key: cord-0831459-rt5yi5hc authors: Cleary, E. G.; Jackson, M. J.; Folchman-Wagner, Z.; Ledley, F. D. title: Foundational research and NIH funding enabling Emergency Use Authorization of remdesivir for COVID-19 date: 2020-07-06 journal: nan DOI: 10.1101/2020.07.01.20144576 sha: 789a5d443ba59b6f088e73c191f138c6a5865f66 doc_id: 831459 cord_uid: rt5yi5hc Emergency Use Authorization for remdesivir months after discovery of COVID19 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 the biological target of remdesivir, RNA-dependent RNA polymerase (RdRp), or parent chemical structure, nucleoside analogs (NcAn), through 2019, as well as NIH funding for this research from 2000 to 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 COVID19. 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. 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. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint The Emergency Use Authorization of remdesivir for treating SARS-CoV-2 (COVID-19) (1) four months after the discovery of this pathogen is unprecedented. Typically, decades are required to translate research evidence into clinical practice or approved products.(2) For example, a study characterizing the research and development timelines of 113 first-in-class drugs approved from 1999-2013 described a median 20-year lag between the initial identification of a drug target, pathway, or chemotype, and first drug approval. (3) Similarly, studies with an analytical model of research maturation estimated the time from initiation of research related to a novel drug target to first approval of a drug against that target was more than 30 years. (4, 5) While efforts to reduce this translational lag commonly focus on the length of time required for clinical trials and regulatory review,(6) evidence suggests the longer, ratelimiting step is the time required for the basic research required to establish the requisite scientific foundation for successful development. (3-5, 7, 8) Basic research is funded primarily by the public sector.(9) Previous studies have shown that NIH funding contributed to published research underlying every new drug approved from 2010-2016, with >90% of this funding representing basic research on the biological target, rather than applied research on the drugs themselves. (10, 11) These studies also show that this research often involves substantial spillover effects, in which research performed in various therapeutic areas contributes to the scientific foundation for products in another area. (12) Research on strategic product development in different fields of technology has identified predictable patterns in the advance of science or technology. These studies also demonstrate the enabling role for a mature foundation of research and technology readiness in successful product development. (13, 14) The same pattern is evident in biomedical research . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint and targeted drug development. Analytical modeling demonstrates that few targeted therapeutics are successfully developed until foundational research on both the biological target and the nature of the molecular entity passes a defined established point. (4, 5, 8, 15) This work examines the body of research on remdesivir's biological target, RNAdependent RNA polymerase (RdRp), and its parent chemical structure, nucleoside analogs (NcAn). Specifically, we quantify the number of research publications in these two areas, model the advance of this research and thresholds of maturation, describe the number of investigational products targeted to RdRp and timelines of development for the three RdRp inhibitors currently in clinical use, and detail the NIH investments made in this research. Collectively, these data describe the foundational research, and NIH investment in this research, that enabled rapid development of remdesivir in response to the COVID-19 pandemic. These results are considered in the context of intense societal debate over the potential pricing of remdesivir by its manufacturer, Gilead Sciences. (16) (17) (18) One aspect of this debate concerns investments made by the public sector in the early development of this drug and its subsequent application to 20) This work provides an estimate of the NIH contribution to remdesivir through the end of 2019 by considering the foundational research that enabled the discovery and development of this product as well as the NIH contribution to this work. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint Publications on Remdesivir's Target and Chemical Type. PubMed searches using optimized search terms (Supplemental Table 1 ) identified 6,567 PubMed Identifiers (PMID) related to RdRp and 11,073 PMID related to NcAn (Table 1) . Research on RdRp originated in the 1950s, grew exponentially from the 1980s, and has been level from 2011 to the present ( Figure 1A ). Research on NcAn also dates from the 1950s, increased exponentially beginning in the 1980s in conjunction with the emergence of HIV, and has been decreasing slightly from the late 1990s to the present ( Figure 1B ). CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 6, 2020. Figure 1D ). is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint publications, this function exhibits the logistic "S-curve" characteristic of technology maturation models in other fields.(13) Figure 3A and Figure 3B show annual publications and TIME model curve fit for RdRp and NcAn respectively. Figures 3C and 3D show cumulative publications and the TIME model curve plotted on log scale. In this projection, it is evident that RdRp research progressed through two successive S curves. The first has a calculated initiation point (Ti) of 1962 and exhibited exponential growth through the late 1960s. The second exhibited exponential growth through the 1990s and early 2000s, reaching a calculated established point (Te) of 2008. This pattern of successive S-curves is consistent with evidence from other fields that technological progress classically proceeds through a series of novel innovations, each of which introduces a new period of exponential advance leading to a limit. (13, 14) PharmaProjects lists 97 investigational drugs targeted against RdRp since 1989. Figure 3C shows the clinical development timelines for the two approved products, sofosbuvir and dasabuvir, as well as remdesivir. Also shown is the distribution of first reported development for 94 drugs that have been discontinued or remain in clinical development. These data show that each of the products now in clinical use entered clinical trials only after RdRp technology reached the established point and were approved 5, 8, and 12 years after this point ( Figure 3C ). Of the 97 investigational drugs targeted against RdRp, 47 are NcAn. This includes two in clinical use, sofosbuvir and remdesivir, 40 discontinued, and five in development at the end of 2019. Of the 50 that are not NcAn, one is approved, dasabuvir, and three remain in development, including silibinin sodium hemisuccinate (approved in the EU) as well as CC-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. Table 2 ). This result is similar to the total described in a recent KEI Briefing Note detailing the role of the federal government in the development of remdesivir (20). The KEI Briefing Note tracked specific events in product development from 2014 through May 2020, identifying seven NIH Projects mentioned in the acknowledgements and having Project Costs in RePORTER (Supplemental Table 2 ). The methods used in the KEI Briefing note and the present work differ substantially. The KEI Briefing Note included total Project Costs of each NIH Project acknowledged in these publications, but explicitly excluded the Costs of Program Projects and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. Table 3 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. The first NcAn drugs arose from the discovery of naturally occurring products comprising nucleobases with anticancer activity (31) . Early studies on NcAn compounds . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. NcAn respectively. Third, this method does not include funding for research not reported through NIH RePORTER, such as funding from Department of Defense, philanthropies, and international sources. Thus, the total public sector funding for research underlying remdesivir is likely substantially greater than the amount described here. Finally, this analysis does not account for investments in applied research and development by industry, which are estimated to be as much as $1.5 billion in out-of-pocket costs for each new drug approval. (6) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint 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. All analyses were performed in PostgreSQL, Excel and Tableau. 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. This asymmetric sigmoidal function, exhibits the common logistic sigmoid function over log scales. The parameters were fit to time series publication data using a non-linear least squares implementation of the Levenberg-Marquardt algorithm (LMFIT, version 1.0.1). The initiation and established points, representing the beginning and end of the exponential growth phase are defined as the points of maximum and minimum acceleration respectively, or logN''(t)max,min. These points are analytically determined by: . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint A. Liu, Gilead should be allowed "real pricing" for remdesivir-and a sizable profit, analyst says. In Fierce Phama, (June 11, 2020). 19. G. Kolata, How remdesivir, new hope for Covid-19 patients, was resurrected. New York Times (May 1, 2020). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 6, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint 30 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted July 6, 2020. . https://doi.org/10.1101/2020.07.01.20144576 doi: medRxiv preprint