How to Win Clinical Studies of Orphan Products Addressing Unmet Needs of Rare Diseases (R01) Clinical Trials Required (RFA-FD-23-001)

Section V. Application Review Information 1. Criteria Only the review criteria described below will be considered in the review process. General Information FDA grants management and program staff will review all applications sent in response to this funding opportunity announcement. To be responsive, an application must be submitted in accordance with the requirements of this notice. Applications found to be non-responsive will receive notice that the application will not be reviewed. Program Responsiveness Review Criteria The following criteria will be used to decide whether or not an application is responsive to this RFA. 1. Applications must propose clinical trials intended to provide safety and/or efficacy data for rare diseases or conditions. Applications must use the generic name of the proposed product(s). 2. The requested time must not exceed 4 years. 3. The Rationale Section of the Research Strategy must contain information documenting that the disease or condition to be treated meets the definition of a rare disease or condition, as defined in 21 U.S.C. 360ee. FDA generally considers drugs, devices, and medical foods potentially eligible for grants under the OPD grant program if they are indicated for a disease or condition that has a prevalence, not incidence, of fewer than 200,000 people in the United States (or in the case of an acute disease (i.e., less than 1 year duration), the annual incidence of the disease must be less than 200,000 per year; or in the case of a vaccine or diagnostic, information to support that the product will be administered to fewer than 200,000 people in the United States per year). Applications may be considered for the use of a product in an orphan subset of a non-rare disease or condition when the applicant can explain based on a characteristic or feature of the product (e.g., mechanism of action, toxicity profile, prior clinical experience) why the product will be limited to use in the subset of question. An orphan subset is not based on an unmet need, or how a sponsor may wish to study or indicate a product. The explanation for the orphan subset must make it clear to OOPD that the product would not be appropriate in the disease or condition outside of the subset, including pediatric subpopulations. Diagnostics and vaccines are considered potentially eligible for such grants only if the U.S. population to whom they will be administered is fewer than 200,000 people in the United States per year. Prevalence calculations should be provided along with citations. For studies proposing to assess multiple rare diseases, supportive prevalence data for each rare disease is required. If a designation by the Office of Orphan Products Development has been received by the institution submitting the grant for the drug for the disease subject to the grant, the designation number and date of designation should be provided in this section. 4. There must be an explanation in the Rationale Section of the Research Strategy of how the proposed clinical trial will support of a new indication or change in labeling of a product(s). 5. To support a new indication or change in labeling, the study protocol proposed in the grant application (including studies of already approved products evaluating new orphan indications) must comply with the applicable regulations in 21 CFR 312 for drugs and biologics and 21 CFR 812 for devices, with the exceptions noted below for medical foods and non-significant risk devices. The protocol and all other required documents must be submitted to the applicable FDA IND/IDE review division a minimum of 30 days before the grant application deadline. The IND must be active (not on clinical hold or exempted) or the IDE must be approved to qualify the grant application for review. Only medical foods that do not need pre-market approval and medical devices that are classified as non-significant risk (NSR) are free from these IND/IDE requirements. Applicants studying an NSR device should provide a letter in the grant application from the FDA Center for Devices and Radiologic Health indicating the device is an NSR device. Note: The final version of the protocol submitted to OOPD in the grant application is the protocol that MUST be submitted to an IND/IDE. The IND/IDE number and the date that the final version of the protocol was submitted to that IND/IDE should be included with the title of the project on the face page of the grant application. 6. If the sponsor of the IND/IDE is other than the principal investigator listed on the application, a letter from the sponsor permitting access to the IND/IDE must be submitted in both the IND/IDE and in the grant application. The name(s) of the Principal Investigator(s) named in the application and in the study, protocol must be submitted to the IND/IDE. 7. Appropriate documentation is needed including the protocol, informed consent form, and documentation and justification of innovative and efficient trial approach (if applicable). These should be submitted as appendices to the application. Letters of support regarding the availability of product, study sites, and patient engagement are also required. 8. Page limits, font size and margins should comply with the Application Guide, Electronic Submission of Grant Applications (https://grants.nih.gov/grants/how-to-apply-application-guide.html), with the exceptions noted in the Page Limitations section above for Resubmissions. 9. Additional information may be required upon request after submission of an application to determine responsiveness, for example, regarding population estimate and rationale. This additional information may be required, in part, to assure that human clinical trials of drugs are eligible to receive funding under the OPD grant program per 21 U.S.C. 360ee(b)(1)(A). Applicants are strongly encouraged to contact FDA to resolve any questions about criteria before submitting their application. Please direct all questions of a technical or scientific nature to the OPD program staff and all questions of an administrative or financial nature to the grants management staff (see Agency Contacts in Section VII of this document). Responsive applications will be reviewed and evaluated for scientific and technical merit by a panel of experts in the subject field of the specific application. Consultation with the proper FDA experts may also occur during this phase of the review to determine whether the proposed study will provide acceptable data that could contribute to product approval. Funding decisions will be made by the Commissioner of Food and Drugs or his designee. By submitting an application in response to this RFA, applicants understand and agree that members of the objective review panel of experts may be provided access to non-public information contained in the grant application, as necessary for evaluation of the application and are subject to the necessary restrictions on the further disclosure of the information. A score will be assigned to each application based on the scientific/technical review criteria. The review panel may advise the program staff about the appropriateness of the proposal to the goals of the OPD grant program. Scored Review Criteria Reviewers will provide an impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). All the criteria below will be weighted equally when scored. Reviewers will consider each of the review criteria below in the determination of scientific merit. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field. In addition, an application with moderate correctable weaknesses in a criterion may still receive a high overall impact score because one or more of the other review criteria are critically important to the research and have significant strengths. The relative importance of strengths and weaknesses, not simply the number of strengths and weaknesses, are considered in developing the impact score. 1. Rationale: The soundness of rationale in relation to the current understanding of the rare disease(s) and the likelihood the proposal will facilitate a clinical trial in support of a new indication(s) for use or change in labeling of a product(s) to address unmet needs in a rare disease(s). Description of the state of existing knowledge, including literature citations and highlights of relevant preliminary studies and previous preclinical and/or clinical data, including the natural history of the disease(s) in relation to the proposed safety/efficacy evaluation. Explanation of the importance of knowledge gap(s) and critical barrier(s) to progress in the field such as lack of treatments that the proposed project will address. Explanation of how the proposed study will provide essential data needed to support a new indication or a change in labeling. 2. Study Design: The quality and appropriateness of the study design, research methodology, and data analyses to accomplish the specific aims of the proposed study and its potential to make an impact for rare diseases. Description of the study including a clear hypothesis, study aims, and experimental design, including the appropriateness of the eligibility criteria and endpoints for the proposed study population and how data will be collected, analyzed, and interpreted. Explanation of the trial design and how it will meet the objectives efficiently (e.g., the use of basket, umbrella, platform trials, etcetera should be explicitly stated). Depending on the phase of development, these trials may need to include an appropriate comparator, such as a placebo, a concurrent external control, or a historical control. Description of how the study may have potential to provide a broad and positive impact for rare diseases. Description of the statistical analysis plan in adequate detail to show that the power of the study and data analyses will be sufficient to detect a meaningful benefit. Description of plans for ensuring data quality including but not limited to standardized data collection, data entry, data access, data monitoring, and data sharing. Description of plans for protecting the rights, safety, and welfare of study participants in compliance with federal law. Description of how data will be collected according to Good Clinical Practice Guidelines. Discussion of challenges, potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims within a stated timeframe. 3. Inclusion of Patient Input: The inclusion of patient and caregiver perspectives in the planning and design of the clinical study to improve protocol design and medical product development. Description of plans to include early and ongoing patient/stakeholder input in the study (e.g., protocol design, data elements, feasibility, data sharing). Description of plans to reduce patients' burden to participate in the study, impact on daily living, and potential issues with trial design feasibility. 4. Investigator, Infrastructure, and Financial Resources: The probability of success of the proposed project given the environment in which the work will be done. Description of the competence of the PI(s), collaborators, and other support staff in conducting the proposed research, including their academic qualifications, research experiences, productivity, and any special attributes. If applicable, description of the rationale, leadership approach, governance, and organizational structure for a multi-PD/PI project. Description of the applicant's ability to recruit and complete the proposed study within budget and stated time limits, including a detailed recruitment plan and timeline for implementation of the project upon funding. Description of institutional support, equipment, and other resources, such as with existing research networks, industry, academia and/or patient organizations and resource sharing plans as appropriate. Evidence that the product(s) to be studied is available to the applicant in the form and quantity needed for the clinical trial. Description of any additional funds expected to be contributed by other sources (including the applicant) prior to FDA grant funding and those to be used during the proposed funding period. Explanation of sustainability plans for acquiring additional funding for further phases of development beyond the proposed funding period, including a description of plans for leveraging FDA funding for additional resources needed for the proposed trial/overall development of the product(s). For some products (such as gene therapy products) that may require long-term safety follow-up, an outline of a sustainability plan is needed. 5. Ability to Advance the Current Field: The ability of the project to shift current research or clinical practice paradigms towards future product development and to exert a significant influence on product development. Explanation of how the proposed study will exert a sustained, powerful influence on the research field. Explanation of novel or improved concepts, approaches, or methodologies, instrumentation or interventions to be developed or used, such as with pharmacokinetic, pharmacodynamic modeling or clinical study design (e.g., adaptive design trials, modeling, or simulations), and/or outcome measures, and their advantages over existing approaches. Explanation of sustainability plans beyond the proposed funding period, including a description of plans for leveraging data for use in further phases of development beyond the proposed funding period. Additional Review Criteria As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items. Protections for Human Subjects For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials. For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects. Inclusion of Women, Minorities, and Individuals Across the Lifespan When the proposed project involves human subjects and/or FDA-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research. Biohazards Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed. For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous objective review group and changes made to the project. The adequacy of the responses to comments from the most recent scientific review group will be assessed including the appropriateness of the improvements in the resubmission application. Renewals For Renewals, the committee will consider the progress made in the last funding period. Revisions For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous objective review group are adequate and whether substantial changes are clearly evident. Additional Review Considerations As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score. Applications from Foreign Organizations Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries, and either are not readily available in the United States or augment existing U.S. resources. Select Agent Research Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s). Resource Sharing Plans Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS). Authentication of Key Biological and/or Chemical Resources: For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources. Budget and Period of Support Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research. 2. Review and Selection Process Applications will be evaluated for scientific and technical merit by an Objective Review Committee, using the stated review criteria. As part of the objective review, all responsive applications: Will receive a written critique. Appeals of objective review will not be accepted for applications submitted in response to this FOA. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. The following will be considered in making funding decisions: Scientific and technical merit of the proposed project as determined by objective review. Availability of funds. Relevance of the proposed project to program priorities. 3. Anticipated Announcement and Award Dates Successful applicants will be notified of additional information that may be required or other actions leading to an award. The decision not to award a grant, or to award a grant at a particular funding level, is discretionary and is not subject to appeal to any FDA or HHS official or board.