EXPERT REACTION: WHO restarts hydroxychloroquine trials after study data raises concerns

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The WHO has restarted the hydroxychloroquine arms of its trials after earlier suspending them over safety concerns. The news comes as notices of concern are raised by two of the world's leading scientific journals, The Lancet* and NEJM,  over data from a company called Surgishere that was used in two studies which suggested hydroxychloroquine was associated with a higher mortality rate in Covid-19 patients and increased heart problems.The governance committees for the AustralaSian COVID-19 Trial (ASCOT) have also unanimously agreed that ASCOT should proceed with randomising patients to the hydroxychloroquine arms of the study. Below, Australian experts comment

UPDATE 5 June 2020: The Lancet have now retracted the paper after three authors "were unable to complete an independent audit of the data underpinning their analysis. As a result, they have concluded that they "can no longer vouch for the veracity of the primary data sources."

Organisation/s: The University of Adelaide, The Australian National University, The University of Sydney, The University of Melbourne, Australian Catholic University

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Associate Professor Steven Tong, is the ASCOT Principal Investigator, and a Royal Melbourne Hospital infectious diseases clinician and co-lead of clinical research at the Doherty Institute

The Trial Steering Committee for ASCOT strongly supports the ongoing need for data from randomised clinical trials in order to clarify the efficacy and safety of hydroxychloroquine in patients hospitalised with COVID-19,” said Associate Professor Tong.

In light of the inherent limitations of observational data, we welcome the governance committees’ decision to allow us to continue to randomise participants to arms containing hydroxychloroquine.

Randomised controlled trials are considered the ‘gold standard’ when it comes to testing treatments in humans as they remove any bias, therefore providing the robust evidence that’s required to make safe and informed decisions about the ongoing use of a treatment.

ASCOT is also an adaptive trial, which means that we are able to stop the trial if one of the treatments gives us enough evidence that it will work, or drop any treatment that looks like it will not work before the trial would typically finish.

Further, as evidence is generated from other trials around the world about other promising treatments, we are able to seamlessly introduce these new treatments into our study.

Last updated: 25 Jun 2020 1:04pm
Declared conflicts of interest:
Steven Tong, is the ASCOT Principal Investigator - The ASCOT trial is investigating hydroxychloroquine and lopinavir/ritonavir (kaletra) for the treatment of COVID19
Professor Andrew McLachlan is Head of School and Dean, Sydney Pharmacy School at The University of Sydney

UPDATED COMMENT: "The study used data from an international registry curated by a US company including 96,000 people with COVID-19, 671 hospitals across 6 continents. People treated with hydroxychloroquine or chloroquine had a higher death rate. This was a surprising and controversial finding (hydroxychloroquine has been used safely for malaria and autoimmune diseases for decades). On the back of these results a number of trials investigating hydroxychloroquine in COVID-19, including a WHO trial, were suspended, after a reassessment of the possible harms from hydroxychloroquine. Subsequently, many commentators and groups called into question the veracity of the registry data in the Lancet study, how it was collected, and aspects of the analysis. While the authors published a clarification, it failed to address major issues or provide the primary registry data (and agreements) to allow a transparent review of the research findings. A statement from the Lancet indicated that three of the authors of the paper have retracted their study because they could not “complete an independent audit of the data underpinning their analysis. The study itself (and most commentators) concluded that high-quality randomised controlled trials of hydroxychloroquine in COVID-19 were needed – especially to clarify possible harms and establish which COVID-19 patients would benefit. Many considered suspending ongoing clinical trials involving hydroxychloroquine in COVID-19 as premature. All the ongoing randomised controlled trials involve careful screening and monitoring of well-known adverse effects (on heart rhythm and eye toxicity). The numerous trials should continue; they can be conducted safely and when complete will answer the important question of whether hydroxychloroquine is a safe and effective drug to treat or prevent COVID-19 in the global pandemic."

PREVIOUS COMMENT:

The Lancet investigated outcomes for hospitalised people with COVID-19 treated with hydroxychloroquine or chloroquine alone, or in combination with an antibiotic. The study utilised data from an international registry curated by a US company including 96,000 people with COVID-19, 671 hospitals across 6 continents. People treated with hydroxychloroquine or chloroquine had a higher death rate. This was a surprising and controversial finding (hydroxychloroquine has been used safely for malaria and autoimmune diseases for decades).

On the back of these results a number of trials investigating hydroxychloroquine in COVID-19, including a WHO trial, were suspended, after a reassessment of the possible harms from hydroxychloroquine. Subsequently, many commentators and groups have questioned the veracity of the registry data in the Lancet study, how it was collected and aspects of the analysis.

While the authors published a clarification, it failed to address major issues. However, the original real world study had an observational design, it could explore associations but not attribute causality (due to potential confounding factors). The study itself (and most commentators) concluded that high quality randomised controlled trials (RCTs) of hydroxychloroquine in COVID-19 were needed – especially to clarify possible harms and establish which COVID-19 patients would benefit.

Many considered suspending ongoing clinical trials involving hydroxychloroquine in COVID-19 as premature. All the ongoing RCTs involve careful screening and monitoring of well known adverse effects (on heart rhythm and eye toxicity). The numerous RCTs should continue, they can be conducted safely and when complete will answer the important question of whether hydroxychloroquine is a safe and effective drug to treat or prevent COVID-19 in the global pandemic.

Last updated: 23 Jun 2020 6:09pm
Declared conflicts of interest:
None declared.
Dr Gaetan Burgio is Group leader and head of the transgenesis facility, John Curtin School of Medical Research, at the Australian National University

UPDATED COMMENT:

Hydroxychloroquine has been widely publicised as a potential treatment for COVID19 infection, all started from a small French trial 3 months ago. However, to date, we only have series of evidences from small studies demonstrating its lack of efficacy and potential cardiac side effects. Large studies are desperately needed to assess whether or not hydroxychloroquine treatment is efficacious for COVID19

Three weeks ago, a large observational study published in the Lancet on over 90,000 COVID19 infected patients from 6 continents and 671 hospitals demonstrated a lack of efficacy of hydroxychloroquine and over 35% increase of serious cardiac side effects. The results of this study has sparked a temporary halting in the WHO large clinical trial on over 60 countries and 3,500 patients called SOLIDARITY to assess safety of hydroxychloroquine treatment. However recent reports have raised serious research misconduct concerns regarding the data reported in the Lancet study and how these data were obtained from a company called surgisphere. This has logically resulted in a retraction of the paper published by the Lancet today.

In short to date efficacy of Hydorxychloroquine treatment for COVID19 is still unproven on COVID19. Large trials are desperately needed to determine whether or not Hydroxychloqoruine treatment is efficacious for COVID19.

As now the WHO has determined the hydroxychloroquine for the clinical trial is safe, it has logically resumed and this is a very good news. It would have been not ethical to stop in the middle of the trial as many patients have been already enrolled.

Overall, while the efficacy of hydroxychloroquine treatment for COVID19 as a prophylaxis or curative is still unproven and in my view should not be provided outside of a clinical trial.Iit is critical to continue the existing clinical trial in Australia or elsewhere to assess the efficacy of this treatment. There are patients affected with COVID19 in the middle of this.

PREVIOUS COMMENT:

Hydroxychloroquine has been widely publicised as a potential treatment for COVID19 infection, and all started from a small French trial 3 months ago. However, to date, we only have evidence from small studies demonstrating its lack of efficacy and potential cardiac side effects. Large studies are desperately needed to assess whether or not hydroxychloroquine treatment is efficacious for COVID19.

Three weeks ago, a large observational study published in the Lancet on over 90,000 COVID19 infected patients from 6 continents and 671 hospitals demonstrated a lack of efficacy of hydroxychloroquine and an over 35% increase of serious cardiac side effects. The results of this study has sparked a temporary halting in the WHO large clinical trial in over 60 countries and 3,500 patients called SOLIDARITY to assess safety of hydroxychloroquine treatment. However, recent reports have raised serious concerns regarding the data reported in the Lancet study and how these data were obtained from a company called Surgisphere. This has led to serious allegations of research misconduct and a notice of concern from the Lancet outlining the Surgisphere data concerns was published yesterday.

In short, to date efficacy of Hydroxychloroquine treatment for COVID19 is still unproven and large trials are desperately needed to determine whether or not Hydroxychloroquine treatment is efficacious for COVID19. 

As the WHO has now determined that the Hydroxychloroquine clinical trial is safe, it has logically resumed and this is very good news. It would have not been ethical to stop in the middle of the trial as many patients have already been enrolled.  

Overall, the efficacy of hydroxychloroquine treatment for COVID19 as a prophylaxis or curative is still unproven and in my view should not be provided outside of a clinical trial. However, it is critical to continue the existing clinical trial in Australia or elsewhere to assess the efficacy of this treatment. There are patients affected with COVID19 in the middle of this.

Last updated: 05 Jun 2020 10:34am
Declared conflicts of interest:
None declared.
Dr Ian Musgrave is a Senior Lecturer in the Faculty of Medicine, School of Medicine Sciences, within the Discipline of Pharmacology at the University of Adelaide.

UPDATED COMMENT:

Events have indeed moved quickly and the Lancet article has been retracted. This reinforces my statement that the scientific community must remain vigilant. I hope this will led to better rules around big data and data transparency in publications. But it needs to be emphasised that despite this articles retraction, there is still no good evidence that hydroxycholoquine is effective.

PREVIOUS COMMENT:

The news of the WHO restarting clinical trials ironically come as another study was published in the New England Journal of Medicine which showed no effect of hydroxychloroquine as pre-exposure prophylaxis for COVID-19. The decision by the WHO to pause trials was appropriate at the time, and the decision to reopen after careful review is also appropriate.

Even if we completely discount the Lancet studies, there is still significant evidence of lack of efficacy and potential harm that restarting clinical trials should be done carefully. And clinical trials are still needed. The rapid pace of the COVID outbreak means that the early data we collect may be misleading or incomplete. While hydroxychloroquine has been given undue attention (and its potential harms minimised) there may still be some benefit to its judicious use. The Lancet case shows us that the scientific community must remain vigilant even with results we agree with and that data transparency and data sharing are even more important when we need to make good conclusions quickly in uncertain times.

Last updated: 05 Jun 2020 10:23am
Declared conflicts of interest:
None declared.
Dr Roger Lord is a lecturer (Medical Sciences) with the Faculty of Health Sciences at The Australian Catholic University and Research Fellow with The Prince Charles Hospital (Brisbane).

It is of great concern that the recent peer reviewed study in The Lancet examining the effects of hydroxychloroquine or chloroquine for treating hospitalised COVID-19 patients may contain falsified data.

The COVID-19 pandemic has given rise to an epidemic of preliminary, unverified and misinterpreted research that makes scientific scrutiny that more difficult.

The Lancet is an eminent peer reviewed journal and has lodged an expression of concern regarding the publication examining the antimalarials and is now investigating the status of the reported findings which halted clinicals being conducted by the WHO and the Peter Doherty Institute for Infection and Immunity conveners of the AustralaSian COVID-19 trial (ASCOT).

If The Lancet publication does prove to contain fabricated data this will be very disappointing both for the journal and the health and scientific community which rely on the high standards of peer review provided by this publication.

It is still of great importance to stress the dangers of using hydroxychloroquine or chloroquine to treat or prevent COVID-19 infection in the absence of any reliable independent peer reviewed evaluation of its use clinically.

Last updated: 04 Jun 2020 4:11pm
Declared conflicts of interest:
None declared.
Dr Phillip Reece is a consultant to the pharmaceutical and biotechnology industry and an Honorary Senior Fellow in the Department of Pharmacology and Therapeutics at the University of Melbourne

Reports that data underlying recent COVID-19 publications in the Lancet and New England Journal of Medicine are unreliable are disturbing. 

The worldwide spread of COVID-19 has created an urgent need for antivirals and treatments that are safe and effective for treating and preventing the infection.  Private and public institutions and individuals have joined the search and numerous developments are underway.  The urgency of the situation has put pressure on usual drug development pathways through a need to identify effective antivirals as quickly as possible without compromising safety. 

Drug development is normally highly regulated and requires extensive preclinical studies followed by clinical studies initially in healthy volunteers and subsequently in patients.  The development path for a marketed drug where a new indication is being sought, such as COVID-19, is simplified by the need for fewer safety studies as these will have been completed for approval to market and additional safety information will have been generated through post-marketing surveillance of adverse events. 

However, even in this case, precaution is warranted as the safety profile could be different in patients with COVID-19.  Differences in dose size, dose frequency or duration for the new indication will further complicate the situation and change the safety profile.  It is therefore imperative that the urgency of the current situation with COVID-19 does not result in the short-circuited development of potential antivirals that present a greater risk to subjects than the disease itself. 

It is equally important that clinical studies of COVID-19 are conducted and reported to the highest standard.  Given the current controversy around the safety and efficacy of hydroxychloroquine for the treatment and prophylaxis of COVID-19 infections, in addition to the clinical studies currently underway, there remains a need for small Phase I studies in healthy volunteers to address the question of safety at a higher doses and different dosage regimens. 

These studies can also address questions such as the concentration of free drug in plasma and at the site of the infection, for example, in lung sputum in the case of COVID-19.  Such concentrations should exceed the effective concentration required for the drug against the virus.

Last updated: 04 Jun 2020 12:25pm
Declared conflicts of interest:
None declared.

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