Enabling SUD Digital Therapeutics Research to Improve Payor Adoption (R44- Clinical Trial Only)

Purpose and Research Objectives Substance use disorders (SUDs) profoundly affect nearly every aspect of society. Drug and alcohol use in the United States costs $1.4 trillion in economic loss and societal harm annually. This includes $578 billion in economic loss and $874 billion in societal harm through quality-of-life adjustment and premature loss of life. There are safe and effective FDA-approved pharmacological treatments for tobacco and opioid use disorders, but reaching long-term remission remains challenging. Moreover, during the COVID-19 pandemic, traditional methods of delivering in-person treatment by trained professionals have demonstrated limitations related to treatment access. Therefore, additional tools in the SUD treatment armamentarium are urgently needed. Digital therapeutics (DTx) represent a new opportunity to address this significant public health challenge. In context of this FOA, the White House Office of National Drug Control Policy (ONDCP) has recently identified “reimbursement for digital treatment for addiction” as the priority in expanding access to evidence-based treatment. DTx is evidence-based therapeutic interventions enabled by high-quality software programs, aiming to prevent, manage, or treat a medical disorder or disease. DTx are used as a new therapeutic modality for the prevention, management, or treatment of chronic, behavior-modifiable diseases, including SUDs. As many of these indications are currently treated with an evidence-based behavioral or psychological mode of management, DTx, in its simplest form, allows patients to utilize services, that were previously only offered in-person, through an adjunct digital product. DTx may also take different patient-facing digital forms, such as smartphone applications, videogames, virtual reality programs, etc. Clinical evidence and real-world outcomes are required for all DTx medical products. DTx products must be reviewed and cleared or certified by regulatory bodies, as required to support product claims of risk, efficacy, and intended use. Similar to canonical biopharmaceuticals and medical devices, DTx undergo regulatory review and are cleared or approved by the U.S. Food and Drug Administration (FDA) and are either available as OTC or prescribed by physicians (e.g. "prescription digital therapeutics," or PDTx). DTx are used independently or as combination products, in concert with medications, devices, or other therapies to optimize patient care and health outcomes. DTx incorporate advanced technology in addition to best practices relating to design, clinical validation, usability, and data security. As of today, 6 PDTx have been authorized and dozens more are in the pipeline, signaling a growing investment in this space. Increased awareness and knowledge of PDTx among patients, providers, payers, and other key stakeholders will help drive uptake and ensure that opportunities for access are optimized for this new treatment modality. DTx stands apart from the Digital Medicine (DM) approaches, which include evidence- based software and/or hardware products that measure and/or mediate in the service of human health, and Digital Health (DHT) approaches, which includes technologies, platforms, and systems that engage consumers for lifestyle, wellness, and health-related purposes; capture, store or transmit health data; and/or support life science and clinical operations. While clinical evidence is required for DM products, the requirements for regulatory oversight may vary. DHT typically do not require clinical evidence, do not meet the regulatory definition of a medical device and do not require regulatory oversight. This FOA is intended to provide research support neither for DM nor DHT approaches. While a number of digital therapeutics have gone through the regulatory process and successfully secured an FDA marketing approvals, DTx manufacturers often experience several additional hurdles ahead, including physician uptake, building pathways to reimbursement, and, importantly, patient acceptance. Usually, after FDA approval or clearance, public and private organizations that pay for health care (payors) and the professionals who provide health care (providers) decide whether to cover, pay for, or use a DTx. Often, the data submitted by medical device/DTx manufacturers to demonstrate safety and effectiveness to the FDA may not be sufficient to meet the needs of payors to make coverage determinations. As a result, after FDA approval or clearance, there may be a delay in coverage, payment and use decisions that may ultimately delay patient access to medical devices/DTx. The recommendations for DTx for OUD developers to collect more robust evidence of the clinical effectiveness and broader impact of new DTx were recently published. In addition to evidence on safety and effectiveness in the short term, collection of additional data was suggested, for example, the durability of beneficial clinical effects, the impact on health care utilization, the impact on clinician productivity, the usability as measured by clinician and patient experience, the security of IT components, the generalizability of results to diverse patient populations and health systems, and the scalability to larger populations. Additional considerations for DTx coverage decisionmaking are expectation that clinical evidence of a digital therapeutic product will be reviewed in comparison to standards of care and will demonstrate that DTx improves quality of care. As with traditional drug therapies and biologics, evidence of cost-effectiveness is also important to support payors’ coverage decisions. In support of achieving coverage, FDA's Center for Devices & Radiological Health (CDRH) established the Payor Communication Task Force (https://www.fda.gov/about-fda/cdrh-innovation/payor-communication-task-force ) to facilitate communication between device manufacturers and payors to potentially shorten the time between FDA approval or clearance and coverage decisions. By communicating earlier in development porcess, DTx manufacturers may design their clinical trials to produce the data required for regulatory approval or clearance and for positive coverage determinations, which may expedite patient access. Payors include public payors, such as Centers for Medicare & Medicaid Services (CMS), private health plans, health technology assessment groups, and others who provide input into coverage, procurement, and reimbursement decisions. Understanding and overcoming obstacles to effective reimbursement of DTx is a key element to movement of DTx into the clinical practice and to the patients. Focused research activities illustrating the rigor of DTx product development and clinical testing, as to be similar to traditional prescription therapeutic products, is crucial in achieving acceptance from payors, clinicians, and patients. Overcoming the DTx challenges in coverage and reimbursement, using evidence generated in FDA-required randomized controlled trials will enable broader access and utilization. Specific Areas of Research Interest As more DTx gain FDA marketing approvals, they still face hurdles ahead in getting insurance reimbursement and garnering adoption among patients and physicians. In this FOA, the engagement with FDA's Center for Devices & Radiological Health (CDRH) Early Payor Feedback Program to obtain payor input on clinical trial design or other plans for gathering clinical evidence needed to support positive coverage decisions is strongly encouraged and will be evaluated during the peer review. The research projects supported by this FOA could include, but not limited to, the following: Clinical trials; clinical trial designs can be developed in coordination with the FDA to support a DTx’s safety, effectiveness and other plans for gathering clinical evidence needed to support positive coverage decisions; Research to address the considerations of cybersecurity and data rights as the preconditions for the mass adoption of DTx; cybersecurity design controls; Research to integrate the role of the patient and/or the caregiver, e.g. as a user, as a tester, as a design partner; Research to address the product designs that engage patients over long time periods, particularly, for older patients that may be less comfortable with smartphones or tablets; Research to assure that DTx fit into prescribing physicians' workflows; Post marketing surveillance studies. This FOA invites two types of applications from small businesses: Fast-Track: The fast-track process allows the applicant to submit both Phase I and Phase II in one application for review. The Fast -Track mechanism can minimize the funding gap between phases but requires a fully developed Phase II application/plan at the time of submission. Direct to Phase II: If applicant’s project has already demonstrated feasibility, but the applicant has not received a Phase I SBIR or STTR previously, the applicant can apply for a Direct to Phase II award and bypass Phase I. Special Considerations 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. 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. 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.