A concept describes the purpose, scope, and objectives of a potential funding opportunity. Approved concepts are usually developed into Requests for Applications (RFAs), in which funds are set aside by the Institute to stimulate a specific program of research. Concepts are being posted to give interested researchers additional time to plan for application submissions.
Please send questions regarding specific concepts to the program contact listed in the description. Please also note that to avoid any conflicting information, once a concept has been finalized as a published RFA (or similar funding announcement), it is deleted from this early notification, concept clearance list.
- Loyalty and Reward Program to Increase Medication Assisted Treatment (MAT) Compliance
- Modeling HIV Neuropathology Using Microglia from Human iPS Cells and Cerebral Organoids
- Responding to the Opiate Crisis through Scalable, Data-Driven Justice-Behavioral Health Partnerships
- Respiratory Stimulants to Reverse Drug-Induced Respiratory Depression (RD)
- Research Coordinating Center (RCC) to Facilitate and Support the Initiative, “HIV, HCV and Related Comorbidities in Rural Communities Affected by Opioid Injection Drug Epidemics in the United States: Building Systems for Prevention, Treatment and Control Initiative” (RFA-DA-17-014) and the “Companion Laboratory Infrastructure Development Initiative” (RFA-DA-17-023)
- Pre-Exposure Prophylaxis for HIV Prevention and Treatment for Substance Using Populations
- Identifying Neural Mechanisms Linking Psychosocial Stress to Pain and Opioid Use Disorder
- Co-operative and Competitive Use of ABCD Data
- Science-Based Quality Measurement and Management Development for Opioid Use Disorder Treatment
- Medications Development to Prevent and Treat Opioid Use Disorders and Overdose
In 2015, more than 2.6 million Americans were diagnosed with opioid use disorder (OUD) and 33,000 died of overdose involving one or more opioids, a death rate which has tripled since 2000. Not enough patients have access to the gold standard of treatment, medication assisted treatment (MAT) plus behavioral therapy, and thus, increasing negative consequences including relapse.
One possible solution to increase medication and therapy adherence is through contingency management, a practice where patients are given tangible rewards to reinforce positive behaviors such as abstinence. Studies conducted in both methadone and psychosocial treatment programs have demonstrated that incentive-based interventions are highly effective in increasing treatment retention and promoting abstinence from various drugs.
Despite its efficacy, CM studies are not widely disseminated. The primary reason for the hindered dissemination is due, in part, to cost and lack of clear regulatory and reimbursement strategies. However, as a result of the digital technology coming into fruition and the passage of the 21st Century Cures Act which clarified FDA’s regulation of medical software, this may change.
Two companies have recently received key FDA approval for breakthrough digital technologies. The first, received permission to market the first mobile medical application to help treat SUDs. The device delivers cognitive behavioral therapy to patients to teach the user skills that aid in the treatment of SUD and are intended to increase abstinence from substance abuse and increase retention in outpatient therapy programs. The second, a combination product, a drug with a digital ingestion tracking systems which records that the medication has been taken.
The approval of these technologies, coupled with the high cost of relapse, has created an opportunity for the development and commercialization of contingency management as a digital therapeutic which can be used to supplement current treatment or increase medication adherence.
To develop a digital therapeutic based on the principals of contingency management that acts as a combination product to increase medication adherence or supplements existing behavioral interventions to increase drug abstinence.
Will M. Aklin, Ph.D., Division of Therapeutics and Medical Consequences
HIV-associated neurological disorders (HAND) persist in up to 50% of HIV-patients even when HIV replication is suppressed by cART. HIV does not infect neurons, but infects microglia and macrophages in the brain, causing HAND associated neuropathology. How microglia affect neurons and glia in human brains are not understood. Currently there are no effective approaches for live human brain studies or realistic HIV animal models for HIV neuropathology.
Recent technological advancements have allowed generating microglia and cerebral organoids from human iPSC lines. These microglia have been shown to be fully functional, secreting cytokines and phagocytosing neural debris, when introduced into cerebral organoids.
This initiative will support studies using human iPSC to generate cerebral organoids and microglia to study HIV neuropathology. This includes the following:
Establish iPSC lines from HIV-patients and HIV-free controls, and use these cells to generate cerebral organoids and microglial cells. Microglia can then be infected by HIV and introduced into the organoids.
Characterize and compare the morphology, neuronal composition, oligodendrocyte and astrocyte differentiation, synaptic density and other basic measures of neurodevelopment in HIV-latent, HIV-infected, and HIV-free organoids.
Study how HIV-infected microglia alter neuronal structure, physiology, and function in the brain.
Answer questions such as: How do substances of abuse impact these processes? Can genetic and genomic editing alleviate neuropathology in HAND?
Da-Yu Wu, Ph.D., Division of Neuroscience and Behavior
Responding to the Opiate Crisis through Scalable, Data-Driven Justice-Behavioral Health Partnerships
Since 1990, NIDA has funded large initiatives focused on understanding substance use treatment in the criminal and juvenile justice systems (DATOS, CJ-DATS 1, CJ-DATS 2, JJ-TRIALS, STTR-Justice). NIDA’s current large-scale justice initiative, JJ-TRIALS, will end in 2018. These initiatives have each generated important insights into how to intervene to address substance use within justice settings. The CJ-DATS MAT protocol, for example, yielded a model for developing justice-behavioral health partnerships to connect individuals exiting secure settings to MAT. JJ-TRIALS focused on the juvenile justice system and provides a model for rigorous multi-site implementation science RCTs that offer practical, actionable insights into how to improve justice-behavioral health partnerships to reduce unmet needs among justice-involved youth. JJ-TRIALS adapted ideas from HIV services cascade, leading to the development of the behavioral health services cascade. This data-driven tool is used to facilitate interagency partnerships to ensure youth with substance use needs are referred and retained in appropriate services (Belenko et al., 2017). Importantly, this tool is flexible and can easily be further adapted to criminal justice and other settings where multiple systems must collaborate to meet the needs of patients.
This initiative will support a new cooperative research program that will result in exploratory and hypothesis-driven research projects that:
- Emphasize responding to the opioid crisis with comprehensive evidence-based services matched to patient needs. The overall goal is to facilitate justice-behavioral health partnerships that provide comprehensive evidence-based services to address opioid use in justice populations. These partnerships will enhance the capacity of the justice system to respond to the opioid crisis with comprehensive evidence-based services, including the full range of MAT as well as evidence-based behavioral interventions. This collaborative approach will help improve the capacity of systems to connect patients to the right service at the right time to reduce relapse, overdoses, and recidivism.
- Utilize an implementation science framework, with an emphasis on rigorous testing of scalable, practical implementation strategies. This initiative will build on the advances made by prior NIDA justice initiatives, in particular expanding the development of the behavioral health services cascade to provide a data-driven focus on interagency collaborations between justice systems and behavioral health providers using a data-driven decision making framework to drive organizational change goals (see Belenko et al., 2017). The target will be to identify and test implementation strategies that can be scaled and advance our understanding of how to speed the pipeline from science to service.
- Emphasize technology-facilitated data infrastructure and intervention tools. Recent technological innovations offer opportunities to enhance bidirectional data sharing, data-driven goal setting and decision making within organizations, and enhanced engagement with community-based justice populations. This initiative will require proposed studies to be designed to leverage existing and newly developed technology and health information platforms to facilitate and enhance the capacity of the justice system to partner with behavioral health systems. A recent NIDA-NIJ meeting identified several opportunities for technology to facilitate progress in these ways.
Tisha Wiley, Ph.D., Division of Epidemiology, Services, and Prevention Research
The National Institute on Drug Abuse (NIDA) has an interest in reducing the impact of drug addiction on the health and well-being of the American people. At the current time, we are in a wave of mortalities based on drug-induced respiratory depression (RD). This disorder occurs when a high dose of an opioid or other sedating drug / combination, activates receptors in the brain stem, which serve to respiratory circuits. The effect is to weaken the respiratory drive to an extent that either the patient ceases to breathe, or the drive is insufficient to prevent aspiration of vomit into the lungs.
The current best pharmacological practice to counter drug-induced RD is to administer naloxone, an opioid receptor antagonist that occupies receptors, making them unavailable for opioids to activate. Until recently naloxone has proven to be an effective strategy, but today, inexpensive, high-potency opioids such as fentanyl and carfentanil are becoming commonplace in the illicit drug supply. The pharmacology and physiochemistry of fentanyl differs from morphine; it provides a very rapid onset of effect, and is both more potent and efficacious than morphine. Given that the end user of illicit opioids is frequently unaware of the exact composition of their drug purchase, these pharmacological differences are key drivers of the current wave of opioid overdoses and mortalities.
Naloxone is a competitive antagonist, it can only act to block vacant receptors and many synthetic opioids only slowly unbind from receptors. This means that to treat high potency opioid overdoses, naloxone must be provided at a high enough dose for a long period. Unfortunately, naloxone is eliminated rapidly from a patient’s circulation and so responders must remain observant and ready to repeatedly administer increasingly high doses in order to counter RD caused by synthetic opioids. In dependent opioid users, large doses of naloxone may unfortunately precipitate immediate withdrawal.
Given the assumption that economics will continue to drive the inclusion of (potentially increasingly) potent opioids in the illicit drug supply, NIDA wishes to facilitate the development of agents that can safely reverse RD without engaging opioid receptors. Pharmacologies have been demonstrated that can reverse opioid-induced RD by stimulating non-opioid sensitive components of the respiratory system. By facilitating the full exploitation and development of such agents, NIDA hopes to reduce morbidity and mortality associated opioid use, without regard to whether opioid receptors are occupied with potentially lethal concentrations of potent agonist.
To develop a lead compound and potential backup molecule (ideally from distinct structural classes) in a formulation that acts to reverse RD by mechanisms other than antagonizing the mu opioid receptor.
To demonstrate the efficacy of the lead compound in preclinical models of RD that include opioid-induced RD and / or RD induced by drugs or drug combinations that frequently cause life threatening RD in the real world. This can include alcohol, when in combination with other drugs such as benzodiazepines or opioids, or combinations of drugs that demonstrably cause significant risk of mortality in post-operative settings.
Project Activities and Expected Deliverables
The project may include medicinal chemistry to optimize the efficacy or other drug-like features of the lead compound, provided that a suitable assay system exists that both models real world situations adequately and provides sufficient through-put to allow for successful optimization.
The project may also include other studies that advance a molecule and at least one back up molecule with demonstrated efficacy, towards establishing the level of evidence of safety and efficacy required by FDA to allow clinical testing. Such studies might include preclinical efficacy and pharmacokinetic studies in a rodent and non-rodent species, manufacturing scale up chemistry, cGMP synthesis and formulation, toxicology and final formulation stability studies.
By the end of phase 1 sufficient data must exist to indicate that the medication can be administered via a route known to be safe and reliable in an unconscious individual.
The medication should reach efficacious concentrations at the site of action within a time period commensurate with the indication, i.e., to save the life of an RD patient discovered by a first responder shortly after RD has set in.
The persistence of the pharmacological action should exceed that of currently available alternatives, i.e., it should be able to reverse RD for more than four hours following a single administration.
The Phase I application must include:
- Go/no-go decision tree with quantitative, milestones
- Objective measures that demonstrate efficacy of the molecule against RD induced by several pharmacological mechanisms.
- Objective measures that demonstrate the mechanism of action (unless previously established) of pharmacological agent.
- Studies designed to address project-specific questions of feasibility.
- Detailed discussion of potential pitfalls, side effects and safety issues and how these concerns are to be mitigated.
Phase II Activities and Expected Deliverables
- Phase II involves execution and completion of studies on lead/backup molecule required to form a Drug Masterfile (DMF) sufficient to satisfy FDA IND requests for clinical testing.
- Development, submission and acceptance of the DMF by FDA CDER.
Aidan Hampson, Ph.D., Division of Therapeutics and Medical Consequences
Research Coordinating Center (RCC) to Facilitate and Support the Initiative, “HIV, HCV and Related Comorbidities in Rural Communities Affected by Opioid Injection Drug Epidemics in the United States: Building Systems for Prevention, Treatment and Control Initiative” (RFA-DA-17-014) and the “Companion Laboratory Infrastructure Development Initiative” (RFA-DA-17-023)
The purpose of this RFA is to fund a cooperative agreement that will provide support, coordination and operational infrastructure activities related to 8 UG3/UH3 cooperative agreement projects and 1 U24 cooperative agreement laboratory that were funded in August 2017. The UG3/UH3 projects are biphasic research activities that will integrate and augment available data related to opioid injection and its consequences. The initial activities funded under the UG3 will inform community responses in the UH3 projects that promote comprehensive, integrated approaches to prevent HIV and hepatitis C virus (HCV) infection, along with associated comorbidities such as hepatitis B virus (HBV) infection and sexually transmitted diseases (STDs), among people who inject drugs (PWID) in rural US communities. Integrated approaches are expected to be responsive to local needs and may include expanded access to services, stronger linkages between funding and service delivery systems, engagement of diverse stakeholders, delivery of innovative services, and/or implementation of novel policies. These projects should yield evidence of the effectiveness of community response models and best practices in responding to opioid injection epidemics that can be implemented by public health systems in similar rural communities in the US. The U24 lab supports an HCV next-generation sequencing (advanced molecular detection) using Global Hepatitis Outbreak and Surveillance Technology (“GHOST”) to be developed in collaboration with CDC’s Division of Viral Hepatitis. These cooperative agreements are interagency collaborations that include funding and participation from NIDA, CDC, SAMHSA and the Appalachian Regional Commission.
The UG3/UH3 projects are multi-disciplinary research activities combining qualitative and quantitative research methods, document review and consideration of existing data. The UH3 phases will conduct implementation research projects that promote service integration across public health and substance use. Successful projects will include collaborations with state and local health departments and local service providers, as well as the federal partners. Project coordination occurs through an Executive Steering Committee (ESC) composed of funders and project PIs. The ESC is augmented by a protocol Chair from outside the project network, who chairs meetings and provides input on project development. Successful implementation of these projects as a research program will require construction of cross-site datasets, harmonization of data, and consultation regarding research methods and statistical analysis, as well as support for meetings, logistics and construction of databases. Development of the UG3 projects has involved substantially more harmonization than originally planned will result in the potential for a unique descriptive database regarding the rural opioid epidemic. The currently projected UG3 projects also would benefit from having a harmonized data set based on data elements collected in the UG3 phase to provide comparable outcomes across different interventions.
The Research Coordinating Center (RCC) will provide support, coordination and operational infrastructure activities for the UG3/UH3 sites and the U24 lab, supporting policies and procedures for obtaining, accessing, and sharing data on participants from outside sources within the network and with the scientific community, and the planning and coordination of collaborative activities. The RCC will have the following responsibilities, performed under the guidance of the ESC:
- Organize and coordinate meetings and other functions of the ESC and the working groups established to support common activities and enhance scientific collaborations.
- Track, summarize, and report on project activities in both internal and public venues.
- Operational support for project protocols, collaborations and other projects (e.g. conduct of trainings, development of manuals of operation, maintenance of network website, communications and conference calls, convening committees and meetings, etc.)
- Establish and maintain a website for the storage and dissemination of project documents and products.
- Support research related activities (e.g. DSMP reporting, GCP/GCLP, clinical trials registration, etc.)
- Lead the development and implementation of common measures, data elements, and advanced statistical tools
- Provision of mechanisms and metrics to monitor subject screening, recruitment, retention, and dropout, and procedures for adjustment if enrollment targets are not being met
- Ensure state-of-the-art approaches to statistical methods are consistently applied across the network.
- Provision of a data sharing policy with explicit plans, procedures, milestones, and timelines to make the data and bio specimens available for access and analysis by the research community as appropriate
- Preparation of public-use files for archiving and sharing results of each study according to NIH policies
Richard Jenkins, Ph.D., Division of Epidemiology, Services & Prevention Research
Antiretroviral treatment (ART) used prophylactically in the form of pre-exposure prophylaxis (PreP; e.g., emtricitabine and tenofovir disoproxil fumarate [Truvada®]) is recommended for populations at high risk for HIV acquisition,, including individuals who have injected drugs in the past 6 months and have shared needles or works or been in drug treatment in the past 6 months. The seminal trial to date on the efficacy of PreP among injecting populations is the Bangkok Tenofovir Study, in which there were 17 HIV infections among the 1,204 participants taking tenofovir, compared with 33 infections among the 1,207 participants taking placebo (49% reduction in risk of HIV acquisition among those receiving tenofovir). The sample was recruited from methadone clinics and no data were reported on drug use or injection behavior, and no drug testing was performed (Choopanya K. et al. 2013). Consequently, the actual efficacy of PreP for active injectors, adherent methadone users or even non-injectors who actively use opiates and other drugs is unknown.
NIDA has funded surprisingly little research on the several key question related to PreP use among substance using populations The primary goal of this RFA is to examine the role of PreP in substance use trajectories and or treatments, including:
- To what degree do substance use or HIV providers recommend or adopt PreP for substance using patients at risk for HIV (e.g., injection drug use)?
- To what degree does substance use affect access and adherence to PreP?
- How does drug use interact with PrEP efficacy, including injection as well as polydrug use with substances that independently affect immune function?
- Where does PreP fit within a comprehensive program for prevention of HIV acquisition?
This concept is squarely in line with high overarching HIV/AIDs priorities (NOT-15-137):
- Reducing Incidence of HIV/AIDS, including: developing and testing pre-exposure prophylaxis candidates and methods of delivery, especially those that mitigate adherence issues; and developing, testing, and implementing strategies to improve HIV testing and entry into prevention services.
- Next generation of HIV therapies with better safety and ease of use including: developing and testing HIV treatments that are less toxic, longer acting, have fewer side effects and complications, and easier to take and adhere to than current regimens. Additionally, implementation research to ensure initiation of treatment as soon as diagnosis has been made, retention and engagement in these services, and achievement and maintenance of optimal prevention and treatment responses.
Shoshana Y. Kahana, Ph.D., Health Scientist Administrator, Services Research Branch, Division of Epidemiology, Services and Prevention Research
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 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.
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:
- Widening use of the ABCD dataset
- Enhancing rigor and reproducibility towards better predictive models
- Facilitating collaboration between clinical and computational researchers on SUD research
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.
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.
Sarah Duffy, Ph.D., Associate Director for Economics Research, Division of Epidemiology, Services and Prevention Research
Description: Given the current opioid use and overdose crisis in the country, the purpose of this Funding Opportunity Announcement is to support research that accelerates the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose. This project is part of the NIH initiative to establish a public-private partnership to address the opioid crisis via more effective and safe ways to prevent and treat opioid use disorders and overdose (https://www.nih.gov/opioid-crisis)
Application may include preclinical or clinical research studies that will have high impact and quickly yield the necessary results to advance closer to FDA approval medications that are safe and effective to prevent and treat OUDs and overdose.
The compounds to be evaluated can be small molecules or biologics. They can be tested in pre-clinical models and/or for the clinical manifestations of OUDs such as withdrawal, craving, relapse, or overdose. Applications may focus on the development of new chemical entities, new formulations of marketed medications available for other indications, or combinations of medications that hold promise for the treatment of OUDs and overdose.
Through this FOA, NIDA seeks to fast-track the discovery and development of medications to prevent and treat OUDs or opioid overdose and to advance them in the FDA's drug development approval pipeline.
Ivan Montoya, M.D., Division of Therapeutics and Medical Consequences