[G] Multi-target therapies: Weight of evidence supporting repurposed drugs

Multi-target therapies have an important place, both for when vaccinated and unvaccinated people become infected with Sars-Cov-2. [i] Pervasive uncertainties around the duration and efficacy of protection against current and potential new variants, it is urgent that an integrative treatment regime is available to prevent hospitalisation and death. The New Zealand Ministry of Health current advice on pharmaceutical treatments is rudimentary[ii] [iii] [iv] and appears to rely on other English-speaking nations which also have limited consultation on the potential merits of repurposed drugs (which have often come off patent) in multitarget treatment protocols. Many exciting new therapies in development, unfortunately have potential for adverse side effects or result in harmful interactions with other drugs. Hence it is important to weigh repurposed drugs with a long history of safe use differently from uncertain new treatments.

Why should these drugs be used?

Multi-target therapies are particularly important for protecting vulnerable populations. The mRNA treatment has been shown to wane more quickly in elderly, male and immunosuppressed populations.[v] There is significant uncertainty around which month following injection, that the mRNA treatment will wane in. It is evident that vaccinated populations spread infection (remembering the early clinical trials did not evaluate this).[vi] There is also for these groups, uncertainty as to how they will tolerate the mRNA treatment, which is associated with side effects and death.

New Zealand treatment protocols are rudimentary

The New Zealand Ministry of Health has released limited advice on treatment protocols for those who become infected, the absence of clear and confident messages concerning treatment for infected individuals, has left people in a state of fear. Elsewhere, medical physicians and scientists have released treatment protocols which can act to reduce hospitalisation and death following infection:

Front Line COVID-19 Critical Care Alliance - Prevention & Treatment Protocols for COVID-19 (FLCCC)
Canadian Covid Care Alliance Treatment Protocols

In the current COVID-19 pandemic, regulatory agencies emphasise the importance of randomised control trials (RCTs) in providing the ‘evidence’ that a treatment or therapy will clearly improve outcome. This narrows the scope of data that regulators will consider. It means that public health agencies deliberately exclude data that does not fit within this ‘scope’. This is unprecedented. COVID-19 is a complex disease and requires the targeting of treatments – corticosteroids, anti-inflammatory, immunomodulatory, anti-thrombotic, and sepsis treatments that interact to reduce symptoms and relieve stress on the body. These treatments overlap, they must not cause adverse drug interactions. RCTs often under-dose as they can’t shift with the changing environment, and they can exclude populations that more greatly reflect the health profile of the population at large. They do not account for adverse interactions with drug mixtures (polypharmacy).

The public interest supports acting swiftly when there is evidence of risk to reduce harm. Black and white randomised control trials lack the ‘intelligence’ required in fluid environments, they often exclude interacting ‘dynamic’ factors, such as risk from drug interactions. Instead, reviewing the totality of evidence, and having appreciation of the causal links for which there is evidence of support, particularly where the drug has presents low risk of an adverse drug event, is a more responsive and responsible approach.

Combinatory therapies which act to support and modulate the immune system[vii] [viii] [ix] appear to be outside of government discussion.[x] Multi-target therapies include immunomodulatory therapies to reduce the rate and quantity of viral replication and reduce viral injury to patients’ organs.[xi] Antivirals are increasingly viewed as useful [xii], including drugs with antiviral activity[xiii] as well as antithrombotic medication. [xiv] Immunosuppressive corticosteroids may alleviate severe Covid-19.[xv] [xvi] [xvii]

Dexamethosone and Tocilizumab are the two drugs considered ‘beneficial’ by the Ministry of Health in July 2021.[xviii] However, the supportive data in the scientific literature is scarce. Dexamethasone is a corticosteroid and the drug is known to have severe side effects.[xix] A single, widely cited randomized clinical control trial reported that dexamethasone reduced deaths by one-third in COVID-19 patients that were mechanically ventilated, and by one-fifth in patients receiving oxygen only. Results for patients with comorbidities were not reported. [xx]

Tocilizumab as a has weak evidence to support its use and no randomized trials have been published.[xxi] ‘ A July 2021 paper states ‘the hypothetical justification for treating patients with tocilizumab in the context of COVID-19 stems from indirect findings’.[xxii] Most recently a 2021 a randomized trial did not find evidence that tocilizumab improved outcomes.[xxiii]

Yet these drugs have been approved.

Yet hydroxychloroquine[xxiv] and ivermectin[xxv], with a long history of use, remain outside Ministry of Health deliberation. For practitioners in New Zealand, the current data that supports use of these politically controversial medications, which for decades have not been controversial, is now in the realm of ‘forbidden knowledge’ knowledge considered too sensitive, dangerous, or taboo to produce. Sociologists have suggested that forbidden knowledge is a ‘useful rubric for thinking about debates about the limits of properly conducted inquiry and legitimately produced knowledge’ and that forbidden knowledge requires that experts reconcile a contradiction between their principles and their practice.’[xxvi]

Repurposed medication & the low-side-effects argument.

A persistent problem for physicians and groups with chronic diseases, is the safe management of multiple medication (or polypharmacy). As these groups are frequently prescribed multiple medications, therapies targeted to ensuring good outcomes from COVID-19 must critically – not react badly with existing medications.

This is why doctors and medical experts have strongly emphasised the potential benefits of repurposing existing medication with a long record of prescription. Simply put, the risks of older drugs are better understood, and so can be better managed. Importantly, scientists have observed that combinatory therapies often work well, increasing the potential for a positive outcome when infected, while reducing risk of iatrogenic harm.[xxvii] [xxviii] [xxix] [xxx] [xxxi]

Repurposed drugs have an additional benefit, as they have often come off-patent they can be cheaper for drug buying agencies such as Pharmac to buy in. Home-based outpatient medical kits were supplied to the regions of Goa and Uttar Pradesh. These kits included ‘Paracetamol tablets, Vitamin C, Multivitamin, Zinc, Vitamin D3, Ivermectin 12 mg [quantity #10 tablets], Doxycycline 100 mg [quantity #10 tablets]. Other non-medication components included face masks, sanitizer, gloves and alcohol wipes, a digital thermometer, and a pulse oximeter. cost less than $10.[xxxii] [xxxiii]

Ivermectin is an historically ‘safe’ drug (as no drug comes without risks) with antiviral, antinflammatory properties. A broad range of studies suggest that the mechanisms of action of Ivermectin, place it as a potential conjoint therapy in COVID-19 management. [xxxiv] [xxxv] [xxxvi] [xxxvii] Ivermectin has numerous mechanisms of action. In Sars-Cov-2 it has been found to bind tightly to the ACE-2 protein (in this study it had the highest binding affinity to the ACE-2 protein), which blocks the potential for the virus to replicate.[xxxviii] With new variants, and the mRNA treatment revealed to be leaky and insufficiently therapeutic, ivermectin – in combination with other drugs – can be applied with dosing strategies altered to reflect the patients personal disease profile. Legal action is increasingly being taken when hospitals and medical centres deny use of ivermectin.[xxxix]

Rheumatology drugs have many characteristics which may make them suitable for use in COVID-19.[xl] Fluvoxamine, a common anti-depressant, may help reduce hospitalisation.[xli]

However, the evidence on ivermectin remains uncertain. Recently a widely publicised paper drew attention to the problem of data fraud[xlii] in ivermectin studies. [xliii] The authors subsequently readjusted[xliv] [xlv] and readjusted again to establish that there was no effect on mortality. [xlvi] However, the weight of evidence continues to support that ivermectin is safe and broadly effective. [xlvii]

The Ministry of Health defers to the Roman[xlviii] study (June 2021) which concluded that Ivermectin was ineffective.[xlix] The Ministry of Health state ‘The conclusions by Roman et al align with the Australian Guidelines, the Infectious Disease Society of America Guidance, and WHO Guidance suggesting not to use ivermectin outside of clinical trials as there is insufficient evidence of therapeutic benefits.’ There is no evidence of deeper consultation beyond the comparison of the two meta-studies.’ [l]

Neil and Fenton responded to the Roman study, pointing out that classical modelling techniques pay insufficiently sensitive attention to nuances of risk. [li] Others have pointed out the potential bias reflected in the Roman paper. [lii] We consider that a more appropriate health response is to increase the weight of causal links and acknowledge that a broader, overarching, structural response is required in order to address the complex array of symptoms and disease pathologies observed in patients with COVID-19.[liii] [liv]

The Tokyo Medical Association’s perspective appears to differ from the Japanese state policy.[lv] The connections may stem from the fact that Japanese microbiologist Ōmura Satoshi, received the Nobel Prize for his work that contributed to the discovery of Ivermectin. Satoshi, and colleagues have published papers which have considered the potential for Ivermectin as a COVID-19 treatment.[lvi] [lvii]

An Australian study treated 600 Australian residents with a combination of ivermectin (24 mg per day), doxycycline (100 mg bd), and zinc (50mg per day), for 10 days within 48 hrs of obtaining a positive PCR test for Covid-19, between June and September 2021. The study was capped from including further study participants due to the Australian regulator prohibiting further prescription of ivermectin.[lviii]

However, these points do not negate the problem of fraud and the challenges in both navigating patient confidentiality in research – and providing sufficient transparency to ensure that the data is robust.

Molnupiravir – the media darling but it does what?

Another example of benefits of repurposing is the cheapness of off-patent drugs. The new Merck drug Molnupiravir [lix] comes with a treatment cost of US$700 per patient.[lx] Widespread media coverage of Molnupiravir have reported that in a trial of 775 patients, risk of hospitalisation or death was cut by 50%.[lxi] Others report less positive results.[lxii] Molnupiravir carries with it a risk of mutagenicity.[lxiii] Ivermectin is also manufactured by Merck. After 40 years of research ivermectin-related side effects are relatively well known[lxiv] while Molnupiravir’s side effects remain uncertain.[lxv] Treatment costs for ivermectin cost under US$1.[lxvi] A member of the Australian Parliament has drawn attention to the data supporting ivermectin in the Parliament.[lxvii]

Caution is warranted concerning the claims of trial outcomes. The potential for trial authors to gloss over results producing so-called ‘zombie randomised trials’ is an institutional problem. It is likely that rates of global false medical trials are underestimates. Often the problem is not recognised until the data is explored, and manuscripts presented for publication often reveal little indication of a deeper problem. Scientists have argued that insufficient data has been provided concerning the transparency and safety of vaccine trials.[lxviii] Measures of treatment efficacy in the clinical trials may not have been accurately reported.[lxix] Groups may be under-represented, such as including more healthy participants than is represented in the general population.[lxx]

Investment in new medicine is vastly more expensive that the use of repurposed drugs. The budgeted cost for purchasing vaccines for New Zealand is $964.3 million, which works out to approximately $190 per person, while the total cost for the roll out is estimated at $273 per person.[lxxi]

Current Ministry of Health guidelines[lxxii] carry little discussion on risk of thromboinflammatory disease.[lxxiii] Scientists have emphasised the importance of preventative (prophylactic) anticoagulation treatment to prevent thrombotic episodes, which are part of the presentation of severe Covid-19. There does not appear to be guidance on preventative or emergency treatment using antiplatelet agents or anticoagulants by the Ministry of Health.

NEXT: [H] mRNA Vaccine Mandates

REFERENCES

[i] Halperin et al. Revisiting COVID-19 policies: 10 evidence-based recommendations for where to go from here. BMC Public Health (2021) 21:2084 https://doi.org/10.1186/s12889-021-12082-z

[ii] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[iii] COVID-19: Advice for all health professionals https://www.health.govt.nz/our-work/diseases-and-conditions/covid-19-novel-coronavirus/covid-19-information-health-professionals/covid-19-advice-all-health-professionals

[iv] MoH 2021 Interim Guidance – Clinical Management of COVID-19 in Hospitalised Adults. November https://www.health.govt.nz/system/files/documents/pages/clinical_management_of_covid-19_in_hospitalised_adults_0.pdf

[v] Nordström et al. Effectiveness of Covid-19 Vaccination Against Risk of Symptomatic Infection, Hospitalization, and Death Up to 9 Months: A Swedish Total-Population Cohort Study. http://dx.doi.org/10.2139/ssrn.3949410

[vi] Singanayagam et al. Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. The Lancet (2021). Doi 10.1016/S1473-3099(21)00648-4

[vii] Costagliola et al. Could nutritional supplements act as therapeutic adjuvants in COVID-19? Italian Journal of Pediatrics. 47:32 https://doi.org/10.1186/s13052-021-00990-0

[viii] Kory et al 2021. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther. 2021 May-Jun; 28(3): e299–e318

[ix] McCullough et al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Reviews in Cardiovascular Medicine (2020) 21:4: 517-530 DOI: 10.31083/j.rcm.2020.04.264

[x] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[xi] Mohamed et al. Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review. Bioorg Chem. (2021) Jan; 106: 104490

[xii] Wu et al. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID-19). Journal of Internal Medicine, (2020) 288; 128–138

[xiii] Wehbe et al. Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities. Front. Immunol. 12:663586. (2021) doi: 10.3389/fimmu.2021.663586

[xiv] Gasecka et al. Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis, and Treatment. Cardiovascular Drugs and Therapy (2021) 35:215–229

[xv]Halpin et al . Inhaled corticosteroids and COVID-19: a systematic review and clinical perspective. Eur Respir J 2020; 55: 2001009

[xvi] Mongardon et al. Impact of late administration of corticosteroids in COVID-19 ARDS. Intensive Care Med (2021) 47:110–112

[xvii] Cusacovich et al. Corticosteroid Pulses for Hospitalized Patients with COVID-19: Effects on Mortality.Mediators of Inflammation. (2021) https://doi.org/10.1155/2021/6637227

[xviii] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[xix] Noreen et al 2021 Dexamethasone: Therapeutic potential, risks, and future projection during COVID-19 pandemic. European Journal of Pharmacology https://doi.org/10.1016/j.ejphar.2021.173854

[xx] Horby et al 2020. Dexamethasone in Hospitalized Patients with Covid-19. NEMJ. 384:693-704

[xxi] Lane. Tocilizumab for severe COVID-19: a systematic review and meta-analysis Int J Antimicrob Agents. 2020 Sep; 56(3): 106103.

[xxii] Cortegiani et al 2021. Rationale and evidence on the use of tocilizumab inCOVID-19: a systematic review. Pulmonology 2021;(27):52-66.

[xxiii] Rosas et al Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med 2021;384:1503-16.

DOI: 10.1056/NEJMoa2028700

[xxiv] HCQ for COVID-19: real-time meta analysis of 294 studies. Covid Analysis. October 19, 2021. https://hcqmeta.com/

[xxv] Database of all ivermectin COVID-19 studies. 126 studies, 82 peer reviewed, 64 with results comparing treatment and control groups. October 31, 2021. https://c19ivermectin.com/

[xxvi] Kempner et al. Forbidden Knowledge: Public Controversy and the Production of Nonknowledge. Sociological Forum. 26:3:475-500. DOI: 10.1111/j.1573-7861.2011.01259.x

[xxvii] Kory et al 2021. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther. 2021 May-Jun; 28(3): e299–e318

[xxviii] Tate et al 2021. Uptake of treatment practice standards during a pandemic in an academic medical system. Infection Control & Hospital Epidemiology doi:10.1017/ice.2021.137

[xxix] Ahsan et al 2021. Clinical Variants, Characteristics, and Outcomes Among COVID-19 Patients: A Case Series Analysis at a Tertiary Care Hospital in Karachi, Pakistan. Cureus 13(4): e14761. DOI 10.7759/cureus.14761

[xxx] Ravindra et al 2021. Retrospective Assessment of Treatments of Hospitalized Covid-19 Patients. DOI 10.1101/2021.04.20.21255792

[xxxi] Abdulamir et al 2021. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection Open Forum Infectious Diseases, ofab358, https://doi.org/10.1093/ofid/ofab358

[xxxii] Dr John Campbell. Home ivermectin based kits in India. https://www.youtube.com/watch?v=eO9cjy3Rydc

[xxxiii] United News of India Home isolations monitoring kits for Covid-19 launched. Oct 9 2020. http://www.uniindia.com/~/home-isolation-monitoring-kits-for-covid-19-launched/States/news/2193980.html

[xxxiv] Morgenstern et al. Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: APropensity Score-Matched Retrospective Cohort Study. (2021) 13(8): e17455. DOI 10.7759/cureus.17455

[xxxv] Yagisawa et al. Global trends in clinical studies of ivermectin in COVID-19. The Japanese Journal of Antibiotics. 44:44-95

[xxxvi] Bryant et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. American Journal of Therapeutics, 28, e434–e460, July 2021

[xxxvii] Ivermectin for COVID-19: real-time meta analysis of 65 studies. Unpublished. https://ivmmeta.com/

[xxxviii] Eweas et al. Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2. Front. Microbiol. 11:592908. doi: 10.3389/fmicb.2020.592908

[xxxix] Hearing Set in ICU Doctor’s Lawsuit: Do Doctors or Administrators Determine Treatment for Critical COVID Patients?

[xl] Manoj et al. Repurposing Drugs: Lessons from Rheumatology in the COVID‑19 Pandemic. Indian Journal of Rheumatology. (2021) 16:2;179-186

[xli] Reis et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. The Lancet. https://doi.org/10.1016/S2214-109X(21)00448-4

[xlii] Lawrence et al. The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable. Nature Medicine

[xliii] Bryant et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. American Journal of Therapeutics, 28, e434–e460, July 2021

[xliv] Reardon S. Flawed ivermectin preprint highlights challenges of COVID drug studies. Aug 2, 2021. https://www.nature.com/articles/d41586-021-02081-w

[xlv] Bryant et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. American Journal of Therapeutics, 28, e434–e460, July 2021

[xlvi] Hill et al. Ivermectin for COVID-19: addressing potential bias and medical fraud. Research Square October 25^th. 2021

[xlvii] Ivermectin for COVID-19: real-time meta analysis of 65 studies. Unpublished. https://ivmmeta.com/

[xlviii] Roman et al. Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials. MedRxiv, 2021.05.21.21257595. https://doi.org/10.1101/2021.05.21.21257595

[xlix] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[l] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[li] Neil & Fenton. Bayesian Meta Analysis of Ivermectin Effectiveness in Treating Covid-19 Disease. ResearchGate, doi:0.13140/RG.2.2.31800.88323 (Preprint) (meta analysis)

[lii] Crawford, M. (2021). The Meta-Analytical Fixers: An Ivermectin Tale. Retrieved July 7, 2021, https://roundingtheearth.substack.com/p/the-meta-analytical-fixers-an-ivermectin

[liii] Neil & Fenton. Bayesian Meta Analysis of Ivermectin Effectiveness in Treating Covid-19 Disease. ResearchGate, doi:0.13140/RG.2.2.31800.88323 (Preprint) (meta analysis)

[liv] The uses and abuses of systematic reviews: the case of ivermectin in Covid-19

[lv] Japanese Tokyo medical Association Recommends Ivermectin Treatments. https://rumble.com/vlph6k-japanese-tokyo-medical-association-recommends-ivermectin-treatments.html

[lvi] Yagisawa et al. Global trends in clinical studies of ivermectin in COVID-19. The Japanese Journal of Antibiotics. 44:44-95

[lvii] Santin et al. Ivermectin: a multifaceted drug of Nobel prize-honoured distinction with indicated efficacy against a new global scourge, COVID-19. New Microbe and New Infect 2021; 43: 100924

[lviii] Borody et al. Combination Therapy for COVID-19 based on Ivermectin in an Australian population. October 2021. https://www.covidmedicalnetwork.com/media/TrialSite-media-release-19.10.2021.pdf

[lix] Smyth J. Merck says Covid antiviral pill halves risk of hospitalisation and death October 2 2021. https://www.ft.com/content/e1a059dc-ab09-47c0-b7b9-2b79dd1c911b

[lx] Barber & Gotham 2021. Estimated cost-based generic prices for Molnupiravirfor the treatment of Covid-19 infection. https://scholar.harvard.edu/files/melissabarber/files/estimated_cost-based_generic_prices_for_molnupiravir_for_the_treatment_of_covid-19_infection.pdf

[lxi] Reed J. Covid antiviral pill can halve risk of hospitalisation. BBC News October 3, 2021. https://www.bbc.com/news/health-58764440

[lxii] Singh S. Two Indian drugmakers to end trials of generic Merck pill for moderate COVID-19. Reuters. October 9, 2021. https://www.reuters.com/business/healthcare-pharmaceuticals/aurobindo-pharma-stop-molnupiravir-trial-moderate-covid-19-patients-2021-10-08/

[lxiii] Kabinger et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nature Structural & Molecular Biology. 28:740-246.

[lxiv] Kircik, L.H., Del Rosso, J.Q., Layton, A.M., and Schauber, J. (2016). Over 25 Years of Clinical Experience With Ivermectin:An Overview of Safety for an Increasing Number of Indications. Journal of drugs in dermatology : JDD 15, 325-332.

[lxv] Malone & Campbell 2021. Molnupiravir: coding for catastrophe. Nature Structural & Molecular Biology 28:706-711

[lxvi] Wang et al 2021. Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19. medRxiv Preprint. DOI: 10.1101/2021.06.01.21258147

[lxvii] Parliament of Australia. House of Representatives on 18/02/2021 https://www.aph.gov.au/Parliamentary_Business/Hansard/Hansard_Display?bid=chamber/hansardr/13d69421-5fbf-4e01-89d4-673a36027c10/&sid=0174

[lxviii] Tanveer et al. Transparency of COVID-19 vaccine trials: decisions without data. BMJ Evidence-Based Medicine Epub ahead of print October 2021. doi:10.1136/bmjebm-2021-111735

[lxix] Brown R. Outcome Reporting Bias in COVID-19 mRNA Vaccine Clinical Trials. Medicina (Kaunas). 2021 Mar; 57(3): 199.

[lxx] Pepperrell et al. Making a COVID-19 vaccine that works for everyone: ensuring equity and inclusivity in clinical trials. , Global Health Action, 14:1, 1892309, DOI: 10.1080/16549716.2021.1892309

[lxxi] Budget 2021: Covid-19 vaccine programme revealed to cost $1.4 billion. Stuff May 19, 2021. https://www.stuff.co.nz/national/politics/125179503/budget-2021-covid19-vaccine-programme-revealed-to-cost-14-billion

[lxxii] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[lxxiii] Gasecka et al. Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis, and Treatment. Cardiovascular Drugs and Therapy (2021) 35:215–229

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