25-SOL-125_DRAFT_PROSPR ISO.pdf

ARPA-H-SOL-25-125, PROSPR

Innovative Solutions Opening (ISO) Draft

PROactive Solutions for Prolonging Resilience

(PROSPR)

Proactive Health Office (PHO)

ARPA-H-SOL-25-125

December 23, 2024

Table of Contents

1 Innovative Solutions Opening (ISO) Summary Information

1.1 ISO Purpose

1.2 ISO Questions and Answers

1.3 Proposers’ Day

2 PROGRAM INFORMATION

2.1 BACKGROUND

2.2 PROSPR PROGRAM DESCRIPTION AND SCOPE

2.3 TECHNICAL APPROACH AND STRUCTURE

2.3.1 APPROACH BY TECHNICAL AREA (TA)

2.3.2 PROGRAM STRUCTURE

2.3.3 PROGRAM METRICS AND TIMELINE

2.3.4 DELIVERABLES AND TRANSITION ACTIVITIES

2.3.5 PROSPR DATA SHARING PLAN

3 PROPOSAL AND SUBMISSION INSTRUCTIONS

3.1 GENERAL INSTRUCTIONS

3.2 SOLUTION SUMMARY INSTRUCTIONS

3.2.1 SOLUTION SUMMARIES DUE DATE

3.3 FULL PROPOSAL INSTRUCTIONS

3.3.1 PROPOSAL VOLUME TEMPLATES

3.3.2 MODEL OTHER TRANSACTION AGREEMENT

3.3.3 PROPOSAL TECHNICAL REQUIREMENTS

3.3.4 DATA MANAGEMENT AND SHARING PLAN (DMSP)

3.3.5 FULL PROPOSAL DUE DATE

4 PROPOSAL EVALUATION

4.1 EVALUATION CRITERIA

4.2 REVIEW AND SELECTION PROCESS

4.2.1 SOLUTION SUMMARIES REVIEW PROCESS

4.2.2 FULL PROPOSAL REVIEW PROCESS

4.3 HANDLING OF SELECTION SENSITIVE INFORMATION

5 GENERAL REQUIREMENTS

5.1 PROPOSING TEAMS

5.2 PROSPR PROGRAM MEETINGS AND ATTENDANCE

5.3 REPORTING

5.4 HEALTH DATA PROTECTION AND PRIVACY

5.5 ACCESSIBILITY REQUIREMENTS

5.6 DIVERSITY IN CLINICAL STUDY POPULATIONS

6 ELIGIBILITY INFORMATION

6.1 ELIGIBLE APPLICANTS

6.1.1 FEDERALLY FUNDED RESEARCH AND DEVELOPMENT CENTERS (FFRDCs) AND

GOVERNMENT ENTITIES

6.1.2 NON-U.S. ORGANIZATIONS

6.2 ORGANIZATIONAL CONFLICTS OF INTEREST (OCI)

6.3 AGENCY SUPPLEMENTAL OCI POLICY

7 AWARD INFORMATION

7.1 ISO PROCEDURE AND ACQUISITION STRATEGY

7.1.1 ACQUISITION STRATEGY

7.1.2 OTHER TRANSACTION (OT) AWARDS

7.2 AWARDS

7.2.1 GENERAL GUIDELINES

7.2.2 AWARD NOTICES

7.2.3 ADMINISTRATIVE AND NATIONAL POLICY REQUIREMENTS

7.2.4 SYSTEM FOR AWARD MANAGEMENT (SAM) REGISTRATION AND UNIVERSAL

IDENTIFIER REQUIREMENTS

7.2.5 CONTROLLED UNCLASSIFIED INFORMATION (CUI) OR CONTROLLED TECHNICAL

INFORMATION (CTI) ON NON-DOD INFORMATION SYSTEMS

7.2.6 INTELLECTUAL PROPOERTY

7.2.7 HUMAN SUBJECTS RESEARCH

7.2.8 ANIMAL SUBJECT RESEARCH

7.3 ELECTRONIC INVOICING AND PAYMENTS

7.4 GOVERNMENT-FURNISHED PRPERTY/EQUIPMENT

7.5 ASSOCIATE PERFORMER AGREEMENT (APA)

8 COMMUNICATIONS

8.1 ISO QUESTIONS AND ANSWERS

9 PROPOSERS’ DAY

10 APPENDIX

10.1 A: Associate Performer Agreement (APA)

9.2 APPENDIX B: Eligibility and Conformance Certification Sheet

10.2 APPENDIX C: Eligibility and Conformance Certification Sheet ...... Error! Bookmark not defined.

11 Attachment 1: OT Bundle Templates

1 Innovative Solutions Opening (ISO) Summary Information

Federal Agency: Advanced Research Projects Agency for Health (ARPA-H), Proactive Health Office (PHO)

Program Title: PROactive Solutions for Prolonging Resilience (PROSPR)

Announcement Type: Solicitation

ISO Solicitation Number: ARPA-H-SOL-25-125

Dates (all times listed are Eastern Time):

o Proposer’s Day: January 24, 2025 o Questions & Answers (Q&A) Due: January 31, 2025 o Solution Summary Due Date: February 10, 2025 o Full Proposal Due Date*: estimated as no later than March 24th, 2025

Anticipated awards: Multiple Other Transaction Agreements (OTs)

Agency Contact: All inquiries shall be sent to PROSPR@ARPA-H.GOV

*See ISO Sections 3 and 4 for additional information about Solution Summary and Full Proposal Submissions (e.g., to be eligible to submit a Full Proposal, a Proposer must have submitted a timely Solution Summary and received feedback from the government).

1.1 ISO Purpose

ARPA-H seeks proposals from all eligible entities (see Section 3, Eligibility Information) to accomplish the PROSPR program goals as described in this solicitation package. Ultimately, ARPA-H intends to negotiate multiple OT Agreements with Proposers whose proposals are most advantageous to the government.

1.2 ISO Questions and Answers

All questions regarding this ISO must be submitted to PROSPR@arpa-h.gov. ARPA-H will post Q&As to the PROSPR program website on an on-going basis and will not respond to questions directly. All questions must be submitted in English and must include the name, e-mail address, and telephone number of a point of contact. Proposers submitting questions to individual government team members (e.g., Program Manager) should not expect a response. ARPA-H will attempt to answer questions in a timely manner; however, questions submitted after the Q&A due date may not be answered. Further, duplicative questions may be combined and rephrased to streamline responses.

1.3 Proposers’ Day

mailto:POSEIDON@ARPA-H.GOV

ARPA-H is intending to host a Proposers’ Day on January 24, 2025 in support of the PROSPR program and details will be posted in the Special Notice (ARPA-H-SN-25-125) on SAM.gov.

The purpose of the event is to provide potential Proposers with information on the PROSPR program, promote discussion, and encourage team networking. Interested Proposers are not required to attend; materials formally presented at the Proposers’ Day will be posted to www.SAM.gov.

ARPA-H will not reimburse potential Proposers for participation at the Proposers’ Day (nor for time and effort related to the submission of Solution Summaries or full proposals).

2 PROGRAM INFORMATION

2.1 BACKGROUND

Despite major advances in scientific discovery and clinical interventions that have added years to life expectancy, there has not been a corresponding increase in healthspan, the number of years spent in good health. Instead, the prevalence of chronic diseases in American adults has dramatically increased, particularly worsening with age. In the United States and elsewhere, medicines and scientific research are heavily focused on reactionary, post-symptomatic illness treatment, despite overwhelming evidence that early interventions are far more effective, and many diseases are preventable.

The Proactive Health Office (PHO) at ARPA-H is seeking solutions to extend the healthspan for Americans, with a focus on interventions aimed at early disease prevention. The PHO believes that population-level improvements in access to and adoption of disease prevention and wellness-promoting behaviors, novel early-detection methods, and prophylactic interventions could drastically improve Americans’ health throughout their lives, and that system-level innovations are required for effective proactive health delivery.

In the United States, age-related chronic diseases come with an annual healthcare cost burden of nearly $1 trillion. The healthcare costs for the aging population is projected to increase by 75% if nothing is done to prevent the progressive loss of physical functioning during aging, according to a Pew Research Center Study, which will place an immense strain on our healthcare and economic resources. Currently, no preventive treatments exist for the general health decline that inevitably occurs during aging and geriatric medicine remains focused on post-symptomatic treatments.

Four major factors limiting progress in healthspan extension have been identified:

1. Health decline during aging is accepted as normal.

Aging is the most significant risk factor for a variety of diseases and yet age-associated health decline is not researched nor treated like other risk factors, such as hypertension or pre-diabetes. A major contributor to the acceptance of fatigue, muscle weakness, reduced memory, worsening hearing and vision, and many other non-disease symptoms as a “normal” part of aging, is likely because we lack therapeutic options to prevent these general health declines. However, considering that some individuals maintain excellent health far longer than others, it is clear aging does not automatically necessitate poor health and accumulation of disease but rather extending healthspan for the majority should be possible. In fact, animal http://www.sam.gov/ https://www.pewresearch.org/short-reads/2024/01/09/us-centenarian-population-is-projected-to-quadruple-over-the-next-30-years/#:%7E:text=There%20are%20currently%20roughly%2062,estimated%2023%25%20of%20the%20population https://www.pewresearch.org/short-reads/2024/01/09/us-centenarian-population-is-projected-to-quadruple-over-the-next-30-years/#:%7E:text=There%20are%20currently%20roughly%2062,estimated%2023%25%20of%20the%20population studies with parabiosis, exercise, and caloric restriction demonstrate that a youthful healthy state can be maintained in older ages.

2. Geriatric medicine focuses on post-symptomatic disease treatments.

Because the early decline in health during aging is not the focus of geriatric medicine, much of the progress in healthspan research has been incidental, following specific disease targeting. This roundabout fortuitous approach slows larger-scale advancements. Aging is now known to involve systemic changes such as increased inflammation and metabolic dysfunction, which often precede age-related diseases. Drugs like Rapamycin, Ozempic, and Metformin have shown pleiotropic effects, though most studies are limited to individuals with various diseases. Our lack of attention to the aging community before significant ailments arise contributes to a limited understanding and lack of therapeutic options for the health declines that begin for many in their 40s.

3. Clinical trials are too costly and time-consuming for age-induced health outcomes.

Clinical trials are not feasible for most researchers and biotech companies despite a growing interest in therapeutics that facilitate healthy aging. For this reason, scientists are forced to conduct studies with shorter outcomes, such as those in age-related diseases after the onset of symptoms. A clinical trial with healthspan changes as the outcome could take 20-50 years, as this is time required for a typical 35-year-old to develop recognized clinical endpoints such as mortality or accumulation of disease. Considering the average clinical trial for diseases costs about $2 billion to conduct, a healthspan study could cost well over $6 billion.

4. Lack of validated surrogates for healthspan.

The major limiting factor that contributes to the cost and time requirements for human clinical trials on healthspan is the designated clinical endpoint. For some diseases, a surrogate biomarker can be demonstrated to accurately predict the clinical endpoint and can be approved by the FDA as a validated surrogate clinical endpoint. If we had a validated surrogate endpoint for long-term, age-induced outcomes, we could dramatically reduce the time and cost required for these trials. One way to measure age-induced general health is through intrinsic capacity (IC), a score generated by assessing a wide-range of physical and mental abilities. IC progressively declines with age, transitioning from peak physical health and highly functioning systems in young adulthood to a frail state or diseased state until death. Low IC has recently been demonstrated to roughly correlate with an increased risk of future chronic disease development. Blood-derived biomarkers, particularly those associated with inflammation and metabolism, have shown promising correlations with IC in older adults.

However, IC studies are in their infancy, being performed in small scale, short duration studies and have not been used to generate a 20-year mortality or morbidity prediction. Further, the generalizability of current IC research is limited by low population diversity and minimal data from adults younger than 60. Now that initial studies have demonstrated the potential of IC to predict health outcomes, standardization and refinement of IC measures and analysis on a larger scale are necessary to enable their implementation in clinical and healthcare settings.

While these challenges are significant, there is progress being made in each area that will serve as the basis for exponential growth through the PROSPR program.

2.2 PROSPR PROGRAM DESCRIPTION AND SCOPE

The PROSPR program aims to develop interventions that extend healthspan by 20 years by targeting the underlying causes of age-induced health loss and thereby prevent the onset of multiple age-related diseases simultaneously.

To facilitate the study and testing of healthspan interventions, PROSPR will first reduce the time and cost investments that currently prevent a thriving healthspan therapeutics industry from developing. By directly demonstrating that human age-induced health outcomes can be predicted by biochemical and physiological measures in a single composite IC score, PROSPR will remove the need for 20-year clinical efficacy trials. By focusing second-generation interventions on those that target early health loss, PROSPR aims to preserve health in aging individuals before chronic diseases can develop. This will transform geriatric medicine into a personalized, comprehensive, preventive care model.

2.3 TECHNICAL APPROACH AND STRUCTURE

The PROSPR program has established detailed objectives for each Technical Area (TA) in Table 1, and quantifiable and qualitative program metrics for each TA in Tables 2-5. Table 5 lists deliverables for each TA. Status reports outlining technical and financial updates from performers will be required at meetings with the Program Manager (PM). ARPA-H may request performer data as deemed necessary throughout the program to validate technical progress.

These updates, in comparison to the metrics and milestones below, will be used to evaluate the progress of performer teams and their success within each phase. Performers will be required to coordinate within their team and with other performers, as directed by ARPA-H, the PROSPR PM and the agreed upon contract.

2.3.1 APPROACH BY TECHNICAL AREA (TA)

PROSPR is a 5-year program which aims to provide all Americans 20 additional years of good health as they age by developing new therapies and creating the data to allow short-duration clinical trial capability that predicts long-term health outcomes. The PROSPR TAs are as follows and each include sequential Phases

Technical Area 1 (TA1): PROSPR intrinsic capacity score (see Table 2 for metrics)-60 months

• TA1 Phase I (12 months) includes developing IC score (v1.0) and IC assessment technology (v1.0) and preparing for a clinical observational study to measure IC score.

• TA1 Phase II (12 months) includes refinement of IC score (v1.1) and IC assessment technology (v1.1) using data from the clinical observational study.

• TA1 Phase III (12 months) includes conducting a lifestyle intervention study to test the intervenability of IC score (v1.2) and detection capacity of the IC technology (v1.2).

• TA1 Phase IV (12 months) includes refining IC score (v2.0) and IC assessment technology (v2.0) using data from lifestyle intervention study.

• TA1 Phase V (12 months) focuses on deployment and commercialization.

TA1 will define a single score (PROSPR IC) comprised of human physiological and biochemical components, that predicts 20-year health outcomes. Performers will harmonize existing human datasets (see metrics for details) to identify the weighted contribution of each IC component to an overall, sex-specific PROSPR IC score. Performers can include any number of physiological and biochemical components in their initial testing but must at least include all five components of WHO-defined IC and DNA methylation. Components should be included or excluded in the final composite PROSPR IC score based on their contribution to the accuracy of the score to predict 20-year health outcomes. TA1 will label the PROSPR IC score as an improved version of intrinsic capacity to leverage the existing ICD-11 (Internal Classification of Disease-11) code, accelerating its clinical use. Once a composite PROSPR IC score is generated, TA1 performers will build the technology necessary for in-home PROSPR IC measurement (in-home PROSPR IC assessment technology). PROSPR envisions a digital health platform (app) that connects with common existing health monitoring devices and wearables to assess different components of the PROSPR IC score. The platform will include methods for minimally-invasive collection of biological samples as necessary, such as blood spots or saliva, for DNA methylation and other biochemical analyses. This platform must also provide educational information in easy-to-understand language to promote health ownership.

TA1 will validate and enhance the accuracy and user-friendliness of the in-home PROSPR IC assessment technology in a 1-year study (PROSPR study). Participants will report monthly PROSPR IC score with the in-home PROSPR IC assessment technology, while clinicians conduct the same assessments during clinic visits at baseline, six months, and at the end of the study.

Each participant must be assigned a coach to virtually assist with the technology, facilitate regular engagement, and provide feedback to the performers. Starting with version 1.0, the PROSPR IC score will undergo iterative updates, progressing to version 2.0 by the end of the program. Each version will incorporate refinements and improvements based on data collected from participants in the PROSPR study, enhancing the predicative accuracy of the score over the course of the study.

To demonstrate the intervenability of the PROSPR IC score, at the end of the PROSPR study, a subset of participants will be recruited to continue in a one-year multimodal life-style intervention trial (PROSPR lifestyle intervention study). The lifestyle intervention must include at least four of the following lifestyle management options for participants, weighted for their needs established during the PROSPR study: diet, exercise, stress, social engagement, sleep, poor habit management, mental health, or others. After the one-year PROSPR lifestyle intervention study, participants will continue to report their PROSPR IC score for an additional year without the coach to determine whether the PROSPR IC score remains improved, returns to baseline, or follows another trajectory.

Additionally, TA1 performers will collaborate with TA2 performers as they further validate the responsiveness of the PROSPR IC score to pharmacological intervention in a phase 3 clinical trial with FDA-approved drugs (see TA2 Track 2b). TA1 performers will present the data to the FDA to demonstrate that the PROSPR IC score is responsive to multiple interventions that improve health outcomes and is therefore suitable for use as a validated surrogate endpoint.

Additionally, TA1 performers will work with ARPA-H PATIO and its partners to commercialize the in-home PROSPR IC score assessment technology. Commercialization efforts will focus on making the technology affordable for consumers and deployable in health system workflow.

Technical Area 2 (TA2): Repurposing FDA-approved interventions for healthspan extension (see Table 3 for metrics)-60 months

• TA2 Phase I (12 months) includes identifying intervenable biomarkers and preparing for a phase 3 decentralized clinical trial for drug repurposing.

• TA2 phase II (12 months) includes finalizing clinical trial study requirements and sharing identified biomarkers.

• TA2 Phase III (12 months) focuses on conducing the phase 3 decentralized clinical trial.

• TA2 phase IV (12 months) continues data collection and monitoring.

• TA2 phase V (12 months) concludes phase 3 trial and involves engaging with the FDA for regulatory approval.

TA2 will accelerate the creation of a healthspan industry by identifying healthspan extension biomarkers and providing first generation therapies using FDA-approved pharmacologics.

First, TA2 performers will conduct comprehensive omics analysis on blood samples previously collected from multiple existing clinical trials with demonstrated broad health improvements to identify biochemical markers (genes, metabolites, proteins, etc.) consistently responsive across interventions. These biomarkers will be shared with TA1 performers for potential inclusion in the composite PROSPR IC score.

Second, TA2 performers will strategically repurpose FDA-approved drugs with excellent long-term safety profiles for testing in a 3-year, phase 3 randomized clinical trial, conducted in a decentralized manner (DCT). Drug candidates will be selected based upon compelling evidence of their ability to reduce multimorbidity in humans or on strong preclinical data demonstrating improvements in healthspan, frailty, or lifespan. Up to two interventions will be selected to test their efficacy in improving PROSPR IC, the biomarkers identified in phase 1 of TA2, and health outcomes in 60-year-old participants. Beyond accelerating the development of healthspan extension therapeutics, TA2 in collaboration with TA1, will demonstrate that the PROSPR IC score is responsive to interventions that result in age-induced health outcomes.

Additionally, TA2 will establish a consensus around decentralized clinical trials for aged, non-diseased populations, improving participant retention and engagement.

Technical Area 3 (TA3): Second-generation interventions (see Table 4 for metrics)-54 months

• TA3 Phase I (18 months) includes pre-clinical validation using aged animal models.

• TA3 Phase II (18 months) includes IND-enabling studies to evaluate the safety, pharmacokinetics, and behavior of second-generation interventions.

• TA3 Phase III (6 months) focuses on establishing IRB approval and preparing for clinical trial.

• TA3 Phase IV (12 months) focuses on the first-in-human clinical testing of second-generation intervention to assess safety and efficacy in a Phase 1b clinical trial.

TA3 focuses on identifying the most efficacious interventions that can extend human healthspan. TA3 performers will propose interventions with strong evidence of extending healthspan, lifespan, or reducing frailty symptoms in pre-clinical rodent models. Performers must provide evidence of optimized intervention delivery and address treatment-specific challenges to enable long-term use in animals as part of the supporting data in their proposal.

In phase 1, TA3 performers will conduct a 1-year study of their intervention in outbred rodents, evaluating the efficacy of the intervention to maintain or improve health (cognitive ability, metabolic function, muscle strength, immune function, cardiovascular function, sensory function, etc.) during aging. TA3 performers must ensure reproducibility of results through external validation by an independent group at an independent research site. TA3 will assess model health using a method they develop to test components of the PROSPR IC, as closely identified in TA1, ideally using automated, non-subjective measures. Innovative therapeutics with the highest safety profile and greatest efficacy in aged animal models will be prioritized for the phase 1b human clinical trials conducted within this TA. Performers may propose various interventions such as small molecules, organelle transplant, or lifestyle mimetics.

The overall program goals are listed in Table 1, metrics and timeline are listed in Tables 2-4.

In addition to frequent performance reviews throughout the phases, performers must provide an end-of-phase report that summarizes all efforts and data for each completed PROSPR phase.

Table 1: The general program objectives by TA

TA1: PROSPR IC

Score:

Predict 20-year health outcomes

• Harmonize existing datasets to identify key physiological and biochemical changes of age-induced health outcomes.

• Develop a sex-specific PROSPR IC score for predicting 20-year mortality and multi-morbidity outcomes.

• Build in-home PROSPR IC assessment technology for consistent monitoring of health and allow proactive health management.

• Establish a multi-modal decentralized or hybrid lifestyle intervention study to collect data on the responsiveness of the PROSPR IC score and biochemical markers (from TA2) to lifestyle interventions.

• Collect empirical evidence demonstrating that these lifestyle interventions can improve or maintain general wellness in relatively healthy, aging individuals.

• Engage with the FDA to advance PROSPR IC and biochemical markers toward validated surrogate endpoint designation in collaboration with TA2.

• Engage with the FDA to obtain approval of in-home PROSPR assessment technology.

• Commercialize PROSPR IC assessment technology (<$100 out of pocket)

• Begin strategies for securing insurance coverage to enable early health intervention and preventive care.

TA2: Repurposing FDA-approved interventions:

Accelerate creation of a healthspan industry

• Identify common biochemical changes shared between multiple health improving drugs using omics data from blood samples obtained from existing clinical trials.

• Demonstrate the utility of PROSPR IC (from TA1) and biochemical markers as surrogate endpoints in place of disease accumulation or mortality in phase 3 clinical trials.

• Utilize repurposed drugs to provide first-generation healthspan therapeutics and generate the clinical data necessary for establishing feasibility of short-term efficacy trials for healthspan extension.

• Build a consensus on decentralized trials for non-diseased populations.

TA3: Second-generation interventions:

Extend human health by 20 years

• Test second-generation interventions that target age-related health decline through rigorous efficacy and safety preclinical trials.

• Develop a preclinical method in rodents to assess the components of PROSPR IC as closely as identified in TA1.

• Test safety and efficacy of candidate intervention in Phase 1b human clinical trial.

Accessibility Requirements

Performers must develop solutions that account for health inequalities, considering cost and accessibility of care, and ensure protection of all protected groups. These considerations must be addressed prior to program onset.

2.3.2 PROGRAM STRUCTURE

The PROSPR program structure is based on the timeline shown in Figure 1. PROSPR will depend on multidisciplinary teams to bring expertise in various scientific domains and technologies and has been designed to transfer information across the TAs. Performers may submit proposals that address any one of three TAs or can combine more than one TA or sub-tracks to address broader, multi-disciplinary challenges. However, regardless of the number of TAs included in the proposal, performers must plan for integration and data sharing with other teams. Any performer that does not meet the accessibility, data sharing plan, and attendance requirements may not progress to subsequent phases. Progression into future phases is determined by the ARPA-H PM and is based on funding availability, performer progress toward phase metrics and probability of success in future phases. Performers who remain in the program must continue to meet all the required metrics, including the following integration areas:

• TA1 performers will provide PROSPR IC technology to TA2 performers before the end of Phase 2 to use in their phase 3 clinical trial design using FDA-approved repurposed drugs. Data from this trial will support the designation of PROSPR IC as a surrogate endpoint to shorten timelines for healthspan extension trials.

• TA1 performers will provide PROSPR IC technology to TA3 performers before the end of TA3 Phase IV to incorporate measures into phase 1b clinical trial of second-generation intervention design.

• TA1 Track 1a and Track 1b performers will collaborate for the duration of the program to coordinate the PROSPR IC score with the assessment technology.

• TA2-Track 2a performers will share identified biochemical biomarkers with TA1 and TA2-Track 2b performers during TA2 Phase 2 (see below) to allow performers to validate these biomarkers as surrogate endpoints in the lifestyle intervention trial and phase 3 trial for FDA-approved drug repurposing, respectively.

• TA1 performers are responsible for preparing the FDA submission package for PROSPR IC and biochemical markers as validated surrogate endpoints. All PROSPR performers are required to share data with TA1 performers for the FDA discussions as needed.

TA1: PROSPR-IC score: Predict 20-year health outcomes TA1 will include two interconnected tracks, outlined below. Performers will have the option of submitting a single proposal addressing a single track or combined tracks. Assuming equal capabilities and proposal plans, preference will be given to proposals that cover both TA1 tracks. ARPA-H may choose to fund only a portion of the proposal. All performers are expected to collaborate with each other throughout the life of the program and will therefore have Associate Performer Agreement (APA) language included in their respective award; see Appendix A.

Track 1a (PROSPR IC score): This team will be responsible for developing the PROSPR IC score by harmonizing data from existing longitudinal studies with physiological and biochemical measurements from adult (35 – 64 years old) and elderly (65+ years old) individuals. In year 2, Track 1a will validate and improve the accuracy of the PROSPR IC score using data provided by the decentralized or hybrid study conducted by Track 2b performers (see below). In years 3 and 4, Track 1a will validate the intervenability of the PROSPR IC using data provided by the multi-modal lifestyle intervention clinical trial conducted by Track 1b performers (see below).

Additionally, Track 1a performers will collaborate closely with Track 1b to guide technology development based on the components of the PROSPR IC score identified during the data harmonization in year 1. They will continue to guide refinements in later phases as the score improves.

Throughout the duration of the program, performers will discuss the data and prepare submission packages for the FDA, for surrogate endpoint designation of PROSPR IC and biochemical surrogates. .

Track 1b (PROSPR IC assessment technology): In year 1, Track 1b performers will incorporate insights gained from the components of PROSPR IC score from Track 1a to develop PROSPR IC assessment technology. Upon development and distribution of PROSPR in-home assessment technology, performers will test the accuracy and user-friendliness to measure PROSPR IC in a one-year decentralized or hybrid PROSPR study. Proposals will be accepted from performers seeking to extend already existing large-scale longitudinal studies of human measures, provided they add the PROSPR TA1 track 1b study requirements (see Table 2).

Feedback on IC assessment technology accuracy, usability, and user-friendliness from participants in the TA1 track 1b PROSPR study will be continuously integrated into the refinement of the IC assessment technology. Starting with version 1.0, the technology will evolve through iterative updates, including milestones such as version 1.1 and 1.2, leading to version 2.0 by the end of the TA1 track 1b study. Each version will incorporate refinements and improvements based on participant feedback, ensuring the technology is progressively optimized throughout the study.

In year 3, Track 1b performers will recruit a subset of participants from the TA1 track 1b PROSPR study into a 1-year in-home lifestyle intervention study with continued PROSPR IC monitoring facilitated by a coach and using the PROSPR IC assessment technology. The lifestyle intervention will end in year 4, and performers will continue to collect participants’ PROSPR IC with PROSPR IC assessment technology to determine if health improvements are sustained or return to baseline.

In year 5, performers will work with ARPA-H PATIO to commercialize the IC assessment technologies and discuss approval of the PROSPR IC assessment technology with the FDA for clinical and in-home use of the IC assessment for patient IC measurement. Further, track 1b performers will work with payers to develop a strategy for covering the consumer costs and propose a plan for in-home screening and monitoring outside the FDA-regulated clinical diagnosis pathway.

Note: Annual discussions with the FDA are a requirement for TA1 (track 1a and 1b) performers to advance to the next phase of the program. The FDA encourages early engagement so that they may provide guidance on where additional data may be needed for validation. TA1 performers must provide an update on their progress with these FDA interactions to the PROSPR PM as part of the quarterly status meetings.

TA2: Repurposing FDA-approved interventions TA2 will include two tracks, outlined below. Performers will have the option of submitting a single proposal addressing a single track or combined tracks. TA2 track 2a findings will be shared with TA2 track 2b and TA1 track 1a for validation in clinical trials. Track 2b funding will begin in the third quarter of year 1 (Y1Q3). All TA2 track2a and 2b performers are expected to collaborate with each other throughout the life of the program. Therefore, TA2 track2a and 2b performers will have Associate Performer Agreement (APA) language included in their respective award; see Appendix A.

Track 2a (Biochemical markers): Performers will collect clinical data and blood samples from existing clinical trials where a therapeutic intervention has demonstrated improvements in multi-morbidity. We encourage performers to consider trials of the following treatments:

rapamycin, metformin, GLP-1, acyclovir, naltrexone, and somatostatin. Performers must have letters from trialists agreeing to share the stored blood samples for omics analysis. Track 2b will conduct comprehensive omics analyses on these blood samples to identify biochemical changes during an 18-month funding period. Throughout the funding period, Track 2a will collaborate closely with TA1 track 1a and 1b performers to integrate identified biochemical markers into the TA1 track 1a-developed PROSPR IC score and TA track 1b-developed PROSPR study design. The biochemical markers identified by Track 2a will be tested by Track 2b in a Phase 3 clinical trial using FDA-approved drugs to determine whether the biomarkers are responsive to these interventions.

Track 2b (FDA-approved drugs): TA2 track 2b performers will identify two FDA-approved drugs with strong safety data and evidence of multimorbidity reduction in humans or evidence of healthspan, frailty, or lifespan improvement in preclinical animal models and conduct a decentralized clinical trial collecting TA1 track 1a-developed PROSPR IC at regular intervals.

Track 2b performers will work with the FDA on decentralized clinical trial design and validated surrogate endpoints for healthspan. Track 2b performers will also share IC data with Track 1b team during the clinical trial to allow Track 1b to determine whether PROSPR IC is responsive to pharmacological interventions in humans.

TA3: Second-generation pharmacological interventions TA3 will include 4 teams with funding beginning in the third quarter of the first year (Y1Q3).

TA3 performers are expected to collaborate and share data, both among the TA3 performers (specifically the preclinical method of IC assessment) and with performers in TAs 1 and 2 to ensure the overall success of the program. Therefore, performers will have Associate Performer Agreement (APA) language included in their respective award; see Appendix A.

During TA3 phase I, performers will test their intervention in outbred rodents in a one-year study to thoroughly assess the safety and efficacy of each intervention in preserving or improving animal health during aging. This phase also includes development of preclinical IC component measures that closely align with the human PROSPR IC score defined in TA1.

Although each team is responsible for developing pre-clinical IC measures, the PROSPR PM may require performers switch to another team’s rodent PROSPR IC protocol at any time during the program. The down-selection process for TA3 teams will occur in two phases: the first at the end of the phase I (Y2), and the second at the conclusion of IND-enabling studies (Y4).

Ultimately, only one team will be selected to proceed to human clinical trials. The final team must work with TA1 and TA2 performers at least six months before the end of Y4 to incorporate TA1 track1a-developed PROSPR IC and biochemical surrogates into their clinical trial design.

Figure 1: The PROSPR Timeline and TA interactions. Note: TA3 is a single track with four initial teams, represented by 3.a, 3.b, 3.c, 3.d.

2.3.3 PROGRAM METRICS AND TIMELINE

The metrics illustrated in Tables 2-4 will be used to track progress throughout the duration of the program. Performers will be required to formally report progress against these metrics on a quarterly basis or as needed to the PROSPR PM and to the designated collaborating team(s).

Technical progress toward the program metrics, data sharing, and collaboration with teams from other TAs are significant factors for continuation into subsequent phases.

Table 2: Expected milestones and metrics per phase in TA1 (PROSPR IC score)

12 months TA1 Phase I (v1.0 development)

Start End Milestones

Y1Q1 Y1Q4

Develop PROSPR IC Score v1.0

• Ingest existing longitudinal databases with physiological measures and long-term health outcomes from multiple studies.

• Harmonize the data to identify IC components and utilize machine learning to account for missing components in each individual dataset. Include any new measures or defined subdomains not previously considered.

• Perform DNA-methylation or other sequencing and analysis using existing biospecimens with linked clinical data, if necessary.

• Determine the weighted contribution of each IC component and generate a composite sex-specific PROSPR IC score.

Establish PROSPR study

• Establish SOP for collecting IC measurements, biospecimen, and analysis.

• Establish a decentralized study to measure PROSPR IC from >1K diverse participants aged 35-75.

• Obtain IRB approval for PROSPR study.

• Train clinical staff for new study protocol.

• 100% completion of electronic informed consent from all participants.

• Establish ID links between study participants and wearables

• Recruit patients with no chronic health conditions, non-extreme end BMI, and no cognitive dysfunction with diversity requirements as described in Section 4.7.

Develop in-home PROSPR IC assessment tech v1.0

• Develop in-home PROSPR IC assessment technology, focusing on user interface design, wearables and sensor integration, and real-time data processing capabilities for use in the decentralized PROSPR study.

• Develop methods to collect biospecimens (blood spot, saliva, sweat, etc.) for biochemical analysis (e.g. DNA methylation, proteomics, etc.).

Specifications

PROSPR IC

score (v1.0)

Metrics

• Must ingest data from at least three of the following databases: Canadian Longitudinal Study of Aging (CLSA), All of Us, Baltimore Longitudinal Study of Aging (BLSA), Mass General Brigham Biobank, Coronary Artery Risk Development in Young Adults (Cardia), and UK Biobank.

• Combined data from study participants must be generalizable and include adult datasets starting from at least 35 years of age.

• IC measures must include validated assessments for each of the five IC subdomains: cognition, locomotion, vitality, sensory, psychological capacities.

• Minimum IC indicator factor loading ≥ 0.3 with no significant cross-loading.

• PROSPR IC score must show a clear distribution across different age groups in adults >35.

• Capability Demo (v1.0): 20-year mortality or multi-morbidity prediction, AUC ≥ 0.90, 95% CI, R2 ≥ 0.5.

Additional requirements

• IC measures must be compatible with digital health platforms, including wearables, to enable continues monitoring and data sharing.

• IC measures that require biospecimen collection should prioritize non-invasive methods (e.g. blood spots or saliva) with minimum assessment time.

• Demonstrate reliability and high internal consistency of measures.

• Validate PROSPR IC score against multiple outcomes, including functional ability, hospitalization, multi-morbidity, and mortality.

• Components of PROSPR IC should be weighted independently for females and males to generate a sex specific composite PROSPR IC score.

• PROSPR IC score must be composite that combines physiological measures and biochemical data as identified to contribute to 20-year health outcomes.

• Database study participants must reflect diverse ethnicities, genders, and socioeconomic statuses, and geographical regions.

PROSPR

study

Metrics

• Must account for collecting PROSPR IC and biological specimen from at least 1k participants (35-75yr) in a decentralized manner with an attrition rate < 15%.

• Study must include coaches to support participants with technology orientation and conduct regular check-ins, at least once every three months.

Additional requirements

• Must use in-home PROSPR IC assessment tech (v1.0) to measure PROSPR IC score (v1.0) monthly over the course of 1 year. These assessments must align with the tests performed by a clinician at baseline, 6 months, and at the end of the study.

• Plan for blood draws and other biospecimen collection during at-home or clinic visits.

• PROSPR study participants must reflect diverse ethnicities, genders, and socioeconomic statuses, and geographical regions.

In-home

PROSPR IC

assessment tech (v1.0)

Metrics

• Real-time data synchronization (≤ 5 sec) and analysis capabilities (≤ 10 sec) with ≤ 99.9% uptime.

• User-friendliness aiming for Task Success Rate (TSR) >80%, a low (2-5 min) Time to Task (TOT), anduser satisfaction rating ≥ 3.5/5.0 using standardized questionnaire to assess overall usability and navigation.

• Scalable to support at least 4K participants.

Additional requirements

• Must integrate with various available wearable devices and sensors to assess the physiological components of PROSPR IC v1.0.

• Include error detection and correction system for data quality assurance (QA).

• Include methods for collecting non-invasive biospecimens, (e.g. blood spot, saliva, etc.) for biochemical analysis.

• Include a patient education platform that explains each component of PROSPR IC (v1.0), the meaning of scores, and the significance of score changes in lay terms.

• Must ensure data privacy and security and compliance with data protection regulations.

• Should provide options for data sharing with healthcare providers and researchers with user consent.

• Must have a plan for software updates and feature enhancements based on user feedback and technological advancements.

• Must be compatible with decentralized study protocols.

• The cost of v1.0 should be justifiable and aligned with established metrics for device evaluation.

Additional requirements

• Data security and protection measures must meet industry regulations (e.g., HIPAA, GDPR) and data governance best practices.

• Data must be stored by performer and accessible and interoperable with ARPA-H data commons.

• Use standard data formats and APIs to ensure interoperability with the ARPA-H Data Commons, continuity of data use, and measurement of long-term health outcomes.

• Data should be collected, stored, and managed using industry standard data models or formats (e.g. OMOP, CDSIC, LinkML, etc for electronic health records; FASTA, VCF, etc for genomic data; DICOM for radiography imaging).

• Make data FAIR (findable, accessible, interoperable, reusable), preference is for standard and open APIs such as FHIR, the Global Alliance for Genomics and Health (GA4GH) APIs (DRS, Passports, Phenopackets, etc), or similar access mechanisms.

Deliverable

• Secure storage of PROSPR IC score (v1.0) data in cloud infrastructure.

• In-home PROSPR IC assessment technology (v1.0) delivered to participants of the PROSPR IC study.

• Establishment of PROSPR IC study.

• ML models for data imputation and feature inference packaged.

• Approved IRB study protocol before the end of Phase I.

• Clinical procedures and SOPs drafted.

• Report outlining study protocol and analysis.

• Authentication procedures for ARPA-H researchers to access data established.

12 months TA1 Phase II (v1.1 development)

Start End Milestones

Y2Q1 Y2Q4

• Begin decentralized data collection from participants.

• Conduct regular check-ins (at least once every three months) with participants to encourage consistent engagement with the technology and improve participant retention.

• Validate the accuracy and reproducibility of PROSPR IC score (v1.0) with emergent data from PROSPR IC study.

• Refine and enhance the accuracy of PROSPR IC score (v1.1) by the end of Phase II.

• Determine the detection accuracy of the in-home PROSPR IC assessment tech (v1.0) with emergent data from PROSPR study.

• Enhance detection accuracy and improve features of the in-home PROSPR IC assessment tech (v1.1) based on emergent data and user feedback by the end of Phase

II.

Specifications

PROSPR IC

score (v1.1)

Metrics

• Capability Demo (v1.1): 20-year mortality or multi-morbidity prediction AUC ≥0.95, 95% CI, R2 ≥ 0.5.

• Similar AUC (±0.05) when analyzing different age groups.

• Similar AUC (±0.05) when analyzing males and females.

Additional requirements

• Individual IC measurements must remain statistically correlated with changes in PROSPR IC score (v1.1).

• Use TA2 intervenable biochemical surrogates to inform any refinements to the in-home PROSPR IC assessment technology (v1) for measuring new markers, if applicable.

PROSPR IC study

• Maintain attrition rate < 15%.

• ≥ 80% data completion for all data sources.

• Maintain robust quality assurance measures to ensure high inter-rater reliability ICC ≥ 0.75 and data consistency ≥ 90% across all sources throughout the study.

In-home PROSPR-IC assessment tech (v1.1)

• Data accuracy and consistency: ≥80% correlation between device measurement and clinician assessments, measurements should yield at least 90% consistency over repeated trials.

• Reliability: ≥ 95% successful sync rate with wearable devices and sensors, and ≥ 99% uptime.

• User experience: user satisfaction rating ≥ 4.0/5.0 on standardized usability scales. Task Success Rate (TSR) >80%, low (2-5 min) Time to Task (TOT) (Note: user experience should demonstrate progressive improvement throughout the program, if necessary).

Additional requirements

• Determine whether TA2-identified biomarkers can be validated using samples collected from PROSPR study participants by the end of Y2 to establish baseline measures.

Deliverable

• PROSPR IC score (v1.1) with enhanced accuracy based on newly collected data.

• In-home PROSPR IC assessment kit (v1.1) with improved features.

• Completed 1 year of study with ~1K diverse participants.

• Baseline data collected and logged for all participants throughout the 12-month study.

• In-home PROSPR IC assessment technology (v1.1) delivered to participants of the TA2 clinical trial.

12 months TA1 Phase III (v1.2 development)

Start End Milestones

Y3Q1 Y3Q4

• Begin data collection from participants in intervenable lifestyle study.

• Determine intervenability of PROSPR IC score (v1.1) with emergent data from lifestyle effects.

• Refine and enhance the accuracy of intervenable PROSPR IC score with emergent data on lifestyle effects by the end of Phase III (v1.2).

• Assess detection accuracy of in-home PROSPR IC assessment tech (v1.1) with emergent data on lifestyle effects.

• Enhance detection accuracy and improve features of the in-home PROSPR IC assessment tech based on emergent data and user feedback by the end of Phase III (v1.2).

• Continuously improve and adapt coaching and educational features based on user feedback, usage patterns, ratings, and emerging data quality.

• Conduct regular check-ins (at least once every three months) with participants to encourage consistent engagement with the technology and improve participant retention.

• Determine whether TA2-identified biochemical markers of health improvement are changed in the PROSPR lifestyle intervention study participants.

Metrics Specifications

PROSPR IC

score (v1.2)

Metrics

Capability Demo (v1.2): 20-year mortality or multi-morbidity prediction AUC ≥0.95, 95% CI, R2 ≥ 0.5.

• Similar AUC (±0.05) when analyzing different age groups.

• Similar AUC (±0.05) when analyzing males and females.

• Determine whether TA2 intervenable biomarkers are changed in samples collected from PROSPR lifestyle intervention participants by the end of Y3. AUC ≥ 0.70 in predicting lifestyle intervention response. Correlation coefficient ≥ 0.5 between biomarker changes and clinical outcomes.

• Determine whether TA2 intervenable biomarkers are changed in samples collected by TA2-Track2b from participants in the phase 3 drug-repurposing clinical trial by the end of Y3. AUC ≥ 0.80 in predicting pharmacological intervention response. Correlation coefficient ≥ 0.5 between biomarker changes and clinical outcomes.

Additional requirements

• Measurements must remain statistically correlated with changes in PROSPR IC score (v1.2).

PROSPR

study (Lifestyle intervention)

Metrics

• Attrition rate < 30%.

• ≥ 80% data completion for all data sources.

• Maintain robust quality assurance measures to ensure high inter-rater reliability ICC ≥ 0.75 and data consistency ≥90% across all sources throughout the study.

Additional requirements

• Multimodal lifestyle intervention study must include at least exercise/activity, diet, and stress management techniques, but will consider the inclusion of others such as mental health, sleep, or social improvements.

In-home PROSPR IC assessment tech (v1.2)

• Data accuracy and consistency: ≥ 80% correlation between device measurement and clinician assessments; measurements should yield at least 90% consistency over repeated trials.

• Reliability: ≥ 95% successful sync rate with wearable devices and sensors, and ≥ 99% uptime.

• User experience: user satisfaction rating ≥ 4.5/5.0 on standardized usability scales. Task Success Rate (TSR) >80%, low (2-5 min) Time to Task (TOT). (Note: user experience should demonstrate progressive improvement throughout the program, if necessary)

• Coaching feature effectiveness: demonstrated improvement in user behavior including increased physical activity and improved dietary habits, significant improvement in PROSPR IC score over year 1, and reduced risk of functional decline, multi-morbidity, and mortality (OR ≥0.70, 95% Cl).

Deliverable

• Intervenable PROSPR IC (v1.2) with enhanced accuracy based on newly collected data.

• In-home PROSPR IC assessment kit (v1.2) with improved features and enhanced…