DOD Grant for Pilot Clinical Trials in Amyotrophic Lateral Sclerosis (ALS)

The FY24 ALSRP Pilot Clinical Trial Award supports the rapid implementation of clinical trials with the potential to have a significant impact on the treatment or management of ALS. Projects may range from phase 1 to small-scale phase 2 trials and should aim to de-risk and inform the design of more advanced trials by investigating safety, feasibility, biomarker application, and therapeutic efficacy in relevant patient populations. Clinical trials may be designed to evaluate promising drugs, biologics, or devices with anticipated therapeutic impact that is supported by strong scientific rationale and existing preliminary studies and/or preclinical data. Clinical trials aimed to improve aspects of patient care and ALS symptom management are also applicable to this award mechanism.

Funding from this award mechanism must support a clinical trial. A clinical trial is defined as a research study in which one or more study participants are prospectively assigned to one or more interventions (which may include a placebo or another control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes. For more information, a Human Subject Resource Document is provided at https://cdmrp.health.mil/pubs/pdf/Human%20Subjects%20Resource%20Document_DEC2022.pdf. Principal Investigators (PIs) seeking funding for a preclinical research project should consider one of the other FY24 ALSRP program announcements being offered. Studies that do not seek to measure safety, effectiveness, and/or efficacy outcome(s) of an intervention are not considered clinical trials.

Projects proposing a therapeutic intervention (drug, biologic, and/or device) must incorporate biomarkers specific to the intervention into the trial design. Applicants must clearly describe a biomarker-driven approach and its potential to de-risk and improve the design of anticipated later-stage trials. For further description, see Attachment 13, Biomarker Statement. Biomarker development and characterization can include target engagement biomarkers, pharmacodynamic biomarkers to measure the biological effect of an investigational therapeutic, and/or predictive/cohort-selective biomarkers that indicate whether a specific therapy will be effective in an individual patient or patient subgroup.

Key aspects of the FY24 ALSRP Pilot Clinical Trial Award mechanism include:

• Impact: Potential impact from a pilot clinical trial is not whether an intervention is ready at the conclusion of the trial, but rather if the outcomes will improve and accelerate future larger trials or clinical care and symptom management. Applications submitted to this award can have outcomes that focus on specific subpopulations of ALS patients or potentially even individual patients.
• Biomarker-Driven Interventions: Therapeutic outcomes should directly and substantially de-risk and inform the design of anticipated later-phase trials of the intervention under investigation.
• Clinical Care: Improving aspects of clinical care and symptom management should have near-term impact on patients. All interventions must offer significant potential impact for individuals affected by ALS; however, this may include just specific subpopulations or potentially even individual patients.
• Employing Community Collaborations to Optimize Research Impact Is Required. Research funded by the FY24 ALSRP Pilot Clinical Trial Award should be responsive to the needs of people with ALS, their families, and/or their care partners. Research teams are therefore required to establish and utilize effective and equitable collaborations and partnerships with Community members to maximize impact potential of the proposed research. These collaborations are expected to facilitate accessible, efficient, and humane clinical trials. Applications to the FY24 ALSRP Pilot Clinical Trial Award must name at least one Community partner (e.g., person with ALS, family member and/or caregiver, representative of a community-based organization) who will provide advice and consultation throughout the planning and implementation of the research project. Scientific researchers and Community members will collaborate and contribute equitably on all aspects of the project, which may include needs assessment, planning, research intervention design, implementation, evaluation, and dissemination. Interactions with other team members should be well integrated and ongoing, not limited to attending seminars and semi-annual meetings. Examples for implementing collaborative research approaches include:
• Person Living with ALS, Family Member, and/or Caregiver: The research team includes a person with ALS, their family member, or caregiver (past or present) as a project advisor who will provide advice and consultation throughout the planning and implementation of the research project.
• Partnership with a Community-Based Organization: The research team establishes partnerships with at least one Community-based organization that provides advice and consultation throughout the planning and implementation of the research project. Community-based organizations may include advocacy groups, service providers, policymakers, or other formal organizational stakeholders.
• Community Advisory Board: A Community advisory board is composed of multiple Community stakeholders and can take many forms, from a board of people with ALS, their family members, or caregivers to a coalition of Community-based organizations or any combination thereof. As with people living with ALS and organizational partners, the Community advisory board provides advice and consultation throughout planning and implementation of the research project.
• Clinical Trial Start Date and Intervention Availability: The proposed clinical trial is expected to begin no later than 12 months after the award date or 18 months after the award date for Food and Drug Administration (FDA)-regulated studies. The application should demonstrate the documented availability of and access to the drug/compound, device, and/or other materials needed, as appropriate, for the proposed duration of the study.
• Study Population: The application should demonstrate the availability of and access to a suitable patient population that will support a meaningful outcome for the study. The application should include a discussion of how accrual goals will be achieved, as well as the strategy for inclusion of women and minorities in the clinical trial appropriate to the objectives of the study.
• Research Personnel and Environment: The application should demonstrate the study team’s expertise and experience in all aspects of conducting clinical trials, including appropriate statistical analysis, knowledge of FDA processes (if applicable), and data management. The application should include a study coordinator(s) who will guide the clinical protocol through the local Institutional Review Board (IRB) of record and other federal agency regulatory approval processes, coordinate activities from all sites participating in the trial, and coordinate participant accrual. The application should show strong institutional support and, if applicable, a commitment to serve as the FDA regulatory sponsor, ensuring all sponsor responsibilities described in the Code of Federal Regulations, Title 21, Part 312 (21 CFR 312), Subpart D, are fulfilled.
• Statistical Analysis and Data Management Plans: The application should include a clearly articulated statistical analysis plan, a power analysis reflecting sample size projection that will answer the objectives of the study, and a data management plan that includes use of an appropriate database to safeguard and maintain the integrity of the data. If FDA-regulated, the trial must use a 21 CFR 11-compliant database and appropriate data standards. For more on data standards, see https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ FormsSubmissionRequirements/ElectronicSubmissions/UCM511237.pdf.
• Transition Plan: Applications should include a transition plan (including potential funding and resources) showing how the intervention will progress to the next clinical trial phase and/or improve current standards of care after the successful completion of the FY24 ALSRP Pilot Clinical Trial Award.
• Milestone meeting: The Principal Investigator (PI) will be required to present an update on progress toward accomplishing the goals of the award at annual, virtual In Progress Review meetings to be held during the period of performance. The PI should ideally include their Community collaboration partner(s) in the meeting. The In Progress Review Meeting will be attended by members of the ALSRP Programmatic Panel, CDMRP staff, the USAMRAA Grants/Contracts Officer, and other stakeholders.

The FY24 ALSRP Pilot Clinical Trial Award supports the rapid implementation of clinical trials with the potential to have a significant impact on the treatment or management of ALS. Projects may range from phase 1 to small-scale phase 2 trials and should aim to de-risk and inform the design of more advanced trials by investigating safety, feasibility, biomarker application, and therapeutic efficacy in relevant patient populations. Clinical trials may be designed to evaluate promising drugs, biologics, or devices with anticipated therapeutic impact that is supported by strong scientific rationale and existing preliminary studies and/or preclinical data. Clinical trials aimed to improve aspects of patient care and ALS symptom management are also applicable to this award mechanism.

Funding from this award mechanism must support a clinical trial. A clinical trial is defined as a research study in which one or more study participants are prospectively assigned to one or more interventions (which may include a placebo or another control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes. For more information, a Human Subject Resource Document is provided at https://cdmrp.health.mil/pubs/pdf/Human%20Subjects%20Resource%20Document_DEC2022.pdf. Principal Investigators (PIs) seeking funding for a preclinical research project should consider one of the other FY24 ALSRP program announcements being offered. Studies that do not seek to measure safety, effectiveness, and/or efficacy outcome(s) of an intervention are not considered clinical trials.

Projects proposing a therapeutic intervention (drug, biologic, and/or device) must incorporate biomarkers specific to the intervention into the trial design. Applicants must clearly describe a biomarker-driven approach and its potential to de-risk and improve the design of anticipated later-stage trials. For further description, see Attachment 13, Biomarker Statement. Biomarker development and characterization can include target engagement biomarkers, pharmacodynamic biomarkers to measure the biological effect of an investigational therapeutic, and/or predictive/cohort-selective biomarkers that indicate whether a specific therapy will be effective in an individual patient or patient subgroup.

Key aspects of the FY24 ALSRP Pilot Clinical Trial Award mechanism include:

• Impact: Potential impact from a pilot clinical trial is not whether an intervention is ready at the conclusion of the trial, but rather if the outcomes will improve and accelerate future larger trials or clinical care and symptom management. Applications submitted to this award can have outcomes that focus on specific subpopulations of ALS patients or potentially even individual patients.
• Biomarker-Driven Interventions: Therapeutic outcomes should directly and substantially de-risk and inform the design of anticipated later-phase trials of the intervention under investigation.
• Clinical Care: Improving aspects of clinical care and symptom management should have near-term impact on patients. All interventions must offer significant potential impact for individuals affected by ALS; however, this may include just specific subpopulations or potentially even individual patients.
• Employing Community Collaborations to Optimize Research Impact Is Required. Research funded by the FY24 ALSRP Pilot Clinical Trial Award should be responsive to the needs of people with ALS, their families, and/or their care partners. Research teams are therefore required to establish and utilize effective and equitable collaborations and partnerships with Community members to maximize impact potential of the proposed research. These collaborations are expected to facilitate accessible, efficient, and humane clinical trials. Applications to the FY24 ALSRP Pilot Clinical Trial Award must name at least one Community partner (e.g., person with ALS, family member and/or caregiver, representative of a community-based organization) who will provide advice and consultation throughout the planning and implementation of the research project. Scientific researchers and Community members will collaborate and contribute equitably on all aspects of the project, which may include needs assessment, planning, research intervention design, implementation, evaluation, and dissemination. Interactions with other team members should be well integrated and ongoing, not limited to attending seminars and semi-annual meetings. Examples for implementing collaborative research approaches include:
• Person Living with ALS, Family Member, and/or Caregiver: The research team includes a person with ALS, their family member, or caregiver (past or present) as a project advisor who will provide advice and consultation throughout the planning and implementation of the research project.
• Partnership with a Community-Based Organization: The research team establishes partnerships with at least one Community-based organization that provides advice and consultation throughout the planning and implementation of the research project. Community-based organizations may include advocacy groups, service providers, policymakers, or other formal organizational stakeholders.
• Community Advisory Board: A Community advisory board is composed of multiple Community stakeholders and can take many forms, from a board of people with ALS, their family members, or caregivers to a coalition of Community-based organizations or any combination thereof. As with people living with ALS and organizational partners, the Community advisory board provides advice and consultation throughout planning and implementation of the research project.
• Clinical Trial Start Date and Intervention Availability: The proposed clinical trial is expected to begin no later than 12 months after the award date or 18 months after the award date for Food and Drug Administration (FDA)-regulated studies. The application should demonstrate the documented availability of and access to the drug/compound, device, and/or other materials needed, as appropriate, for the proposed duration of the study.
• Study Population: The application should demonstrate the availability of and access to a suitable patient population that will support a meaningful outcome for the study. The application should include a discussion of how accrual goals will be achieved, as well as the strategy for inclusion of women and minorities in the clinical trial appropriate to the objectives of the study.
• Research Personnel and Environment: The application should demonstrate the study team’s expertise and experience in all aspects of conducting clinical trials, including appropriate statistical analysis, knowledge of FDA processes (if applicable), and data management. The application should include a study coordinator(s) who will guide the clinical protocol through the local Institutional Review Board (IRB) of record and other federal agency regulatory approval processes, coordinate activities from all sites participating in the trial, and coordinate participant accrual. The application should show strong institutional support and, if applicable, a commitment to serve as the FDA regulatory sponsor, ensuring all sponsor responsibilities described in the Code of Federal Regulations, Title 21, Part 312 (21 CFR 312), Subpart D, are fulfilled.
• Statistical Analysis and Data Management Plans: The application should include a clearly articulated statistical analysis plan, a power analysis reflecting sample size projection that will answer the objectives of the study, and a data management plan that includes use of an appropriate database to safeguard and maintain the integrity of the data. If FDA-regulated, the trial must use a 21 CFR 11-compliant database and appropriate data standards. For more on data standards, see https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ FormsSubmissionRequirements/ElectronicSubmissions/UCM511237.pdf.
• Transition Plan: Applications should include a transition plan (including potential funding and resources) showing how the intervention will progress to the next clinical trial phase and/or improve current standards of care after the successful completion of the FY24 ALSRP Pilot Clinical Trial Award.
• Milestone meeting: The Principal Investigator (PI) will be required to present an update on progress toward accomplishing the goals of the award at annual, virtual In Progress Review meetings to be held during the period of performance. The PI should ideally include their Community collaboration partner(s) in the meeting. The In Progress Review Meeting will be attended by members of the ALSRP Programmatic Panel, CDMRP staff, the USAMRAA Grants/Contracts Officer, and other stakeholders.