NIH Research Initiative on Post-Acute Sequelae of SARS-CoV ...

NIH Research Initiative on Post-Acute Sequelae of SARS-CoV-2 Infection (PASC):

Technical Assistance Webinar March 1

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, 2021

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Technical Assistance Webinar March 1, 2021

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Technical Assistance Workshop: Overview

Purpose: To enhance potential applicant understanding of the Research Opportunity Announcements and facilitate their preparation of responsive applications

Topics: • Overview of the vision and specific objectives of PASC initiative• Key scientific/research elements of the 3 ROAs including the three

cores and the three specific research components• Overview of the OT mechanism, application process, and

requirements• Addressing prospective applicant questions

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Overview

Why Study PASC? • Patients vary in the timing and extent of their recovery

from SARS-CoV-2 infectiono Many recovering quickly; others experience important

post-acute sequelae of SARS-CoV-2 Infection (PASC) Reported symptoms range from mild to

incapacitating, may involve multiple organs andsystems, and can adversely affect overall qualityof life In some cases, new symptoms and findings are

reported that appear linked to the timing of acuteinfection but emerge subsequently and evolveover time

• Public health impact is currently unknown butpotentially large given the numbers of individualsacross the age spectrum who have been/will beinfected

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NIH PASC Research: Toward Recovery from SARS-CoV-2 Infection

GoalGoal

Rapidly improve our understanding of and ability to treat and prevent PASC

Key Scientific Questions Key Scientific QuestionsWhat are the clinical spectrum of and biology underlying recovery from acute SARS-CoV-2 infection over time?

For those patients who do not fully recover, what is the incidence/prevalence, natural history, clinical spectrum, and underlying biology of this condition? Are there distinct phenotypes of patients who have prolonged symptoms or other sequelae?

Does SARS-CoV-2 infection initiate or promote the pathogenesis of conditions or findings that evolve over time to cause organ dysfunction or increase the risk of developing other disorders?

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NIH SARS-CoV-2 Recovery

Cohort

Acute SARS-CoV-2

Infection Cohorts

Post-Acute SARS-CoV-2

Infection Cohorts

What are the clinical spectrum of and biology underlying recovery from acute SARS-CoV-2 infection over time?

For those patients who do not fully recover or develop new sx/sequelae, what is the clinical spectrum and Underlying biology?

Does SARS-CoV-2 infection initiate or promote the pathogenesis of conditions or findings that evolve over time to cause organ dysfunction or increase the risk of developing other disorders?

EHR- and Other Real World Data-Based Studies 8

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Research Approach to rapidly enable:

• SARS-CoV-2 infection case-driven and multi-disciplinary prospectiveassessment of PASCo Incidence/prevalence, epidemiology, clinical spectrum, outcomes, risk

factorsoLeverage ongoing fit-for-purpose cohorts as well as new cohort

studieso Includes children and adults (including pregnant women) and inclusive

participationoProactive community engagement as integral elementoWill inform design of treatment and prevention strategies

Leverage EHR- and Other Real World Data-Based Studies

Autopsy Cohort Studies

1• Establish a SARS-CoV-2 Recovery Cohort

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3•

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Notes:

Includes Peds Cohorts

Studies

Includes new and leveraged

ongoing studies

Broad Spectrum of

Recovery Phenotypes

SARS-CoV-2 Recovery Clinical Study

SARS-CoV-2 Recovery Cohort

Clinical Characterization/Phenotyping Streamlined core protocol elements (exam, labs, functional tests, imaging)

to capture spectrum of PASC

Examples of assessments could include: ▪ Imaging (CT, MRI, Echo) ▪ Functional Assessments (PFTs, 6MW, ETT)

▪ Neuropsychiatric assessments (screening, questionnaires, testing)▪ Psychosocial Factors, SDoH ▪ Immunophenotyping ▪ Biospecimens (Biomarkers, Multi-omics)

• More in-depth assessments as indicated (e.g., fpgPET)

Enrolled at time of COVID+ dx Enrolled when present with Post-Acute sx

… Acute Cohort

Acute Cohort

Acute Cohort

Acute Cohort

… Post-Acute Cohort

Post-Acute Cohort

Post-Acute Cohort

Post-Acute Cohort

PASC‐A PASC‐A' PASC‐B PASC‐C PASC‐F NO PASCControlsPASC‐D PASC‐E

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PASC Initiative Components SARS-CoV-2 Recovery Meta-Cohort

• Clinical Recovery Cohort• Autopsy Cohort (Acute and PASC)• EHR- and Other Real World Data-

Based Studies

Investigator Consortium

to achieve speed and scale:

• Develop a streamlined set of common coreprotocol elements (specific hypotheses, designelements, screening evaluations, exams, labtests, functional assessments, imaging, etc.)

• Conduct rapid systematic screening and follow-upevaluations of infected individuals, to provide aresource for in-depth multi-disciplinary phenotyping,and to pool data and share biospecimens and datafrom across studies

All study investigators will work together

This Photo by Unknown Author is licensed under CC BY-SA-NC

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PASC Initiative Components The goals of the Recovery Cohort and Investigator Consortium will be supported by administrative coordination and oversight as well as three cores:

• Clinical Science Core• Data Resource Core• PASC Biorepository Core

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Key Features • Collaborative governance structure

o Community/stakeholder involvement at multiplelevels

o Diverse/inclusive• Integration and coordination of components• Flexibility and nimbleness to adapt; formation of

new multi-disciplinary teams• Informed consent for future use of data and

biospecimens• Data sharing following FAIR principles, FHIR

standards, etc.• Collection and sharing of high quality

biospecimens This Photo by Unknown Author is licensed under CC BY-ND

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Key Dates and Review Process

Feb. 5

NOITP issued

Research Opportunity Announcementsissued

Technical Assistance Workshop

PASC Core Proposals due

PASC Research Study Proposals due

Award decisions anticipated

PASC Consortiumconvened

(Target)

Feb 23

Mar 1 Mar 16 Mar 23 Early Apr Apr

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Research Opportunity Announcements (ROA) Components

Clinical Recovery Cohort (1/2) C O M P O N E N T S K E Y I N F O R M AT I O N

Overarching Purpose

• To systematically examine the characteristics of individuals who do and do notdevelop post-acute sequelae of SARS-CoV-2 infection (PASC)

• To characterize the epidemiology, natural history, and clinical spectrum of PASC• To examine how infection and subsequent recovery from SARS-CoV-2 infection or the

impact of mitigation strategies influence risk of developing new orworsening chronic diseases and disorders

This ROA will support two types of clinical research efforts to rapidly leverage new and existing infrastructure, processes, data, and biospecimens from longitudinal studies: • Objective 1: To support studies of individuals newly infected with SARS-CoV-2 to

understand the heterogeneity in recovery processes• Objective 2: To support studies of individuals previously infected with SARS-CoV-2 with

either new or persistent symptoms and appropriate controls to understand the basis andnatural history of continued disability.

Sample research areas of interest include: • Incidence of PASC and sub-phenotypes • Association of concomitant treatments• Multi-level factors in disparities of PASC • Deep phenotyping• Predictors and prediction models

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Specific Objectives

Special Considerations

Clinical Recovery Cohort (2/2) C O M P O N E N T S K E Y I N F O R M AT I O N

Required Elements

• Rapid access to patient population OR existing cohort (and comparators)• Willing to use common data standards• Able to identify patient representatives

• Strong track record of collaborative epi, • Capacity to enrollobservational, & clinical research • Adults: ≥ 1,000 acute or 200 PASC

• Expertise with underserved populations cases• Pediatric: ≥ 250 acute or 50 PASC

cases

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Features of Ideal Proposals

Autopsy Cohort (1/2) C O M P O N E N T S K E Y I N F O R M AT I O N

Overarching Purpose

• To better understand the pathophysiology of SARS-CoV- 2 infection and its lasting impact on the humanbody

• Comprehensively evaluate the pathophysiology of recovery from acute COVID-19 and PASC throughautopsies and tissue analyses

Awardees will participate in the Investigator Consortium and are expected to: • Develop and adopt a common set of core measures and descriptors as part of their pathology protocols• Share pathology tissues, data, and methodology with Consortium members and more broadly with the

research community

• Substantiate expertise/ability to perform sufficient # of autopsies to conduct proposed studies• Have access to sufficiently detailed information regarding pre-mortem medical history• Perform autopsies prospectively and within 24h post-morte m interval• Employ tissue handling SOPS that meet CAP/CDC guidance for biospecimens and COVID-19

biospecimens• Collect and freeze tissue in accordance with appropri ate biohazard considerations at time of autopsy• Perform quantitative PCR assessment of viral load in tissue as well as histomorpholoca lization of virus

in tissue• Share EHR, clinical data, pathology data and whole slide imaging with the Data Resource Core• M eet CAP biobanking requirements for the storage of research tissue under this protocol

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Specific


Objectives

Elements Required

Autopsy Cohort (2/2) C O M P O N E N T S K E Y I N F O R M AT I O N


• May focus on adult and/or pediatric patients. Inclusio n of PASC, MIS-C, and MIS-A cases is highlydesirable

• ≥10% of subjects should be in the subacute phase (d15-60 post-infection ) to enable reference of theearliest stages of tissue injury/repair

• Majority of subjects should be those with PASC together with appropriate controls, i.e., those who werepreviously infecte d but who recovered to their pre-morbid functional baseline

• Autopsies should be comprehensive pathologic examinations and collection of tissue should includeov ersampling of all organs routinely evaluated at autopsy and including those that demonstrated

dysfunction during the acute phase of infection in that individual• Examination of the CNS should be included in the protocol and must be pursued when consented• When feasible, inclusion of post-mortem MRI is highly desirable but not required• Examination of the CNS should be included in the protocol and must be pursued when consented• Ancillary studies will be allowed to perform high impact intensive investigation (imaging, single-cell

analysis, transcriptomics, electron microscopy, etc.

1919

EHR- and Other Real World Data-Based Studies (1/2)C O M P O N E N T S K E Y I N F O R M AT I O N

• Advance the understanding and management of the post-acute effects of COVID-19 inboth children and adults, by making innovative use of RWD such as EHRs, health systemsdata, digital health data, and other large datasets; by further expanding the capabilities ofexisting data resources; and by working in an integrated fashion with other components ofthe coordinated NIH response to address the post-acute sequelae of COVID-19

• Use RWD (such as EHR, digital health, environmental, and administrative data) to developpost-acute COVID phenotype definitions

• Augment and integrate existing RWD resources through secure, privacy-preservinglinkages to other data resources and data types

• Identify and address post-acute COVID-19 health disparities discernible in RWD• Create, deploy, and validate workflows for using large RWD resources to enhance post-

COVID-19 clinical research and practice• Help to standardize and to democratize the landscape of post-COVID-19 data science

research• Develop work products that use RWD to enhance the effectiveness and efficiency of the

care for people with post-COVID-19 sequelae

2020

Overarching Purpose

Specific Objectives

EHR- and Other Real World Data-Based Studies (2/2) C O M P O N E N T S K E Y I N F O R M AT I O N


• Ability to re-contact & consent • Sophisticated training & communication strategies• Attention to inequities • Unique RWD resources

• Capacity of RWD resources • Expertise of team• Ability to package RWD • Data-facing & community-facing activities

• Large, expandable RWD • Cutting-edge data sharing & handling• Multidisciplinary teams • Detailed plan for integrationI

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Required Elements

Features of deal Proposals

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Clinical Science Core (1/2) COMPONENTS KEY INFORMATION

Overarching

Purpose

• To coordinate and support the development, implementation, and execution of PASC

Initiative research programs, as well as to provide expertise on clinical study design,

implementation, and oversight

Specific

Objectives

• Logistical support for administration, execution, and results dissemination from SARS

CoV-2/PASC cohorts. • Expertise in and support for development, implementation, and execution of PASC

protocols. • Development and implementation of PASC protocol monitoring of study performance and

safety. • Expertise in and support for the phenotyping of individuals to characterize the full multi

organ spectrum of SARS-CoV-2 infection. • Fostering of communication within the Investigator Consortium and with external

stakeholders, including Patient Engagement Working Group

Special

Considerations

• Integration with DRC and PASC Biorepository Core • Work with ACC • Working with existing studies and DCCs

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ID) �

Clinical Science Core (2/2) COMPONENTS KEY INFORMATION

Required

Elements

• Experience with large, multi-site studies • Preparing data for general research use • Understanding of clinical goals

Features of

Ideal Proposals

• Evidence of experience working closely with a biorepository and entity with the goals of

the Data Resource Core. • Experience with common data elements • Strong communication plan

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Biorepository Core (1/2) COMPONENTS KEY INFORMATION

Overarching

Purpose

• To establish and maintain a secure central repository for PASC biospecimens and function

as a "virtual" repository, tracking sample availability and location for PASC-related

biosamples maintained at other sites

Specific

Objectives

• Establish a manual of procedures (MOP), SOPs, obtain applicable certifications, ensure

compliance with applicable guidelines and standards for biorepositories• Receive, process, label, store, and make biospecimens available, including relevant

autopsy specimens• Link and integrate biospecimen information with clinical data• Provide training, leadership and guidance to investigators• Maintain catalog of PASC biospecimens stored at other sites

Special

Considerations

• Integration with data; working with DRC and CSC, Autopsy Core• Linking to relevant clinical data• Platform for informing investigators of availability of biospecimens

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ID) �

Biorepository Core (2/2) COMPONENTS KEY INFORMATION

Required

Elements

• Biorepository experience• Adherence to current biorepository standards• Ability to deliver biospecimens to final NIH repository

Features of

Ideal Proposals

• Experience with biorepository, linking to clinical data, training, working with on-going multi

site studies• Adequate storage facilities and specimen quality controls

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� ID)

Data Resource Core (1/2) COMPONENTS KEY INFORMATION

Overarching

Purpose

• Coordinate PASC data management, harmonization, integration, and sharing, and

provide analytical tools and statistical support to the Clinical Science Core

Specific

Objectives

• Coordinate standardized collection of clinical data (i.e. , incorporating common data

elements and case report forms) and less structured data (i.e. , imaging reports, results of

specialized tests) to maximize comparability across the program consortium and

measurement modes • Assist research projects with linking these data with stored biosamples and data from

other sources (e.g. , Census data, Area Deprivation Index, etc. ), electronic health records

(EH R), etc. • Perform quality control, data curation, and analyses, and provide data informatics tools to

monitor program consortium progress and performance • Facilitate the necessary data harmonization, mapping to common data models (e.g. ,

OMOP) and prepare necessary data across all sites, for ingestion into the platforms (e.g. ,

BioData Catalyst and N3C, etc. ) • Provide statistical support to the CSC and Consortium, including input into protocol

development, provision of analyses and analysis tools, and preparation of reports and

publications.

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ID) �



• Consortium investigators will make research data available through the CSC and DRC

at agreed-upon milestones and upon completion of their study.

Required Elements

• Applicants must address the SOMs with specifics (milestones, processes, procedures) for

how they will achieve the required integration with the other components and for resolving

any areas of disagreement.


• Experience with biorepository, linking to clinical Proposers will need to demonstrate prior

work with clinical consortia or networks AND competency as Data Core.

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Other Transaction Authority (OTA)

Framework

� ID)


Overarching

Purpose

• Coordinate PASC data management, harmonization, integration, and sharing, and

provide analytical tools and statistical support to the Clinical Science Core

Specific

Objectives

• Coordinate standardized collection of clinical data (i.e. , incorporating common data

elements and case report forms) and less structured data (i.e. , imaging reports, results of

specialized tests) to maximize comparability across the program consortium and

measurement modes• Assist research projects with linking these data with stored biosamples and data from

other sources (e.g. , Census data, Area Deprivation Index, etc. ), electronic health records

(EH R), etc.• Perform quality control, data curation, and analyses, and provide data informatics tools to

monitor program consortium progress and performance• Facilitate the necessary data harmonization, mapping to common data models (e.g. ,

OMOP) and prepare necessary data across all sites, for ingestion into the platforms (e.g. ,

BioData Catalyst and N3C, etc. )• Provide statistical support to the CSC and Consortium, including input into protocol

development, provision of analyses and analysis tools, and preparation of reports and

publications.

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OTA Framework Considerations

Proposal Formatting:

• OTA review prioritizes content of proposal and focuses evaluation on

requirements as outlined in the ROA.

• Responses should focus on addressing the requirements spelled out in the

ROA and the accompanying OTA package, but note that the format

requirements do not limit you to requirements associated with a grant

application (such as an R01 ).

• An important note, when submitting into ASSIST enter OTA-21-015 andwithin the proposal specify if applying to OTA-21-01 SA or OTA-21-0158.

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ansako

Underline

ID) �


Proposal Content:

• The ROA and accompanying OTA package provide guidance on what mustbe addressed by the proposal.

• With this mechanism, if not otherwise specified, you have flexibility tomake formatting decisions as long as the content requirements areaddressed. For example, the key personnel requirement could be satisfiedby submitting a standard NIH biosketch template, resume, or CV.

• Additional content in the proposal such as biosketches, appendixes, orletters of support will not count towards page limits.

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@

ansako

Underline

ID) �


Budget and Negotiation:

• There is no predetermined level of support established for any individualproposal. Each proposal's budget will be evaluated based on need,number of applications selected for award, and reasonableness of the costbased on proposal justifications along with a number of other factors that

will be set forth in the published ROAs.

• OTAs are milestone driven. In addition to an annualized budget,applicants will be asked provide Operational Milestone-based PaymentSchedules, generally this refers to a percentage of overall budget"unlocked" based on deliverable/milestone schedule. See ROA for details.

• While not yet determined, it is highly likely that research studies, and

possibly cores, may be issued as sub-awards (sub-OT's)

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Submitting Additional Questions

For any questions related to the ROAs, you can reach out to [email protected]

For questions related to eRA submission, you may contact the eRA Service esk through the website, email or phone. All contact information can be found

at: https://grants.nih.gov/support/index.html. D

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