128th Meeting Minutes

Minutes - February 6th

The National Advisory Council on Drug Abuse convened its 128^th meeting at 9:00 a.m. on February 6, 2018 in Conference Rooms C & D, 6001 Executive Boulevard, Bethesda, Maryland.  The closed portion of the meeting held on February 6^th was for reviewing applications for Federal grant assistance and was open only to Council members and Federal employees. The open portion, which was open to the public, began at 10:30 a.m. and was also webcast.  The Council adjourned on February 6, 2018 at 4:32 p.m.

Council Members Present

Anne Andorn, M.D.
Laura Bierut, M.D.
Julie Blendy, Ph.D.
John Carnevale, Ph.D.
Linda Chang, M.D.
H. Westley Clark, M.D., J.D.
Karl Deissesroth, M.D., Ph.D.
Marie Gallo Dyak
Jay Giedd, M.D.
Kenneth Mackie, M.D.
Lisa Marsch, Ph.D.
Edward Nunes, M.D.
Robert Rancourt, J.D.
Steffanie Strathdee, Ph.D.

Council Members Absent
Judith Auerbach, Ph.D.
Eric Verdin, M.D.

Council Chair
Nora Volkow, M.D.

Executive Secretary
Susan Weiss, Ph.D.

Federal Employees Present

Members of the Public Present

Rachel Anderson, Ph.D.—National Institute of Justice
Colm Everard, Ph.D.—Kelly Services, Inc.
Carlos Faraco, Ph.D.—National Institute of Justice
Shannon Givens —Kelly Services, Inc.
Holly Hagle, Ph.D.—Addiction Technology Transfer Center
Emily Howell, M.P.H.—A. Bright Idea, LLC
Nicole Johnston, M.S.—Global Solutions Network
Jennifer McCormack, M.S.—The Emmes Corporation
Phylicia Porter —Kelly Services, Inc.
Victor Prikhodko—Kelly Services, Inc.
Jamie Hwa Sim, M.P.H.—Kelly Services, Inc.
Roy Walker—Synergy Enterprises, Inc.
Patrick Zickler—The Palisades Group, LLC

Closed Portion of the Meeting – February 6, 2018

1. Call to Order

   This portion of the meeting was closed to the public in accordance with sections 552b(c) (4) and 552b(c) (6), Title 5, U.S. Code and section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2).

   Dr. Nora Volkow, Director, NIDA, called the meeting to order and welcomed the Council and staff.  She reminded those present that the Federal Advisory Committee Act applies to Council meetings and that this portion of the meeting was closed to the public. 

   Dr. Susan Weiss, Executive Secretary, summarized relevant NIH policies, provided detailed instructions on Council review procedures, and reminded those present about NIH confidentiality and conflict of interest policies. 

2. Application Reviews

   Drs. Rita Valentino and Carlos Blanco the Directors of NIDA’s Division of Neuroscience and Behavior, Division of Epidemiology, Services and Prevention Research, and Dr. Ivan Montoya, the Acting Director of the Division of Therapeutics and Medical Consequences, presented their Division’s assigned and initially reviewed applications for consideration by the Council.  For each, Council provided unanimous en bloc concurrence with the initial scientific reviews. An Administrative Supplement, a MERIT Award, and several foreign applications were presented to Council for Special Council Review, and Council agreed with program assessments. The initial reviews of all Trans-NIH Initiatives, including NIH Common Fund applications and NIDA Secondary applications, also received Council concurrence.

   Council and staff were recused from the Council meetings during discussion of, and voting on, individual applications from their own institutions or other applications for which there was a conflict of interest, real or apparent.  Conflicts of interest statements were signed by each member of the Council.  Members were not required to leave the room if an application in conflict with that member was acted upon en bloc.

Open Portion of the Meeting – February 6, 2018

1. Call to Order

   Dr. Nora Volkow, Director, NIDA, called the open portion of the meeting to order and welcomed all attendees.   She reminded the Council and audience that the meeting was open to the public in compliance with the Government in the Sunshine Act and indicated that time would be provided for public comment.

   She then called attention to future Council meetings:  May 15, 2018, May 16, 2018 (CRAN), and September 5, 2018.

2. Consideration of the Minutes of Council

   The Minutes of the NIDA October 2017 meeting were unanimously approved as written. 

3. NIDA Director’s Report – Nora Volkow, M.D., Director, NIDA

   Dr. Volkow began by announcing some NIDA staff changes, including the recent addition of Dr. Redonna Chandler as the Director of the AIDS Research Program, where she will be responsible for the development, planning, and coordination of high priority research on HIV and AIDS and drug use within NIDA and across other NIH Institutes. She will also oversee NIDA's annual Avant-Garde Award competition, which stimulates high-impact research that may lead to groundbreaking opportunities for the prevention and treatment of HIV/AIDS in drug users. Dr. Chandler’s new position marks a return to NIDA, where she previously served as the Acting Director for the Division of Epidemiology, Services and Prevention Research, as well as the Chief of the Services Research Branch. More recently, Dr. Chandler was Deputy Director for the Division of Clinical Innovation (DCI) at the National Center for Advancing Translational Sciences, providing executive leadership for that Division’s scientific, financial, managerial, and administrative components. Dr. Chandler replaces the recently retired Dr. Jacques Normand, whom Dr. Volkow thanked for his leadership, contributions and service to NIDA.  She then provided a brief update on the status of hiring a director of the Division of Therapeutics and Medical Consequences (DTMC); the search committee, led by Dr. Chris Austin, Director of the National Center for Advancing Translational Sciences (NCATS), has completed interviewing candidates and is in the process of making its final decision. Dr. Volkow then announced the recent retirement of Dr. Mark Swieter, Director of the Office of Extramural Policy and Review, who will be missed for his dedication and support of NIDA activities.

   Dr. Volkow then presented an update on the budget. The Federal Government was under a Continuing Resolution, which caps NIDA’s spending and planning activities to FY 2017 levels. NIDA’s total budget in FY 2017 was $1,070,846, and the President’s 2018 Budget called for NIDA to receive $854,998 for the upcoming fiscal year. NIDA’s FY 2017 budget included 38% of its research funding within the Division of Neuroscience and Behavior, 28% in the Division of Epidemiology, Services & Prevention, 15% in the Division of Therapeutics and Medial Consequences, and the remaining budget supported the Center for the Clinical Trials Network, the NIDA Intramural Program, and NIDA’s research support and management activities.

   As an overview of recent initiatives across NIH, Dr. Volkow highlighted the NIH BRAIN Initiative.  The 21^st Century Cures Act significantly increased funding for this initiative--the projected lifetime support for BRAIN is $4.2 billion through 2025, with $550 million already received since its initiation.  The National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH) launched an effort to assess progress of the BRAIN Initiative, building on the initial effort to map the awards to the BRAIN 2025 goals.  A set of assessment questions and metrics, along with a list of data sources and timelines, are being developed to evaluate BRAIN Initiative progress towards its stated goals.  The goals are to: 1) revisit the balance of investment between tool and technology development and the use of those tools to address fundamental questions about the brain; 2) consider when to pivot from small independent investigator-driven projects to large-scale, coordinated efforts; 3) focus on specific topics/questions that can now be interrogated given the emerging set of tools and technologies; and 4) scan the evolving neuroscience landscape for new priority areas that should be integrated into BRAIN. NIH will formally revisit BRAIN 2025’s priorities to provide an updated scientific vision to guide the second half of the Initiative. Dr. Volkow also summarized the Notice of Support for Research on the Fundamental Neurobiology of Pain Processing. NIH welcomes BRAIN Initiative applications targeting central nervous system nociceptive and pain circuits, as appropriate to the goals and requirements of specific BRAIN Initiative funding opportunity announcements (FOAs).  It is expected that the unique opportunities of the BRAIN Initiative will enable production of detailed maps of pain circuits, and the adoption of powerful new tools for monitoring and modulating pain circuit activity.  Dr. Volkow also announced that the position of Director of the BRAIN Initiative, continues to be open. 

   Dr. Volkow then summarized several recent NIDA activities and events.  The update from the University of Michigan’s 2017 Monitoring the Future Study, involving almost 45,000 students from across the U.S., indicates that over the past 20 years there has been a notable decline in the use of both alcohol and cigarette smoking among adolescents. There has also been a recent decline in the use of e-cigarettes among high school seniors. However, marijuana use among 8^th, 10^th and 12^th graders remains mostly steady, and teens continue to report past month marijuana use at higher rates than cigarettes (5.8% vs. 4.2%).  71% of high school seniors do not view regular marijuana smoking as very harmful, although 64% say they disapprove of regular marijuana smoking. 

   Dr. Volkow then provided updates on the ABCD Study.  Since its launch in September 2015, the ABCD Consortium has recruited 7,508 children.  The Fast Track Data have been released, containing unprocessed neuroimaging data from 4,750 participants, aged 9-10 years old, as well as basic participant demographics (age, sex), including: high-resolution structural data (3D T1 and T2-weighted scans); advanced diffusion MRI (multiple b-values and directions); resting state fMRI; task fMRI (monetary incentive delay, stop-signal, and emotional N-back), along with raw E-Prime task files.  Curated Data, including assessment domains and computational analysis pipelines, will be released annually, starting in early 2018 with the first 4,500 participants.  Dr. Volkow commended Drs. Gaya Dowling and Susan Weiss on the success of this project thus far, as well as NIDA’s many institute partners, including the National Institute on Alcohol Abuse, and Alcoholism (NIAAA), the National Institute of Mental Health (NIMH), the National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke (NINDS), and others.

   She then summarized aspects of cannabis laws in the United States.  Marijuana laws differ state by state. 29 states have legalized medical marijuana, along with the District of Colombia, Guam, and Puerto Rico.  Each state varies on the allowable conditions and routes of administration, dispensaries or home growth and registries, and testing or regulatory requirements.  In addition, states with recreational laws vary on marketing, product labeling, distribution, and taxation.  Dr. John Carnevale, NACDA member and NIDA Cannabis Policy Workgroup Chair, presented a more detailed summary of the workgroup’s report findings and recommendations for NIDA’s cannabis policy research agenda in the afternoon session.

   Dr. Volkow then addressed the opioid health crisis. A CDC map showing rates of overdose in 1999 vs. 2016 illustrates the tremendous increases occurring across the country.  In 2016 compared to 2015, overdose rates increased 22%, predominantly driven by illicit fentanyl, and to a lesser extent, cocaine.  It is postulated that the increase in cocaine (and methamphetamine) fatalities may reflect adulteration with fentanyl or similar opiate drugs.  One strategy to prevent deaths related to overdose is the use of Medication Assisted Treatment (MAT), which has been shown to decrease opioid use, opioid-related overdose deaths, criminal activity, and infectious disease transmission. MAT can also improve social functioning, and retention in treatment. However, the three approved MATs on the market today are highly underutilized. Strategies are needed to expand access to MAT in both the healthcare system and the criminal justice system. Relatedly, Bhatraju et al. (“Public Sector Low Threshold Office-Based Buprenorphine Treatment in Primary Care”.  Addiction Science Clinical Practice, 2017 Feb 28; 12(1):7) reported that treatment retention in primary care with unobserved induction and no psychosocial intervention was equivalent to office-based opioid treatment at 38 weeks. Thus, low threshold treatment protocols, as compared to national guidelines, may expand access to buprenorphine.  A second study, by Watkins et al., (“Collaborative Care for Opioid and Alcohol Use Disorders (OAUDs) in Primary Care.” JAMA Intern. Med. 2017; 177(10):1480-88) showed that in primary care, a collaborative care intervention increased abstinence from both alcohol and drug use compared to usual care.  In prison, use of opioid medication therapy (OMT) led to a 75% reduction in mortality in the first month post release; and post-incarceration overdose deaths decreased by 60% in 2017 vs. 2016 after implementation of OMT in a Rhode Island statewide correctional system.

   The above data were discussed at a multi-agency meeting held in Bethesda, MD on December 11, 2017 entitled “Using Science to Inform Practice and Policy: A Coordinated Approach to Research Priority Setting.” The meeting was sponsored by NIDA, in partnership with the Emergency Care Research Institute (ECRI). Recommended priorities for future research included: strengthen connections between research and practice; explore, maximize, and expedite available data sources and study designs; engage citizen scientists to help develop outcome and quality measures; determine criteria to indicate the need for inpatient vs. outpatient treatments; identify treatment interventions for mild OUD or subclinical opioid misuse; and encourage research to address costs and sustainability. 

   A challenge is to improve compliance and retention, for which extended release formulations, drug combinations, and additional interventions need to be developed and introduced. Two new MATs have been shown to help with abstinence, the first having received FDA approval on November 30, 2017, named Sublocade (buprenorphine ER), a once monthly injectable that showed the same efficacy as the immediate-release medication.  Also, Braeburn Pharmaceuticals is developing a subcutaneous extended release buprenorphine that also may support efficacy and benefits with a once monthly dosing. 

   Dr. Volkow then spoke about NIH Public Private Partnership efforts to address the opioid crisis. Two focus areas were identified: A: Enhance medications for OUD and to prevent/reverse overdoses; and B: Pain. Goals for addressing focus area A Medications include: Develop new formulations and combinations of medications to treat OUD and prevent overdose; develop more potent and longer lasting opioid antagonists to reverse overdoses from fentanyl or its derivatives; and develop and validate alternative endpoints besides abstinence that are acceptable to FDA for approval of new medications. Goals for focus area B Pain include: Establish a data sharing collaborative between industry groups, with NIH serving as a neutral broker; determine objective measures to understand and predict responses to pain; and establish a clinical trials network to accelerate research on common and rare pain syndromes and to evaluate biomarkers.  In addition, NIDA has established an Advisory Council Workgroup on Opioids chaired by Dr. Edward Nunes. The mission of this workgroup is to provide guidance on the development and implementation of NIDA’s public-private response to address the opioid crisis.  Additional steps include appointing members, convening the workgroup, and completing and issuing a final report by July 2018.

   Dr. Volkow then summarized a new funding opportunity announcement (FOA) RFA-DA-19-002 “Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)” with a continuous submission process through January, 2018.  The UG3/UH3 is a Phased Innovation Cooperative Agreement, which supports a UG3 component that contains specific milestones to be accomplished by the end of 2-years; and a UH3 component to provide funding for three additional years to projects successfully completing the UG3 phase.  Applicants responding to this FOA must address both phases of the study.

   On November 30, 2017, NIDA and the Addiction Policy Forum (AFP), a non-government organization, submitted a letter of intent (LOI) to the FDA indicating the intention to lead a Patient-Focused Drug Development (PFDD) meeting for OUD.  On December 22, 2017, the FDA determined that “gathering patient perspectives on OUD will be of great value...” FDA then proposed the transition of the meeting from externally-led to FDA-led. FDA will plan and host the meeting, working closely with APF and NIDA, to be held on April 17, 2018.

   Dr. Volkow then discussed another of NIDA’s priority themes, HIV and Drugs. She presented two studies that have found an increased risk of drug overdoses within HIV infected populations.  Green et al.’s (“HIV infection and risk of overdose: meta-analysis.” AIDS. 2012; 26 (4): 403-417) paper indicates that having HIV is associated with increased risk of mortality, with a risk ratio of 1.74. Another study, by Weisberg et al.  (“Long-term prescription opioids and/or benzodiazepines and mortality among HIV-infected and uninfected patients,” Journal of Acquired Immune Deficiency Syndrome. 2015 June 1; 69(2): 223-233) showed significant interactions between opioids, benzodiazepines, HIV, and mortality; with hazard ratios of 1.46 in HIV+ patients vs. 1.25 in HIV- patients.  This suggests that HIV infected populations are more vulnerable to overdose from lower doses of opioids, which could be related to changes in the metabolism of opioids because of the antiretroviral medications or other variables.

   NIDA has recently re-released RFA-DA-18-019: NIDA Avant-Garde Award Program for HIV/AIDS and Drug Use Research (DP1, Clinical Trial Optional).  The purpose of this FOA is to support individual scientists of exceptional creativity who propose high-impact research that will open new areas of HIV/AIDS research relevant to drug abuse and/or lead to new avenues for prevention and treatment of HIV/AIDS among drug abusers. The term “Avant-Garde” is used to describe highly innovative approaches that have the potential to be transformative. The application receipt date is April 17, 2018.

   Dr. Volkow then summarized the report of the President’s Commission on Combating Drug Addiction and the Opioid Crisis that was released on November 1, 2017.  It included 56 comprehensive recommendations addressing multiple priorities: 1) Federal funding and programs to create uniform block grants that allow more resources to be spent on life-saving programs; 2) opioid addiction prevention, including prescribing guidelines, regulations and education, Prescription Drug Monitoring Program (PDMP) enhancements, and supply reduction and enforcement strategies; 3) opioid addiction treatment, overdose reversal, and recovery. The Commission recommended that HHS and other federal agencies incorporate quality measures that address addiction screening and treatment. For research and development, federal agencies including HHS, should engage in a comprehensive review of existing research programs and establish goals for pain management and addiction research, and address both prevention and treatment.

   Dr. Volkow also reminded Council about the National Drug and Alcohol Facts Week (NDAFW) that was scheduled to take place from January 22-28, 2018. NDAFW is a national health observance week linking teens to science based facts to shatter the myths about drugs.  The event has global reach, with 2,320 events taking place across the U.S. and in 16 other countries. Unfortunately, due to the government closure, the 2018 Chat Day event was canceled.  It has been a very successful event, and NIDA has engaged partners from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute of Mental Health (NIMH) to answer questions about drugs, alcohol and mental health from middle and high school students across the country.  Over 12,000 questions have been answered in prior years.

   Council thanked Dr. Volkow for her presentation and commended NIDA on rising to the challenge of addressing the opioid crisis, especially in times of limited resources. Council members also encouraged NIDA’s continued support for research related to marijuana use in youth. Additional comments included recommendations to further support science regarding implementation in the justice, education and healthcare systems to better inform policy, public health strategies, and treatment options.

4. The VAs Future Research Agenda, VA Office of Research and Development​ – Rachel Ramoni, DMD, Sc.D., Chief Research and Development, Officer, Department of Veterans Affairs
   
   Dr. Ramoni began her presentation by introducing the other presenters from her team, Grant Huang, M.P.H, Ph.D., Audrey Kusiak, Ph.D., and Ronald Przygodski, M.D. She then gave an overview on the Office of Research and Development (ORD), which is an intramural program at the VA, and shared that the ORD has a two-year budget of approximately $640 million for FY18/19.  Dr. Ramoni then unveiled her newly released strategic priorities: 1) Expand Veterans’ access to high quality clinical trials. There is a need to initiate clinical trials at the VA more efficiently, as well as to refer veterans outside of the VA when there are trials that might benefit them. 2) Increase substantial real-world impact of VA research; this can be achieved by committing to and encouraging research results sharing across the country; and 3) Transform VA data into a national resource, especially related to clinical priorities that effect veteran’s issues. Relevant cross-cutting clinical priorities include suicide, opioids, post-traumatic stress disorder, and traumatic brain injury.  Dr. Ramoni then indicated that the focus of the remainder of the presentations will be on the opioid clinical priority, as the ORD and NIDA have been collaborating to address the opioid crisis.  She then introduced her colleague, Dr. Huang, Acting Director for the Cooperative Studies Program at the ORD.

   VA Cooperative Studies Program and NIDA Collaborative Research—Grant Huang, M.P.H., Ph.D., Acting Director, VA, Cooperative Studies Program, ORD, VA

   Dr. Huang began his presentation with an overview of the Cooperative Studies Program (CSP), which has as a goal to better understand VA capabilities, particularly in clinical trials and clinical research. The CSP is a national trials infrastructure program embedded in the VA healthcare system. It includes many data coordinating centers, statistical coordinating centers that are staffed with biostatisticians, project managers, and other administrative staff, and epidemiology centers that focus on data use and analysis. In addition, the CSP has a presidential award-winning pharmacy coordinating center that manufactures, packages, and ships pharmaceuticals throughout the VA. A recent innovation is the Network of Dedicated Enrollment Sites (NODES) that help recruit patients into the VA Cooperative Studies Trials.

   The CSP has collaborated with NIDA’s Division of Therapeutics and Medical Consequences (DTMC) for 27 years. The goals of this alliance are to identify and develop alternative indications for on-market pharmaceuticals to treat addictive disorders and certain comorbid illnesses. CSP provides statistical support, data and data analysis, and pharmaceutical center services for NIDA-sponsored clinical trials. NIDA-CSP study topics have addressed opioid and cocaine use, as well as smoking, methamphetamine and alcohol use, and led to many publications in peer reviewed journals. One of the greatest successes of this partnership has been the FDA approval of opioid addiction medications, notably, buprenorphine and levo-a-acetylmethadol (LAAM).

   Dr. Huang then turned the presentation over to his colleague, Dr. Audrey Kusiak, to present on other activities at the ORD.

   Opioids and Pain Management—Audrey Kusiak, Ph.D., Scientific Program Manager,Regenerative Medicine, Spinal Cord Injury and Neuropathic Pain Programs, Rehabilitation Research & Development Service, VA

   Dr. Kusiak began her presentation by listing the conditions and topics she and her colleagues are addressing as they relate to opioids and pain management.  First, the presence of a mental health condition, such as depression, PTSD, or anxiety, or dementia significantly impacts how chronic pain is managed.  Second, the transition of soldiers from active duty to Veteran status and transitions from acute to chronic pain.  Third, understanding why and when opioids help with pain management, and what are the recommended durations and dosages.  Fourth, the VA has Patient Aligned Care Teams (PACT) to ensure that Veterans are involved in the management of their pain, and offer a menu-based treatment program that includes pharmaceuticals, biobehavioral approaches, and other complimentary approaches. A fifth topic of interest is strategies for tapering Veterans off opioid use, especially those with coexisting conditions, without incurring harm or undue pain. 

   She then provided the goals of Pain Management Research: to understand the role of disparities and biopsychosocial mechanisms underlying pain management (acute, transition, and chronic pain); to develop and test alternative therapies to opioids, while avoiding harm; and to educate providers and Veterans about these alternative therapies.

   Another research area that the ORD is focused on relates to opioid use disorder and accidental deaths.  The VA is conducting provider training on treatment of vulnerable subpopulations of Veterans (co-existing mental health and chronic pain). It has developed the Stratification Tool for Opioid Risk Management (STORM) clinical dashboard designed to minimize adverse behavioral outcomes. The ORD is also studying what alternative pain management strategies Veterans may use while tapering off opioids. Recently, the Opioid Education and Naloxone Distribution (OEND) was released to 100,000 Veterans. This, along with the Opioid Safety Initiative (OSI), are used to taper opioid use safely and effectively while preventing accidental overdose.

   Dr. Kusiak then presented some possible areas for collaboration with NIDA. Regarding pain management and research, opportunities exist to better understand the pain state considering sex, race, age and gender; to develop non-opioid alternatives to pain management, such as sodium channel blockers (NaV blockers), endocannabinoids, and endomorphines; and to develop drug delivery systems for local administration. In opioid use disorder and management research, it is possible to develop strategies for recognizing when Veterans are prescribed opioids from both VA and non-VA providers; to conduct comparative effectiveness research on opioid tapering and pain management strategies across health systems; to evaluate the effectiveness of the use of non-pharmacological strategies as a supplement or replacement for opioid therapy; and to better identify types of patients suited for specific alternative pain management strategies during opioid tapering.  She then passed the presentation on to Dr. Ronald Przygodzki.
   
   Genomics and Opioid Use—Ronald M. Przygodski, M.D., Associate Director, Genomic Medicine, ORD, VA
   
   Dr. Przygodski began his presentation by emphasizing the abundance of studies in animal models that link genomic markers with addiction, including opioid and dopamine receptors, among others; human studies are less conclusive.  Nevertheless, Neiderhiser stated in his article (Perspectives on Psychological Science 2016) that “…most associations between environmental measures and psychological traits are significantly mediated genetically.”

   Dr. Przgodski then described some of the pharmacogenomic studies being conducted in collaboration with NIDA at the VA.  One is on major depressive disorder with a projected enrollment of 2,000 individuals, looking at pharmacogenomic markers of treatment response. Another study is looking at key pathways involved in opioid metabolism, such as cytochrome P450. Variables to consider include that some of the polymorphisms among key cytochrome isotypes are single genes, while 2D6 can occur in some individuals in multiple copies. Additionally, the identified genes code for proteins that have different roles within metabolism, biotics and xenobiotics.  Larger databases and additional analyses seem necessary to help identify a way to calculate appropriate dosage.  Furthermore, copy number is important. It seems likely that polymorphisms within different ethnic groups, e.g.,  may augment or decrease expression and activity of key cytochromes. 

   The Clinical Pharmacogenetic Implementation Consortium has tentatively associated codeine, tramadol and oxycodone with CYP2D6 functioning, and fentanyl and buprenorphine with CYP3A4; however, different expression patterns are found in different races.  The *1B (A-392G 5 promoter) is in an upstream promoter that blocks this expression in approximately half of African Americans.

   The ORD has also established the Million Veteran Program, with 650,000 veterans currently enrolled to help clarify these findings with enough genotyping and other data to discover important relationships.

   Dr. Ramoni thanked her staff for their presentations, and thanked NIDA Council and Dr. Volkow for their time and attention. She concluded the presentation by bringing attention to another collaborative opportunity with NIDA, regarding the use of medical marijuana within the VA population.

   Dr. Volkow and Council members thanked Dr. Ramoni and her staff for their presentations. Multiple comments related to difficulties in accessing VA resources and data by the broader research community, which seems addressable.  Dr. Ramoni indicated that additional funding might provide the necessary resources to help improve access. The VA is currently working with the University of Chicago and the National Cancer Institute to help make some of the data public. Council encouraged the VA to continue to seek congressional and other federal agency support.

5. Enhancing Partnerships between NIDA and NICHD—Diana W. Bianchi, M.D., Director, NICHD, NIH

   Dr. Bianchi began by providing the history of the Eunice Kennedy Shriver part of the National Institute of Child Health and Development (NICHD) name.  Ms. Shriver was President Kennedy’s sister, who suggested to her brother that there should be an institute devoted to research across the life span with a focus on people with intellectual disabilities. NICHD devotes 18% of its budget to fund child health research. In addition, 6.5% of NICHD’s budget funds the National Center for Medical Rehabilitation Research (NCMRR), directed by Alison Cernich, which supports research on pain and amputations in adults, a relevant topic to veterans. She then described several areas of overlapping interest between NICHD and NIDA. Both institutes are currently supporting the Adolescent Brain Development and Structure (ABCD) Study, and working on Neonatal Opioid Withdrawal Syndrome (ACT NOW).  Future opportunities could include studying marijuana exposure during pregnancy, and the effects of opiates and other drug exposures on fetal and infant brain development.

   She continued with how the ABCD study aligns with NICHD’s mission, to increase understanding of healthy brain development during adolescence and how it relates to behavior, achievement and wellness outcomes.  The research questions being addressed by the ABCD study have never been studied in one very large, representative cohort. This includes effects of sleep on brain development and function, roles of genetic and environmental exposures, and roles of social and family relations.  The ABCD study is expected to provide important data on traumatic brain injuries (TBI) during adolescence, what secondary conditions to adolescent TBI may occur, and brain and functional outcomes over time. Also, the shared data will be invaluable to investigators addressing NICHD research interests in typical and atypical adolescent development.

   Dr. Bianchi them discussed the shared interest area of the Neonatal Opioid Withdrawal (NOW) Syndrome.  NOWS is the updated nomenclature for “Neonatal Abstinence Syndrome”. It refers to the signs and symptoms in newborns prenatally exposed to opioids, and is characterized by variable symptoms including irritability, tremors, feeding issues, vomiting, diarrhea, sweating, seizures, and an inability to be soothed.  She then described the health and fiscal impact of opioid use during pregnancy. On average, women take between 3-5 prescription medications during pregnancy; there is an increased prevalence of opioid use during pregnancy, with a five-fold increase in NOWS; in 2012, nearly 22,000 infants were born with NOWS in the U.S. The cost in the United States is about $1.5 billion for hospital care for infants with NOWS. Infants with NOWS use NICU facilities that are also needed for other critically ill neonates. In 2015, one Wisconsin county spent over $1 million on child welfare placements, largely because of parental opioid addiction. Prevention of NOWS starts with prenatal care. Many women using opioids receive little or no prenatal care; many are reluctant to disclose substance use. Some experts argue that screening pregnant women for substance use should be universal; there are, however, uncertainties regarding a potential second screening approach (improved biomarkers within e.g. urine samples) since current tests may not distinguish between occasional and regular users and overuse. The purpose of screening pregnant women is to obtain appropriate care. Both the WHO and the American Society of Addiction Medicine support methadone and buprenorphine as medication options for pregnant women. Importantly regarding Naltrexone, it is unclear whether medically supervised withdrawal is safe for pregnant women and their fetus.

   Infants exposed to opioids do not generally die because of opioid exposure. Most babies are born in a hospital and are resuscitated if they do not breathe. Also, not all newborns exposed to high dosages of opioids develop significant signs of withdrawal soon after birth.  In newborns prenatally exposed to methadone, signs of NOWS often appear within 3-5 days from birth, which is often after discharge from the hospital. There is also considerable variability in the way that babies are cared for.  There are very few specialized centers in the country, such as Lily’s Place in WV, that provide combined treatments for mother and baby. Breastfeeding is encouraged and is associated with decreased severity of NOWS, and with enhanced maternal-child bonding. Breastfed infants are less likely to need pharmacologic treatment compared to formula fed infants; however, rates of breastfeeding are low, with about half of women on methadone stopping breast feeding within six days of delivery. 

   Dr. Bianchi then summarized what NICHD is doing in response to the public health crisis of NOWS. The Obstetric-Fetal Pharmacology Research Unit Network of NICHD is supporting research on the prevention of Neonatal Abstinence Syndrome (R01), evaluating the administration of ondansetron treatment for pregnant, opioid-using women just prior to delivery, followed by 3-day period of administration to the neonate. In addition, pharmacokinetic/pharmacodynamic (PK/PD) studies on buprenorphine (U54) to better identify optimal dosing based on objective physiological measures and additional measures of satiety.  Given such uncertainties, in April 2016, NICHD held a workshop specifically addressing opioid use in pregnancy, neonatal abstinence syndrome, and child outcomes. An executive summary of the workshop was published in the Obstetrics and Gynecology Journal, June 2017, and has identified the following immediate research needs.  1) Basic research: identify neurodevelopmental consequences of in utero exposure to opioids; 2) obstetric research: determine optimal screening, treatment, and care during pregnancy; 3) neonatal research: develop a new screening tool for neurobehavioral assessment of newborn’s functioning, identify additional and optimal approaches to treatment; and 4) long-term research: study outcomes of opioid exposure and treatment on brain development, cognitive function and overall child health. 

   Dr. Bianchi then summarized a new FOA:  Opioid Use Disorder in Pregnancy (RFA-HD-18-036).  Its research goals are to support clinical studies of maternal medically-supervised opioid withdrawal examining maternal, fetal, and neonatal outcomes; to support PK/PD studies of medications used to treat opioid use disorder in pregnant and/or post-partum women; and to characterize pharmacogenomic, genetic and epigenetic factors correlated with the effects of opioid use during pregnancy on fetal and neonatal outcomes. She then summarized the ACT NOW: Advancing Clinical Trials in NOWS initiative, whose initial funding was received in August 2017 from the NIH Director’s Discretionary Fund. NICHD is partnering with Environmental influences on Child Health Outcomes (ECHO) and NIDA with the following FY 2018 goals: To develop a survey to obtain information on the sites, local practices, demographics, and volume of patients affected by NOWS; to develop and conduct an observational study to obtain prospective data to inform development of a clinical trial; and to pilot a common protocol to generate evidence to inform best practices. So far, three Neonatal Research Network, and 17 Institutional Development Award (IDeA) States’ Pediatric Clinical Trails Network sites have been established. Progress to date from the ACT NOW initiative includes:  Four protocols have been established to 1) reduce drug exposure for neonates using simplified scoring tool; 2) determine best practices for clinical care of infants with NOWS; 3) reduce drug exposure for neonates through conservative approaches to pharmacologic treatment; and 4) prospective randomized trial for methods to wean infants off pharmacologic treatment.

   Another collaborative opportunity that Dr. Bianchi summarized relates to Marijuana use in pregnancy. According to the American College of Obstetricians and Gynecologists (ACOG), the self-reported prevalence of marijuana use during pregnancy ranges from 2% to 5% in most studies, but increases to 15-28% among young, urban, and socioeconomically disadvantaged women. Higher rates are found when querying women at the time of delivery rather than at prenatal visits as some users do not seek prenatal care. A recent study noted that 18% of pregnant women reporting marijuana use in the past year met the criteria for marijuana abuse, dependence, or both.  Marijuana is typically used during pregnancy to control nausea and vomiting.  Adverse pregnancy outcomes may include: hypertensive disorders during pregnancy, increased risk of stillbirth, spontaneous preterm birth, and small for gestational age. More research is needed to determine marijuana’s effects on pregnancy and lactation, and long-term effects of marijuana exposure on the fetus. 

   Dr. Bianchi then spoke about how the NICHD can share its resources with NIDA. NICHD’s Neonatal Research Network (NRN) Infrastructure is organized for randomized double-blind placebo controlled and management trials with the capability to follow short-term (clinical effects) and long-term (neurodevelopmental outcomes) outcomes.  It can also perform observational and longitudinal studies in the neonatal intensive care unit setting, and the Data Coordinating Center provides the clinical centers with the computing infrastructure necessary for network data entry and transmission. Additionally, the Maternal-Fetal Medicine Units (MFMU) Network conducts clinical studies to improve maternal, fetal, and neonatal health, emphasizing randomized-controlled trials; it provides resources for multidisciplinary staff to efficiently develop, implement, and conduct multiple, complex, research projects simultaneously, and to disseminate findings and research results. The clinical centers investigate problems in clinical obstetrics in a collaborative manner. The Data Coordinating Center was selected based on its experience with the coordination of multi-center clinical trials, with proven expertise in study design, data management, and bio-statistical analysis.    

   She concluded by emphasizing the dearth of clinical trials on the effects of medications and substance use, such as opioids used by pregnant and lactating women. These and other NICHD resources offer opportunities for collaboration between the two Institutes.

   Dr. Volkow and Council members thanked Dr. Bianchi for her presentation. Council engaged in a discussion that addressed questions regarding marijuana use during pregnancy, and the public perception that it is a natural remedy for pregnancy-associated symptoms such as nausea. There was concern regarding potential negative effects of higher THC levels on both the mother and infant.  Council members encouraged NICHD to also establish evidence based resources for both primary care and the obstetrics field regarding issues related to contraception, treatment, and care of pregnant women with substance use and addiction disorders.

6. Cannabis Policy Workgroup Recommendations—John Carnevale, Ph.D., President and CEO, Carnevale Associates, LLC and Current NACDA Council Member

   Dr. Carnevale began by describing the Cannabis Policy Workgroup’s history and charge. It was formed in January 2017 to provide advice on policy research agenda responding to the landscape and challenges associated with the liberalization of cannabis laws. The scope includes identifying research priorities related to consumption of all forms of psychoactive cannabis, including both medical and non-medical use. The intent of the workgroup is to inform NIDA regarding policy research gaps; to advise on relevant overlaps with priorities pertinent to NIDA’s mission; and to identify research priorities, including those that might be under purview of other federal agencies.  He then listed the workgroup members including another NACDA member, Dr. Kenneth Mackie, as well as the NIDA staff contributors.

   Dr. Carnevale then described the process of the workgroup communications:  multiple telephonic conference meetings, one in-person meeting, and continuous discussions via e-mail. The workgroup developed interim questions, including: What should the workgroup address from a funding agency perspective? What policies are likely to be effective at reducing adverse effects of cannabis use? What research programs could inform the workgroup of possible effects of these policies?  The workgroup leveraged these questions relative to the charge to develop a set of guiding principles to engage the process of developing a policy research agenda.  The eight identified principles are: 1) NIDA’s research mission is understood to be inclusive, flexible, and public health oriented; 2) research must be neutral about actions, laws, and policies set by any jurisdiction regarding cannabis; 3) priorities should focus on behaviors and consequences that are associated with the greatest harms or benefits and the policies that ameliorate or exacerbate those harms; 5) research should consider both short and long-term effects; 6) research should be sensitive to the realities of cannabis laws and policies; 7) research should be sensitive to cannabis production, marketing, and use; and 8) research should acknowledge that, sometimes, large gaps can emerge between a law or policy as written and its implementation. 

   The workgroup set five research priorities and recommendations. 1) Cannabis use: explore the possibility of constructing a standardized dose; establish standards for measuring cannabis intoxication and impairment; conduct research on the relationship between cannabis and other drug use; develop better ways of measuring levels and types of consumption; and determine whether there is a specific dose under which functional impairment does not occur and there is no detectable health risk for adults. 2) Epidemiology:  conduct research to better understand the epidemiology and trends in cannabis use, frequent use, and cannabis use disorders; develop a knowledge base on the risks for cannabis use disorders overall and among diverse populations; expand information sources about use, impairment, and its consequences; and study differences in patterns of use across jurisdictions with different policies and the effect of the greater availability in one jurisdiction on use in adjoining jurisdictions. 3) Health and Social Consequences: develop effective roadside tests for cannabis impairment that can be practically employed by law enforcement; determine the prevalence of and factors related to cannabis use and cannabis-involved automobile accidents, other types of injury or property damage, and other risky behaviors; assess the impact of cannabis use on human capital development; understand the effects within the family; expand information sources on neurological, cognitive, and physical health impacts; and research health consequences of cannabis use above and beyond those caused by cannabis itself.  4) Structure, Behavior, and Conduct of the Industry:  including the effects of retail sales, promotion, and marketing; taxes and prices; alternative business models for retail distribution for both medical and non-medical products; and alternative regulatory models for public health and public safety.  5) Prevention and Treatment: design and develop the most effective prevention strategies, messages, and materials suitable for cannabis within this new context for varied audiences; design and develop more effective community/environmental prevention approaches through public policy; develop an evidence base for treating cannabis use disorders and addiction, and develop recovery supports that encompass behavioral and pharmacological interventions; identify and assess the effectiveness of prevention strategies that target social norms and accidents/risky behaviors; develop effective regulations that limit the impact of cannabis advertising on use; improve the efficacy of cessation efforts that occur outside the formal treatment system; and explore the effect of higher-potency cannabis and increased availability of cannabis on treatment need, models, and outcomes.

   Dr. Carnevale concluded that NIDA is the leader and is looked up to by many other federal agencies to set the key research priorities, and to work with other federal agencies to help address many of these priorities.

   Dr. Volkow personally thanked Dr. Carnevale for his leadership and efforts in chairing the workgroup. Council members thanked Dr. Carnevale for his presentation and for the workgroup’s efforts and for producing a comprehensive report and list of recommendations.

7. Developing a Strategic Plan for the NIH Office of Disease Prevention—David Murray, Ph.D., Associate Director for Prevention, Director, ODP, NIH

   Dr. Murray began by providing background information on the Office of Disease Prevention (ODP). The ODP is within the Division of Program Coordination, Planning, and Strategic Initiatives in the Office of the Director, NIH. Its mission is to improve the public health by increasing the scope, quality, dissemination, and impact of prevention research supported by the NIH; and to provide leadership for the development, coordination, and implementation of prevention research in collaboration with ICs and other partners. ODP’s current activities include managing the $100 million Tobacco Regulatory Science Program; serving as the NIH liaison to other DHHS activities, such as the U.S. Preventive Services Task Force, and the Healthy People 2020 initiative; and offering trainings and education, for example, Mind the Gap, and the Gordon Lecture, among many other projects.

   Dr. Murray then presented five proposed strategic priorities for fiscal years (FY) 2019-2023, along with related challenges, progress, and proposed objectives. The first ODP priority is to Systematically Monitor NIH Investments in Prevention Research and the Results of that Research. The initial challenge in 2013 for this strategic priority was that existing portfolio analysis methods had unknown sensitivity and specificity; they provided inadequate detail on features like outcome, exposure, study type, design, etc.; they could not accurately characterize levels or trends for awards or dollars; they could not identify areas with inadequate support; and they could not be used effectively to address this priority.  Progress since 2013 includes: the ODP’s development of a taxonomy for prevention research with eight categories and 135 topics; the coding of 5,612 type 1 R01 abstracts for FY10-15; in collaboration with the Office of Portfolio Analysis, development of machine learning tools to automate the coding process; coding over 15,000 R, P and U awards from FY12-17, (expect to publish the findings in 2018 in collaboration with other I/Cs).  The proposed objectives for this priority are: to characterize and report on the NIH prevention research portfolio based on their taxonomy for prevention research; to regularly assess the progress and results of NIH investments in prevention research; and to partner with NIH I/Cs and Offices to disseminate the ODP portfolio analysis tools and related data.

   The second priority for the ODP is to Identify Prevention Research Gaps for Investment or Expanded Efforts by the NIH.  The challenges faced in 2013 were that I/Cs looked to ODP for advice on areas and topics for new or expanded prevention research. However, there was a need for improved portfolio analysis methods, as well as regular interactions with key stakeholders. Thus, the ODP has improved coordination between NIH and the U.S. Preventive Services Task Force, including an annual survey of Insufficient Evidence statements to monitor progress and identify opportunities. ODP has also increased efforts to disseminate the Insufficient Evidence findings of the Community Preventive Services Task Force (CPSTF) to the research community. It has partnered with HHS’ Office of Disease Prevention and Health Promotion (ODPHP) and the ICs to support Healthy People 2020 and develop Healthy People 2030; and has offered Pathways to Prevention (P2P) workshops. The proposed objectives for this priority are to work with a variety of stakeholders to identify needs in prevention research; to compare identified needs in prevention research with the current NIH portfolio to identify gaps; and to work with NIH ICs and Offices to identify the most promising and feasible prevention research gaps for investment or expanded efforts.

   The third priority is to Promote the Use of the Best Available Methods and Support the Development of Better Methods. The challenges faced so far have been that evidence showed that the best methods were not always used, that program and review staff were not always up to date, that review panels often lacked necessary methodological expertise and steps were needed to ensure applications with strong methods were distinguished from those with weak methods. In response, the ODP created and posted online a seven-part course on Pragmatic and Group Randomized Trials in Public Health and Medicine; it added language to the Application Guide and Review Criteria for clinical trials applications and created ResearchMethodsResources.nih.gov; it used the Prevention Research Expertise Survey to create a web-based tool for Scientific Review Officers (SROs) to identify methods experts for review panels; and it telecast Medicine: Mind the Gap webinars exploring prevention methods. The proposed objectives for this priority are to provide resources for review staff to identify experts in prevention research methods for recruitment to review panels; to provide training in prevention science methods to NIH program and review staff, to NIH investigators, and to investigators external to NIH; to serve as a resource to other ICs in prevention science; and to collaborate with other ICs and Offices to strengthen NIH policies and procedures to encourage the use of the best available methods.

   Dr. Murray then continued with the fourth priority, Promote Collaborative Prevention Research Projects and Facilitate Coordination of such Projects. The challenges in 2013 were that all the ICs supported prevention research in their own areas, and in order to have better outcomes and more efficient use of resources, enhanced collaboration and coordination among ICs was needed. Since then, the ODP has been collaborating with existing Scientific Interest Groups to increase the focus on prevention research, and has created five new Scientific Interest Groups:  1) Childhood Screening; 2) Adult Screening; 3) Genetics of Prevention; 4) Environmental and Policy-Level Interventions; and 5) Interventions to Prevent or Delay the Onset of Multiple Comorbid Diseases. The proposed objectives are to coordinate and support the development of collaborative prevention initiatives to address gaps in prevention research and practice, and to develop a triennial State of Prevention conference highlighting research progress, gaps, and opportunities focused on a specific prevention gap of cross-cutting relevance across the NIH.

   The final strategic priority is to Advance the Understanding of Prevention Research. The challenges are that NIH is focused much more on basic science and on developing and evaluating treatments than on prevention; and the prevention community at NIH asked ODP to take a leadership role in promoting prevention research both at NIH and elsewhere. The ODP responded by expanding its website from 4 to 250 pages; it created a presence on social media; it strengthened partnerships with professional societies; it presented ODP resources at scientific meetings; it provided communication support to all ODP teams, webinars, workshops, and meetings; and it created and posted information and interactive tools for prevention researchers to find valuable resources.  The proposed objectives for this priority are to increase the visibility of information about prevention research; to engage and collaborate with stakeholders to coordinate and enhance communications about disease prevention research; and to support the communications-related efforts of all ODP Strategic Priorities, including the promotion of ODP activities, events and resources. 

   Dr. Murray then described a timeline for developing the new ODP Strategic Plan, which includes the ongoing assembly of input from Advisory Councils, IC Directors, and NIH staff. A revised plan with prepared milestones and timelines will be posted by March 31, 2018, and the prepared staffing plan and resource request will be issued by May 31, 2018. The goal is to submit the package for Dr. Collins’, NIH Director’s, review and approval by June 30, 2018, with the final plan’s release on September 30, 2018. He concluded his presentation by offering ODP services to NIDA and requesting feedback related to any other priorities and cross-cutting themes that ODP should consider supporting its FY19-23 Strategic Plan.

    Dr. Volkow and Council thanked Dr. Murray for his presentation. A common recommendation emerged, to support research on cannabis prevention in adolescents and youth. Another recommendation was to study behaviors that lead to addiction vs. specific substances in the realm of prevention. Responding to a question regarding what may improve prevention, Dr. Murray indicated that usually changes in policies or laws have led to significant improvements related to prevention. Dr. Murray thanked Council for their suggestions and stated that ODP’s goal is to form collaborations between interested parties to determine the best approaches for drug use and abuse prevention, especially environmental and policy-level preventions that can be implemented into schools and public health directives.

8. Concept Clearances – NIDA Staff

   Five total concepts received Council clearance. 

   Richard Jenkins, Ph.D., Prevention Research Branch, Division of Epidemiology, Services & Prevention Research (DESPR) presented: Research Coordinating Center (RCC) to Facilitate and Support the Initiative, “HIV, HCV and Related Comorbidities in Rural Communities Affected by Opioid Injection Drug Epidemics in the United States: Building Systems for Prevention, Treatment and Control Initiative” (RFA-DA-17-014) and the “Companion Laboratory Infrastructure Development Initiative” (RFA-DA-17-023).    

   The Research Coordinating Center (RCC) will provide support, coordination and operational infrastructure activities for the UG3/UH3 sites and the U24 lab, supporting policies and procedures for obtaining, accessing, and sharing data on participants from outside sources within the network and with the scientific community, and the planning and coordination of collaborative activities. The RCC will have the following responsibilities, performed under the guidance of the Executive Steering Committee (ESC):

   Tisha Wiley, Ph.D., Services Research Branch, Division of Epidemiology, Services and Prevention Research (DESPR) presented: Responding to the Opiate Crisis through Scalable, Data-Driven Justice-Behavioral Health Partnerships.   This initiative will support a new cooperative research program that will result in exploratory and hypothesis-driven research projects that:
   • Organize and coordinate meetings and other functions of the ESC and the working groups established to support common activities and enhance scientific collaborations.
   • Track, summarize, and report on project activities in both internal and public venues. 
   • Operational support for project protocols, collaborations and other projects (e.g. conduct of trainings, development of manuals of operation, maintenance of network website, communications and conference calls, convening committees and meetings, etc.)
   • Establish and maintain a website for the storage and dissemination of project documents and products.
   • Support research related activities (e.g. data and safety monitoring plan (DSMP) reporting, Good clinical laboratory practice (GCLP), clinical trials registration, etc.)
   • Lead the development and implementation of common measures, data elements, and advanced statistical tools
   • Provision of mechanisms and metrics to monitor subject screening, recruitment, retention, and dropout, and procedures for adjustment if enrollment targets are not being met
   • Ensure state-of-the-art approaches to statistical methods are consistently applied across the network.
   • Provision of a data sharing policy with explicit plans, procedures, milestones, and timelines to make the data and bio specimens available for access and analysis by the research community as appropriate
   • Preparation of public-use files for archiving and sharing results of each study according to NIH policies
   • Emphasize responding to the opioid crisis with comprehensive evidence-based services matched to patient needs. The overall goal is to facilitate justice-behavioral health partnerships that provide comprehensive evidence-based services to address opioid use in justice populations. These partnerships will enhance the capacity of the justice system to respond to the opioid crisis with comprehensive evidence-based services, including the full range of MAT as well as evidence-based behavioral interventions.  This collaborative approach will help improve the capacity of systems to connect patients to the right service at the right time to reduce relapse, overdoses, and recidivism.
   • Utilize an implementation science framework, with an emphasis on rigorous testing of scalable, practical implementation strategies. This initiative will build on the advances made by prior NIDA justice initiatives; expanding the development of the behavioral health services cascade to provide a data-driven focus on interagency collaborations between justice systems and behavioral health providers using a data-driven decision-making framework to drive organizational change goals (see Belenko et al., 2017). The target will be to identify and test implementation strategies that can be scaled and advance our understanding of how to speed the pipeline from science to service.
   • Emphasize technology-facilitated data infrastructure and intervention tools. Recent technological innovations offer opportunities to enhance bidirectional data sharing, data-driven goal setting and decision making within organizations, and enhanced engagement with community-based justice populations. This initiative will require proposed studies to be designed to leverage existing and newly developed technology and health information platforms to facilitate and enhance the capacity of the justice system to partner with behavioral health systems. A recent NIDA-NIJ meeting identified several opportunities for technology to facilitate progress in these ways.
   
   Da-Yu Wu, Ph.D., Genetics, Epigenetics, and Developmental Neuroscience Branch, Division of Neuroscience and Behavior (DNB) presented:  Modeling HIV Neuropathology Using Microglia from Human iPS Cells and Cerebral Organoids.  HIV-associated neurological disorders (HAND) persist in up to 50% of HIV-patients even when HIV replication is suppressed by cART. HIV does not infect neurons, but infects microglia and macrophages in the brain, causing HAND associated neuropathology. How microglia affect neurons and glia in human brains are not understood. Currently there are no effective approaches for live human brain studies or realistic HIV animal models for HIV neuropathology.

   Recent technological advancements have allowed generating microglia and cerebral organoids from human iPSC lines. These microglia have been shown to be fully functional, secreting cytokines and phagocytosing neural debris, when introduced into cerebral organoids.

   This initiative will support studies using human iPSC to generate cerebral organoids and microglia to study HIV neuropathology. This includes the following:

   • Establish iPSC lines from HIV-patients and HIV-free controls, and use these cells to generate cerebral organoids and microglial cells. Microglia can then be infected by HIV and introduced into the organoids.
   • Characterize and compare the morphology, neuronal composition, oligodendrocyte and astrocyte differentiation, synaptic density and other basic measures of neurodevelopment in HIV-latent, HIV-infected, and HIV-free organoids.
   • Study how HIV-infected microglia alter neuronal structure, physiology, and function in the brain.
   • Answer questions such as: How do substances of abuse impact these processes? Can genetic and genomic editing alleviate neuropathology in HAND?

   Will M. Aklin, Ph.D., Clinical Research Grants Branch, Division of Therapeutics and Medical Consequences (DTMC) presented:  Loyalty and Reward Program to Increase Medication Assisted Treatment (MAT) Compliance.  In 2015, more than 2.6 million Americans were diagnosed with opioid use disorder (OUD) and 33,000 died of an overdose involving one or more opioids, a death rate which has tripled since 2000. Not enough patients have access to the gold standard of treatment, medication assisted treatment (MAT) plus behavioral therapy; thus, increasing negative consequences including relapse.

   One possible way to increase medication assisted therapy adherence is through contingency management (CM), a practice where patients are given tangible rewards to reinforce positive behaviors such as abstinence. Studies conducted in both methadone and psychosocial treatment programs have demonstrated that incentive-based interventions are highly effective in increasing treatment retention and promoting abstinence from various drugs. Despite its efficacy, CM practices are not widely disseminated. The primary reason is cost and lack of clear regulatory and reimbursement strategies. However, because digital technology is coming into fruition, and the passage of the 21st Century Cures Act clarified FDA’s role in regulating of medical software, this may change. The goal of this initiative is to develop a digital therapeutic tool based on the principals of contingency management to increase medication adherence or supplement existing behavioral interventions to increase drug abstinence.

   Aidan Hampson, Ph.D., Clinical Research Grants Branch, Division of Therapeutics and Medical Consequences (DTMC) presented: Respiratory Stimulants to Reverse Drug-Induced Respiratory Depression (RD).  The goal of this initiative is to develop a lead compound and potential backup molecule (ideally from distinct structural classes) in a formulation that acts to reverse RD by mechanisms other than antagonizing the mu opioid receptor. Supported research should demonstrate the efficacy of the lead compound in preclinical models of RD that include opioid-induced RD and / or RD induced by drugs or drug combinations that frequently cause life threatening RD in the real world. This can include alcohol, when in combination with other drugs such as benzodiazepines or opioids, or combinations of drugs that demonstrably cause significant risk of mortality in post-operative settings.

   Project Activities and Expected Deliverables:

   The project may include medicinal chemistry to optimize the efficacy or other drug-like features of the lead compound, provided that a suitable assay system exists that both models’ real-world situations adequately and provides sufficient throughput to allow for successful optimization.

   The project may also include other studies that advance a molecule and at least one back up molecule with demonstrated efficacy, towards establishing the level of evidence of safety and efficacy required by FDA to allow clinical testing. Such studies might include preclinical efficacy and pharmacokinetic studies in a rodent and non-rodent species, manufacturing scale up chemistry, cGMP synthesis and formulation, toxicology and final formulation stability studies.

   By the end of phase 1 sufficient data must exist to indicate that the medication can be administered via a route known to be safe and reliable in an unconscious individual. The medication should reach efficacious concentrations at the site of action within a time commensurate with the indication, i.e., to save the life of an RD patient discovered by a first responder shortly after RD has set in. The persistence of the pharmacological action should exceed that of currently available alternatives, i.e., it should be able to reverse RD for more than four hours following a single administration.

   The Phase I application must include:

   • Go/no-go decision tree with quantitative, milestones
   • Objective measures that demonstrate efficacy of the molecule against RD induced by several pharmacological mechanisms
   • Objective measures that demonstrate the mechanism of action (unless previously established) of pharmacological agent
   • Studies designed to address project-specific questions of feasibility
   • Detailed discussion of potential pitfalls, side effects and safety issues and how these concerns are to be mitigated

   Phase II Activities and Expected Deliverables:

   • Phase II involves execution and completion of studies on lead/backup molecule required to form a Drug Masterfile (DMF) sufficient to satisfy FDA IND requests for clinical testing.
   • Development, submission and acceptance of the DMF by FDA CDER.

9. Public Comments
   None.

10. Adjourn
    The 126^th meeting of the National Advisory Council on Drug Abuse was adjourned at 4:17 p.m. 

Certification

I hereby certify that the foregoing minutes are accurate and complete.

Note: Informational materials provided to the public at the open session of the meeting may be obtained from the Executive Secretary.