Contact: Jane Hettinger
Location: The webinar is open to the public, but registration is required.
These webinars aim to inform and answer participant questions on the NINDS Amyotrophic Lateral Sclerosis (ALS) Intermediate Patient Population Expanded Access (U01 Clinical Trial Required) RFA-NS-23-012. The goal of this announcement is to support the conduct of scientific research utilizing data from expanded access (EA) for investigational drugs or biological products for patients living with ALS who are not eligible for ongoing ALS clinical trials. These webinars will provide an overview of the funding opportunity, including requirements and eligibility, and will include a Q&A session.
All investigators interested in learning about the NINDS ALS Expanded Access program are encouraged to register and participate. You are also encouraged to submit questions before the meeting to Jane Hettinger.
The receipt date for this ALS Expanded Access Funding Opportunity is May 1, 2023.
Frequently Asked Questions
The Accelerating Access to Critical Therapies (ACT) for ALS Act was passed into law on December 23, 2021 (P.L. 117-79). Section 2 authorized a grant program for scientific research utilizing data from expanded access to investigational drugs for individuals who are not otherwise eligible for clinical trials for the prevention, diagnosis, mitigation, treatment, or cure of amyotrophic lateral sclerosis (ALS). The statute limits the grant program to phase 3 clinical sites sponsored by a small business concern.
NIH has released RFA-NS-23-012 in fiscal year 2023 to implement Section 2 of ACT for ALS. In the below frequently asked questions (FAQs), we have pointed out the relevant sections of ACT for ALS that establish the requirements of this NIH grant program.
Eligibility Requirements See ACT for ALS Sec. 2(e) for definition of participating entity and participating clinical trial, and Sec. 2(a) for expanded access New Drug Application (IND) authorization requirements.
Expanded Access Investigational New Drug (EA IND) Applications
Q: Are patients who are already being treated under an ongoing intermediate-sized EA INDs eligible to be included in the studies of that same intervention proposed under RFA-NS-23-012?
A: Inclusion of patients currently treated under existing Intermediate-sized EA INDs may participate in studies proposed under RFA-NS-23-012 if their inclusion may aid proposed research goals. However, applicants are strongly recommended to expand existing EA INDs and prioritize resources to support the addition of new patients not currently treated through expanded access.
Q: How many patients can be included in an intermediate size expanded access protocol?
A: FDA defines “intermediate size patient population expanded access” on their website as “more than one patient, but generally fewer patients than are treated under a typical treatment IND or protocol.” The RFA provides a link to the FDA website defining this terms; the link is also available here.
Q: How does FDA’s review of expanded access requests intersect with NIH’s grant approval process?
A: EA IND authorization is conducted through the FDA. Per the RFA, applicants to RFA-NS-23-012 must submit their EA IND to FDA by the time of NIH grant application submission, and the EA IND must be allowed to proceed prior to award. NIH is not involved in the review or authorization of EA INDs.
Q: Can RFA-NS-23-012 support studies approved under Open Label Extensions?
A: No, studies under Open Label Extensions would not be eligible per the RFA. The proposed study must be conducted under an intermediate-sized EA IND that is in effect.
Q: Is a third party eligible to be the sponsor for the trial?
A: No. The ACT for ALS requires that participating entities seeking grants are “participating clinical trial site or sites sponsored by a small business concern (as defined in section 3(a) of the Small Business Act(15 U.S.C. 632(a))) that is the sponsor of a drug that is the subject of an investigational new drug application under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) to prevent, diagnose, mitigate, treat, or cure amyotrophic lateral sclerosis.”
Q: Can a third party submit and secure IND? Is it possible for two or more PIs to apply for EA IND?
A: EA IND authorization is a function of the FDA. Please contact the FDA with specific questions about their expanded access IND application process. Guidance and contact information can be found at FDA Expanded Access page.
Small Business Eligibility
Q: How is small business concern eligibility determined?
A: A “small business concern” is defined by section 3(a) of the Small Business Act (15 U.S.C. 632(a)) and its regulations at 13 CFR Part 121. We welcome discussing the criteria, although we note that NIH cannot make the determination of eligibility; instead, the drug sponsor must certify their eligibility as a small business concern.
Q: Please comment on the small business definition requirement for companies who are 50% or more owned by private equity, venture capital firms. Once a biotech company has gotten to a Phase 3 trial, it is likely that given the amount of capital needed to get that far they will be over 50% owned by such firms.
A: Businesses concerns can be eligible and be more than 50% owned by multiple venture capital firms, hedge funds, private equity firms, or any combination of these. However, no one venture capital operating company, hedge fund, or private equity firm can own more than 50% of the business concern unless that organization qualifies as a small business concern that is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States. We welcome discussing the criteria, although we note that NIH cannot make the determination of eligibility; instead, the drug sponsor must certify their eligibility as a small business concern within the application.
Q: Can the small business concern drug sponsor apply directly to RFA-NS-23-012?
A: No. Consistent with the ACT for ALS, RFA-NS-23-012 states that “Eligible applicants must be clinical trial sites that participate in a Phase 3/efficacy clinical trial supported by a small business concern that is the FDA-designated sponsor of a drug or biological product which is the subject of an IND under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) to prevent, diagnose, mitigate, treat, or cure ALS.”
Q: If a foreign company is conducting research in the US, is the center or network they are working with able to apply for the grant?
A: ACT for ALS language specifies that the qualifying Phase 3 clinical trial IND sponsor must be a small business concern as defined by section 3(a) of the Small Business Act (15 U.S.C.632(a)). This means that the drug sponsor itself must have a place of business located in the United States, and operate primarily within the United States or make a significant contribution to the U.S. economy through payment of taxes or use of American products, materials, or labor in addition to other criteria. We welcome discussing the criteria, although we note that NIH cannot make the determination of eligibility; instead, the drug sponsor must certify their eligibility as a small business concern.
Q: As a small business foreign entity, what is the best funding opportunity for assistance with. conducting a Phase 2 trial under an IND?
A: The NeuroNEXT clinical trial network run by NINDS is designed to run Phase 2 clinical trials for neurological diseases. A foreign IND sponsor may be allowed for the NeuroNEXT program. We encourage you to reach out to discuss the appropriate funding opportunity for your specific projects.
Q: Are STTR grants for technologies related to rehabilitations strategies to maximize quality of life included in funding opportunity?
A: Not through this RFA, but there are STTR funding opportunities applicable to this type of research. This RFA is not a SBIR/STTR funding opportunity, and, in fact, the small business is unlikely to be eligible as the applicant. The applicant needs to be the Phase 3 clinical trial site. Those kinds of projects, rehabilitation for ALS, are in scope for STTR funding opportunities that NINDS and other NIH ICs participate in. Please reach out to learn more about these opportunities.
Q: Are devices eligible for this EA program?
A: No, devices are not eligible for this program. However, NINDS does have other funding opportunities to support clinical testing of devices in ALS and other neurological indications outside of this RFA. If this is your focus, please reach out for further information.
Clinical Trial Phase and Sites
Q: Does the qualifying ALS Phase 3/efficacy clinical trial need to be ongoing at the time of application?
A: The IND for the ALS Phase 3/efficacy clinical trial must be active at the time of award for applications selected for funding under RFA-NS-23-012.
Q: Does the drug have to be in a Phase 3 trial (registered as 'recruiting" on ClinicalTrials.gov), before the May 1st deadline, in order to be eligible for this RFA?
A: For the Phase 3 clinical trial IND, the Phase 3 trial does not need to be recruiting at the time of application, but the IND needs to be in effect by the time of the award. The trial does not need to be active or recruiting at the time of the application. For the expanded access IND, the intermediate size EA must be submitted to the FDA no later than the date of the submission of the application. The EA IND will need to in effect by the time of award.
Q: If my Phase 3 trial has completed, is my trial site still eligible?
A: If the regulatory determination has NOT been made regarding new drug application, the trial is eligible for this RFA. In other words, the drug or biological product must not be approved under a New Drug Application or licensed under a Biologics License Application. Once the drug or biological product is approved for ALS by the FDA, it becomes ineligible and the NINDS EA funds will be terminated.
Q: How is NIH interpreting the “Phase 3 clinical trial” requirement? Are Phase 2/3 trials eligible? What about Phase 3 trials that have completed but are awaiting regulatory consideration?
A: Phase 2/3 trials, ongoing Phase 3 trials, and concluded Phase 3 trials are eligible until a regulatory determination has been made regarding approval. As noted in the RFA, and consistent with the ACT for ALS, the investigational drug proposed under RFA-NS-23-012 must not be approved under a New Drug Application (NDA) or licensed under a Biologics License Application (BLA) for an ALS indication.
Q: We have a large number of participating clinical sites in our study. Do we need letters of interest signed by all participating sites? Do signatures need to include the Business Official and Principal Investigator (PI)?
A: While interest letters are not required for all participating sites, they are recommended, particularly when recruitment may be a potential issue in the proposed study. While signatures from both the Business Official and PI are recommended, the PI signature alone is adequate.
Q: Are all Phase 2 clinical trials eligible, such as Phase 2A or 2B?
A: Investigational drugs in Phase 2a stage or Phase 2b stage clinical trials are not eligible under the RFA. Investigational drugs in a clinical trial staged as Phase 2/3 or Phase 3 are eligible.
Q: Please clarify whether "in Phase 2/3 trial" is defined as having received "To Proceed Letter " from FDA or the trial has already enrolled the first patient.
A: The IND of the eligible Phase 2/3 or Phase 3 ALS trial must be in effect prior to award.
Q: Will this grant program fund a Phase 1/2 clinical trial of a new chemical entity?
A: No. Only Phase 2/3 trials, ongoing Phase 3 trials, and completed Phase 3 trials awaiting regulatory determination has been made regarding approval are eligible for this RFA. Phase 1/2 are not eligible for this RFA.
Q: Would an investigational product that is in late phase development for another indication be eligible through this RFA?
A: The investigational product must be in an ALS Phase 2/3 trial, ongoing ALS Phase 3 trial, or awaiting regulatory determination after a completed ALS Phase 3 trial. An investigational product in late Phase development for another indication is eligible as long as the product is also being investigated in an ALS Phase 3/efficacy clinical trial.
Q: Are other rare neurodegenerative diseases eligible for the EAP funds?
A: No. Only ALS studies are eligible for this RFA.
Q: Do all clinical trial sites need to be identified for the grant application?
A: The RFA does not require that all clinical sites be identified in the grant application. However, as stated in the Section 5 of RFA-NS-23-012, reviewers will evaluate “Approach” as part of the review process. This would include aspects of recruitment, retention, trial design, and proposed study populations which may be supported by providing detailed information on the clinical trial within the application such as the proposed clinical sites.
Q: Does the PI of the Expanded Access Program need to be the lead PI of the ALS Phase 3 clinical trial?
A: The PI of the application for the Expanded Access study does not need to be the Phase 3 clinical trial lead PI; however, the application must be from a clinical trial site for the ALS Phase 3 clinical trial for that product.
Q: If a clinical trial site funded by this RFA is halted due to futility during the grant award, but the Investigational Medical Product (IMP) appears to be beneficial to a subgroup of participants, would NINDS consider continuing funding the EA clinical trial?
A: This is a complex question and requires discussion on a case-by-case basis. In general, however, status of the Phase 3 clinical trial for the investigational ALS agent is not a factor considered in continued funding of the proposed expanded access study. For cooperative agreement terms and conditions of award, please see Section VI of RFA-NS-23-012.
Budget and Funding
Q: Will there be future funding and future RFAs to support this effort?
A: FY23 funding has been appropriated by Congress for implementing ACT for ALS. Future funding and future RFAs will be determined by congressional appropriations for this program. As with all NIH-funded awards, funding of future years depends on availability of funds.
Q: Regarding the NINDS total $75 million funds available for FY 2023 awards (3-5 awards), are these awards representing the TOTAL budgets for the full projects, or just Year 1 of the projects?
A: NINDS intends to commit up to $75M to applications to RFA-NS-23-012 in FY23. NINDS expects these funds will be allocated to the first-year budget periods of funded projects.
Q: What are the allowed and non-allowed budget items? Are there NINDS guidelines for what can be included in an EAP grant application budget (f ex CRO, lab collection etc.)
A: Per Act for ALS and RFA-NS-23-012 Section IV. Application and Submission Information, funds may be requested for:
- Payment to the manufacturer or sponsor for the direct costs of the investigational drug or biological product of the intermediate EA protocol for ALS, as authorized under section 312.8(d) of title 21, Code of Federal Regulations (or successor regulations)
- Direct costs incurred in providing such drug/biological product consistent with the research objectives of the grant
- Direct and indirect costs of participating clinical trial sites in conducting research with respect to such drug/biological product, including
- Personnel effort, support for study participant travel/meals, and other budget items within the overall budget cap to ensure that the goal of appropriate inclusion is met
- Other associated costs, including:
- Curating data
- Developing supporting documentation
- Formatting data according to accepted community standards, or for transmission to and storage at a selected repository for long-term preservation and access
- De-identifying data
- Preparing metadata to foster discoverability, interpretation, and reuse
- Local data management considerations, such as unique and specialized information infrastructure necessary to provide local management and preservation (for example, before deposit into an established repository).
- Preserving and sharing data through established repositories, such as data deposit fees.
- If the Data Management & Sharing (DMS) plan proposes deposition to multiple repositories, costs associated with each proposed repository may be included.
Q: Will the grant funding available help fund clinicians and clinic staff who often incur the direct and ancillary costs of administering expanded access programs?
A: Costs associated with the treatment and research proposed under RFA-NS-23-012 are eligible per the RFA, the following costs are allowed:
- Payment to the manufacturer or sponsor for the direct costs of the investigational drug or biological product of the intermediate EA protocol for ALS, as authorized under section 312.8(d) of title 21, Code of Federal Regulations (or successor regulations)
- Direct costs incurred in providing such drug/biological product consistent with the research objectives of the grant
- Direct and indirect costs of participating clinical trial sites in conducting research with respect to such drug/biological product
- Personnel effort, support for study participant travel/meals, and other budget items within the overall budget cap to ensure that this goal of appropriate inclusion is met
Q: Are the requirements for an EAP start date following grant award? For example, can a grant awarded in 2023 be for an EAP starting in 2024?
A: The EAP should be submitted to the FDA by the date of RFA application submission. The EAP will need to be approved prior to award. Start-up activities preceding the initiation of the expanded access study are allowable under RFA funding with sufficient justification.
Study Design and Review
Q: Could you highlight some elements that will be important from the review perspective?
A: In addition to providing expanded access to these therapies, one of the main goals of these applications should be to address a research question relevant to ALS. The reviewers will focus on the research question and will use review criteria published in Section V of the RFA. Typically, the major drivers are the approach, rigor of the proposed experiments, and significance of the research question. There will also be evaluation of the impact and how the program will not detract from or interfere with any ongoing clinical trials.
Q: Given NINDS' focus on the need for biomarkers in the Strategic Plan, will NINDS ensure that every clinical trial site measure biomarkers?
A: Applicants are not required to include biomarkers in their proposals. Reviewers will review any research questions that are proposed. The RFA suggests that applicants could include biomarker collection and analysis, but collection of safety outcome information, survival, other significant medical events, patient experience data that is not specifically tied to efficacy, etc., are also acceptable. Outside of this RFA, NINDS recently released a Notice of Special Interest (NOT-NS-23-062) on a number of funding opportunities related to ALS, including opportunities for clinical data harmonization and biomarker studies.
Q: Given that the goal of the bill was to provide EAP to as many people with ALS as possible, how does NINDS decide how many sites to approve so as to minimize administrative and IRB costs and to maximize treatment funding?
A: These studies are designed by investigators. Investigators propose the study sites, number of participants, and budget in their grant application to NIH. NIH reviews and funds grant applications using established grant review processes. If the grant application is deemed meritorious (i.e., scientifically rigorous and important) by peer review and if there are sufficient funds, NIH funds the entire project as proposed by the applicants and does not make decisions at the level of individual study sites unless a concern is explicitly raised during peer review.
Q: Can you confirm that only the large percentage of people who have NOT ever qualified for a clinical trial will be given treatment through expanded access with ACT for ALS funds?
A: The RFA states that applicants must address this issue. The ACT for ALS legislation requires that the EAP should not impede on ongoing clinical trials. The intent is to focus expanded access for individuals who are not otherwise eligible for clinical trial participation. The applicants do have to address how their expanded access plans will not interfere with ongoing clinical trials.
Q: How will the ALS community be involved?
A: Per the RFA, applicants are strongly encouraged to establish relationships with patient advocacy groups and solicit their input on recruitment (including equitable access to investigational drugs by minority and underserved populations), the clinical meaningfulness of the question under study, the relevance of the proposed clinical outcomes, and approaches to minimizing the burden on study participants. Additionally, NIH will include people affected by ALS (people living with ALS, caregivers, or people at risk for developing ALS) in the Scientific Review Group (also known as a study section) that is the first level of review for applications.
Q: What are the necessary components of a complete grant application for both the IND sponsor and research institution?
A: Please see these annotated application forms for a list of application components.
Q: What is a typical length of period of performance?
A: The period allowed is up to four (4) years, though no “typical” period length has been established given the newness of the program. The period of performance should be informed by the project plans, and applicants should consider time for recruitment, time necessary for the sites you are working with, the availability of the drug you are proposing, etc. All of these are factors that would determine a reasonable period of performance for your particular period within the limit of four years. Four years are not required.
Other
Q: How can I enroll as a participant in an expanded access trial?
A: NIH is not involved in recruitment. The clinical sites or networks that receive grants through this research program are responsible for all aspect of recruiting study participants.
Q: Is an EA clinical trial required to register and submit results information to ClinicalTrials.gov?
A: Yes. Like any other NIH-funded clinical trial per the NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information, registration and results information submission to ClinicalTrials.gov is expected for clinical trials in expanded access programs.
Inquiries
Please direct all inquiries to:
Emily Caporello, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)/Division of Translational Research
Email: emily.caporello@nih.gov
Lumy Sawaki-Adams, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)/Division of Clinical Research
Email: lumy.sawaki-adams@nih.gov
Amelie Gubitz, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)/Division of Neuroscience
Email: gubitza@nih.gov
Webinar slides(pdf, 3150 KB)