Foundational research and NIH funding enabling Emergency Use Authorization of remdesivir for COVID-19

  1. Ekaterina Galkina Cleary
  2. Matthew J. Jackson
  3. Zoë Folchman-Wagner
  4. Fred D. Ledley

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Abstract

Emergency Use Authorization for remdesivir months after discovery of COVID-19 is unprecedented. Typically, decades of research and public-sector funding are required to establish the mature body of foundational research requisite for efficient, targeted drug discovery and development. This work quantifies the body of research related to remdesivir’s biological target, RNA-dependent RNA polymerase (RdRp), or parent chemical structure, nucleoside analogs (NcAn), through 2019, as well as NIH funding for this research 2000–2019. There were 6,567 RdRp-related publications in PubMed, including 1,263 with NIH support, and 11,073 NcAn-related publications, including 2,319 with NIH support. NIH support for RdRp research comprised 2,203 Project Years with Costs of $1,875 million. NIH support for NcAn research comprised 4,607 Project Years with Costs of $4,612 million. Research Project grants accounted for 63% and 48% of Project Years for RdRp and NcAn respectively, but only 19% and 12% of Project Costs. Analytical modeling of research maturation estimates that RdRp and NcAn research passed an established maturity threshold in 2008 and 1994 respectively. Of 97 investigational compounds targeting RdRp since 1989, the three authorized for use entered clinical trials after both thresholds. This work demonstrates the scale of foundational research on the biological target and parent chemical structure of remdesivir that supported its discovery and development for COVID-19. This work identifies $6.5 billion in NIH funding for research leading to remdesivir, underscoring the role of public sector investments in basic research and research infrastructure that underlie new drugs and the response to emergent disease.

SIGNIFICANCE STATEMENT

Emergency Use Authorization of remdesivir for treating COVID-19 four months after discovery of this virus was enabled by decades of research on the drug’s biological target as well as other medicines with related chemical structures. The NIH contributed 6,800 years of grant funding to this research, totaling $6.5 billion (2000–2019), including funding for both investigator-initiated research and research infrastructure. Of this, $46.5 million was for research directly related to remdesivir. This analysis demonstrates the importance of a robust body of foundational research in responding rapidly to emergent diseases, and the substantial NIH contribution to this research. It also underscores the scale and significance of the public-sector investments that enable new drug discovery and development.

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    SciScore for 10.1101/2020.07.01.20144576: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Text analysis was performed on abstracts, titles, MeSH descriptors, and MeSH qualifiers to quantify mentions of specific positive-strand ssRNA or negative-strand ssRNA viruses targeted in drug discovery programs(21) as well as terms related to oncology and immunology.
    MeSH
    suggested: (MeSH, RRID:SCR_004750)
    Technology Maturation Model: The bibliographic Technology Innovation Maturation Evaluation (TIME) model fits the cumulative number of publications resulting from a PubMed search to an exponentiated logistic function as described previously.(4) The equation has the form:

    Where N is the number of publications, L is the presumed upper limit of publications, r is the growth rate, t is time, and t0 is midpoint of the exponential growth.

    PubMed
    suggested: (PubMed, RRID:SCR_004846)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    In the case of remdesivir, successful development required extensive prior knowledge of the structure-activity relationship of RdRp from different viral species as well as established strategies for circumventing the limitations of NcAn compounds as pharmaceutical products. The relationship between the accumulation of research on RdRp and the emergence of effective RdRp inhibitors is consistent with previous studies demonstrating that few targeted therapeutics are approved before research on the biological target passes an established maturity point.(4, 5, 8) Specifically, while 97 products targeted to RdRp entered development since 1989, the first clinical successes were achieved only after research on both the drug target and parent drug structure passed the established point. The first approved nucleoside drugs (e.g., cytarabinine approved in 1969) were natural products discovered through phenotypic methods, which are commonly approved before there is a mature body of basic research on the drug target.(5, 8) Nevertheless, the current generation of nucleoside analogues designed to inhibit RdRp are also products of a mature body of research on nucleoside chemistry and pharmacology. This analysis also demonstrates the substantial cost of establishing this mature body of foundational research. NIH-funding contributed to 20% of RdRp publications, totaling $1,875 million (2000–2019). Of this amount, $547 million was contributed before the established point in 2008. NIH funding a...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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