Biology:COVID-19 drug development

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Short description: Preventative and therapeutic medications for COVID-19 infection

COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research (506 total candidates in April 2021), with 419 potential COVID-19 drugs in clinical trials, as of April 2021.[1]

As early as March 2020, the World Health Organization (WHO),[2] European Medicines Agency (EMA),[3] US Food and Drug Administration (FDA),[4] and the Chinese government and drug manufacturers[5][6] were coordinating with academic and industry researchers to speed development of vaccines, antiviral drugs, and post-infection therapies.[7][8][9][10] The International Clinical Trials Registry Platform of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections,[11][12] with numerous established antiviral compounds for treating other infections under clinical research to be repurposed.[7][13][14][15]

In March 2020, the WHO initiated the "SOLIDARITY Trial" in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy.[2][16] A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates.[12]

Drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound.[17] Several national regulatory agencies, such as the EMA and the FDA, approved procedures to expedite clinical testing.[4][18] By June 2021, dozens of potential post-infection therapies were in the final stage of human testing – phase III–IV clinical trials.[19]

Background

Drug discovery cycle schematic

Drug development is the process of bringing a new infectious disease vaccine or therapeutic drug to the market once a lead compound has been identified through the process of drug discovery.[17] It includes laboratory research on microorganisms and animals, filing for regulatory status, such as via the FDA, for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug.[20][21] The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials – to approved vaccine or drug normally takes more than a decade.[17][20][21]

The term "preclinical research" is defined by laboratory studies in vitro and in vivo, indicating a beginning stage for development of a preventative vaccine, antiviral or other post-infection therapies,[7] such as experiments to determine effective doses and toxicity in animals, before a candidate compound is advanced for safety and efficacy evaluation in humans.[22] To complete the preclinical stage of drug development – then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) – is a process likely to require 1–2 years for COVID-19 therapies, according to several reports in early 2020.[9][23][24][25] Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the entire drug development process for treating infectious diseases is only 19%.[26]

Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate therapeutic efficacy against the COVID-19 disease at ascending dose levels (efficacy based on biomarkers), while closely evaluating possible adverse effects of the candidate therapy (or combined therapies), typically in hundreds of people. A common trial design for Phase II studies of possible COVID-19 drugs is randomized, placebo-controlled, blinded, and conducted at multiple sites, while determining more precise, effective doses and monitoring for adverse effects.[27]

The success rate for Phase II trials to advance to Phase III (for all diseases) is about 31%, and for infectious diseases specifically, about 43%.[26] Depending on its duration (longer more expensive) – typically a period of several months to two years[27] – an average-length Phase II trial costs US$57 million (2013 dollars, including preclinical and Phase I costs).[28] Successful completion of a Phase II trial does not reliably forecast that a candidate drug will be successful in Phase III research.[29]

Phase III trials for COVID-19 involve hundreds-to-thousands of hospitalized participants, and test effectiveness of the treatment to reduce effects of the disease, while monitoring for adverse effects at the optimal dose, such as in the multinational Solidarity and Discovery trials.[2][17][30]

Candidates

Evidence network of COVID-19 clinical trials of 15 therapeutic candidates.[31] Circles represent interventions or intervention groups (categories). Lines between two circles indicate comparisons in clinical trials.[31]

According to one source (as of August 2020), diverse categories of preclinical or early-stage clinical research for developing COVID-19 therapeutic candidates included:[19]

Pivotal Phase III trials assess whether a candidate drug has efficacy specifically against a disease, and – in the case of people hospitalized with severe COVID-19 infections – test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection.[2][11][32] For an already-approved drug (such as hydroxychloroquine for malaria), Phase III–IV trials determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection.[32] As of August 2020, over 500 candidate therapeutics were in preclinical or a stage of Phase I–IV development, with new Phase II–III trials announced for hundreds of therapeutic candidates during 2020.[19]

Numerous candidate drugs under study as "supportive" treatments to relieve discomfort during illness, such as NSAIDs or bronchodilators, are not included in the table below. Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials,[19] are also excluded. Drug candidates in Phase I–II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval.[20][29] Once having reached Phase III trials, therapeutic candidates for diseases related to COVID-19 infection – infectious and respiratory diseases – have a success rate of about 72%.[26]

COVID-19: candidate drug treatments in Phase III–IV trials
Drug candidate Description Existing disease approval Trial sponsor(s) Location(s) Expected results Notes,
references
Remdesivir antiviral; adenosine nucleotide analog inhibiting RNA synthesis in coronaviruses investigational[33] Gilead, WHO, INSERM, NIAID China, Japan initially; extended internationally in Global Solidarity and Discovery Trials, and US NIAID ACTT Trial Mid-2020 (Chinese, Japanese trials) [19][34][35] selectively provided by Gilead for COVID-19 emergency access;[36][37] both promising and negative effects reported in April[38][39][40]
Hydroxychloroquine or chloroquine antiparasitic and antirheumatic; generic made by many manufacturers malaria, rheumatoid arthritis, lupus (International)[41][42] CEPI, WHO, INSERM Multiple sites in China; global Solidarity and Discovery Trials June 2020 (discontinued by WHO) multiple side effects; possible adverse prescription drug interactions;[41][42] discontinued in June from WHO Solidarity trial and UK Recovery trial as "having no clinical benefit in hospitalised patients with COVID-19";[43][44] trials[19][34]
Favipiravir antiviral against influenza influenza (China)[45] Fujifilm China April 2020 [19][8][46]
Lopinavir/ritonavir without or with interferon beta-1a antiviral, immune suppression investigational combination; lopinavir/ritonavir approved[47] CEPI, WHO, UK Government, Univ. of Oxford, INSERM Global Solidarity and Discovery Trials, multiple countries mid-2020 [19][34]
Sarilumab human monoclonal antibody against interleukin-6 receptor rheumatoid arthritis (US, Europe)[48] Regeneron-Sanofi Multiple countries Spring 2020 [19][49]
ASC-09 + ritonavir antiviral combination not approved; ritonavir approved for HIV[47] Ascletis Pharma Multiple sites in China Spring 2020 [19][50]
Tocilizumab human monoclonal antibody against interleukin-6 receptor immunosuppression, rheumatoid arthritis (US, Europe)[51] Genentech-Hoffmann-La Roche Multiple countries mid-2020 [19][52] Roche announced in late July that its Phase III trial of tocilizumab for treating pneumonia in hospitalized people with COVID-19 infection was ineffective[53]
Lenzilumab humanized monoclonal antibody for relieving pneumonia new drug candidate Humanigen, Inc. Multiple sites in the United States September 2020 [19][54]
Dapagliflozin sodium-glucose cotransporter 2 inhibitor hypoglycemia agent[55] Saint Luke's Mid America Heart Institute, AstraZeneca Multiple countries December 2020 [19][56]
CD24Fc antiviral immunomodulator against inflammatory response new drug candidate OncoImmune, Inc. Multiple sites in the United States 2021 [19][57]
Apabetalone selective BET inhibitor investigational Resverlogix Corp United States 22 March 2022 [19][58]

Repurposed drug candidates

Drug repositioning (also called drug repurposing) – the investigation of existing drugs for new therapeutic purposes – is one line of scientific research followed to develop safe and effective COVID-19 treatments.[15][59] Several existing antiviral medications, previously developed or used as treatments for Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, are being researched as COVID-19 treatments, with some moving into clinical trials.[13]

During the COVID-19 pandemic, drug repurposing is the clinical research process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection.[13][15][60] In the usual drug development process,[17] confirmation of repurposing for new disease treatment would take many years of clinical research – including pivotal Phase III clinical trials – on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection.[13][60] In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19.[2][13][15]

Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious side effects) and post-infection efficacy, and can rapidly access existing drug supply chains for manufacturing and worldwide distribution.[2][13][61] In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international Phase II–III trials on four promising treatment options – the SOLIDARITY trial[2][62][63] – with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory, corticosteroid, antibody, immune, and growth factor therapies, among others, being advanced into Phase II or III trials during 2020.[19][13][60][64]

In March 2020, the United States Centers for Disease Control and Prevention (CDC) issued a physician advisory concerning remdesivir for people hospitalized with pneumonia caused by COVID-19: "While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for compassionate use through the manufacturer for patients with clinical pneumonia."[37]

Novel antibody drugs

Convalescent plasma

Convalescent plasma collected at a blood donor center during the COVID-19 pandemic.

Passive immunization with convalescent plasma or hyperimmune serum has been proposed as a potential treatment for COVID-19. As of May 2021, there is strong evidence that convalescent plasma treatment is not associated with clinical improvements for people with moderate or severe disease and does not decrease the risk of dying.[65] The potential for adverse effects associated with convalescent plasma treatment is unknown.[65]

In the United States, the FDA has granted temporary authorization to convalescent plasma (plasma from the blood of people who have recovered from COVID-19, which thus contains antibodies against SARS-CoV-2) as an experimental treatment in cases where the person's life is seriously or immediately threatened.[66] As of May 2021, at least 12 randomized controlled trials on the effectiveness of convalescent plasma treatment were published in peer-reviewed medical journals.[65] In addition, as of May 2021, 100 additional trials were 'ongoing' and 33 studies were reported as 'competed' but not yet published.[65]

Argentina, Brazil, Costa Rica, and Mexico have pursued development of antisera.[67] Brazil began development of an equine hyperimmune serum, obtained by inoculating horses with recombinant SARS-CoV-2 spike protein, in mid-2020. A consortium of Instituto Vital Brazil, UFRJ, the Oswaldo Cruz Foundation and the D'Or Institute for Research and Education in Rio de Janeiro began preclinical trials in May 2020,[68] while Instituto Butantan in São Paulo completed animal testing in September.[67] In December 2020, Argentina granted emergency authorization to CoviFab, a locally developed formulation of equine hyperimmune serum, for use in cases of moderate to severe COVID-19, based on the initial results of a single phase 2/3 trial which suggested reductions in mortality, ICU admission, and mechanical ventilation requirements in patients who received the serum.[69][70] This was harshly criticized by the Argentine Intensive Care Society, which stated that the trial failed to achieve its primary or secondary endpoints and did not demonstrate any statistically significant differences between the serum and placebo groups.[70]

Bamlanivimab/etesevimab

This section is an excerpt from Bamlanivimab/etesevimab[ edit ]

Bebtelovimab

This section is an excerpt from Bebtelovimab[ edit ]

Casirivimab/imdevimab

This section is an excerpt from Casirivimab/imdevimab[ edit ]

Regdanvimab

This section is an excerpt from Regdanvimab[ edit ]

Sotrovimab

This section is an excerpt from Sotrovimab[ edit ]

Tixagevimab/cilgavimab

This section is an excerpt from Tixagevimab/cilgavimab[ edit ]

Vilobelimab

This section is an excerpt from Vilobelimab[ edit ]

Novel viral replication inhibitors

Molnupiravir

This section is an excerpt from Molnupiravir[ edit ]

Novel protease inhibitors

Ensitrelvir

This section is an excerpt from Ensitrelvir[ edit ]

Nirmatrelvir/ritonavir

This section is an excerpt from Nirmatrelvir/ritonavir[ edit ]

Other

Sabizabulin

This section is an excerpt from Sabizabulin[ edit ]

Planning and coordination

Early planning

Over 2018–20, new initiatives to stimulate vaccine and antiviral drug development included partnerships between governmental organizations and industry, such as the European Innovative Medicines Initiative,[71] the US Critical Path Initiative to enhance innovation of drug development,[72] and the Breakthrough Therapy designation to expedite development and regulatory review of promising candidate drugs.[73] To accelerate refinement of diagnostics for detecting COVID-19 infection, a global diagnostic pipeline tracker was formed.[74]

According to a tracker of clinical trial progress on potential therapeutic drugs for COVID-19 infections, 29 Phase II–IV efficacy trials were concluded in March 2020 or scheduled to provide results in April from hospitals in China – which experienced the first outbreak of COVID-19 in late 2019.[19] Seven trials were evaluating repurposed drugs already approved to treat malaria, including four studies on hydroxychloroquine or chloroquine phosphate.[19] Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April.[19] Other potential therapeutic candidates under pivotal clinical trials concluding in March–April are vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2, among others.

The COVID-19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data, and 4) facilitate sharing of clinical trial outcomes before publication.[11] A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April.[12]

By March 2020, the international Coalition for Epidemic Preparedness Innovations (CEPI) committed to research investments of US$100 million across several countries,[75] and issued an urgent call to raise and rapidly invest $2 billion for vaccine development.[76] Led by the Bill and Melinda Gates Foundation with partners investing US$125 million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and scale up potential treatments.[77] The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments.[11] In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19.[7][13][19]

During March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise US$2 billion for vaccine research and development,[78] and committed to investments of US$100 million in vaccine development across several countries.[75] The Canadian government announced CA$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities,[79][80] with plans to establish a "vaccine bank" of new vaccines for implementation if another COVID-19 outbreak occurs.[80][81] The Bill & Melinda Gates Foundation invested US$150 million in April for development of COVID-19 vaccines, diagnostics, and therapeutics.[82]

Computer-assisted research

In March 2020, the United States Department of Energy, National Science Foundation, NASA, industry, and nine universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google, for drug discovery.[83][84] The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy.[83][84] The Consortium used up 437 petaFLOPS of computing power by May 2020.[85]

The C3.ai Digital Transformation Institute, an additional consortium of Microsoft, six universities (including the Massachusetts Institute of Technology, a member of the first consortium), and the National Center for Supercomputer Applications in Illinois, working under the auspices of C3.ai, an artificial intelligence software company, are pooling supercomputer resources toward drug discovery, medical protocol development and public health strategy improvement, as well as awarding large grants to researchers who proposed by May to use AI to carry out similar tasks.[86][87]

In March 2020, the distributed computing project Folding@home launched a program to assist drug developers, initially simulating protein targets from SARS-CoV-2 and the related SARS-CoV virus, which has been studied previously.[88][89][90][91][92][93]

Distributed computing project Rosetta@home also joined the effort in March. The project uses computers of volunteers to model SARS-CoV-2 virus proteins to discover possible drug targets or create new proteins to neutralize the virus. Researchers revealed that with the help of Rosetta@home, they had been able to "accurately predict the atomic-scale structure of an important coronavirus protein weeks before it could be measured in the lab."[94]

In May 2020, the OpenPandemics – COVID-19 partnership between Scripps Research and IBM's World Community Grid was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19".[95]

International Solidarity and Discovery Trials

In March, the World Health Organization (WHO) launched the coordinated "Solidarity Trial" in 10 countries on five continents to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and anti-inflammatory agents not yet evaluated specifically for COVID-19 illness.[2][16] By late April, hospitals in over 100 countries were involved in the trial.[96]

The individual or combined drugs undergoing initial studied are 1) lopinavir–ritonavir combined, 2) lopinavir–ritonavir combined with interferon-beta, 3) remdesivir or 4) (hydroxy)chloroquine in separate trials and hospital sites internationally.[2][16] Following a study published by The Lancet on safety concerns with hydroxychloroquine, the WHO suspended use of it from the Solidarity trial in May 2020,[97][98] reinstated it after the research was retracted,[99] then abandoned further use of the drug for COVID-19 treatment when analysis showed in June that it provided no benefit.[43]

With about 15% of people infected by COVID-19 having severe illness, and hospitals being overwhelmed during the pandemic, WHO recognized a rapid clinical need to test and repurpose these drugs as agents already approved for other diseases and recognized as safe.[2] The Solidarity project is designed to give rapid insights to key clinical questions:[2][100]

  • Do any of the drugs reduce mortality?
  • Do any of the drugs reduce the time a patient is hospitalized?
  • Do the treatments affect the need for people with COVID-19-induced pneumonia to be ventilated or maintained in intensive care?
  • Could such drugs be used to minimize the illness of COVID-19 infection in healthcare staff and people at high risk of developing severe illness?

Enrolling people with COVID-19 infection is simplified by using data entries, including informed consent, on a WHO website. After the trial staff determines the drugs available at the hospital, the WHO website randomizes the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website. The design of the Solidarity trial is not double-blind – which is normally the standard in a high-quality clinical trial – but the WHO needed speed with quality for the trial across many hospitals and countries.[2] A global safety monitoring board of WHO physicians examine interim results to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy.[2][100] A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by INSERM (Paris, France).[2][34]

The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries – including those with poorly-developed infrastructure for clinical trials – yet needs to be conducted rapidly. According to John-Arne Røttingen, chief executive of the Research Council of Norway and chairman of the Solidarity trial international steering committee, the trial would be considered effective if therapies are determined to "reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems."[30]

During March, funding for the Solidarity trial reached US$108 million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management.[97]

A clinical trial design in progress may be modified as an "adaptive design" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment.[101][102] The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge.[11][34][103] Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.[29][102][104]

Adaptive COVID-19 Treatment Trial

The US National Institute of Allergy and Infectious Diseases (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID-19 people at 100 sites in multiple countries. Beginning with use of remdesivir as the primary treatment over 29 days, the trial definition of its adaptive protocol states that "there will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s)."[38]

Operation Warp Speed

This section is an excerpt from Operation Warp Speed[ edit ]

RECOVERY Trial

A large-scale, randomized controlled trial named the RECOVERY Trial was set up in March 2020, in the UK to test possible treatments for COVID-19. It is run by the Nuffield Departments of Public Health and of Medicine at the University of Oxford and is testing five repurposed drugs and also convalescent plasma. The trial enrolled more than 11,500 COVID-19 positive participants in the U.K by June 2020.[44][105][106]

During April, the British RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was launched initially in 132 hospitals across the UK,[107] expanding to become one of the world's largest COVID-19 clinical studies, involving 5400 infected people under treatment at 165 UK hospitals, as of mid-April.[108] The trial is examining different potential therapies for severe COVID-19 infection: lopinavir/ritonavir, low-dose dexamethasone (an anti-inflammatory steroid), hydroxychloroquine, and azithromycin (a common antibiotic).[105] In June, the trial arm using hydroxychloroquine was discontinued when analyses showed it provided no benefit.[44]

On 16 June the trial group released a statement that dexamethasone had been shown to reduce mortality in patients receiving respiratory support.[109] In a controlled trial around 2,000 hospital patients were given dexamethasone and were compared with more than 4,000 who did not receive the drug. For patients on ventilators, it cut the risk of death from 40% to 28% (1 in 8). For patients needing oxygen, it cut the risk of death from 25% to 20% (1 in 5).[110]

By the end of June 2020, the trial had published findings regarding hydroxychloroquine and dexamethasone.[44][111] It had also announced results for lopinavir/ritonavir which were published in October 2020. The lopinavir-ritonavir and hydroxychloroquine arms were closed to new entrants after being shown to be ineffective.[44][112][113] Dexamethasone was closed to new adult entries after positive results and by November 2020, was open to child entries.

PANORAMIC trial

Launched in December 2021, the PANORAMIC trial will test the effectiveness of molnupiravir and nirmatrelvir/ritonavir in preventing hospitalisation and helping faster recovery for people aged over 50 and those at higher risk due to underlying health conditions.[114][115] PANORAMIC is sponsored by the University of Oxford and funded by the National Institute for Health Research (NIHR).[114] As of March 2022 has over 16,000 people enrolled as participants making it the largest study into COVID-19 antivirals.[116]

See also

References

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  19. ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 19.18 19.19 19.20 "COVID-19 vaccine and treatments tracker (Choose vaccines or treatments tab, apply filters to view select data)". Milken Institute. 21 June 2021. https://airtable.com/shrSAi6t5WFwqo3GM/tblEzPQS5fnc0FHYR/viwJJuMA1ioIgAcPs?blocks=hide. 
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  25. ↑ "Responding to Covid-19 – A Once-in-a-Century Pandemic?". The New England Journal of Medicine 382 (18): 1677–1679. February 2020. doi:10.1056/nejmp2003762. PMID 32109012. 
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  28. ↑ "Innovation in the pharmaceutical industry: New estimates of R&D costs". Journal of Health Economics 47: 20–33. May 2016. doi:10.1016/j.jhealeco.2016.01.012. PMID 26928437. https://dukespace.lib.duke.edu/dspace/bitstream/handle/10161/12742/DiMasi-Grabowski-Hansen-RnD-JHE-2016.pdf;sequence=1. Retrieved 24 March 2020. 
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  30. ↑ 30.0 30.1 "Flooded by the torrent: the COVID-19 drug pipeline". Lancet 395 (10232): 1245–1246. April 2020. doi:10.1016/S0140-6736(20)30894-1. PMID 32305088. 
  31. ↑ 31.0 31.1 "A real-time dashboard of clinical trials for COVID-19". The Lancet. Digital Health 2 (6): e286–e287. June 2020. doi:10.1016/S2589-7500(20)30086-8. PMID 32363333. 
  32. ↑ 32.0 32.1 "What are the phases of clinical trials?". American Cancer Society. 2020. https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/what-you-need-to-know/phases-of-clinical-trials.html. 
  33. ↑ "Remdesivir approval status". Drugs.com. 24 March 2020. https://www.drugs.com/history/remdesivir.html. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 "Launch of a European clinical trial against COVID-19". INSERM. 22 March 2020. https://presse.inserm.fr/en/launch-of-a-european-clinical-trial-against-covid-19/38737/. "The great strength of this trial is its "adaptive" nature. This means that ineffective experimental treatments can very quickly be dropped and replaced by other molecules that emerge from research efforts. We will therefore be able to make changes in real time, in line with the most recent scientific data, in order to find the best treatment for our patients" 
  35. ↑ "A closer look at the Ebola drug that's become the top hope for a coronavirus treatment". BioPharma Dive. 5 March 2020. https://www.biopharmadive.com/news/coronavirus-remdesivir-gilead-antiviral-drug-covid-19/573261/. "There's only one drug right now that we think may have real efficacy. And that's remdesivir." said Bruce Aylward, a senior advisor and international leader of the World Health Organization's joint mission to China" 
  36. ↑ "Emergency access to remdesivir outside of clinical trials". Gilead Sciences. 1 April 2020. https://www.gilead.com/purpose/advancing-global-health/covid-19/emergency-access-to-remdesivir-outside-of-clinical-trials. 
  37. ↑ 37.0 37.1 "Information for clinicians on therapeutic options for COVID-19 patients". US Centers for Disease Control and Prevention. 21 March 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html. 
  38. ↑ 38.0 38.1 Clinical trial number NCT04280705 for "Adaptive COVID-19 Treatment Trial (ACTT)" at ClinicalTrials.gov
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  41. ↑ 41.0 41.1 "Hydroxychloroquine sulfate". Drugs.com. 31 March 2020. https://www.drugs.com/monograph/hydroxychloroquine-sulfate.html. 
  42. ↑ 42.0 42.1 "Chloroquine phosphate". Drugs.com. 31 March 2020. https://www.drugs.com/monograph/chloroquine-phosphate.html. 
  43. ↑ 43.0 43.1 "Hydroxychloroquine halted in WHO-sponsored COVID-19 trials". Bloomberg. 17 June 2020. https://www.bloomberg.com/news/articles/2020-06-17/hydroxychloroquine-testing-halted-in-who-sponsored-covid-trial. 
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  45. ↑ "Fujifilm Announces the Start of a Phase III Clinical Trial of Influenza Antiviral Drug Avigan (favipiravir) on COVID-19 in Japan and Commits to Increasing Production". Drugs.com via Fujifilm Toyama Chemical Co., Ltd. 31 March 2020. https://www.drugs.com/clinical_trials/fujifilm-announces-start-phase-iii-clinical-trial-influenza-antiviral-avigan-favipiravir-covid-19-18505.html. 
  46. ↑ "Coronavirus: Japanese anti-viral drug effective in treating patients, Chinese official says". The Independent. 18 March 2020. https://www.independent.co.uk/news/world/asia/coronavirus-treatment-anti-viral-drug-favipiravir-avigan-wuhan-china-a9408066.html. 
  47. ↑ 47.0 47.1 "Ritonavir". Drugs.com. 2020. https://www.drugs.com/international/ritonavir.html. 
  48. ↑ "Kevzara". Drugs.com. 7 March 2019. https://www.drugs.com/kevzara.html. 
  49. ↑ "Sanofi begins trial of Kevzara against COVID-19 complications". PharmaPhorum. 31 March 2020. https://pharmaphorum.com/news/sanofi-begins-trial-of-kevzara-against-covid-19-complications/. 
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  51. ↑ "Tocilizumab". Drugs.com. 7 June 2019. https://www.drugs.com/mtm/tocilizumab.html. 
  52. ↑ "FDA approves Phase III clinical trial of tocilizumab for COVID-19 pneumonia". Cancer Network, MJH Life Sciences. 26 March 2020. https://www.cancernetwork.com/news/fda-approves-phase-iii-clinical-trial-tocilizumab-covid-19-pneumonia. 
  53. ↑ "Roche provides an update on the phase III COVACTA trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 associated pneumonia". Hoffmann-La Roche. 29 July 2020. https://www.roche.com/media/releases/med-cor-2020-07-29.htm. 
  54. ↑ Clinical trial number NCT04351152 for "Phase 3 Study to Evaluate Efficacy and Safety of Lenzilumab in Hospitalized Patients With COVID-19 Pneumonia" at ClinicalTrials.gov
  55. ↑ "Dapagliflozin: MedlinePlus Drug Information". 20 April 2020. https://medlineplus.gov/druginfo/meds/a614015.html. 
  56. ↑ Clinical trial number NCT04350593 for "Dapagliflozin in Respiratory Failure in Patients With COVID-19 (DARE-19)" at ClinicalTrials.gov
  57. ↑ Clinical trial number NCT04317040 for "CD24Fc as a Non-antiviral Immunomodulator in COVID-19 Treatment (SAC-COVID)" at ClinicalTrials.gov
  58. ↑ An Open-Label Study of Apabetalone in Covid Infection. 20 May 2021. https://clinicaltrials.gov/ct2/show/NCT04894266. Retrieved 24 May 2021. 
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  66. ↑ "FDA now allows treatment of life-threatening COVID-19 cases using blood from patients who have recovered". 24 March 2020. https://social.techcrunch.com/2020/03/24/fda-now-allows-treatment-of-life-threatening-covid-19-cases-using-blood-from-patients-who-have-recovered/. 
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  69. ↑ "Argentina aprueba uso de suero equino que reduce en un 45% las muertes por COVID-19" (in es). Deutsche Welle. 11 January 2021. https://www.dw.com/es/argentina-aprueba-uso-de-suero-equino-que-reduce-en-un-45-las-muertes-por-covid-19/a-56193399. 
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  72. ↑ "Critical Path Initiative". U.S. Food and Drug Administration (FDA). 23 April 2018. https://www.fda.gov/science-research/science-and-research-special-topics/critical-path-initiative. 
  73. ↑ "Breakthrough Therapy". U.S. Food and Drug Administration (FDA). 4 January 2018. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy. 
  74. ↑ "SARS-CoV-2 Diagnostic Pipeline". Foundation for Innovative New Diagnostics. 2020. https://www.finddx.org/covid-19/pipeline/. 
  75. ↑ 75.0 75.1 "Epidemic response group ups coronavirus vaccine funding to $23.7 million". Reuters. 10 March 2020. https://www.reuters.com/article/us-health-coronavirus-vaccines-cepi/epidemic-response-group-ups-coronavirus-vaccine-funding-to-23-7-million-idUSKBN20X1PO. 
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  77. ↑ "COVID-19 Therapeutics Accelerator: Bill & Melinda Gates Foundation, Wellcome, and Mastercard Launch Initiative to Speed Development and Access to Therapies for COVID-19". Bill and Melinda Gates Foundation. 10 March 2020. https://www.gatesfoundation.org/Media-Center/Press-Releases/2020/03/COVID-19-Therapeutics-Accelerator. 
  78. ↑ "CEPI welcomes UK Government's funding and highlights need for $2 billion to develop a vaccine against COVID-19". Coalition for Epidemic Preparedness Innovations, Oslo, Norway. 6 March 2020. https://cepi.net/news_cepi/2-billion-required-to-develop-a-vaccine-against-the-covid-19-virus/. 
  79. ↑ "Government of Canada funds 49 additional COVID-19 research projects – Details of the funded projects". Government of Canada. 23 March 2020. https://www.canada.ca/en/institutes-health-research/news/2020/03/government-of-canada-funds-49-additional-covid-19-research-projects-details-of-the-funded-projects.html. 
  80. ↑ 80.0 80.1 "Canada to spend $192M on developing COVID-19 vaccine". Global News. 23 March 2020. https://globalnews.ca/news/6717883/coronavirus-canada-vaccine-spending/. 
  81. ↑ "Vaccine watch: These are the efforts being made around the world". CTV News. 31 March 2020. https://www.ctvnews.ca/health/coronavirus/vaccine-watch-these-are-the-efforts-being-made-around-the-world-1.4875920. 
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  85. ↑ Wiggers, Kyle (28 May 2020). "COVID-19 HPC Consortium pours 437 petaflops of compute power toward virus research". VentureBeat. https://venturebeat.com/2020/05/28/covid-19-hpc-consortium-pours-437-petaflops-of-compute-power-toward-virus-research/. 
  86. ↑ "C3.ai, Microsoft, and Leading Universities Launch C3.ai Digital Transformation Institute". 26 March 2020. https://c3.ai/c3-ai-microsoft-and-leading-universities-launch-c3-ai-digital-transformation-institute/. 
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  88. ↑ "Help Cure Coronavirus with Your PC's Leftover Processing Power". 3 March 2020. https://www.tomshardware.com/news/folding-fight-coronavirus. 
  89. ↑ "Folding@home takes up the fight against COVID-19 / 2019-nCoV". 27 February 2020. https://foldingathome.org/2020/02/27/foldinghome-takes-up-the-fight-against-covid-19-2019-ncov/. 
  90. ↑ "Folding@home Turns Its Massive Crowdsourced Computer Network Against COVID-19". 16 March 2020. https://www.hpcwire.com/2020/03/16/foldinghome-turns-its-massive-crowdsourced-computer-network-against-covid-19/. 
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  95. ↑ "OpenPandemics – COVID-19". IBM. 2020. https://www.worldcommunitygrid.org/research/opn1/overview.do. 
  96. ↑ "'Solidarity' clinical trial for COVID-19 treatment". World Health Organization. 27 April 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. 
  97. ↑ 97.0 97.1 "WHO Director-General's opening remarks at the media briefing on COVID-19". World Health Organization. 25 May 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---25-may-2020. 
  98. ↑ "WHO pauses hydroxychloroquine coronavirus trial over safety concerns". Global News (The Associated Press). 25 May 2020. https://globalnews.ca/news/6983283/who-hydroxychloroquine-trial/. 
  99. ↑ "WHO restarts HCQ trial after Lancet concern over paper that trashed it". The Indian Express. 4 June 2020. https://indianexpress.com/article/coronavirus/who-hydroxychloroquine-trail-restart-lancet-6441507/. "When contacted, Soumya Swaminathan, chief scientist at WHO, told The Indian Express: Our data safety monitoring board reviewed the mortality data in Solidarity... They did not have concerns related to mortality between HCQ and standard of care. Hence, we have decided to resume the trial." 
  100. ↑ 100.0 100.1 "WHO to launch multinational trial to jumpstart search for coronavirus drugs". STAT. 18 March 2020. https://www.statnews.com/2020/03/18/who-to-launch-multinational-trial-to-jumpstart-search-for-coronavirus-drugs/. 
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