to improvised devices?
- Long Term Actions:
- Public private partnerships could develop technologies to:
- Detect and intervene in an overdose;
- Predict risk for an OUD;
- Predict relapse risk;
- Promote adherence and retention in treatment.
- Vaccines and other biologics:
- NIH partnerships could help incentivize pharma to invest in these areas;
- NIH could help with negotiating prices for necessary but expensive components of vaccine production.
- Research on the health impacts and long term outcomes associated with long-term medication use
- What is the optimum strategy for long-term management of patients who have been induced on medications for opioid addiction?
- Developing predictive biomarkers of risk for OD and to identify OUD
- Public private partnerships could develop technologies to:
- Embed translational research into clinical trials;
- Engage CMS and other payers to consider reimbursement issues that limit pharmaceutical and biotech company investment in this area.
- Consider challenges related to NIH funding:
- Develop an expedited process for grant review and funding.
- The typical grant funding cycle doesn’t work for medications development in a pharmaceutical company. They can’t wait 9 months to see if they have funding.
- Develop a dedicated FOA for development of medical devices in this area, with a special study section.
- NIH outreach to venture capital companies:
- Decision making is often based on a poor understanding of the field. NIH can help to educate these companies on the potential in this area.
- The Foundation for NIH is exploring the possibility of creating a Venture Capital like mechanism for supporting medications development and clinical trials; there are many legal hurdles to be overcome but worth exploring.
- Develop an expedited process for grant review and funding.
- Address Regulatory Barriers:
- Consider incentives for pharmaceutical and biotech company investment:
- Examples include incentives related to rare diseases.
- Address barriers to conducting research on schedule I substances, including cannabinoids:
- Significant research suggests that cannabinoids have potential for treating both pain and addiction.
- Use fast-track designation when possible to speed up the FDA approval process.
- FDA highlighted that medications do not need to be produced using current good manufacturing practices (cGMP) for clinical trials.
- Promote awareness of the guidance on this topic.
- Consider incentives for pharmaceutical and biotech company investment:
Potential Next Steps
NIH will consider setting up subgroups to further explore ideas for a public private partnership in the following areas:
- Development of new formulations of existing medications;
- Development of medical devices to treat OUD and to prevent and treat overdose;
- Research on healthcare delivery models for improving access to and delivery of evidence-based treatments for OUD and overdose, including research on measures of quality of treatment.
NIH may also consider approaches to:
- Engage CMS to consider reimbursement challenges for medications as well as medical devices that currently disincentivize industry from investing in this area;
- Explore use of special study sections to review grants that include development and testing of medical devices;
- Explore mechanism to expedite review of grants to develop therapeutics for OUD and overdose prevention and reversal;
- Evaluate opportunities to develop networks of healthcare providers, including emergency departments, that can serve as infrastructure to rapidly deploy research;
- Explore options for developing economies of scale within the clinical trials infrastructure, such as standing protocols and industrialization of screening and toxicology testing.