Re: Chloroquine and hydroxychloroquine in covid-19 - the need for rational approaches to evaluating new treatments
Mark T Sullivan1, Carl M Kirkpatrick2, Edward J Mills3, Craig R Rayner4
1. Medicines Development for Global Health, Melbourne, and University of New South Wales, Sydney Australia
2. Monash Institute of Pharmaceutical Sciences, Melbourne, Australia
3. Cytel Inc., Boston, Massachusetts, USA
4. Certara Inc., Princeton, New Jersey, USA
The rapid response to this article from Professor Hoy(1) suggests that the evaluation of ivermectin as a potential therapeutic option for SARS-CoV-2 should be prioritised.
The pivotal question in the repurposing of a licensed therapy for a new disease is determining the well tolerated and effective dose. Rayner et al submitted a letter to the editor of Antiviral Research in response to Caly et al's paper on in vitro effects of ivermectin on SARS-CoV-2. In this, it was determined that the in vitro inhibitory concentration in 50% of Vero cells (IC50) was >9-fold and >21-fold higher than the day 3 human plasma and lung tissue maximum concentrations (Cmax), respectively, simulated using a high dose ivermectin regimen of 600 μg/kg dosed daily for 3 days. The same reference includes cautionary comments from the United States Food and Drug Administration and Dr François Noël on safety associated with high dose ivermectin (2) .
Our greatest risk in the urgency of the pandemic is to fill the gap between the data we have and what we want to achieve clinically with hope instead of evidence. With rare exceptions, scientific advancement requires iteration of learning through data generation. The fundamental principles of pharmaceutical medicine are, for compounds with promise, to identify an effective dose range through in vitro then in vivo models of the disease and pharmacokinetic/pharmacodynamic modelling before clinical evaluation(3). We still have only the most rudimentary data about ivermectin’s effect on SARS-CoV-2, achieved in vitro at biologically implausible concentrations. Until such time that new peer reviewed scientific evidence presents an alternate and credible argument for translating the in vitro pharmacology for patients, we should avoid exposing patients infected with SARS-CoV-2 to ivermectin.
Health claims database analyses and other real-world assessments should not be a substitute for establishing a sound scientific basis for translation to the clinic. Nor should such evidence be combined to argue for skipping key steps in the drug development process including dose finding and proof of concept. It is this type of decision making that has led to an inefficient clinical trials process with COVID-19 to date, as evidenced by 126 largely redundant trials with hydroxychloroquine, examined alone or in combination, involving approximately 180,000 participants(4,5).
Our desire to provide therapeutic options is understandable but we should guard against moving straight to the clinic because we have familiarity with the agent. Clinical trials should not be undertaken lightly (6). All interventions have risk and inconvenience for the participant and cost for society. Even randomised, controlled trials, our highest standard of evidence, rely on more than just the design to be meaningful - the arms of the study, the endpoints chosen, the presence or absence of blinding, the scope of safety data collected, which patient population included, clinical and statistical methodologies employed, amongst other factors, are critical factors for success.
Professor Hoy is right to suggest the use of existing tools to address an important medical issue. However, we must bring rational design to our work or else these good intentions will squander our opportunity for credible science and meaningful outcomes.
1. Ferner RE, Aronson JK. Chloroquine and Hydroxychloroquine in covid-19. BMJ. 2020 Apr 8;369:m1432. doi:10.1136/bmj.m1432
2. Bray M, Rayner CR, Noel F, Jans D, Wagstaff K. Ivermectin and COVID-19: A Report in Antiviral Research, Widespread Interest, an FDA Warning, Two Letters to the Editor and the Authors' Responses. Antiviral Res. 2020 Apr 21;178:104805. doi: 10.1016/j.antiviral.2020.104805)
3. Hartman D, Kern S, Brown F, Minton SK, Rayner CR. Time to step up: A call to action for the clinical and quantitative pharmacology community to accelerate therapeutics for COVID-19. Clin Transl Sci. 2020 May 22. doi: 10.1111/cts.12824
4. Thorlund K, Dron L, Park J, Hsu G, Forrest JI, Mills EJ. A real-time dashboard of clinical trials for COVID 19. Lancet Digit Health. 2020
6. World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310(20):2191–2194. doi:10.1001/jama.2013.281053
Competing interests: No competing interests