Novel drug therapies and COVID-19 clinical trials

COVID-19: Keeping the baby in the bath (Part 6)

Extraordinary claims require extraordinary evidence

Carl Sagan 1979

Every day there seems to be a new “magic bullet” drug therapy in the news headlines and another pre-print of a drug trial fast-tracked into publication. However, some of these studies are methodologically flawed, subject to bias, and are at high risk of medical reversal once well designed clinical trials are completed. For example, one study appeared in a high profile journal (the New England Journal of Medicine) with clear industry conflicts while offering no real evidence of a clinically important benefit and was most notable for having nearly as many authors as there were patients enrolled (Grean et al, 2020). Meanwhile in another high profile journal (JAMA), a study was published with outcome data even though about 80% of the patients were still being treated in ICU (Richardson et al, 2020). This led to a sensational reaction among the medical community and in the media (“nearly 90% die…”) and required subsequent correction of the ventilated mortality rate by the journal – but with far fewer corrections appearing in the lay press that had reported on it. 

As a case in point, the chloroquine/ hydroxychloroquine story is both interesting and somewhat disturbing. Interest in these 4-aminoquinolines comes from findings in vitro suggesting that chloroquine may inhibit SARS-CoV-2 (Wang et al, 2020). They have also previously been shown to have in vitro activity against multiple different viruses in the past with a variety of mechanisms proposed (Ferner & Aronson, 2020). Earlier this year, a small open-label non-randomised control study, involving 42 patients (though only data from 36 patients was reported), found a reduction in SARS-CoV-2 viral load after treatment with hydroxychloroquine in combination with azithromycin (Gautret et al, 2020). This trial has been heavily criticised for its poor methods and high risk of bias. Of note, six patients dropped out of the treatment arm (two were admitted to ICU and another died!), viral load was only assessed at day 6 of treatment, and no clinical endpoint was measured (Ferner & Aronson, 2020). Nevertheless, on March 28, the FDA in the USA authorised the emergency use of these agents for COVID-19 (see authorisation letter here) and off-label prescribing has surged around the world, to the point where there are concerns of potential shortages of hydroxychloroquine in Australia leading to new prescribing restrictions and difficulty obtaining hydroxychloroquine to conduct clinical trials. Although there are more than 80 registered trials of chloroquine or hydroxychloroquine to determine if their use in treating COVID-19 is safe and effective (Ferner & Aronson, 2020), conducting these trials when these drugs are already being widely prescribed is challenging. This is also despite these agents having never been found to be clinically effective against any of the other viruses against which they have in vitro activity (Ferner & Aronson, 2020). Already, a more sober picture of the risk-to-benefit ratio of using 4-aminoquinolones is developing. The CloroCOVID-19 randomised trial, which included only 81 out of an intended 440 hospitalised COVID-19 patients, had to be stopped early due to increased mortality in those receiving higher dose chloroquine (600mg twice daily for 10 days or total dose 12g) compared with lower dose chloroquine (450mg for 5 days, twice daily only on the first day, or total dose 2.7g) (Borba et al, 2020).  A retrospective observational study (in preprint) from the USA has found an association of increased overall mortality in COVID-19 patients treated with hydroxychloroquine (Magagnoli et al, 2020). There are also tragic reports of fatalities in the lay media of people (including at least one doctor) taking 4-aminoquinolones as either treatment or prophylaxis for COVID-19.

What is going on here? The unprecedented nature of the COVID-19 pandemic seems to have amplified the ever-present tensions that permeate the early adoption of therapies in medicine. There is a delicate balance between the need for rapid knowledge dissemination to save lives as soon as possible, and the dangers of getting things wrong and harming patients, with subsequent medical reversal when better evidence becomes available. This balance gets tilted when other drivers come to the fore – such as being overwhelmed with numerous critically ill patients with “only” supportive care to offer, fear for one’s own safety in the midst of protective personal equipment (PPE) shortages, the financial interests of drug companies, the scrutiny of a desperate public, and the “game changing” ravings of a President and a celebrity doctor (neither of whom are renowned for their critical thinking). Reports from clinician believers making extraordinary claims should be treated with skepticism until they are backed up with extraordinary evidence.

We need to learn from the past. It is common for novel therapies with biological plausibility to fail to show their purported benefits when studied in well designed trials. Examples in critical care are numerous, including decompressive craniectomy for traumatic brain injury (Cooper et al, 2011), intensive glycaemic control (NICE-SUGAR Study Investigators, 2009), and for septic shock alone include activated protein C for septic shock (Ranieri et al, 2012), nitric oxide inhibitors (Lopez et al, 2004) and most recently vitamin C (Fujii et al, 2020). It is a long road from the bench to the bedside. This is particularly so for agents that target the inflammatory and coagulation cascades in critical illness, which are interwoven, complex, and still poorly understood (Rice & Jansz, 2020). 

No novel therapy is benign, they come at a cost and patients are at risk from their uncontrolled use. Among the most concerning adverse effects from chloroquine and hydroxychloroquine, according to the Australian Therapeutic Goods Administration webpage, include “cardiac toxicity including fatal cardiomyopathy, severe hypoglycaemia (low blood sugar) with loss of consciousness, QT interval prolongation, severe cutaneous reactions, and irreversible retinal damage”. The more medications a patient receives the more likely a harmful drug interaction becomes (Kane-Gill et al, 2012), and many medications used in ICU cause QT prolongation and increase the risk of life-threatening dysrhythmias, including azithromycin which was used as a co-therapy in the study by Gautret et al (2020). Even among drug therapies that have been shown to be efficacious, there have been hundreds that subsequently needed to be withdrawn due to adverse effects detected by post-marketing surveillance (Onakpoya et al, 2019). Undue emphasis on these experimental therapies can distract healthcare teams and hinder them from optimising the myriad aspects of intensive care that helps save lives. 

In our fight to save lives at the bedside, we should keep our trust in randomised, not random, therapies. As always, the onus is on those who make claims of benefit to demonstrate their claims scientifically. As clinicians we can help by ensuring that our patients are enrolled in well designed clinical trials.

Next we will conclude with Overcoming uncertainty in the Age of COVID-19.


Further reading

Please refer to these pages from the LITFL Critical Care Compendium for overviews of the key concepts discussed in this blogpost:

COVID-19: Keeping the baby in the bath series

  1. COVID-19: Keeping the baby in the bath (Introduction)
  2. “Silent hypoxaemia” and COVID-19 intubation
  3. Is COVID-19 ARDS? What about lung compliance?
  4. COVID-19: “To PEEP, or not to PEEP”?
  5. MacGyverism and “hacking COVID-19”
  6. Novel drug therapies and COVID-19 clinical trials
  7. Overcoming uncertainty in the Age of COVID-19

References

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

Critical care physician and health services researcher bringing the tools of social science and outcomes research to improve the care of patients with critical illnesses. I practice as an intensivist at the University of Michigan’s and the Ann Arbor VA's Critical Care Medicine units, where we work to bring the latest science and the best of clinical practice to patients  | iwashyna-lab  | @iwashyna |

Intensivist in Wellington, New Zealand. Started out in ED, but now feels physically ill whenever he steps foot on the front line. Clinical researcher, kite-surfer  | @DogICUma |

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