Developing Regulated Therapeutic and Diagnostic Solutions for Patients Affected by Opioid and/or Stimulants use Disorders (OUD/StUD) (R43/R44 - Clinical Trial Optional)

According to the Centers for Disease Control and Prevention (CDC), more than 100,000 deaths from overdose were reported from April 2020 to April 2021 alone. Data shows an increase in overdoses due to natural and semi-synthetic opioids, synthetic opioids, predominantly fentanyl, and psychostimulants, such as methamphetamine or cocaine. In fact, in the year ending in April 2021, fentanyl was the leading cause of death for adults ages 18-45, more than car accidents, suicide, COVID, and cancer. The scope and complexity of the current drug crisis are staggering, and there is an urgent need for a comprehensive effort to offer new medical products to the affected individuals, families, and communities. Scientific advances and product development based on those scientific advances can provide solutions to help overcome the crisis. For example, medical products regulated by the U.S. Food and Drug Administration (FDA), including pharmacotherapeutics and medical therapeutic and diagnostic devices, offer promising means to monitor, diagnose, and treat patients suffering from opioid use disorders (OUD) and stimulant use disorders (StUD). There are currently five pharmacotherapies approved by the U.S. Food and Drug Administration (FDA) for treating OUD and mitigation of opioid withdrawal symptoms: methadone, buprenorphine, extended-release naltrexone, naloxone, and lofexidine. While these effective medications exist, they are underutilized due, partly, to patient retention in treatment regimens, policy barriers that limit the prescription of medications approved for the treatment of OUD, and stigma around opioid agonist medications. Recent data from SAMHSA (2020) shows that only a minimal percentage of patients affected by substance use disorders, including OUD/StUD, receive any treatment. Moreover, given the diverse nature of OUD, patients may have limited responses to available medications, and additional options could benefit more patients. There are currently no FDA-approved medications for StUD, including cocaine or methamphetamine use disorders. Similarly, there are currently five medical devices intended for patients suffering from substance use disorders cleared by the FDA. The list includes percutaneous or transcutaneous nerve stimulation devices designed to reduce symptoms of opioid withdrawal in conjunction with standard medications. The FDA also approved software as medical device solutions, also known as digital therapeutics, intended to deliver behavioral therapy to SUD patients as an adjunct to clinician-supervised treatment. While these technologies offer essential solutions for patients affected by SUD, significant constraints still limit patients' access. Examples of such restrictions include lack of FDA-cleared devices with specific indications for patients affected by StUD, lack of devices intended as a stand-alone treatment, lack of devices approved for use in patients under 18 years of age, and reduced adoption due to limited payor reimbursement. Additionally, existing FDA-cleared diagnostic devices for OUD/StUD are limited, and there are no wearable devices intended to monitor or diagnose OUD/StUD. This funding opportunity announcement strives to contribute to the emergence of new solutions by seeking applications to conduct research and development activities for novel medical products which would address the needs of patients suffering from OUD/StUD. Investigators and developers of biomedical technologies that lead to the prevention, monitoring, diagnosis, and treatment of OUD/StUD are highly encouraged to apply. Applications received under this FOA may fall within two FDA-regulated technical/scientific areas: (1) pharmacotherapeutics (small molecules and biologics) and (2) medical therapeutic and diagnostic devices, including software as a medical device. Small business companies that developed currently marketed technologies or are developing technologies for different indications and are interested in demonstrating that their FDA-regulated product has a potential application in the OUD/StUD space are especially encouraged to apply. Area 1: OUD/StUD pharmacotherapeutics Projects proposed under Area 1 may include but are not limited to developing the following categories of pharmacotherapeutics for OUD/StUD: Small or large molecule agents. Biologics, including antibodies and therapeutic vaccines. Natural products. Longer-acting formulations of existing addiction medications. Longer-acting formulations of agonists or antagonists, e.g., longer-lasting naloxone formulations and new medications. Advanced drug delivery systems. Development and characterization of biomarkers. Pharmacotherapeutics modalities other than those listed above may also be considered. Applications may include the following activities and steps in the R&D process: Target identification or validation. Assay development, confirmation of hits, and hit to lead studies. Lead optimization of compound(s) or biologic(s). In vivo pharmacokinetic, pharmacodynamic, and toxicology studies. In vivo preclinical efficacy studies. Formulation development studies. Process development to support clinical manufacturing (e.g., scale-up feasibility). Other activities leading to the selection of a development candidate. Specific proposed objectives will vary among applications. Appropriate objectives in Area 1 include but are not necessarily limited to the following examples: Development of in vitro pharmacological assays that cover a broad range of targets, including receptors, ion channels, transporters, enzymes, and secondary messengers to identify lead compounds, to define the mechanism of action, and to identify off-target activities. Completion of in vivo preclinical efficacy studies. Demonstration of acceptable safety (e.g., toxicity in rodents and/or large animals). Manufacturing of acceptable clinical dosage form [e.g., meeting Good Manufacturing Practices (GMP) quality]. Clinical Proof of Concept (Phase I and/or Phase II clinical trials). Applicants should propose and conduct activities that will eventually lead to the filing of an Investigational New Drug (IND) application, as well as clinical studies to support the filing of either a New Drug Application (NDA) or a Biological License Application (BLA). Applications may include biomarkers that assess the probability of OUD/StUD or allow an assessment of the treatment trajectory in patients under treatment for OUD/StUD. Recently issued FDA guidance on OUD: “endpoints for demonstrating effectiveness of drugs for treatment guidance for industry” (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/opioid-use-disorder-endpoints-demonstrating-effectiveness-drugs-treatment-guidance-industry) is a valuable resource in guiding R&D activities. For OUD, the proposed drug product must have a clear advantage over existing competing products and a clearly defined path with the ultimate goal of commercialization. Therefore, applicants are encouraged to establish a Target Product Profile (TPP) for the proposed products (https://wayback.archive-it.org/7993/20190907022334/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/target-product-profile-strategic-development-process-tool). Area 2: Medical therapeutic and diagnostic devices, including software as a medical device Projects proposed under Area 2 may include, but are not necessarily limited to, research and development of the following categories of medical devices: Imaging technologies for investigating brain function and enhancing the diagnosis of OUD/StUD. Devices that directly diagnose and reduce craving and withdrawal symptoms or increase retention in outpatient therapies. Therapeutic devices (e.g., neuromodulation) intended to improve OUD/StUD treatment outcomes and recurrence prevention. Devices, including digital therapeutics, intended to identify and treat newborns exposed to opioids and stimulants, along with other drugs, to improve both short- and long-term developmental outcomes; novel approaches to managing neonatal abstinence syndrome (NAS). Devices intended for the treatment of pediatric patients (e.g., neonates, infants, adolescents) including use of extrapolation methods to treat pediatric patients following FDA’s pediatric extrapolation guidance:https://www.fda.gov/regulatory-information/search-fda-guidance-documents/leveraging-existing-clinical-data-extrapolation-pediatric-uses-medical-devices. Devices, including digital therapeutics, with treatment indications for pregnant mothers suffering from OUD/StUD. In vitro diagnostic assays such as Point-of-Care analytical tools for blood, saliva, or urine (e.g., lab-on-a-chip biosensors that allow remote performance of chemical or biological assays outside of a laboratory environment). Stand-alone or adjunctive digital therapeutics (e.g., Software as a Medical Device, Software in Medical Device) focused on behavioral health interventions to diagnose, treat, prevent, and mitigate OUD/StUD. Devices, including wearables and connected digital therapeutics at point-of-care, intended to detect, diagnose, and treat opioid-induced respiratory depression. Data science and cloud-based technologies empowered by artificial intelligence intended to collect, integrate, analyze, and visualize multimodal data related to diagnosis/treatment of OUD/StUD, including disorder progression and risk of recurrence. Technologies that integrate sensors, wearables, environmental and social factors to analyze behavior patterns, social interactions, ecological momentary assessment of triggers, and identifying stress responses to personalize just-in-time treatment interventions. For projects in Area 2, applicants should propose activities that will lead to the successful filing of FDA premarket application for clearance/approval (e.g., 510(k) or DeNovo application, Premarket Approval (PMA) application). Such activities include early engagement with the FDA Center of Devices and Radiological Health (CDRH) via the presubmission program to receive feedback on proposed intended use, preclinical testing, and study design protocols. Please see for reference the FDA Q-submission guidance:https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program. Additional specific proposed activities may include, but are not limited to, the following examples: Studies supporting an Investigational Device Exemption (IDE) application, where applicable, for significant risk devices (see https://www.fda.gov/medical-devices/investigational-device-exemption-ide/ide-application). Process development for manufacturing. Non-clinical safety studies (e.g., toxicology, biocompatibility, electromagnetic compatibility, electrical safety). Safety studies in animal models. Clinical trials. Non-Responsive Activities The following activities will be considered non-responsive: Applications solely focused on disorders other than OUD/StUD (e.g., Alcohol Use Disorders), as defined in the DSM-5. Applications pursuing non-FDA-regulated products. Applications pursuing FDA-regulated medical products for pain as a sole focus without addressing OUD/StUD monitoring, diagnosis, treatment, overdose prevention, and/or reversal. Words Matter Drug addiction is a chronic but treatable disorder with well-understood genetic and social contributors. NIDA encourages preferred language that accurately describes addiction and substance use in all submitted materials without perpetuating stigma and bias. Research shows that using person-first language—such as "person with a substance use disorder"—instead of "substance abuser" or "addict" can reduce negative associations and punitive attitudes among clinicians and researchers. Further, the term "substance abuse" has no clinical relevance, as it is no longer included in the DSM-5 terminology. Instead, NIDA encourages the use of "addiction" or "substance use disorders" or other specific terminology, such as "opioid use disorders," "cocaine use disorders," as included in the DSM-5. In addition to using person-first language, NIDA recommends avoiding the term "substance abuse" and its derivatives in favor of "use," "misuse," or "use disorder(s)" where appropriate. Similarly, "abuse potential" may be replaced with "addiction liability." NIDA encourages using the term "medications for opioid use disorder" (MOUD) instead of "medication-assisted treatment" (MAT) or "opioid substitution therapy" (OST) when referring to medications prescribed for the treatment of OUD. The term MOUD appropriately frames these life-saving medications as effective, frontline treatments. In contrast, the term MAT implies that medication should have a supplemental or temporary role in treatment. OST reinforces the misconception that MOUD "substitutes" one drug for another instead of supporting recovery. The terminology shift to MOUD aligns with the way other psychiatric medications are understood (e.g., antidepressants, antipsychotics) as critical tools central to a patient's treatment plan. These small but powerful substitutions may help address stigma in patients and study participants, which research shows reduces willingness to seek and accept treatment, among other adverse health outcomes. For more information on preferred language in addiction care, visit NIDAMED: https://www.drugabuse.gov/nidamed-medical-health-professionals/health-professions-education/words-matter-terms-to-use-avoid-when-talking-about-addiction. The SBIR program is a phased program. An overall objective of the SBIR program is to increase private sector commercialization of innovations derived from federally supported research and development. The main objective in SBIR Phase I is to establish the technical merit and feasibility of the proposed research and development efforts. In contrast, the SBIR Phase II objective is to continue the R&D efforts to advance the technology toward ultimate commercialization. Beyond the scope of this FOA, it is anticipated and encouraged that the outcomes of successful SBIR projects will help attract strategic partners or investors to support the ultimate commercialization of the technology as a publicly available product or service. This FOA invites four types of applications: Phase I. The objective of Phase I is to establish the technical merit, feasibility, and commercial potential of the proposed R/R&D efforts and determine the quality of performance of the small business awardee organization before proceeding to Phase II. Phase II. The objective of Phase II is to continue the R&D efforts initiated in Phase I. Funding is based on the results achieved in Phase I and the scientific and technical merit and commercial potential of the project proposed in Phase II. Therefore, NIDA evaluates that investigators have established technical and commercial feasibility in Phase I before deciding on Phase II support. Fast Track. In an NIH SBIR fast-track both Phase I and Phase II are submitted and reviewed as one application to reduce or eliminate the funding gap between phases. Fast-Track (Phase I/ Phase II) applications should include a clear rationale of the technical and commercial feasibility of the proposed approach and technology in the OUD/StUD area; demonstrate a high probability of commercialization; include clear, appropriate, measurable, clinically meaningful milestones to be achieved before initiating Phase II; and indicate potential Phase III support/interest (non-SBIR) from future commercialization partners. The objective of Phase II (as a part of Fast Track applications) is to continue the R&D efforts initiated in Phase I to advance technologies to potential commercialization. Projects proposed for Phase II are based on the results achieved in Phase I (or equivalent) and aim to demonstrate scientific and technical merit and commercial potential. Therefore, NIDA evaluates that investigators have established technical and commercial feasibility in Phase I and that proposed milestones are met before deciding on Phase II support. Direct to Phase II. NIH can issue a Direct to Phase II award for a small business that has already demonstrated scientific and technical merit and feasibility but has not received a Phase I award for that project. The NIH Direct to Phase II will accept Phase II submissions regardless of the funding source for the proof of principle work on which the proposed Phase II research is based. Small businesses eligible to submit Phase II applications for projects supported with a Phase I SBIR award are expected to submit the regular Phase II application as a "Renewal" application based on the awarded Phase I SBIR or STTR project. Only one Phase II application may be awarded for a specific project supported by a Phase I award. First-time applicants may submit a Phase I, Fast-Track, or Direct-to-Phase II application. Special Considerations National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects: The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential and dependence or addiction liability to human subjects. Therefore, potential applicants are encouraged to obtain and review these recommendations of the Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Web site at http://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects. Points to Consider Regarding Tobacco Industry Funding of NIDA Applicants: The National Advisory Council on Drug Abuse (NACDA) encourages NIDA and its grantees to consider the points it has set forth concerning existing or prospective sponsored research agreements with tobacco companies or their related entities and the impact of acceptance of tobacco industry funding on NIDA's credibility and reputation within the scientific community. For additional details, please see https://www.drugabuse.gov/about-nida/advisory-boards-groups/national-advisory-council-drug-abuse-nacda/points-to-consider-regarding-tobacco-industry-funding-nida-applicants. Data Harmonization for Substance Abuse and Addiction via the PhenX Toolkit: NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org). Please see NOT-DA-12-008 (http://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html) for further details. Establishment of a Standard delta-9-THC Unit to be used in Research: Applications proposing research on cannabis or its main psychotropic constituent delta-9-THC are required to measure and report results using a standard delta-9-THC unit in all applicable human subjects’ research. The goal is to increase the comparability across cannabis research studies. A standard delta-9-THC unit is defined as any formulation of cannabis plant material or extract that contains 5 milligrams of delta-9-THC. A justification should be provided for human research that does not propose to use the standard unit. Please see https://grants.nih.gov/grants/guide/notice-files/NOT-DA-21-049.html for additional details.