Revised February 2018
Closed Session - September 6th
- Call to Order - Nora Volkow, M.D. Director, NIDA
- Review of Policy and Procedures - Susan Weiss, Ph.D., Executive Secretary, National Advisory Council on Drug Abuse, Director, Division of Extramural Research, NIDA
Council Review of Grant Applications - Nora Volkow, M.D. Director
- Division of Epidemiology, Services, and Prevention Research (DESPR) - Carlos Blanco, M.D., Ph.D., Director
- Division of Therapeutics and Medical Consequences (DTMC) - Ivan Montoya, M.P.H., M.D., Acting Director
- Division of Neuroscience and Behavioral (DNB) - Rita Valentino, Ph.D., Director
- Office of Science Policy Communications - Jack Stein, MSW, Ph.D., Director
- End of Closed Session
Open Session - September 6th
- Opening and Welcome New Members - Nora Volkow, M.D. Director, NIDA
- NIDA Director's Report - Nora Volkow, M.D., Director, NIDA
- Council Discussion - Council Members
- Lunch Break
- Addressing the Opioid Epidemic through Public Private Partnerships for New Medications Development - Francis Collins, M.D., Ph.D., Director, NIH
- Follow up Discussion (Director’s Report)
- Clinical Trials Stewardship Update: Policies and Definitions - Dr. Michael Lauer, Director, Office of Extramural Research, NIH
- Update from the IRP - Antonello Bonci, M.D., Scientific Director, Intramural Research Program, NIDA
- Concept Clearances - NIDA Staff
- Public Comments
Minutes - September 6, 2017
The National Advisory Council on Drug Abuse convened its 127th meeting at 9:00 a.m. on September 6, 2017 in Conference Rooms C & D, 6001 Executive Boulevard, Bethesda, Maryland. The closed portion of the meeting held on September 6th 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, began at 10:30 a.m. and was also webcast. The Council adjourned on September 6, 2017 at 3:57 p.m.
Council Members Present
Judith Auerbach, Ph.D.
Laura Bierut, M.D.
Julie Blendy, Ph.D.
John Carnevale, Ph.D.
Linda Chang, M.D.
H. Westley Clark, M.D., J.D.
Arthur Dean, M.A.
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.
Eric Verdin, M.D.
Council Members Absent
Anne Andorn, M.D.
Nora Volkow, M.D.
Susan Weiss, Ph.D.
Federal Employees Present
Jane Acri, Ph.D.
David Liu, M.D.
Members of the Public Present
Sheila Harley—Harley Business Group, LLC
Estelle Ntowe—Kelly Services, Inc.
Victor Prikhodko—Kelly Services, Inc.
Dena Procaccini—Kelly Services, Inc.
Ann Rea—Kelly Services, Inc.
Juli Rose—A. Bright Idea, LLC
Hwa “Jamie” Sim—Kelly Services, Inc.
Jen Sizemore—A. Bright Idea, LLC
Peter Strumph—Amygdala Neurosciences
Roy Walker—Synergy Enterprises, Inc.
Lori Whitten—Synergy Enterprises, Inc.
Patrick Zickler—The Palisades Group, LLC
Closed Portion of the Meeting – September 6, 2017
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.
In turn, the Director for the Division of Epidemiology, Services and Prevention Research, the Division of Therapeutics and Medical Consequences, the Division of Neuroscience and Behavior, and the Office of Science Policy and Communications 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, foreign applications, and a MERIT Award. 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 – September 6, 2017
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: February 6, 2018, May 15, 2018, May 16, 2018 (CRAN), and September 5, 2018.
Consideration of the Minutes of Council
The Minutes of the NIDA May 2017, as well as the CRAN May 2017 meetings were unanimously approved as written.
NIDA Director’s Report – Nora Volkow, M.D., Director, NIDA
Dr. Volkow began with a brief update on the status of hiring a director of the Division of Therapeutics and Medical Consequences (DTMC); although the HHS hiring restrictions continue, the position has been released and advertised due to its importance to NIDA. A search committee has been designated and is led by Dr. Chris Austin, Director of the National Center for Advancing Translational Sciences (NCATS).
The next topic was an update on the budget, the FY 2018 President’s Budget indicates a decrease to both NIDA AIDS, and Non-AIDS funding. Compared to FY 2017 NIDA total budget of $1,070,846, the President’s 2018 Budget called for NIDA to receive only $854,998 for the upcoming fiscal year.
Turning to what is new at NIH, Dr. Volkow highlighted the NIH Next Generation Researchers Initiative. This initiative arose from the challenges facing the scientific research community: too many researchers vying for limited resources and many highly meritorious applications going unfunded. These issues are particularly challenging for early-stage and mid-career investigators. The goal of the Next Generation Researchers Initiative is to focus support for early-stage (ESI: within 10 years of terminal degree) and early established investigators (EEI: within 10 years of first major NIH competing award as an ESI). NIH hopes to support a combined additional 400 ESIs and EEIs in FY 2017, ramping up to 1.1 billion per year after five years.
Another NIH initiative is implementation of new policies regarding application, review and oversight processes for Clinical Trials. The definition of what constituted a Clinical Trial was broadened a few years ago and is now defined as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effect of those interventions on health-related biomedical or behavioral outcomes. Clinical Trials need to: respond to a clinical trial-specific Funding Opportunity Announcement (FOA); address additional review criteria specific for clinical trials; and be registered in ClinicalTrials.gov. Implementation of the new policies begins with clinical trials applications received on or after January 25, 2018.
Dr. Volkow then moved on to the NIH BRAIN Initiative, which has been very successful since its inception in FY 2014. The FY 2017 budget is close to $250 million and was used to support 24 Funding Opportunity Announcements (FOAs) that cover all 8 BRAIN scientific areas. There is increased interest and funding in the areas of Human Imaging and Neuromodulation, and to establish a census of brain cell types, as well as the area of neuroethics. Dr. Volkow highlighted two specific BRAIN FOAs: New Concepts and Early-Stage Research for Large-Scale Recording and Modulation in the Nervous System (R21) (RFA-EY-17-002), with an application receipt date of October 26, 2017; as well as Research on the Ethical Implications of Advancements in Neurotechnology and Brain Science (R01) (RFA-MH-18-500), with an application receipt date of December 7, 2017. In addition, she encouraged attendance at a symposium on: Exciting New Tools and Technologies Emerging from the BRAIN Initiative that will be chaired by Dr. Joshua Gordon, Director of the National Institute on Mental Health, as well as a BRAIN initiative Networking Satellite, sponsored by the BRAIN Initiative Alliance at the upcoming 2017 Annual Society for Neuroscience meeting in Washington DC.
Dr. Volkow then spoke about recent NIDA activities and events. She began with an ABCD Study update. Since its launch in September 2015, the ABCD Consortium has recruited 4,819 children. Its Fast Track Data has been released and contains unprocessed neuroimaging data from 4750 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. Annual Curated Data, including assessment domains and computational analysis pipelines, will be released annually, starting in December 2017 with the first 4700 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), and the National Institute of Neurological Disorders and Stroke (NINDS).
She then shifted to the opioid crisis and referenced a New York Times article that was published on September 2, 2017 titled “Fentanyl Overtakes Heroin as Leading Cause of U.S. Drug Death.” According to the article that is based on CDC MMWR Report 2017, drug overdoses killed roughly 64,000 people in the USA in 2016; a 22% rise over 2015 with fentanyl and fentanyl analogues changing the equation. The death rate in the state of Maryland alone last year outpaced that in Kentucky and Maine combined. The graph presented indicates that overdose deaths related to fentanyl have skyrocketed and surpassed overdose deaths related to prescription opioids, and heroin going from approximately 3000 to over 20,000 deaths just in the past year. In addition, there has also been a noted rise in overdose deaths related to cocaine use; the numbers show a doubling in the past year, which corresponds with the increase of cocaine in this country as the Office of the National Drug Control Policy has been stating.
The Office of Science Policy and Communications, led by Dr. Jack Stein, along with the support of Dr. Francis Collins, coordinated a series of cutting edge scientific meetings focused on strategies to end the opioid crisis. Three meetings were held: the first, “Medications Development for Opioid Use Disorders and for Overdose Prevention and Reversal” was held on June 5, 2017; the second “Development of Safe, Effective, and Non-Addictive Pain Treatments,” was held on June 16, 2017; followed by “Understanding the Neurobiological Mechanisms of Pain” that was held on July 7, 2017. Representatives from industry, academia, and regulatory agencies, including the FDA, were invited to attend the meeting series and try to identify action items that address and move forward the scientific topics presented. The goal of the first meeting was to stimulate innovative directions in preventing and treating opioid use disorders and overdoses. Key meeting topics included opioid-based targets, non-opioid-based targets, biologics (vaccines, monoclonal antibodies), overdose treatment, and the challenges posed by synthetic opioids. The goal of the second meeting was to expedite the screening and development of promising agents with little or no potential for misuse or addiction to treat chronic pain. Key topics for this meeting were: molecular libraries for screening analgesics; novel or re-purposed agent profiles and mechanisms of action; new analgesic development; genetic data on pain sensitivity; and other treatment modalities. The last meeting in this series focused on understanding the neurobiological mechanisms of pain to accelerate the development of novel pain treatments. The key topics were pain neural circuitry and maladaptive plasticity, pain and immune function, acute-to-chronic pain transition, and heterogeneity of pain syndromes. The series focused on the potential for public-private partnerships to help solve the opioid problem.
Dr. Volkow noted Medication Assisted Treatment (MAT) for opioid use disorders is available, yet it is highly underutilized. Available MATs include daily dosing with the full agonist methadone; the partial agonist buprenorphine given 3-4 times per week; and antagonists, Naltrexone Extended Release (Vivitrol) given once a month. NIDA has funded many research studies that have shown a positive correlation between MAT and cessation of opioid use; as well as decreases in opioid-related overdose deaths, criminal activity, and infectious disease transmission. MAT has also been shown to improve social functioning, retention in treatment, and outcomes with neonatal abstinence syndrome. Dr. Volkow emphasized the need for alternative interventions to expand the types of approaches used for opioid use disorder, along with implementation science to support the cascade of care—i.e., the various steps required to achieve continuous abstinence form opioid use. She highlighted multiple opportunities for public private partnerships in the development of longer acting formulations and/or drug combinations to improve treatment compliance and retention; for sharing of compounds and de-risking potential new targets for treatment of OUD; and for sharing reagents and de-risking vaccines or monoclonal antibodies for treatment of OUD.
Working with partners from industry, academia and regulatory agencies, key challenges to medications development for OUD were discussed, such as: minimal industry involvement, lack of infrastructure for OUD treatment, lack of reimbursement for OUD medications, and the requirement for abstinence as the main outcome for medication approval by the FDA. Ways to help reduce these challenges include: incentives to encourage private industry investment; better surveillance and long-term outcome data on MAT and OD; and funding. The next steps for NIH to take to address these challenges include: expanding the clinical network to rapidly deploy clinical trials and to conduct epidemiological studies; engage CMS to address reimbursement; engage the FDA for alternative outcomes for medication approval; and explore mechanisms to expedite NIH review of grant applications. Dr. Volkow informed council and the audience that Dr. Francis Collins will be presenting this afternoon on the Public Private Partnership efforts that NIH will be launching for new medications development to address the opioid crisis.
Dr. Volkow moved on to discuss NIDA’s Treatment Interventions priority area. One of the challenges in treatment interventions is management of pain, and especially chronic pain. Multiple studies have shown that women suffer more pain in many categories: severe headache or migraine, low back pain, and neck pain; and they are prescribed more opioids. This is also reflected in the increased percentage of women using heroin, with the number of deaths from natural and semi-synthetic opioid use reaching equal numbers among men and women. In order to address the issue of pain measurement, NIDA has published an SBIR and STTR Funding Opportunity Announcement: Development of a Device to Objectively Measure Pain (R43/R44) RFA-DA-18-012, and (R41/R42) RFA-DA-18-013. The goal is to encourage small business concerns to develop a tool to objectively measure pain for research or clinical purposes.
She then spoke about another NIDA priority area, HIV and Drugs. NIDA has recently released two new Funding Opportunity Announcements in this area: HIV-Associated Neuropathic Pain and Opioid Interaction (R01) RFA-DA-18-015: and HIV/HCV Co-Infections in Substance Abusers (R01) PAS-17-311. The latter solicits innovative research on impact of substance abuse on HIV, HIV/HCV co-infection disease progression; interactions between HIV and HCV; hepatic and non-hepatic co-morbidities associated with HIV/HCV co-infections and SUD; and the effectiveness of interferon-free direct acting antivirals (DAAs) to treat HIV/HCV co-infections in SUDs.
Dr. Volkow concluded her presentation with the 2017 Intel International Science and Engineering Fair Addiction Science Awards. This event encourages high school students to enter the field of addiction science. The three winners this year were: In first place, Anusha Zaman from Baton Rouge Magnet High School in Louisiana for her topic “Epigenetic and Biotransformation Effects of Hookah Smoke Extract on Human Oral Keratinocytes.”; in second place, Nkima Stephenson from Rockdale Magnet School of Science and Technology in Conyers, Georgia for her topic “Data Analysis of the Epigenetics of Drug and Alcohol Dependence.”; and in third place, Kashfia Rahman from Brookings High School in Brookings, South Dakota on her topic “ dynamics of habituation: a neural study of the effects of repeated exposures to risky behaviors on cognitive control and emotional responses in the adolescent brain.”
Another event that Dr. Volkow highlighted is the 2017 Frontiers in Addiction Research Mini-Convention hosted by NIDA and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). It will be held on November 10 at the Walter E. Washington Convention Center in Washington DC. It will include sessions on: understanding the role of astrocytes in nervous system function; social stressors, immune response and substance use disorders; and novel approaches to translational research and drug discovery.
Council thanked Dr. Volkow for her presentation. One suggestion was to ensure that as medication therapy becomes a priority with the opioid crisis; a focus should also be on psychosocial counseling, and other non-medication components, such as digital and science-based therapeutic technologies and tools. This will help ensure support to patients, and especially those with co-occurring disorders such as PTSD, anxiety, and other mental illnesses. Dr. Volkow assured Council that social support, as well as other treatment and prevention implementation strategies are top priorities to NIDA. One council member encouraged educating the public that relapse is part of addiction, and that addiction therapy is a process. Another Council member wanted to remind Dr. Volkow and the audience that more potent versions of cocaine are being mass produced; he encouraged NIDA to keep Congress and the public abreast of emerging drugs and maintain the theme of addiction at a global level to minimize the impact and avoid another crisis similar to the opioid crisis.
Public-Private Partnerships Related to Opioid Use Disorder and Pain – Francis S. Collins, M.D., Ph.D., Director, NIH
Dr. Collins began his presentation by thanking Dr. Volkow for her leadership and scientific vision during this intense period in the health of the nation. He showed side-by-side maps of the United States from the CDC/NCHS, National Vital Statistics System, one from 1999 and the other from 2015 reflecting the increased overdose death rates nationally. Some areas of the nation, particularly in Appalachia and the South West have rates higher than 30 deaths per 100,000 population.
He continued by listing the challenges of the opioid epidemic. More than 25.5 million adults have pain every day; and opioids are overprescribed, although they have been shown to not be effective for many patients for the management of chronic pain. More than 2 million Americans are currently addicted to opioids, with most having started with prescription medicines. Medication Assisted Treatment (MAT) is available for opioid use disorders and to prevent or reverse an overdose; however, MATs are drastically underutilized, and the duration of treatment needed is not yet well understood. Research has revolutionized the understanding of addiction and pain; but alternatives to treat addiction and overdose are limited, and new, non-addictive pain medicines are urgently needed.
NIH has begun an Opioid Research Initiative using research to end the opioid crisis by addressing 3 target areas: Opioid Addiction Treatment with a focus on new and innovative medications and technologies; Overdose Reversal by searching for interventions to reduce mortality and link overdose victims to treatment; and Pain Management; finding safe and more effective strategies. The case for a public-private partnership for pain and opioid use disorders is that this is an urgent public health crisis with a need for better alternatives for treatment of addiction and a need for more potent treatments for overdose. Currently there is an absence of highly potent alternatives to opioids. The emergence of numerous potential drug targets is at a slower rate than that of the crisis. There is a need to develop and validate biomarkers for pain relief, to try to take what is largely a subjective effort and make it more in the nature of digital reporting, all while being able to distinguish subsets of pain syndromes that may have different pathophysiologies as well as different treatment pathways. And there is strong support at the highest level of the U.S. government, including an exhortation that was given personally by President Trump in March 2017 for all hands on deck. FDA leadership have also been very clear in their determination to assist with the regulatory processes; and to encourage additional industry involvement and incentives.
Dr. Collins then presented the Accelerating Medicines Partnership (AMP) project that began at NIH 3 years ago to collaborate with industry and academic scientists at the NIH and the FDA. It has allowed progress that simply would not have happened without that kind of arrangement. NIH has partnered with the Foundation for the NIH, which serves as the project manager for the AMP, as well as the FDA, 10 biopharmaceutical firms, multiple non-profits, including patient advocacy groups, to: increase the number of new diagnostics and therapies, and reduce the time and cost of developing them. It is investing $230M over five years on three pilot projects 1) Alzheimer’s disease; 2) Type 2 Diabetes; and 3) Autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. The AMP model is now expanding to Parkinson’s disease and Cancer. This is a very vigorous effort with the executive committee being co-chaired by Dr. Collins, Michael Dolsten of Pfizer, Jan Lundberg of Lilly, and Paul Stoffels of J&J. They are the heads of Research and Development at their respective companies, and everyone meets monthly to ensure that the projects are on track. Each one of the projects has a steering committee co-chaired by an industry and an academic member, and is built upon a very explicit set of milestones and a work plan that includes all participants and holds each accountable to the milestones.
Some of the lessons learned are: to start by identifying a need that cannot be met readily by partners working alone; convene scientific experts from all relevant sectors to design a possible work plan, which requires leadership from the relevant NIH Institute(s); identify a few champions from industry; and including advocates and the FDA; then refine the work plan, develop milestones, deliverables, Go-No-Go decision points and detailed budget; design and implement the work plan. FNIH is highly effective in this role; and aware of partnership fatigue.
Dr. Collins then presented two projects. Project #1: Develop New Formulations and Combinations of Medications to Treat Opioid Use Disorders (OUD), Prevent and Reverse Overdose. The goal of this project is to increase effectiveness of strategies to prevent, treat opioid use disorders and overdose, and to support long-term recovery. Some of the strategies include new treatments for OUD such as extended release formulations of buprenorphine, and alternative therapeutics, i.e., vaccines and antibodies; stronger formulations of Naloxone to reverse overdose from powerful synthetic opioids like fentanyl; as well as devices to prevent opioid misuse safely at home. Project #2: Accelerate Development of New Non-Addictive Pain Therapies. The goal is to provide scientific solutions for pain to end the opioid crisis including, advance pain therapeutics in the current pipeline, determine objective measures to understand and predict responses to pain, and to establish collaborative data sharing between industry groups, with NIH serving as an honest broker.
The current Administration has also supported this initiative with the President’s Commission on Combating Drug Addiction and the Opioid Crisis. The recommendation from the interim report states: “Instruct the NIH to begin to immediately work with the pharmaceutical industry in two areas; the development of additional MAT options and the development of new, non-opioid pain relievers based on research to clarify the biology of pain.” NIH is pursuing two Public-Private Partnerships to develop new formulations and combinations of medications to treat OUD, Prevent and Reverse Overdose, and to accelerate development of new non-addictive pain therapies. A number of meetings have taken place in 2017 to partner and begin planning with industry. The next steps are an overall work plan for research initiative in development. This will be informed by three cutting edge scientific meetings. Meeting with biopharmaceutical groups to develop a plan; the plan will include major goals, action steps, key partners, deliverables, timeline and the associated costs. The final version will be posted for public viewing at https://www.nih.gov/opioid-crisis.
Dr. Collins concluded his presentation with a metaphorical edifice using science to end the opioid crisis that has three pillars: Pain, Addiction, and Test Effective Treatments. NIH needs to address this crisis with strategies to treat opioid addiction successfully, and to prevent and reverse overdose. NIH needs a national resource network to test new therapies; NIDA supports a clinical trial network, as well as emergency room networks, the ECHO program which focused on childhood environmental exposures, and has a pediatric research network. NIH would like to ensure that all equities are coordinated in a way to continue to move the agenda forward as quickly as possible.
Dr. Volkow and Council members thanked Dr. Collins. Council commended Dr. Collins on his efforts and commitment to prioritize the opioid crisis. One Council member recommended also including in the public-private partnership digital health technology companies as an unprecedented opportunity to learn about health behavior and outcomes. Another member suggested implementation of the Precision Medicine in conjunction with the PPP initiative.
Clinical Trials Stewardship Update – Michael Lauer, M.D., Deputy Director, Office of Extramural Research, NIH, and Jon Lorsch, Ph.D., Director, NIGMS
Dr. Lauer began by discussing a paper published by Joseph S. Ross and Deborah A. Zarin et al. “Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis.” BMJ 2011; 2011; 344:d7292 doi: 10.1136/bmj.d7292 (Published 3 January 2012). It states, “there are many [NIH-funded] trials not covered by [FDA Amendments Act], such as trials of behavioral interventions and surgical procedures. No policies exist to make sure that the public has access to results from NIH funded research that is not published.” In response to this article, Dr. Lauer and his colleagues looked at 244 consecutive cardiovascular trials that had been completed over a period of ten years and published the results under the title “Publication of trials funded by the National, Heart, Lung and Blood Institute.” N Engl J Med 2013; 369: 1926-34. The results indicate that for studies with clinical end points, approximately 20 percent of funded studies, results were published approximately 2 years post study completion. However, for the majority of the studies funded, that did not include specific clinical end points but rather surrogate end points, with only 40 percent published 2 years after completion of the study. The paper concluded that “a number of parties share responsibility, including funders, investigators, academic medical centers, clinical research organizations, and…journals.”
Another study conducted at Yale University by Chen et al. “Publication and reporting of clinical trial results cross sectional analysis across academic medical centers.” BMJ 2016; 352: i637 looked at 4300 trials that were completed between 2007 and 2010 that were based at 51 major academic medical centers in the United States. The outcome they looked for was whether or not the main results of the trial were published within 2 years of completion, or if not published, posted on ClinicalTrials.gov. The authors concluded that “despite the ethical mandate and expressed values of academic institutions, there is poor performance and noticeable variation in the dissemination of clinical trial results across leading academic medical centers.” The lead on this study, Dr. Harlan Krumholz, wrote a follow up column on the NPR website with the headline “academic medical centers get an F in sharing research results.” He continued to state that “we have a bottleneck at our nation’s bastions of research excellence. Too many times, study results are neither reported on the government website, clinicaltrials.gov, nor published in a journal…the failure to share results is so pervasive that it seems inappropriate to blame individuals. Instead, it is a systemic problem.” Harlan goes on, “not reporting results violates the basic principle of the scientific method. It hurts patients, society and science. It dishonors the people who gave their consent and bore the risk of participating… the holding back of the results impedes progress toward scientific breakthroughs, corrupts the medical literature and wastes research funding.”
Dr. Lauer stated that this is problem number one. Which is that NIH has a large number of studies that are being funded, being completed, and not being reported out in a timely way. Another problem, in a report from the United States Government Accountability Office (GAO) released March 2016 to congress “Additional data would enhance the stewardship of clinical trials across the agency.” The GAO stated that “NIH’s OD reviews some data on clinical trial activity across the NIH but has not finalized what additional data it needs or established a process for using these data to enhance its stewardship. NIH is limited in its ability to make data-driven decisions regarding the use of its roughly $3 billion annual investment in clinical trials.”
Leadership from across NIH worked collaboratively in response to these problems, and in October of 2014 NIH released a revised definition of a clinical trial, a Request for information (RFI) was published for public comment in November 2014 (and received over 240 comments), and in 2016 under the egis of the Office of Science Policy, a final rule was released as part of a regulation. This new policy signed by Dr. Collins states “a fundamental premise of all NIH-funded research is that the results must be disseminated… In research involving human beings, scientists have an ethical obligation to ensure that the burden and risk that volunteers assume comes to something, at the very least ensuring that others are aware of the study…” It continues to read “we disagree with commenters who suggested that there is no need for coverage of certain types of trials. The benefit of transparency and the need to fulfill the ethical obligation to participants is as relevant to these types of trials as to any other type. We believe that 12 months represents an appropriate balance between investigators’ interests and the interest of the public in having access to the results of a publicly funded trial.”
Dr. Lauer then showed graphics of the lifecycle of a clinical trial from the conception of an idea and receiving Good Clinical Practice training, to publication of the results on ClinicalTrials.gov. He also previewed the updated Office of Extramural Research (OER) website page on Clinical Trial Requirements for Grants and Contracts. This page includes the NIH definition of clinical trials, a questionnaire to help researchers discover if their study meets the new criteria, as well as the requirements for registering and reporting NIH-funded clinical trials on clinicaltrials.gov.
In an essay that was written by Drs. Collins, Hudson and Lauer “Toward a new era of trust and transparency in clinical trials.” JAMA 2016 (online September 16, 2016) it says “to realize the benefits of a clinical trial, the data must be broadly shared quickly. The DHHS has released a regulation for registration and summary results reporting. The NIH will withhold clinical trial funding if the agency is unable to verify adequate registration and results reporting…” Dr. Lauer concluded his presentation by reiterating that NIH is being acknowledged for realizing that there is a problem, and more so, for its efforts in trying to solve it.
Dr. Volkow and Council members thanked Dr. Lauer for his presentation. Council engaged in a discussion and brought up many questions about observational studies, and Dr. Lauer confirmed that the ABCD study is not a clinical trial and provided further examples that qualify a study as a clinical trial. A suggestion was made to ensure the ease of use of the data generated from ClinialTrials.gov by other agencies that use research to determine policy, such as the Department of Justice.
The NIDA Intramural Research Program Update – Antonello Bonci, M.D., Scientific Director, Intramural Research Program, NIDA
Dr. Bonci opened his presentation with his vision for the Intramural Research Program (IRP), which is to create a world class Neuroscience Institute on Substance Use Disorders (SUD); to develop and maintain an environment where cutting edge science, human studies and drug abuse related initiatives can thrive; and to have a highly interactive intramural-extramural environment.
He then showed a schematic of the current NIDA IRP organizational structure. It consists of very strong and independent core facilities, branch chiefs, programs, committees and administrative personnel. He continued by listing and thanking IRP leadership: Dr. Amy Newman, Deputy Scientific Director, and Director of Medication Development; Dr. Karran Phillips, Clinical Director; Capt. Dr. Michelle Leff, Chief of Staff and NIDA Technology Development Coordinator; Dr. Steve Heishman, Associate Director for Education and Training; Dr. Marisela Morales, Director of Core Facilities; and Dr. Michelle Jobes, Associate Director for Diversity and Outreach. All are strong leaders decentralized from the facility director.
Dr. Bonci then presented a paper recently published by the IRP “chemogenetics revealed: DREADD occupancy and activation via concerted clozapine.” Science 2017; Aug 4; 357 (6350): 503-507. The study revealed that Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) constitute a powerful chemogenetic strategy that can modulate nerve cell activity in freely moving animal preparations. Gomez et al. used radioligand receptor occupancy measurements and in vivo positron emission tomography to show that DREADDs expressed in the brain are not activated by the designer compound CNO (clozapine N-oxide). Instead, they are activated by the CNO metabolite clozapine, a drug with multiple endogenous targets. This may have important implications for the interpretation of results obtained with this popular technology.
The IRP is also responding to the Opioid Epidemic by partnering with Braeburn Pharmaceuticals to develop Dopamine D3 Receptor (D3R) antagonists and partial agonists based on Eticlopride and the D3R crystal structure toward the prevention and treatment of opioid use disorders. Dr. Amy Newman has led this effort and this compound will be used ideally in clinical trials. The IRP is also supporting a total of 42 opioids, pain, and cannabinoid projects in progress or in the planning process. Dr. Bonci listed a number of them. He then spoke about an IRP study that was published, and showed that fontal cortical stimulation with optogenetics in rodents was able to reduce cocaine seeking “developing an optogenetic-based therapy against cocaine use disorders, using transcranial magnetic stimulation (TMS).“ The trial was based on a study published by Chen et al. in Nature 2013; the open label trial was successful as seen by Terraneo et al. EJN 2016; and independent double blind, placebo controlled clinical trials are ongoing at NIDA, and in Italy and Mexico. This method is also going to be applied against heroin and methamphetamine use to see if TMS can reduce those specific drug cravings.
He then moved to Human Research on HIV at the NIDA IRP. Dr. David Epstein is leading two studies: 1) Implantable/injectable buprenorphine for behavioral stability and adherence to antiretroviral therapy (ART). This study randomizes opioid-using HIV-positive participants to a) probuphine (6-month buprenorphine implant), b) CAM2038 (1-month high dose buprenorphine injectable), or c) treatment as usual (office-based sublingual buprenorphine). It seeks to monitor viral load, CD4 count, and behavior for 12 months. The hypothesis is that implantable or injectable buprenorphine, compared to treatment as usual, will produce a “virtuous cycle” of behavioral stability and ART adherence, reflected in more continuous suppression of viral load. Study 2) Machine-learning methods for prediction of HIV transmission hotspots seeks to develop wall-to-wall surface maps of HIV reservoir and transmission risk in Baltimore; to develop algorithms to predict changes in the maps on a time scale of weeks or month; and to help focus pre-exposure prophylaxis (PrEP) and other strategies anticipatorily rather than reactively.
Dr. Bonci then listed other ongoing initiatives at the IRP: Medication development program led by Dr. Amy Newman, diversity and outreach program with fellowships led by Dr. Michelle Jobes, intramural-extramural innovative partnership program led by Dr. Leff, designer drug initiative led by Dr. Baumann, bioengineering partnership with Purdue University led by Dr. Da-Ting Lin, and discovery engine to create a new measure of scientific impact led by Dr. Bonci.
He then presented new IRP tenure-track faculty, and then discussed the IRP’s future plans. These are to deliver new therapies (medications and brain stimulation) for approval to the FDA, to retain basic science faculty, to recruit more clinicians and strengthen the clinical program, and to move faculty to BRC and perhaps to the NIH main campus, due to the lease expiring in 2021.
Dr. Volkow personally thanked Dr. Bonci for his leadership and for turning the IRP into one of the strongest programs at NIH. Council members thanked Dr. Bonci for his presentation and for all the IRP efforts. Dr. Bonci encouraged council members interested in IRP initiatives to reach out to him directly.
Concept Clearances – NIDA Staff
Four total concepts received Council clearance.
John Satterlee, Ph.D., Coordinator for Trans-NIH Programs and Activities, Division of Neuroscience and Behavior (DNB), NIDA presented: Molecular Regulation of HIV Latency in Individuals with Substance Use Disorders (SUDs). Patients with chronic substance use or SUDs can present unique challenges for HIV prevention, treatment, disease progression, medical consequences, potential cure, and responses to vaccines or therapeutics. Understanding the molecular processes regulating HIV latency, especially with respect to SUDs and reservoirs such as the brain, will provide foundational knowledge for the development of future therapeutics to treat HIV in individuals with and without SUDs.
This initiative will support Omics studies (e.g. transcriptomic, epigenomic, epitranscriptomic, proteomic, metabolomic) that address outstanding questions regarding HIV latency or reservoirs in the context of chronic substance use or SUDs. Some of the major questions that we anticipate will be addressed are:
1. What are the detailed molecular mechanisms regulating the formation or reactivation of latent HIV in the genome?
2. How do these molecular mechanisms differ in the different cellular reservoirs that harbor latent HIV?
3. How do addictive substances impact these processes?
The goal of this initiative is to promote basic and clinical research directed at: (1) elucidating the neurobiological and behavioral mechanisms by which psychosocial stress alters pain sensitivity or cognitive/affective processes, biases opioid use, maintains opioid seeking and increases the risk of relapse; and (2) identifying the factors and the associated mechanisms of action underlying resilience or vulnerability to psychosocial stress-induced alterations in pain sensitivity or affective/cognitive functioning as it relates to OUD.
Dr. Sarah Duffy, Associate Director for Economics Research, Division of Epidemiology, Services and Prevention Research (DESPR) presented: Science-Based Quality Measurement and Management Development for Opioid Use Disorder Treatment. Although there are many fine programs, the overall quality of opioid use disorder (OUD) treatment in the United States is suboptimal. The one-size-fits all, episode-based model is still too common. Effective interventions are too seldom provided. Patients are not sufficiently assessed for comorbidities or use of prescribed substances. Payers limit coverage for what is often a chronic condition. Programs and payers still hold that people who relapse are just not ready for treatment, discharge them, and tell them to come back when they are ready. Too often, they never come back. Patients and families have no idea what to look for, and often end up paying tens of thousands of dollars, even with insurance, for programs that were never going to be sufficient.
Over at least the past two decades the field has attempted to develop and implement quality measures as a quality improvement strategy. These include the widely-used treatment initiation and engagement measures, the SAMHSA National Outcome Measures, measures developed and implemented in various State initiatives or by professional organizations, and even outcome measures instituted in the British National Health Service Payment for Results pilot, the main result of which was that fewer patients completed a course of treatment.
Dozens of quality measures exist for substance use disorder treatment, and there are repeated calls to develop more. Those that exist mostly were developed by consensus panels of knowledgeable, well-meaning individuals, and then “tested” to determine if they can be measured adequately in whatever data sources is being used, are at a level where they need to be improved, and so forth. Then, generally, the measures are put on a list, sometimes adopted by states and payers, included pay for performance schemes. Too often, nothing changes. Sometimes, implementing quality measures in this fashion makes things worse.
What has been missing is rigorous, scientific development and examination of the measures, before they are put on a list, of both how they may be improved, and the effects of the improvement, both intended and unintended. The purpose of this proposed initiative is to fund research to do just that.
The goal for this concept is that investigators funded under this activity would identify high-priority targets for improvement in OUD treatment, and develop a plan for how they might be improved. They then would either select existing measures or develop novel measures related to the target area. They would rigorously test these plans for improvement to see if the measures improve and, if they do, whether patient outcomes also improved. They would also carefully examine any unintended consequences, as well as the economics of the measures and improvement activities. They would also consider whether casemix adjustment would be needed to fairly compare clinicians or programs, etc., on these measures. They would also develop materials and disseminate materials to make it easier for other similarly situated entities to implement these measures and improvement strategies.
Vani Pariyadath, Ph.D., Health Scientist Administrator, Integrative Neuroscience Branch, DNB, NIDA presented: Co-operative and Competitive Use of ABCD Data. The Adolescent Brain Cognitive Development (ABCD) Study recently commenced releasing data to the public, and given the size and complexity of the dataset, one concern is how to ensure that the data are widely used. Recently, there has been considerable discussion regarding the need for increased rigor and reproducibility in neuroimaging research. A concern with big datasets is that the large number of analyses being performed combined with the increased likelihood of finding statistically significant effects results in a greater number of false positives being published. One approach towards addressing both the above concerns is to hold competitions and hackathons (meetings where multiple participants gather to engage in collaborative computer programming) geared towards model development where a part of the data remains unseen and therefore available for model validation. The attention deficit hyperactivity disorder 200 (ADHD-200) competition is one example that provided valuable insights into ADHD diagnosis in particular, and development of neuroimaging biomarkers, in general. The ABCD study currently offers a unique opportunity towards encouraging such endeavors in the realm of substance use and other mental disorders because data are collected at 1-2 year intervals and collection is ongoing; datasets beyond the baseline study visit are therefore automatically concealed from model developers.
The purpose of the proposed FOA is to invite applications that utilize ABCD data (baseline measures only) towards enhancing rigor and reproducibility through meetings centered on collaborative- or competition-style use of ABCD data. Applications emphasizing the development of predictive models of group/individual differences, with the overarching goal of predicting behavioral and clinical outcomes in future time-points, are particularly encouraged.
The overall goals of this initiative are:
1. Widening use of the ABCD dataset
2. Enhancing rigor and reproducibility towards better predictive models
3. Facilitating collaboration between clinical and computational researchers on SUD research
Shelley Su, Ph.D., Health Scientist Administrator, Behavioral and Cognitive Neuroscience Branch, DNB, NIDA presented: Identifying Neural Mechanisms Linking Psychosocial Stress to Pain and Opioid Use Disorder. Psychosocial stress, defined as socioenvironmental demands that tax the adaptive capacity of the individual, is a major risk factor for opioid use disorders (OUDs). Psychosocial stress may impact OUD risk by altering cognitive and affective function and facilitating the development of affective disorders. Stressful environments have been associated with pronounced negative affect and affective disorders, and impairments in reasoning, memory, inhibitory and cognitive control. In addition to cognitive and affective outcomes, exposure to psychosocial stress has been shown to modulate pain perception and tolerance to opioid analgesics, which can also contribute to the potential for opioid abuse and addiction. For example, adverse childhood experiences such as verbal and sexual abuse, low family income, and early parental loss, have been associated with an increase in pain-related medical conditions during adulthood.
OUDs show high comorbidity with affective disorders such as major depression and anxiety. Further, opioid misuse rates among chronic pain patients are influenced by negative affect. Neurobiological changes in overlapping brain areas, circuits and neurochemistry have been implicated in chronic pain, depression, anxiety, and substance use disorders. Initial findings suggest that individuals with affective disorders exhibit blunted endogenous opioid function, which is associated with altered pain sensitivity and response to opioid medications. Furthermore, healthy individuals with lower endogenous opioid release are more likely to develop chronic pain and report more pain in laboratory assessments of pain, suggesting that natural variations in the endogenous opioid system produce individual differences in pain severity and processing. Collectively, these data suggest a complex multidimensional relationship between psychosocial stress, cognitive/affective processing, pain, and OUDs. However, important questions remain regarding the underlying mechanisms related to behavior, genetics, epigenetics, neural circuitry, and endogenous opioid function.
The 127th meeting of the National Advisory Council on Drug Abuse was adjourned at 3:57 p.m.
I hereby certify that the foregoing minutes are accurate and complete.
Nora D. Volkow, M.D.
National Advisory Council on Drug Abuse
Susan Weiss, Ph.D.
National Advisory Council on Drug Abuse
Note: Informational materials provided to the public at the open session of the meeting may be obtained from the Executive Secretary.