A. Overview While there are thousands of rare diseases, the number of underlying etiologies is much smaller. Moreover, many disease etiologies underly multiple traditional diseases. This is most readily seen for rare monogenic diseases, where the most common etiologies include premature termination codons, protein misfolding, and abnormal RNA splicing. Other examples of rare disease shared molecular etiologies include, but are not limited to, triplet repeat expansions, epigenetic dysregulation, and signallopathies (e.g., mTOR-opathy, RAS-opathy, etc.). Small businesses are developing drugs targeting shared molecular etiologies. However, the standard approach in clinical trials is to focus on one disease at a time, with the choice of diseases often based on prevalence. This approach inevitably results in clinical trials in only the most common rare diseases, with the exclusion of patients with the least common diseases, even though the scientific rationale for the use of the drug may be as strong, if not stronger, in the lower prevalence rare diseases. One potential solution to this problem is to adapt the basket trial approach that has been developed for tissue agnostic oncology drugs, i.e. for clinical trials of drugs that target molecular defects common to anatomically different cancers. Notably, this approach has already resulted in regulatory approvals from the US FDA (https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions). One potentially important difference between oncology and rare diseases, however, is the relative diversity of clinical outcome measures in rare diseases compared to cancer. The purpose of this FOA is to provide support for basket clinical trials of drugs targeting shared molecular etiologies in more than one rare disease, and in the process to identify and overcome challenges in adapting the oncology basket trial model to rare diseases. Projects proposed for this FOA will require individuals with expertise in carrying out clinical trials in rare diseases. Applicants are strongly encouraged to collaborate with investigators at academic institutions and negotiate an agreement for carrying out the proposed clinical trials. NCATS will give priority to projects involving clinical investigators who are part of the Rare Disease Clinical Research Network (RDCRN) and which focus on diseases under study in the RDCRN. See https://www.rarediseasesnetwork.org/ for additional information. The funding opportunity will utilize a Small Business Innovation Research (SBIR) U44 cooperative agreement to support Investigational New Drug (IND) enabling studies, including translational bench/in vitro, and animal studies as necessary, to support the preparation and submission of the IND. This cooperative agreement will also support the subsequent small clinical trial, involving at least two different rare diseases. It is expected the immediate next steps following completion of the small clinical trial supported under this cooperative agreement will be: future clinical trial design decisions made based on the information and data collected; a larger clinical trial that will lead to a marketing application; or a marketing application if only a small clinical trial is needed. Applicants should have strong supporting data. Innovation and impact will in part be judged on presenting a credible path towards U.S. regulatory submission/Institutional Review Board (IRB) approval at the end of the SBIR. All projects (other than Direct to Phase II applications) will be Fast-Track applications which include both SBIR Phase I and Phase II components. Phase I of the Fast-Track will support translational activities leading to submission of an IND to the FDA, as well as an IRB application. Phase II of the project period will support the clinical trial in rare disease patients. The duration of Phase I of the Fast-Track will depend on the maturity of the project at entry. Only those Phase I projects that have met specific criteria (see below) will be eligible for transition to Phase II of the Fast-Track after NIH administrative review. Phase II of the Fast-Track will support a small clinical trial, as described above. The SBIR U44 cooperative agreement mechanism is milestone-driven and involves significant input from NIH program staff regarding project and milestone planning, monitoring of research progress, and go/no-go decision-making. NIH staff may also provide assistance to investigators in familiarizing them with the regulatory development process and the criteria needed to advance drugs targeting shared molecular etiologies in rare disease patients into clinical trials. Applicants are strongly advised to contact the Scientific/Research contact listed below prior to submission. B. Research Scope Projects must focus on a clinical trial of a single drug targeting a shared molecular etiology that underlies at least two different rare diseases. Examples of such shared molecular etiologies are given above. Including at least two different diseases in the clinical trial is requirement for support under this FOA. Entry criteria: For entry to the program, projects should have: Comprehensive supporting data based on bench, in vitro, and/or in vivo models supporting efficacy in the intended rare disease patient population and indication. Identified at least two different diseases for inclusion in the clinical trial. For both diseases, one or more clinically meaningful outcome measures, based on input from both clinicians and patients, and / or supporting literature, should be specified. A compelling case for a successful IND submission of the clinical trial at the end of SBIR Phase I. Applicants are encouraged, but not required, to consult with FDA via a Pre-Submission meeting prior to applying for funding through this grant mechanism. Fast-Track Phase I scope: Examples of studies that may be proposed during SBIR Phase I include, but are not limited to: Bench-top and animal testing to demonstrate proof of concept and safety. Activities to become current Good Manufacturing Practice (GMP) compliant. Regulatory activities, including pre-submission meetings with FDA. Limited clinical data, e.g. safety studies in human volunteers, is also allowable during SBIR Phase I if it is necessary to support the IND submission for the small clinical trial conducted in SBIR Phase II. Fast-Track Phase II scope: Phase II will support the clinical trial of a single drug targeting a shared molecular etiology, including patients from at least two different diseases. Examples of activities non-responsive to this FOA include: Basic research and studies of disease mechanisms. Animal model development: all necessary in vivo models must be well established and characterized, and available to the applicant. Development of outcome measures or natural history studies. A clinical trial of the drug in a single disease. Clinical trials in cancer. However, rare diseases which have an increased risk of cancer are allowed, as long as the primary clinical outcome measure is not carcinogenesis or tumor progression. Stand-alone SBIR Phase I or Phase II applications. Delayed onset studies that do not have a clinical trial described in the submission. C. Milestones Applications must propose one or more milestones associated with each objective in each year of the project. Milestones are goals that measure success and efficacy that can be used for go/no-go decision-making for the project and should have quantitative criteria associated with them (see Section IV.2 for details). Applications should include quantitative milestones and go/no-go decision points. Projects must include milestones to be used for measuring success in achieving each of the research plan’s objectives. NIH program staff will contact the applicant to discuss and negotiate the proposed milestones and any changes suggested prior to funding the application.The final agreed upon and approved milestones will be specified in the Notice of Award (NoA). Progress towards achievement of the final set of milestones will be evaluated by NIH program staff. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project will be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, portfolio balance and program priorities, competitive landscape, and availability of funds. NIH encourages increasing the rigor and reproducibility of observed results.In some cases, conducting additional critical experiments will be important for NIH to have confidence in making a funding decision.Therefore, NIH Program Staff may recommend additional experiments that should be conducted prior to or during the award. Any additional experiments would be negotiated with the PI as a new or revised milestone of award. In some cases, these studies could be supported with additional funds. Fast-Track Phase I to Phase II transition: An administrative review will be conducted by program staff to decide whether a SBIR Phase I project will be transitioned into SBIR Phase II based on the following: Successful achievement of the defined milestones for SBIR Phase I of the project Obtaining an IND for the clinical trial from FDA Likelihood of success in carrying out the clinical trial Program balance Availability of funds IRB approval(s) Submission of the final clinical protocol and supporting documents to NIH for administrative review, and notification of approval by NIH Agreement on updated timeline, milestones and budget for the clinical trial. D. Pre-application Consultation As a U44 cooperative agreement, NIH program staff will be involved in the planning and execution of the projects.Applicants are strongly encouraged to consult with NIH Scientific/Research staff when planning an application. Early contact provides an opportunity for Scientific/Research staff to provide further guidance on program scope, goals, and developing appropriate milestones, and also to determine whether the proposed project meets the goals of the FOA. Applicants should contact NCATS Scientific/Research staff at least 10 weeks before a receipt date.