120th Meeting Minutes

Minutes - May 5 - 6, 2015

The National Advisory Council on Drug Abuse convened its 120^th meeting at 1:00 p.m. on May 5, 2015 in Conference Rooms C & D, 6001 Executive Boulevard, Bethesda, Maryland.  The closed portion of the meeting held on May 5^th was for the purpose of 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 on May 6, 2015, began at 8:30 a.m.  The Council adjourned on May 6, 2015 at 12:57 p.m.

Council Members Present
Anne Andorn, M.D.
Judith Auerbach, Ph.D.
Laura Bierut, M.D.
Regina Carelli, Ph.D.
Arthur Dean, M.A.
Carl Hart, Ph.D.         
Terry Jernigan, Ph.D.            
James Hildreth, Ph.D., M.D.
Robert Lenox, M.D.
Kelvin Lim, M.D.
Michael Nader, Ph.D.            
John Rotrosen, M.D. 
Steffanie Strathdee, 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
Gary Berkson, J.D.                                        
Katia Howlet, Ph.D. - SEI
Tiffany Kilpatrick                                         
Luz Maheca Martinez                                               
Jen Sizemore - ABI
Roy Walker, M.B.A. - Synergy Enterprises, Inc.
Christopher Weaver, M.B.A.             

Closed Portion of the Meeting – May 5, 2015

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

   In turn, the Director or a designee for the Division of Basic Neuroscience and Behavioral Research, the Division of Clinical Neuroscience and Behavioral Research, the Division of Epidemiology, Services and Prevention Research, and the Division of Pharmacotherapies and Medical Consequences of Drug Abuse presented their applications for consideration by the Council.  For each, Council provided concurrence with the initial scientific reviews en bloc.  Council also approved Administrative Supplements.   Relevant applications were presented to Council for Special Council Review, and Council agreed with program assessments. All Trans-NIH Initiatives, i.e., Common Fund applications and NIDA Secondary applications also received Council concurrence.

   Members must absent themselves from the Council meetings during discussion of, and voting on, individual applications from their own institutions or other applications in which there is 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 if an application in conflict with that member was acted upon en bloc. 

Open Portion of the Meeting – May 6, 2015

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:  September 1-2, 2015, and February 10-11, 2016.  She reminded all attendees that the CRAN Council meeting will take place on February 11, 2016 and will be held at Fischer’s Lane.

2. Consideration of the Minutes of Council

   The Minutes of the NIDA February 2015 meeting were unanimously approved as written.  In addition, the Minutes of the February 2015 CRAN Council meeting were unanimously approved as written.

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

   Dr. Volkow began her presentation with an introduction of the newly created Division of Extramural Research within NIDA and Dr. Susan Weiss as its director.  In addition, a Director for the Division of Epidemiology, Prevention and Services Research (DESPR) has been approved by HHS.  Dr. Carlos Blanco, who is currently at Columbia University, will be assuming this position on June 15, 2015.   He is an epidemiologist with extensive experience in the treatment of substance use disorders, including mental illness as a co-morbidity, as well as developing methodologies for epidemiological research to improve clinical trials.   Dr. Volkow then thanked Dr. Redonna Chandler, Acting Director of DESPR, for her instrumental work in building programs in the substance use and the criminal justice system branch, and all of her other contributions to the Division in the past eighteen months. 

   Dr. Volkow also introduced and welcomed new Council members, Dr. Judith Auerbach, a public sociologist and policy consultant, and Professor of Medicine at the University of California, San Francisco (UCSF); Major General, Arthur T. Dean (U.S. Army, Retired), Chairman and CEO of Community Anti-Drug Coalitions of America (CADCA); Dr. Steffanie Strathdee, Associate Dean of Global Health Sciences, Harold Simon Professor and Chief of the Division of Global Public Health in the Department of Medicine, University of California,, San Diego (UCSD); and Dr. Eric Verdin, Associate Director and Senior Investigator at the Gladstone Institute of Virology and Immunology, and Professor of Medicine at the University of California, San Francisco (UCSF).

   Dr. Volkow then provided Council with an update on the budget.  The Presidential Budget for FY 2016, if approved, would maintain NIDA’s total budget at a little over $1 billion, with the AIDS allocation at approximately one third of the total budget.  She then listed in percent the FY 2014 actual NIDA budget by program.  NIDA spent 43.3% of its budget in Basic and Clinical Neuroscience and Behavioral Research; 24.3% in Epidemiology, Services and Prevention Research; and 13.3% in Pharmacotherapies and Medical Consequences.  There is a general misperception in the extramural community that NIDA spends a greater amount of its budget on medications development research than it does.  The remainder of the budget is spent on Intramural Research at 8%, followed by Clinical Trials Network at 4.4%.

   Turning to what is new at NIH; Dr. Volkow spoke about a published Request for Information to help guide the NIH in creating a longitudinal cohort of 1 million or more Americans who have volunteered to participate in research as part of the President’s proposed Precision Medicine Initiative.  Dr. Volkow pointed out two critical elements that are necessary for the field of substance use to be involved with this initiative:  engaging the scientific community in the field of substance use and abuse; and even more importantly, access of information that relates to substance use disorder in electronic health records.  One priority are of relevance to NIDA in this initiative will be the tracking pain management from acute to chronic pain, and identifying why certain patients become addicted to opioid therapy or unresponsive to opioid medications

   Dr. Volkow next spoke about the Common Fund Epigenomics program.  Dr. John Satterlee from the Division of Basic Neuroscience and Behavioral Research (DBNBR), NIDA, in partnership with National Institute of Environmental Health Sciences (NIEHS) has led this major initiative.  This has resulted in 8 publications in the journal Nature in the month of February alone that cover some of the following topics: integrative analysis of 111 reference epigenomes, haplotypes, 3D structure, autoimmune disease, neuronal differentiation, and cancer cell origin. The cumulative number of epigenomics program publications is 620 since 2008. 

   Dr. Volkow moved on to current activities at NIDA.  She began by stating that the Division of Clinical Neuroscience and Behavioral Research (DCNBR) Review Work Group has just completed its evaluation of the division.  The committee was chaired by Dr. John Rotrosen, current Council member and he will be presenting a summary of their findings to Council later in the morning.

   She then presented CDC’s data updates on overdose related deaths in the U.S.  The number of prescription opioid overdose deaths appears to have plateaued since 2011, although the number remains over 16,000 deaths per year.  However, heroin overdose related deaths have been on a steady incline with a dramatic increase to 8257 deaths in 2013 compared with 5925 in 2012, and 4397 in 2011.  The combined data shows that over 24,000 people died of opioid related deaths in 2013.  Moreover, approximately 75 percent of people that overdosed on heroin had transitioned from opioid medications to heroin.  This is important because reports indicating that strategies to contain the opioid prescription epidemic have been successful do not address the transition to and continued rise of injection heroin use.

   On March 26, 2015 HHS Actions to Address Opioid-Drug Related Overdoses and Death was announced.  The initiative focuses on three priority areas:  1) Improving opioid prescribing practices by improving clinical decision making and reducing inappropriate prescribing; enhancing prescription monitoring [Prescription Drug Monitoring Programs (PDMPs)]; and supporting data sharing to facilitate appropriate prescribing.  2)  Expanded use of Naloxone by accelerating development of new naloxone formulations; disseminating best practices for naloxone distribution; and expanding its use.  3)  Expanded use of Medication-Assisted-Therapy (MAT).  This can be achieved by supporting research on effective use and dissemination of MAT; and increasing access to clinically effective MAT strategies.

   The need for improving opioid prescription practices is supported by the results of recent studies, including  a survey conducted by Gaither, JR et al. indicating that from 2000-2010 less than 40% of opioid prescriptions to HIV positive and uninfected veterans were prescribed according to guidelines.  The NIH Pain Consortium Centers of Excellence in Pain Education, led by NIDA’s David Thomas, is developing curriculum for medical students, as well as physicians and other allied health care providers to improve pain treatment through education.  In addition, the state of Massachusetts has been very aggressive in the implementation of overdose education and  naloxone distribution.  NIDA has also teamed with pharmaceutical companies to develop a lay-friendly administered intranasal naloxone that has a high enough concentration with rapid delivery, which is crucial when trying to reverse an overdose. 

   Dr. Volkow then presented research from France that supports the expanded use of MAT priority area.  Data presented by Ling et al from 1995 through 1999 showed an opioid overdose decrease of 75 percent after buprenorphine was introduced in France.  Similar studies in the U.S. also showed that scaling up methadone for treatment of opioid use disorders was associated with a decrease in overdoses.  A more recent publication in the Journal of the American Medical Association by D’Onofrio found that emergency department-initiated buprenorphine increased engagement in addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services when compared with referral and brief intervention.

   Unfortunately, although methadone, buprenorphine and naltrexone are available at some addiction specialty programs across the U.S., only a small percentage of eligible patients receive such treatments.  From 345 programs surveyed by Knudsen et al., less than 25% offered MAT and within those programs, only 41.3%, 37.3% and 10.9% received methadone, buprenorphine or tablet naltrexone respectively.

   Another complication related to implementation of MAT is that many patients need to obtain methadone on a daily basis directly from a methadone clinic. However, implementation of  MAT is one of HHS priority areas.  Thus, research that NIDA is supporting is looking at buprenorphine implants for the treatment of opioid dependence.  The results so far show that probuphine can release sustained therapeutic drug levels in patients with opioid addiction for up to six months.  The therapeutic level has also been shown to be equivalent to what is achieved with sublingual buprenorphine.

   Dr. Volkow then moved on to the status of marijuana laws in the United States.  Currently, there are four states that have fully legalized marijuana, and many states have legalized marijuana for medicinal purposes.  Each state has different requirements and policies when it comes to medical legalization.  Dr. Pacula did an analysis and found that states that have legalized medical marijuana, allowing for  dispensaries are associated with an increased utilization of marijuana in contrast to states that require patient registration to obtain medical marijuana. This highlights an extraordinary opportunity to understand how policy affects patterns of drug use.

   Further studies looking at prevalence of marijuana use in teenagers indicate there is an increased percentage of use by 12-17 year olds in states that have legalized recreational marijuana at 10.5%, vs. 8.9% in states with only legalization of medical-marijuana, and 6.1% in states banning marijuana.  Data from the state of Colorado shows a significant increase in number of drug-related suspensions and expulsions since the legalization of marijuana in 2010, with the percentage of use by 12-17 year olds being at 11.2% in 2013 vs. 7.5% nationally.  Colorado has reported negative outcomes related to the full legalization of marijuana, including increases in criminal activity and a lower than expected revenue to the state for the sale of marijuana.

   She then posted a slide that had a list of 51 medical conditions for which marijuana is approved in different states.  Although there is some data suggesting cannabinoid CB1 and CB2 agonists have beneficial analgesic effects, as well as other reports pointing to anti-inflammatory properties of marijuana, further research is needed to better understand the positive effects of marijuana in relation to specific diseases and conditions.  Therefore, NIDA, along with other NIH institutes are looking at understanding the endocannabinoid system for pain treatment.  A program announcement entitled “Developing the Therapeutic Potential of the Endocannabinoid System for Pain Treatment (PA-15-188)” has been issued.  It will support projects that will elucidate the therapeutic potential of the cannabinoids and endocannabinoid system in the development of mechanism-base therapies for pain.

   Dr. Volkow then spoke about NIDA’s Treatment Interventions priority area.  She began by highlighting a roadblock for medication development for drug use disorders, including nicotine.  The FDA requires abstinence as the main outcome, and thus medications that would reduce the amount of drug consumed currently would not be considered for approval, except for alcohol.  However, the FDA has indicated it will consider outcomes other than abstinence if data are presented showing that reduced drug use results in a measurable health benefit for the patient.

   As a result, NIDA is supplementing research to find biomarkers that indicate positive outcomes.  One such recent study Lai et al.in the Journal of Addiction Medicine (in press) showed that cocaine abstinence and reduced use were associated with lowered endothelial dysfunction in African Americans.  The results showed that reduction in days of cocaine use were just as significantly beneficial as total abstinence.  This is an area that requires further follow up and support.

   Next, Dr. Volkow presented NIDA’s HIV and Drugs priority area by recapping the recent community outbreak of HIV linked to intravenous drug use of oxymorphone in Indiana.  135 cases of HIV infections were identified in a community of 4200, and of those 114 were found to be co-infected with Hepatitis C.  The drug of choice was Opana, or hydromorphone, which has a shorter half-life than heroin.  Those infected reported of an average of nine syringe-sharing partners, sex partners or other social contacts who might be at risk for HIV infection.  She stated that this incident could have been prevented by implementing well established, research-based steps such as a proper syringe exchange program and Highly Active Anti-Retroviral Therapy to early identified at-risk or newly infected individuals.

   Dr. Volkow presented the NIH Office of AIDS Research’s FY 2016 AIDS budget priorities.  Listed here in order of importance:  1) Prevention Research: prevent transmission and acquisition of HIV, including basic research on HIV that will underpin development of vaccines, microbicides, and other biomedical prevention strategies, including use of HAART prevention.  2) Treatment: research to develop and assess therapies that are more effective in suppressing viral replication; less toxic; longer acting; have fewer side-effects and more likely to achieve eradication of infection.  Address gender, race/ethnicity, age, nutritional status, genetics, and history of violence and trauma that may influence treatment success or failure.  3) Research Toward a Cure: potential for a cure or lifelong remission of HIV, including studies on viral persistence, latency, reactivation, and eradication.  4) Co-Infections, Co-Morbidities and Complications: research on therapies and prevention of HIV-related co-infections, malignancies, neurological, cardiovascular, and metabolic complications.  5) Behavioral and Social Science Research: factors that fuel or mitigate HIV epidemics; stigma; adherence to therapy or prevention strategies.  And 6) Preparing a Diverse and Talented Biomedical Research Workforce: next generation of AIDS researchers around the world. 

   Dr. Volkow then updated Council on the Adolescent Brain Cognitive Development (ABCD) National Longitudinal Study.  NIDA is partnering with NIAAA, NCI, NICHD, NINDS, NIMH, NIMHD, OBSSR and ORWH for a ten year longitudinal study of 10,000 children from age 10-20 years to assess effects of drugs on individual brain development trajectories.  Three Funding Opportunity Announcements (FOAs) have been issued:  RFA-DA-15-014, Adolescent Brain Cognitive Development (ABCD) Study- Coordinating Center (U24); RFA-DA-15-015, ABCD Study- Research Project Sites (U01); and RFA-DA-15-016, ABCD Study- Data Analysis and Informatics Center (U24).  There was a very robust response to the FOAs, and all involved ICs are confident that an outstanding consortium will be established to conduct the study.

   She then presented additional FOAs that NIDA has issued.  Identification of Genetic and Genomic Variants by Next-Gen Sequencing in Non-Human Animal Models (U01) (PAR-15-120), to identify gene variants of traits associated with SUD in selectively bred, and outbred non-human animal models using methodologies of Next Gen-Sequencing, mapping, and genotyping.  Three other FOAs related to Gene-Environment Interplay in SUD; and Advancing Exceptional Research on HIV/AIDS and Substance Abuse (R01) (RFA-DA-16-001) to support highly innovative R01 applications on HIV/AIDS and drug abuse and will complement the Avant-Garde Award Program for HIV/AIDS research.

   Dr. Volkow also showed a slide with new NIH FOAs issued in collaboration with the FDA Center for Tobacco Products.  She then moved on to highlight recent conferences, hearings and briefings related to Opioids and Cannabis in which she recently participated and is going to participate.  Finally, she ended her presentation by stating that an update on NIDA’s Strategic Plan 2016-2020 will be presented later in the morning by Dr. Maureen Boyle.

   Council thanked Dr. Volkow for her presentation.  One line of questions focused on the need for studies and data on effects of marijuana use on adults between the ages of 18-25 years.  This data should also be used to educate that particular population on the risks associated with use of marijuana and to help them make more informed decisions.  One comment that was raised, campaigns and misguided data have driven the public and states to alter policies, as opposed to use of scientific data as the guide.  This has placed physicians and scientists in the position of playing catch-up.

4. Big Data Science at the NIH - Philip E. Bourne, Ph.D., FACMI, Associate Director for Data Science, Office of the Director, NIH

   Dr. Bourne began his presentation by informing Council that during the one year he has been at NIH, he has met with all 27 Institute and Center Directors to set a strategic vision for and lead trans-NIH data science activities and funding initiatives across the NIH.  He then listed what drives the strategic thinking:  1) Being Prepared: Responding to take advantage of the opportunities offered by a major disruption in the biomedical research enterprise arising through digitization and exponential growth; 2) Accelerating discovery during this time of disruptive development and; 3) Continually catalyzing a cultural shift towards a more analytical enterprise while managing expectations.

   Dr. Bourne further went on to explain that a major challenge as well as opportunity has been presented by digitization and the exponential growth it leads to.  While such technological changes need not be disruptive, they can be and it is important to be aware that they can be.  He gave a number of examples including that of the photography industry.  Once a film-based industry, digitization led to the collapse of the film market, the evolution of digital cameras, then replacement of cameras largely with cell phones, to the use of social media platforms to share and distribute digital images.   

   He then presented the Office of Biomedical Data Science mission statement:  To use data science to foster an open digital ecosystem that will accelerate efficient, cost-effective biomedical research to enhance health, lengthen life, and reduce illness and disability.  And then went on to describe the goals of his office, which are: to enable major scientific discovery through the Big Data to Knowledge (BD2K) initiative; to establish and provide evidence of a more sustainable, efficient and productive data science ecosystem both internal and external to NIH; to establish and provide evidence of a well-trained and diverse workforce able to use and develop biomedical data science tools and methods; and to build upon NIH’s leadership and reputation in data science. 

   The BD2K Program, he explained, is central to the mission.  The NIH has invested almost $32 million to increase utility of biomedical research data via the BD2K initiative, and it plans to continue increasing its investment in the program.  Dr. Bourne presented a slide on the elements of the digital enterprise.  It is made up of 3 intersecting elements:  Communities, Policies and Infrastructure.  In addition, the common intersecting elements are: sustainability, efficiency, collaboration and, training.  An example of these elements is a BD2K study that involved MRI images and Genome Wide Association Studies data from over 30,000 people.  The collaboration aspect was that data came from many different sights affiliated with the ENIGMA consortium.  The study used methods to homogenize data from different sites by designing standardized protocols for image analysis, quality assessment, genetic manipulation and association.  The result was five novel genetic variants that influence human subcortical brain structures, and provided insight into the variability of brain development.  This could be applied to study neuropsychiatric dysfunction. 

   Therefore, the elements of the study were:  Community: ENIGMA and BD2K; Policy: improved consent methods, cloud accessibility for human subject data, trusted partners, and data sharing; and Infrastructure: standards, compute resources and software.    

   Furthermore, Dr. Bourne listed current and upcoming examples of the elements:  2015 Communities’ Activities, such as work with GA4GH, FORCE11 and RDA; IDEAS lab with the National Science Foundation; competition with international funders; and software carpentry, hackathons and Pi Day.  Forthcoming policies include, Data Sharing:  Genomic data sharing enforcement such as machine readable plan and repository requirements to include grant numbers.  The Data Citation that has a goal of legitimizing data as a form of scholarship.  And the process for doing so includes: machine readable standard for data citation; endorsement of data citation for inclusion in NIH bib sketch, grants, and reports.  Example formats for human readable data citations, and slowly working into the National Library of Medicine workflow.  And then he discussed The Commons as an example of the infrastructure element.  The Commons is comprised of digital objects with User IDs, indexed metadata searches, and a computing platform.  The computational framework of The Commons uses public cloud platforms such as Google, Amazon, and Azure; supercomputing (HPC) platforms, which are traditionally considered low access by the NIH; and other platforms such as in-house compute solutions, and private clouds with Pharma, the Broad and Bionimbus. 

   He then moved on to the last elements of the digital enterprise:  sustainability and training.  The goal of workforce training is to strengthen the ability of a diverse biomedical workforce to develop and benefit from data science.  The AADS is working on multiple means of doing so, including strengthening a diverse biomedical workforce to utilize data science, for example, BD2K funding of short courses and open educational resources; building a diverse workforce in biomedical data science: BD2K training programs and individual career awards; fostering collaborations: BD2K Training Coordination Center, and the NSF/NIH IDEAs Lab; and expanding NIH data science workforce development center by offering local courses, e.g., Software Carpentry.

   NIDA Council members thanked Dr. Bourne for his engaging presentation.  Multiple comments were made including, the need for the scientific community to better articulate the reasons and public health benefits of obtaining big data in light of recent fears of surveillance that the general public has.  Another comment was the need to address and better connect data with the scientists and informatics experts that are analyzing the big data; as the majority of time, they are from two separate fields of study and thought.  And it would be beneficial to NIH to explore public-private partnerships, as NOAA has done with Google to better understand atmospheric and oceanographic data, for understanding health and health economics related data. 

5. NIDA Strategic Planning: An Update - Maureen Boyle, Ph.D., Chief, Science Policy Branch, Office of Science Policy and Communications, NIDA

   Dr. Boyle began her presentation with the goal of developing a strategy to guide NIDA programs over the next five years, from 2016-2020. The Strategic Plan will include both NIDA-wide as well as division-specific strategic plans that are to be inclusive by engaging a broad range of traditional and non-traditional stakeholders; to be innovative in leveraging recent advances in drug addiction research, the “omics”, biomedical and information technologies;  and to be thoughtful, achieving NIDA’s mission most effectively, given the practical realities, and re-envisioning the landscape of substance use and addiction research.

   She then moved to discuss the strategic planning process.  It is a yearlong, cross divisional process with an anticipated final Strategic Plan release in the fall of 2015.  The process includes a Request for Information (RFI), Bold Goals Challenge, and Priority Area Workgroups.  The RFI was released on December 10, 2014 to solicit public comment on draft priorities, which were:  Understanding of the basic science of drug use, addiction, vulnerability to addiction, and recovery; supporting development of new and better interventions and treatments; increasing the public health impact of NIDA research; and Enhancing the national research infrastructure.  282 comments were received and the general themes that emerged were: greater real world focus, basic science, leveraging technology, policy relevant research, complex patients, accelerating treatments, and training.  Dr. Boyle provided more specific examples for each of the themes listed.

   The next element of the strategic planning process is a Bold Goals Challenge.  This is a challenge that will provide prizes for innovative ideas on the goals within NIDA’s research portfolio, and it will be released on challenge.com at a later date.  And the last element is the priority area workgroups to engage external experts on strategic priorities addressing:  Gene x environment x development interactions (GEDI), complex patients and big data.  She emphasized that these priority areas were not the only ones for NIDA, but that these are the areas that external experts would be most useful in the decision making process.  The GEDI workgroup is being chaired by NIDA’s Naimah Weinberg and Jonathan Pollock and the themes are to prioritize larger datasets and to make sure that any smaller studies can be integrated within larger studies; to initiate longitudinal studies with sophisticated causal modeling; to use a coordinated strategy for identifying promising candidate genes and to move to more comprehensive environment by development research; to develop advanced statistical and analytical methods; to encourage broad sharing of this type of data, with more bi-directional translation of epigenetic findings and epigenomic reference maps and biobanks; and to use a multidisciplinary approach for training and incorporating bioinformatics. 

   The second, Complex Patients workgroup is chaired by Drs. Meyer Glantz and David Liu from NIDA.  And some of the themes from this workgroup include the need to take a broader context and to look at these complex patients from the perspective of the underlying mechanism such as social and environmental factors that influence the multiple comorbidities;  the need for data analysis that incorporates genetics, care utilization, imaging and psychosocial factors; the need for better pre-clinical models of complexities; to address developmental context and lifelong trajectories of substance use disorders; to capture patients before escalation to severe substance use disorders; to integrate these efforts with the Precision Medicine Initiative; to leverage existing data sets such as the NESARC, CTN data, data, etc.; and to improve efforts at reaching the general healthcare providers, who are the first line of defense in this area.

   The third Big Data workgroup is chaired by Drs. Little and Vahabzadeh from NIDA, and Dr. Bourne, NIH Associate Director for Data Science, as one of the external experts that has volunteered his time to help.  The themes associated with this workgroup include data transfer for large data sets; control of access, limitations with consent, discoverability and usability of data,  along with issues related to storage, maintenance, sharing and security and privacy of data.

   Dr. Boyle thanked all the experts, NIDA and external, as well as staff at the OSPC for time in coordinating all efforts.

   She then moved into the last topic, the timeline.  The Strategic Plan draft is expected to be completed by July 2015, which will then be followed by a public comment period.  The Bold Goals Challenge will be released soon and a winner will be selected also by July 2015.  All of this will lead to the submission of a semi-final Strategic Plan to Council for the upcoming October 2015 NACDA round.  Dr. Boyle then thanked Council for their attention and opened the floor for questions.

   Dr. Volkow and Council members thanked Dr. Boyle for her presentation and applauded the Science Policy Branch and the Office of Science Policy and Communications for their efforts in leading NIDA’s Strategic Plan.  One line of questions that was posed by Council was if NIDA planned on increasing and enhancing research in relation to community participatory involvement.  Dr. Stein, Director of OSPC stated that NIDA is currently working closely with SAMHSA, which is a service delivery agency.  Council also recommended a change in the use of “complex patients” to another term that better identifies that they are patients with complexities in their lives that contribute to multiple disorders, diseases, co-morbidities, and health disparities.

6. NIDA Council Subcommittee: DCNBR Portfolio Analysis - John Rotrosen, M.D., Professor, Department of Psychiatry, New York University School of Medicine, NACDA Council Member

   Dr. Rotrosen began by thanking Dr. Volkow for the opportunity to meet so many NIDA staff, and in particular DCNBR staff.  He commented on how impressive it was to experience the diversity, dedication, talent and passion of the overall NIDA program.  Dr. Rotrosen then began by describing the background of the charge to the work group.  The work group was convened in November 2014 by the NIDA Director, Dr. Volkow, with the charge to review DCNBR programs and activities in the context of:  opportunities and challenges presented by scientific and technological advances and cross-cutting NIH initiatives; overlapping science and missions of other NIDA divisions, including the ABCD study; and overall NIDA strategic planning process.  In addition, the work group was asked to provide recommendations to NIDA regarding the structure, function, and overall strategic direction to maximize the impact of clinical neuroscience and neurobehavioral interventions research without constraining considerations to a narrow focus on DCNBR. 

   The work group included Dr. Rotrosen, Chair, and Dr. Terry Jernigan, both from NIDA Advisory Council; as well as other external experts in neuroscience and behavioral research:  Hans Breiter, MD; Kathleen Carroll, PhD; Betty Casey, PhD; F. Xavier Castellanos, MD; Harriet de Wit, PhD; and Lisa Marsch, PhD.  Dr. Rotrosen then went on to thank NIDA’s Ericka Boone, PhD, and Robert Katt, PhD for being the primary liaison and writer, respectively.  And then he thanked SEI staff, Susan Holbrook and Patrice Pettinato, for their assistance for logistics.

   He then listed the dates of teleconference and in-person meetings that were held beginning in November 2014 through April 2015; and listed the groups that the work group met with, including NIDA and DCNBR leadership, as well as other NIDA divisions, branches and offices. He thanked in particular, Dr. Joseph Frascella, Director of DCNBR and the following staff:  Drs. Will Aklin, Cheryl Anne Boyce, Steve Grant, Tessa Hall, Lisa Onken, Dave Thomas and Cora Lee Wetherington.

   Dr. Rotrosen then went on to discuss background of the DCNBR.  It was created in 2004 with a critical role in NIDA’s overall organization with branches focused on development, clinical neuroscience and treatment.  DCNBR also houses the Women and Sex/Gender Research Program and NIDA leadership for the Pain Consortium.  DCNBR also collaborates extensively with the other NIDA divisions and with other NIH institutes.

   The workgroup filtered the three most important DCNBR take-home messages to:  1) the past decade has witnessed advances in addiction neuroscience, pathophysiology, and pharmacologic and behavioral interventions that have outpaced or rivaled those achieved for any other brain disease.  2) No small part of the credit for this is owed to work that DCNBR has led and funded.  And 3) Translational neuroscience and neurobehavioral interventions research must remain among NIDA’s highest priorities.  There is also a great urgency to capitalize on rapid advances in genetics, molecular biology, functional imaging and the NIH Brain and Blueprint for Neuroscience, Precision Medicine and Big Data to Knowledge initiatives.  The work group views the translational neuroscience and neurobehavioral interventions research that DCNBR fosters to be central to NIDA’s capacity to address these challenges and opportunities. 

   Furthermore, Dr. Rotrosen listed the many accomplishments DCNBR has achieved, including the circuitry associated with addiction continuum; neuroeconomic approaches to decision-making, impulsivity, risk-taking; NIH Stage Model for behavioral treatment research; widely adopted behavioral interventions (MI, CM, CBT); foundational work enabling ABCD study, such as pediatric imaging, NIH MRI normal brain development study, human connectome project, and imaging supplement for large adolescent cohort; Centers for Excellence for Pain Education; technology-based interventions; combined behavioral/medication intervention; and the stellar outcomes of research training, in particular the percentage of trainees going on to faculty positions, and percentage of trainees getting subsequent NIH grants, especially R01s.

   He then showed graphs that describe the amount of interaction between DCNBR and all other NIDA divisions in the fields of Clinical Neuroscience Imaging Genetics, and Medications and Behavioral Trials, and listed multiple collaborative initiatives.  The work group was interested in how other institutes; in particular NIAAA and NINDS broke down divisional barriers and encouraged scientific and programmatic collaborations.  NIAAA has within its organizational chart a table of trans-divisional research emphasis and resource development teams.  And at NINDS, the Division of Extramural Research houses all the divisions and branches related to extramural activities. 

   The work group encouraged NIDA to look at etiology, progression, interventions and outcomes along a multidimensional conceptual model that consisted of three domains.  The domains are: addiction continuum ranging from vulnerability through relapse and recovery; brain and behavioral development, ranging from prenatal to adulthood to senescence; and spatial scaled of biological function from the molecular level up through local and distributed circuits, to organisms and social networks. 

   Some of the challenges and opportunities that the work group noted include: the recent loss of developmental imaging expertise with the departure of Dr. Jim Bjork; human behavioral imaging and statistical genetics is not sufficiently covered across NIDA, and not just DCNBR; a gap in leadership and staff in BITB, with the recent departure of Lisa Onken.  Dr. Rotrosen thanked Dr. Aklin for recently single-handedly running this branch successfully that in the past used to include seven full time employees.  He then continued with gaps in translating between animal and human models across NIDA; there is a need for more granularity to understand behavior, particularly out of neuroeconomics.  In addition, there are opportunities around complementarity of behavioral, pharmacologic, and physiologic interventions; and more opportunities for collaborations with other NIDA divisions.

   Dr. Rotrosen then provided a summary of the work group recommendations, which are: 1) to apply the multidimensional model of substance abuse across NIDA, including consideration of individual differences in each dimension; 2) to ensure that the NIDA team has broad expertise across these dimensions and enthusiasm to collaborate across organizational lines; 3) to strengthen functional integration across and within NIDA divisions, focusing on the multi-dimensional model; 4) to take advantage of the ABCD Study to implement functional integration, with a focus on development, throughout NIDA and across other NIH ICs; 5) to encourage multimodal integration of imaging studies across both humans and animal studies; 6) to encourage data-sharing, repositories, and Big Data analytics; and 7) to ensure that data from previously funded RFAs are collated and reviewed to monitor success and ensure that findings are integrated into NIDA’s strategic plans and FOAs.

   Implementation may require NIDA to re-examine its overall structure in the context of pragmatic and policy-based constraints and opportunities beyond the Work Group’s purview.  To aid NIDA leadership the report concluded with a perspective on four major issues, potential options to address these, and advantages and disadvantages for each option.  The options are intended to inform but neither to prescribe nor circumscribe the ways NIDA leadership might address each issue.  Similarly, the set of advantages and disadvantages are offered only as a starting point for deliberation.  There were four implementation issues that the work group pointed out and addressed, with another key implementation issue being that existing DCNBR staff and leadership vacancies need to be filled at a time when NIDA is comparatively overstaffed.

   Dr. Rotrosen listed and addressed each implementation issue beginning with: 1) what is the best home for NIDA translational and neurobehavioral research?  Option 1.1 is to preserve current DCNBR structure and strengthen the key areas for translational neurobehavioral research by re-engineering DCNBR, perhaps renaming it the Division of Translational Neuroscience and Neurobehavioral Research.  Option 1.2 is to merge DCNBR and DBNBR to create a new translational division.  For both options, leadership and staff should have the skill sets required to bridge and integrate the key areas of translational neuroscience, integrate neurobehavioral interventions, and developmental science. 

   Issue 2) how should NIDA foster a robust neurobehavioral interventions program?  Option 2.1 is to strategically strengthen and re-engineer BITB into a new Neurobehavioral Interventions Research Branch (NBIRB).  Option 2.2 is to redistribute the current BITB portfolio by transferring neurobehavioral implementation and services research to DESPR and CCTN.  In both cases, recruit an NBIRB Branch Chief with key leadership skills and fill vacant positions in line with the areas of responsibility of a re-engineered branch.

   Issue 3) what is the best way to incorporate developmental science throughout NIDA?  Option 3.1 is to establish an office, program or center for Developmental Research reporting directly to the NIDA Director or housed in DER, and assign to it the responsibilities of coordinating developmental research across NIDA and administering the ABCD study.  For both functions, draw on scientific and content expertise from across NIDA.  Option 3.2 is to administer the ABCD Study from within the DER but maintain a branch-level unit, either in translational neuroscience division or elsewhere, to focus on a portfolio of developmental science.

   And the final issue 4) how should genetics and modern molecular biology be incorporated across NIDA’s organizational structure?  Option 4.1 is to create within the division housing translational neuroscience a new branch focused on genetics and molecular research in humans.  This branch would manage human genetics-related projects including integrated neurobehavioral interventions research, medications development work, and imaging genetics.  Option 4.2 is to ensure that the division, instead of creating a new branch, housing translational neuroscience has sufficient staff expertise in human genetics and molecular biology in key areas of clinical neuroscience.

   Dr. Rotrosen concluded his presentation by stating that translational neuroscience, development and neurobehavioral interventions research is at the heart of NIDA’s mission and, regardless of how it’s structured, must be strongly supported.

   Dr. Volkow thanked both Dr. Rotrosen and Dr. Jernigan for a remarkable and timely analysis, as NIDA is discussing and forming its strategic planning.  NIDA Council members thanked Dr. Rotrosen for his presentation and provided the following additional recommendations: to continue to pursue the genetic variance and markers of substance abuse and addiction; as well as to ensure that a meaningful translational program includes both the pre-clinical and clinical experts that are able to identify targets and molecules, along with drug discovery research.

7. FDA Work on Medical Products Containing Marijuana - Douglas C. Throckmorton, M.D., Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA)

   Dr. Throckmorton described the focus of his presentation as being on the role of the FDA in drug development and drug regulation of marijuana and its products for use in humans.  He provided the definition of marijuana in the Controlled Substances Act (CSA) of 1970  as “all parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture or preparation of such plant, its seeds or resin...” (21 U.S.C. 802(16)).  This definition, he went on, is very important because, from a drug development perspective, it is not simply a plant but a plant that contains a series of psychoactive compounds.  Thus far, there have been close to 60 compounds that have been identified from marijuana with potentially psychoactive effects and potential therapeutic value. 

   Dr, Throckmorton then explained that as of March 2015, 23 States have statutes recognizing “medical marijuana”; 4 States and the District of Columbia have approved recreational marijuana; and an additional 13 States have statutes recognizing cannabidiol for medical use.  However, the status of marijuana at the federal level has not changed.  It is regulated under Schedule I and is defined as having a high potential for abuse, without accepted medical use, and with a lack of accepted safety for use under medical supervision. 

   There are three federal agencies that play a central role in drug discovery and medication development with marijuana.  They are the National Institute on Drug Abuse (NIDA), the US Food and Drug Administration (FDA) and the US Drug Enforcement Administration (DEA).  NIDA which conducts and supports scientific research with marijuana and its compounds oversees a contract for the cultivation of marijuana at the University of Mississippi.  This is the only source of marijuana permitted by the DEA to be used for medical research.   In order to obtain marijuana from NIDA, investigators need to demonstrate the scientific validity and ethical soundness of their proposed research, they must have submitted an application for an Investigational New Drug to the FDA, and they must have a DEA Schedule 1 controlled substance license.

   The FDA has regulatory, scientific, and enforcement roles in regards to marijuana.  The FDA provides regulatory oversight for products containing compounds from marijuana, it provides scientific assessment (8-factor analysis) on appropriate controls or scheduling for marijuana to HHS and the DEA, and it takes action where necessary against products containing compounds found in marijuana; particularly those that present human health risks or those that make illegal claims in labeling.

   As for the FDA’s role, Dr. Throckmorton noted that the scientific role of the FDA in providing the appropriate controls for scheduling.  Scheduling is defined as the classification of drugs based on their abuse potential, medical use, physical or psychological dependence.--An 8-factor analysis can be conducted to determine what the appropriate schedule is for a substance, and is ongoing for marijuana.  There are five Schedules for control (I-V) in decreasing abuse potential and restriction order, where each schedule is associated with different manufacturing, distribution, and prescribing controls necessary; and the aim is to ensure medical availability while reducing abuse and diversion.  In addition to the regulations, different penalties are also associated with the various Schedules.  He then presented the 8-factor criteria for scheduling  under the CSA, followed by a table on the Regulatory Requirements for Each Schedule. 

   There are four pathways to scheduling:  1) Administrative process, initiated by the DEA, HHS/FDA, or in response to citizen petitions.  He followed  with a graph describing the inter-agency drug scheduling process; the FDA and NIDA are currently working on compiling evidence to make recommendations to the DEA in response to petitions from the governors of Rhode Island and Washington to reclassify medical cannabis from Schedule I to Schedule II; 2) Legislation by Congress to amend the CSA to add, change, or remove a substance from a Schedule.  This typically happens in response to a public health or safety concerns, such as with synthetic cannabinoids present in “Spice;” 3) The DEA can temporarily place an unscheduled substance in Schedule I to avoid an imminent hazard to public safety, and the substance is not being evaluated under IND or NDA; 4) The DEA will schedule or reschedule a substance if required by international treaties.

   The second role that the FDA has with marijuana is supporting drug development.  Currently, there are two products approved and on the market, Marinol and Nabilone (Cesamet).  The two components of marijuana that have been the focus of research are cannabidiol (CBD) and tetrahydrocannabinol (THC)—both are contained in Sativex for cancer pain and Epidiolex (CBD) for childhood seizures.  The FDA provides guidance on the use of botanicals as sources of drugs, with special focus on measures to assure quality manufacturing; they can expedite drug development using available tools such as Orphan Disease designation, Priority Review, and Fast Track designation; and they now have a marijuana work group to coordinate agency work.  In addition Congress has provided the FDA with the authority to use Expanded Access programs that allow access to experimental drugs during development under IND.  This is different from clinical trials using experimental drugs, in that it allows the individual patients to receive the drug while the physician monitors and reports safety effects to the sponsor. This is currently being used to provide Epidiolex to children with severe and uncontrolled epilepsy.

   The final role that FDA plays is an enforcement role to target nationally marketed products making egregious health claims, including products that allege to contain CBD.  The FDA recently issued several warning letters to firms that market unapproved drugs for the diagnosis, cure, mitigation, treatment, or prevention of diseases.  The FDA also works with outside groups on issues related to marijuana, such as providing grants to support clinical research in Colorado; as well as with legislators, advocacy groups, researchers and patients.  And lastly, the FDA is working on gathering safety surveillance information on marijuana and have identified the need for new data sources to help describe relationships between levels of CBD or THC and adverse outcomes, and to characterize at-risk populations.  The current FDA Adverse Event Reporting System (FAERS) doesn’t include sufficient information on marijuana. 

   Dr. Throckmorton summarized his presentation by stating that the FDA will continue to support development of specific new drugs that are safe, effective, and manufactured to a high quality; will support drug development that is grounded in rigorous scientific research essential to determining the appropriate uses of marijuana in the treatment of human diseases; and is committed to making this process as efficient as possible and is looking for ways to speed the availability of new drugs from marijuana for the American public.

   Council thanked Dr. Throckmorton for his informative presentation and for the efforts that FDA has already put in place to ensure marijuana can be used in research, along with its cross agency work with NIDA.

8. There were no Public Comments

9. Adjourn

   The 120^th meeting of the National Advisory Council on Drug Abuse was adjourned at 12:57  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.