June 5, 2023
- January 10, 2023 - Renewal of the Interventions Testing Program (U01 Clinical Trial Not Allowed). See FOA RFA-AG-24-002.
National Institute on Aging (NIA)
The purpose of this Notice is to inform potential applicants of modifications to Funding Opportunity Announcement (FOA) RFA-AG-24-002, “Renewal of the Interventions Testing Program (U01 Clinical Trial Not Allowed.” .
The following sections of RFA-AG-24-002 were modified:
The information below outlines the changes made in each section.
Section I. Funding Opportunity Description
Purpose and Research Objectives
Summary of Change:
A paragraph was added to clarify site details.
Currently Reads:
The ITP aims to achieve the following goals through its renewal:
- Continue the testing of compounds for effects on lifespan in the “four-way cross” mice UM-HET3 using well-established protocols and SOPs. The protocol details for lifespan studies, statistical analyses, and Stage I and II interventions have been evaluated in the review of applications submitted in response to the original and subsequent renewals of the ITP. Several articles detailing the protocols and testing results have been published. Only newly introduced major changes/modifications will be evaluated in response to this FOA.
- Continue pilot studies of optimal drug formulation, stability, and bioavailability for new compounds. Optimal drug formulation and tests of compound stability during preparation and storage should continue for compounds proposed for lifespan studies in Stage I. Pilot testing should include studies of blood levels, potential toxicity, and likely optimal dose based on hepatic response or other biological markers.
- Expand geropathology analyses at a minimum of one time point after starting the intervention and continue pathology studies at time of death. Evaluation of age-related pathological changes and post-mortem organ/tissue examination for diagnosis aimed at assessing and quantifying the impact of tested compounds on the aging of tissues and organs and on chronic diseases of aging (those typically observed in the control cohorts of UM-HET3 mice).
- Introduce transcriptomic analyses (i.e., "bulk" RNA sequencing). The detection of changes in gene expression in selected organs at selected timepoint(s) after starting an intervention will help determine the gene regulatory and molecular pathways at the tissue and/or organ level affected by aging and modified by the interventions.
- Expand tissue collection for ancillary studies. The interventions tested by the ITP may result in perturbations of processes at the molecular, tissue, and organ level that can be associated with aging. Therefore, tissues from treated and matched untreated mice are collected by the ITP and are a highly valuable resource for ancillary studies aimed at elucidating the biology of aging, geropathology, pathways involved in aging, and other questions regarding diseases of aging. Ancillary studies could incorporate a broad range of experimental platforms (e.g., genomics, proteomics, metabolomics, spatial omics, advanced microscopy) and could focus on one or more tissues/organs. Currently, tissues from treated and control animals are made available to the research community through the Collaborative Interactions Program (CIP) that was initiated in a previous iteration of the ITP. Starting with this new funding cycle, all biospecimens will be recorded and managed through the Interventions Biospecimens Repository (IBR, see below).
Modified to Read (changes are in bold italics):
The ITP aims to achieve the following goals through its renewal:
- Continue the testing of compounds for effects on lifespan in the “four-way cross” mice UM-HET3 using well-established protocols and SOPs. The protocol details for lifespan studies, statistical analyses, and Stage I and II interventions have been evaluated in the review of applications submitted in response to the original and subsequent renewals of the ITP. Several articles detailing the protocols and testing results have been published. Only newly introduced major changes/modifications will be evaluated in response to this FOA.
- Continue pilot studies of optimal drug formulation, stability, and bioavailability for new compounds. Optimal drug formulation and tests of compound stability during preparation and storage should continue for compounds proposed for lifespan studies in Stage I. Pilot testing should include studies of blood levels, potential toxicity, and likely optimal dose based on hepatic response or other biological markers.
- Expand geropathology analyses at a minimum of one time point after starting the intervention and continue pathology studies at time of death. Evaluation of age-related pathological changes and post-mortem organ/tissue examination for diagnosis aimed at assessing and quantifying the impact of tested compounds on the aging of tissues and organs and on chronic diseases of aging (those typically observed in the control cohorts of UM-HET3 mice).
- Introduce transcriptomic analyses (i.e., "bulk" RNA sequencing). The detection of changes in gene expression in selected organs at selected timepoint(s) after starting an intervention will help determine the gene regulatory and molecular pathways at the tissue and/or organ level affected by aging and modified by the interventions.
- Expand tissue collection for ancillary studies. The interventions tested by the ITP may result in perturbations of processes at the molecular, tissue, and organ level that can be associated with aging. Therefore, tissues from treated and matched untreated mice are collected by the ITP and are a highly valuable resource for ancillary studies aimed at elucidating the biology of aging, geropathology, pathways involved in aging, and other questions regarding diseases of aging. Ancillary studies could incorporate a broad range of experimental platforms (e.g., genomics, proteomics, metabolomics, spatial omics, advanced microscopy) and could focus on one or more tissues/organs. Currently, tissues from treated and control animals are made available to the research community through the Collaborative Interactions Program (CIP) that was initiated in a previous iteration of the ITP. Starting with this new funding cycle, all biospecimens will be recorded and managed through the Interventions Biospecimens Repository (IBR, see below).
Because this is a testing program, some of the procedures described above have been, and will continue to be, performed at only one site, and other aspects of the experimental work are done at all three sites. Activities performed at only one site can be described in detail by that site. Any activity performed at another site that is essential to the overall testing program can be briefly illustrated. Activities are identified in Section IV.2 of this FOA (see the “Research Strategy” section).
Section IV. Application and Submission Information
PHS 398 Research Plan
Summary of Change:
Information was added to clarify application instructions.
Currently Reads:
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Research Strategy: Lifespan studies. Applicants should provide only a general description of planned lifespan studies, including, but not limited to, acquisition of data such as weight and veterinarian heath report records. The details of protocols for lifespan studies, statistical power analyses, and of Stage I and II designs have been evaluated in the review of applications submitted in response to the previous iterations of the ITP. Several publications detailing the protocols and testing results have been published. Therefore, applicants may refer to and summarize protocols, statistical analyses, and Stages of the study to the extent they help understanding of the program and assessment of the other research activities of the program or if changes are introduced. Changes/modifications to existing protocols should be identified as such and described for evaluation in the renewal application.
Applicants must describe in detail plans for analysis of lifespan data from Stage I and Stage II studies. Plans for survival data analysis should include more than one statistical approach. NIH Biosketches for the statistical experts, and descriptions of their involvement in conduct of the studies and data analysis within the ITP should be included in the renewal applications.
Compound pilot studies. The research strategy should describe the methods selected to develop the formulations of compounds for testing. Strategy and timeline must be included for establishing drug stability during production, shipping, and storage. Experiments must be proposed that are sufficient to support the selection of initial dosage, including, but not limited to, determination of oral bioavailability, drug concentrations in the blood and other organs, as well as changes in the expression of target genes at least in the liver. Procedures for the assessment of drug toxicity must be described. Go/no-go criteria regarding compound(s) to be tested in Stage I must be discussed.
Geropathology assessment. Standardized procedures for a cross-sectional geropathology assessment made at least one time point after starting the intervention and pathology assessment at the time of death should be described. Applicants should provide details regarding schedules and protocols for the collection of biospecimens (e.g., tissues, blood samples) as well as the preservation, storage, and geropathology assessment of treated and untreated mice used in lifespan studies. Applicants must propose and explain the rationale behind the protocols of choice for geropathology assessment, including number of mice evaluated, organ/tissue type, age(s) at collection, staining and field sampling methods, and tissue-specific grading systems used by veterinary pathologist(s). Description of statistical analyses on quantitative geropathology data should be included. A brief description of post-mortem pathology evaluations should also be included.
Transcriptomics. Applicants must describe protocols for cross-sectional transcriptomic analysis (“bulk” RNA sequencing), at least at one time point after starting the intervention, comparing age-associated gene expression changes in treated and untreated mice in the lifespan studies. The rationale for the selection of target organs and tissues, the time(s) at which they are collected, and the number of animals included per condition analyzed in the transcriptomic study must be described. Detailed protocols for organ/tissue collection, storage, RNA processing, sequencing, and plans for transcriptome analysis must be included. The sequencing approach and data analyses must be detailed. Approaches to harmonize mRNA sample preparation and storage protocols among the three testing sites must be described. Discussion of the experimental design and data analysis should be included. A single site or contractor may be chosen as a sequencing core and plans for communicating with that core should be described.
Tissue collection for ancillary studies (Interventions Biospecimens Repository (IBR)). Biospecimens were collected and stored in previous iterations of the ITP. Samples were distributed through the Collaborative Interactions Program (CIP). With this cycle, a more formal Interventions Biospecimens Repository (IBR) will be established. Applicants should describe ongoing practices of biospecimen collection and storage as well as modifications to be implemented. Each procedure should be clearly identified as current or new. Applicants must identify and provide the rationale behind the biological materials to be harvested from animals in the ITP, specifying the age(s) in a life course study for collection, indicating whether during Stage I and/or Stage II, which tissues or organs are selected for the repository, and the protocols for processing and storage. When establishing the size of cohorts of mice treated with effective compounds and controls for biospecimen collection, past records of organ/tissue requests should be taken into consideration. Tissues should be collected using appropriately described methods of tissue preservation (e.g., flash frozen, frozen blocks, various fixation methods) and, based on current state-of-the-science, applicants should identify the compatible analytical/experimental platforms that could be used in follow-up studies (which will be pursued via application to the NIA – see Purpose and Research Objectives, above). Because the electronic inventory of collected and available tissues in the IBR will be accessible through the ITP sites, the ITP DCC, and the NIA website, a description of plans for making available to the ITP DCC and the NIA the list updated in real time of tissues in the IBR must be included in the application.
Applicants must describe how documentation of protocols, statistical approaches and stages of the studies as well as lifespan data will be made available to the ITP DCC and the NIA. Applicants should include plans and methods for sharing with the ITP DCC data from the pilot studies, including drug stability, blood levels and studies of optimal dose. Plans for providing the ITP DCC with information on samples for geropathology/pathology and all results from geropathology/pathology (including, when appropriate, images), and plans for sharing transcriptome data with the ITP DCC must be included.
Modified to Read (changes are in bold italics):
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Progress Report. The progress report should summarize compounds proposed by the research community, making clear why some compounds were chosen, and summarize results of lifespan studies (published and ongoing). The site at which the work was done should be specified for those aspects done at only one site.
Research Strategy:
For all the following components of the Research Strategy, in keeping with the current structure and past practices of this testing program, a single site or contractor may be chosen to perform a part of the experimental procedures. The single site performing such activities should describe the activity in detail.
Lifespan studies. Applicants should provide only a general description of planned lifespan studies, including, but not limited to, acquisition of data such as weight and veterinarian heath report records. The details of protocols for lifespan studies, statistical power analyses, and of Stage I and II designs have been evaluated in the review of applications submitted in response to the previous iterations of the ITP. Several publications detailing the protocols and testing results have been published. Therefore, applicants may refer to and summarize protocols, statistical analyses, and Stages of the study to the extent they help understanding of the program and assessment of the other research activities of the program or if changes are introduced. Changes/modifications to existing protocols should be identified as such and described for evaluation in the renewal application. A single site may be chosen to perform the statistical analyses. That site should describe the methods for statistical analysis and plans for communicating across the three sites of the testing program and providing data to the ITP DCC.
Applicants must describe in detail plans for analysis of lifespan data from Stage I and Stage II studies. Plans for survival data analysis should include more than one statistical approach. NIH Biosketches for the statistical experts, and descriptions of their involvement in conduct of the studies and data analysis within the ITP should be included in the renewal applications.
Compound pilot studies. The research strategy should describe the methods selected to develop the formulations of compounds for testing. Strategy and timeline must be included for establishing drug stability during production, shipping, and storage. Experiments must be proposed that are sufficient to support the selection of initial dosage, including, but not limited to, determination of oral bioavailability, drug concentrations in the blood and other organs, as well as changes in the expression of target genes at least in the liver. Procedures for the assessment of drug toxicity must be described. Go/no-go criteria regarding compound(s) to be tested in Stage I must be discussed. A single site may be chosen to perform all or parts of the pilot studies. That site should describe the experimental procedures and plans for communicating across the three sites of the testing program and providing data to the ITP DCC.
Geropathology assessment. Standardized procedures for a cross-sectional geropathology assessment made at least one time point after starting the intervention and pathology assessment at the time of death should be described. Applicants should provide details regarding schedules and protocols for the collection of biospecimens (e.g., tissues, blood samples) as well as the preservation, storage, and geropathology assessment of treated and untreated mice used in lifespan studies. Applicants must propose and explain the rationale behind the protocols of choice for geropathology assessment, including number of mice evaluated, organ/tissue type, age(s) at collection, staining and field sampling methods, and tissue-specific grading systems used by veterinary pathologist(s). Description of statistical analyses on quantitative geropathology data should be included. A brief description of post-mortem pathology evaluations should also be included. A single site or contractor may be chosen to perform or contract for geropathology. That site should describe the experimental procedures and plans for communicating across the three sites of the testing program and providing data to the ITP DCC.
Transcriptomics. Applicants must describe protocols for cross-sectional transcriptomic analysis (“bulk” RNA sequencing), at least at one time point after starting the intervention, comparing age-associated gene expression changes in treated and untreated mice in the lifespan studies. The rationale for the selection of target organs and tissues, the time(s) at which they are collected, and the number of animals included per condition analyzed in the transcriptomic study must be described. Detailed protocols for organ/tissue collection, storage, RNA processing, sequencing, and plans for transcriptome analysis must be included. The sequencing approach and data analyses must be detailed. Approaches to harmonize mRNA sample preparation and storage protocols among the three testing sites must be described. Discussion of the experimental design and data analysis should be included. A single site or contractor may be chosen to perform the RNAseq. That site should describe the experimental procedures and plans for communicating across the three sites of the testing program and providing data to the ITP DCC.
Tissue collection for ancillary studies (Interventions Biospecimens Repository (IBR)). Biospecimens were collected and stored in previous iterations of the ITP. Samples were distributed through the Collaborative Interactions Program (CIP). With this cycle, a more formal Interventions Biospecimens Repository (IBR) will be established. Applicants should describe ongoing practices of biospecimen collection and storage as well as modifications to be implemented. Each procedure should be clearly identified as current or new. Applicants must identify and provide the rationale behind the biological materials to be harvested from animals in the ITP, specifying the age(s) in a life course study for collection, indicating whether during Stage I and/or Stage II, which tissues or organs are selected for the repository, and the protocols for processing and storage. When establishing the size of cohorts of mice treated with effective compounds and controls for biospecimen collection, past records of organ/tissue requests should be taken into consideration. Tissues should be collected using appropriately described methods of tissue preservation (e.g., flash frozen, frozen blocks, various fixation methods) and, based on current state-of-the-science, applicants should identify the compatible analytical/experimental platforms that could be used in follow-up studies (which will be pursued via application to the NIA – see Purpose and Research Objectives, above). Because the electronic inventory of collected and available tissues in the IBR will be accessible through the ITP sites, the ITP DCC, and the NIA website, a description of plans for making available to the ITP DCC and the NIA the list updated in real time of tissues in the IBR must be included in the application. Tissue collection is required from every site in the testing program, and each site must address this activity.
Applicants must describe how documentation of protocols, statistical approaches and stages of the studies as well as lifespan data will be made available to the ITP DCC and the NIA. Applicants should include plans and methods for sharing with the ITP DCC data from the pilot studies, including drug stability, blood levels and studies of optimal dose. Plans for providing the ITP DCC with information on samples for geropathology/pathology and all results from geropathology/pathology (including, when appropriate, images), and plans for sharing transcriptome data with the ITP DCC must be included.
All other aspects of the FOA remain unchanged.
Tiziana Cogliati, Ph.D.
National Institute on Aging (NIA)
Division of Aging Biology (DAB)
Telephone: 240-397-4596
Email: [email protected]
and Human Services (HHS)
