Novel Drug (DDT) and Medical Device Development Tools (MDDT) to Help Expedite Creation and Regulatory Approvals of New Therapies for Substance Use Disorders (SUD) (R41/R42 Clinical Trial Optional)

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 affected individuals, families, and communities. Scientific advances and product development based on those advances can provide solutions to help overcome the crisis. Medical products regulated by the U.S. Food and Drug Administration (FDA), including pharmacotherapeutics and therapeutic or diagnostic medical devices, offer promising means to monitor, diagnose, and treat patients suffering from substance use disorders (SUD). However, there are currently limited therapeutic and diagnostic options available, leaving a significant gap between existing therapies and meeting the needs of patients and clinicians. Part of the bottleneck with medical product approvals stems from the lack of appropriate regulatory guidance and associated tools available to support research, development, clinical study, and subsequent approval of therapeutics and diagnostics for patients with SUD. Additional factors include stigma surrounding SUD patients and treatment options, lack of broadly accepted clinical endpoints, lengthy and expensive product development timelines, and overall reluctance from industry to engage in the SUD space for these reasons. All medical products including drugs, biologics, and devices that are intended for use as a diagnostic or treatment in patients require approval from the FDA before being marketed in the United States. Large amounts of NIH funding are already spent studying SUD animal models, biomarkers, and clinical outcomes; however, these tools are not currently embraced by regulators. There is a lack of comprehensive understanding of how these research tools are used and what the outcomes mean in the context of regulatory review of SUD studies. Successful approval of future SUD therapeutic and diagnostic products will require better understanding of SUD research tools, which can be achieved through the FDA tool qualification programs aimed at supporting assessment of future SUD regulatory submissions. In order to support medical research tool development and qualification, the FDA has established two programs: the Drug Development Tool (DDT) qualification program (website: https://www.fda.gov/drugs/development-approval-process-drugs/drug-development-tool-ddt-qualification-programs) which is managed by the Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER), and the Medical Device Development Tool (MDDT) program managed by the Center for Devices and Radiological Health (CDRH) (website: https://www.fda.gov/medical-devices/science-and-research-medical-devices/medical-device-development-tools-mddt). Additional tools that fall beyond the scope of the existing DDT framework (e.g. novel pharm/tox assays, AI-based algorithms for drug studies) can alternatively be submitted to the Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program (website: https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/innovative-science-and-technology-approaches-new-drugs-istand-pilot-program). These programs are designed specifically to facilitate medical product development and evaluation by promoting innovation and providing a more efficient framework for regulatory interactions. Once qualified by the FDA, the tool can be used within the qualified Context of Use (COU) to support any regulatory submission for drugs/biologics (DDT) and medical devices (MDDT) without submission of additional information to justify the use of the DDT or MDDT. DDTs are methods, materials, or measures that have the potential to facilitate drug development and regulatory review. A DDT and its proposed COU can be relied upon to have a specific interpretation and application in drug development and regulatory review. DDTs fall into one of three categories: biomarkers, clinical outcome assessments, and non-clinical assessment methods or models. Similarly, MDDTs are methods, materials, or measurements used to assess the effectiveness, safety, or performance of a medical device. A MDDT is scientifically validated and can be qualified for use in device evaluation and to support regulatory decision-making within a specified context of use. MDDTs fall into one of three categories: clinical outcome assessments, assessments of biomarkers, and non-clinical assessment methods or models. The DDT and MDDT programs offer opportunities to obtain formal FDA qualification for the tool which can be subsequently used to support the assessment of future SUD-related drug and device regulatory submissions. The new tools that FDA has “qualified” (or accepted) can be relied upon to have a specific interpretation and application in medical product development and regulatory review. Notably, qualified tools can be commercialized and used by any future researchers to speed up drug and device development and evaluation. Examples of existing qualified tools include validated patient reported outcome measures for various conditions and non-clinical assessment tools for medical device evaluation. The database for DDTs can be found at https://fda.force.com/ddt/s/ and the list of qualified MDDTs can be found at https://www.fda.gov/medical-devices/science-and-research-medical-devices/medical-device-development-tools-mddt. However, neither the DDT nor MDDT programs currently includes any qualified tools that have a COU specific to SUD. The national SUD crisis is time-sensitive and requires action to accelerate research and approval of new treatment options. By supporting development of DDTs and MDDTs, this FOA will help expedite approval of novel drugs and devices by establishing pre-approved tools that grantees can utilize in their product development and testing. These tools will assist companies to address the urgent need for safe and effective novel solutions for SUD patients and represents an important and timely opportunity. Specific Areas of Research Interest Area 1: Drug Development Tools (DDT) Details regarding Drug Development Tool application and qualification can be found in the corresponding FDA Guidance Document here https://www.fda.gov/media/133511/download. The information below comes from the guidance document and provides an overview of the types of tools that will be considered for the DDT program. Details about the three types of DDTs (Biomarkers, clinical outcome assessments, and non-clinical assessment methods) are described below. Biomarkers are defined as biological characteristics objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention. Examples of biomarkers can include: molecular biomarker histologic biomarker radiographic (imaging) biomarker physiologic characteristics Clinical outcome assessments (COAs) are a measurement of a patient’s symptoms, a patient’s overall and mental state, or the effects of a disease or condition on how the patient functions. A COA may be used to determine whether a drug has demonstrated a clinical benefit. Examples of COAs include: patient-reported outcome measures (PRO) clinician-reported outcome measures (CRO) observer-reported outcome measures (ObsRO) performance outcome measures (PerfO) Animal models developed and intended for use in the adequate and well-controlled animal efficacy studies that serve as substantial evidence of effectiveness for drugs developed under the regulations commonly referred to as the Animal Rule (https://www.fda.gov/media/88625/download). Area 2. Medical Device Development Tools (MDDT) Details regarding Medical Device Development Tool description, application, and qualification can be found in the corresponding FDA Guidance Document https://www.fda.gov/media/87134/download. The information below comes from the guidance document and provides an overview of the types of tools that will be considered for the MDDT program. Details about the three types of MDDTs are described below. Clinical outcome assessments (COAs) that produce a score, in addition to clearly defined methods and instructions for administering the tool, a standard form for data collection, and well-documented methods for scoring, analysis, and interpretation of results in the targeted patient population. Examples of COAs include: patient-reported outcome measures (PRO) clinician-reported outcome measures (CRO) observer-reported outcome measures (ObsRO) performance outcome measures (PerfO) Biomarker tests are a test or instrument used to detect or measure a biomarker. It is a defined characteristic that is objectively measured and evaluated as an indicator of normal biological process, pathogenic process, or response to therapeutic intervention. Examples of biomarkers can include: susceptibility/risk biomarker diagnostic biomarker monitoring biomarker prognostic biomarker predictive biomarker pharmacodynamic/response biomarker safety biomarker Non-clinical assessment models developed to measure or predict a parameter of interest which can include the following: in vitro (bench) model ex vivo model animal model computational model Endpoints for OUD Other research and development (R&D) activities needed to meet the requirements and expectations of the relevant regulatory agencies may also be proposed, as necessary and required for commercialization. The recently issued "FDA guidance on Opioid Use Disorder: 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 useful resource in guiding R&D activities in SUD. 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 STTR program is a phased program. An overall objective of the STTR program is to increase private sector commercialization of innovations derived from federally supported research and development. The main objective in STTR Phase I is to establish the technical merit and feasibility of the proposed research and development efforts. In contrast, the STTR 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 STTR 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 three 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 SUD 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. First-time applicants may submit a Phase I, or a Fast-Track 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-subject 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. Non-Responsive Activities Applications to this FOA must include activities that are intended to support development of a tool that can be submitted to the Drug Development Tool program, Medical Device Development Tool program, or Innovative Science and Technology Approaches for New Drugs pilot program as defined above. See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.