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Preclinical Working Group

Charge

Standardize and share preclinical evaluation resources and methods and accelerate testing of candidate therapies and vaccines to support entry into clinical trials. The working group completed its charge as of September 8, 2021.

Objectives

Check mark indicates completion.

✓ Preclinical Resource Map

The working group has developed a master inventory of preclinical testing resources, including for nonhuman primates (NHPs), small animal models, and biosafety level 3/4 laboratories. To facilitate up-to-date information on this inventory of testing resources, the working group created a web-based form to use for collection of data on facilities that can carry out SARS-CoV-2 assays and animal models. The collection of this information is aiding in standardization of animal model testing efforts.

✓ �����鶹��Ƶ Strategy for NHP Preclinical Resources

The working group has helped develop a strategy for COVID-19-related NHP studies, in collaboration with the �����鶹��Ƶ Primate Research Centers, which aims to maximize the research value of scarce NHP resources that are needed to test vaccines and certain therapeutics during the pandemic. The strategy includes:

• A staged approach for animal use aligned with immediate need
• Defined points of interaction between an ACTIV expert panel and the �����鶹��Ƶ Primate Research Center directors
• Recommended clear guidance for animal use and therapeutic testing, including the first ever master protocol for non-human primate research

✓ Pandemic Response Framework

• The working group has developed “Pandemic Mode” operating procedures for accelerated preclinical agent development, including antivirals, immunomodulators, and anticoagulants. The approach to accelerated therapeutic development focuses on critical path activities to capture key aspects of efficacy and safety, as shown in the figure below. This approach is most easily associated with therapeutics that already have clinical data in another therapeutic area.

The standard “traditional” approach to drug development with an abbreviated approach suitable for pandemic conditions. In traditional drug development many experimental studies are done in series: as one study ends, the results are analyzed, and a decision is made whether to begin the next study. In pandemic mode, a therapeutic sponsor could carry out some of these studies in parallel, such that significant time is reduced. In addition, in pandemic mode, it is beneficial to begin the process with a therapy that has already been in humans, but for a different disease; repurposed compounds. These repurposed compounds offer the advantage of being known to be safe in humans. The risk of a repurposed compound is that it was initially made for a different disease and will probably not work as well as a compound made specifically for COVID-19. However, something that shows some efficacy could be the difference between life and death in the pandemic.

✓ Preclinical Testing Network

The working group has created a virtual testing network of biosafety level 3/4 laboratories for triaged drug candidates. The sites can carry out the essential experiments that have been described in the Pandemic Mode process and could rapidly deploy clinical testing in COVID-19 patients.

✓ Preclinical Prioritization

The working group has completed a prioritization framework, using the “Pandemic Mode” procedures described above as a basis, for evaluating and prioritizing preclinical compounds for further preclinical testing. The compounds that have been submitted to ACTIV for review are being evaluated for further preclinical development with the expectation that they may proceed into one of the ACTIV clinical master protocols (see Therapeutics Clinical Working Group).

✓ Preclinical Compound Survey

To assist in developing and prioritizing a complete inventory of potential candidates with different approaches to preventing or mitigating COVID-19 infection, ACTIV created a Clinical & Preclinical Candidate Compound Survey in conjunction with the Therapeutics Clinical Working Group. The survey collected detailed information from sponsors such as preclinical and clinical data on therapeutic candidates. ACTIV is no longer accepting submissions for clinical and preclinical candidate compounds.

✓ Preclinical Animal Model Information Sharing

The working group has created a public database for sharing preclinical data using the located in the NCATS OpenData Portal. Importantly, the portal allows for both the comprehensive sharing of animal model data as well as information on how the data were generated. This facilitates interpretation and comparison of results from multiple experiments on multiple agents that could provide insight on SARS-CoV-2 and treatment approaches not apparent from a single study.

Animal model summaries, field guides, and additional resources have been curated and released on the . Additional information will continue to be added as it becomes available.

Emerging Variant Tracking and Preclinical Data Sharing

The Tracking Resistance and Coronavirus Evolution (TRACE) team are developing processes and infrastructure for monitoring and testing emerging SARS-CoV-2 variants, as well as for standardizing, gathering, and sharing variant sequencing data. This work is being done in collaboration with other US government agencies (e.g. CDC, BARDA, FDA, DoD), academic experts and private partners. The team is following a 5-step approach to variant monitoring and data sharing:

• Monitor global emergence and circulation of SARS-CoV-2 mutations
• Cross-reference initial sequence data against database of experimentally or clinically phenotyped mutants
• Characterization of prioritized mutants in vitro through critical-path assays
• Characterization of prioritized mutants in vivo through critical-path assays
• Rapidly share activity data with ACTIV and scientific community

Currently available information on viral variant characteristics and overviews of preclinical assays used to test them can be found on the within the NCATS OpenData Portal. The summary will be updated periodically and accessible from this website.

Members