Hydroxychloroquine Cancelled Due to RECOVERY Trial

John Locher/AP

"Today’s preliminary results from the RECOVERY trial are quite clear – hydroxychloroquine does not reduce the risk of death among hospitalized patients with this new disease."

"This result should change medical practice worldwide and demonstrates the importance of large, randomized trials to inform decisions about both the efficacy and the safety of treatments."

University of Oxford epidemiologist Martin Landray 

 

"This is a hugely important finding that will likely end use of the drug in hospitalized COVID patients, given the other existing data as well. [He is curious to see the results of other ongoing studies, and that it is still an open question whether the medicine might work earlier in the disease.] We need real answers there as well."

Walid Gellad, director, Center for Pharmaceutical Policy and Prescribing, University of Pittsburgh 

"Dozens if not hundreds [of studies on hydroxychloroquine and lopinavir have been cancelled, funding withdrawn]."

"The scientific community has been no better versed on the complications of COVID than the general public."

"I'm tremendously disappointed in the scientific community and what I see is a lack of critical interpretation of this complex disease."

Edward Mills, Department of Health Research Methods, McMaster University

 

"[A number of trials] are now under substantial threat, as some regulatory agencies have actively stopped ongoing studies."

"Never before have we seen a medical scenario become such a public topic, where you have the president of the United States and the president of other countries weighing in on whether a drug works or not."

"And then you have the public weighing in on whether they agree with that individual, based on their own politics. This is unheard-of."

Sir Nick White, Oxford University tropical-medicine professor

Early results on hydroxychloroquine released in June by British scientists in their study of the drug as a potential treatment for COVID-19, had the effect of cancelling just about all trials -- and there were many -- that examined the use of the anti-malarial in various stages and for a number of purposes in the trajectory of the pandemic virus causing COVID-19. But the conclusion was that for patients whose condition was severe enough with the virus to be hospitalized, no evidence exists that the controversial malaria drug had a positive effect.

The same finding resulted for the HIV therapy lopinavir, the findings dramatically affecting how funding bodies went on to end "dozens if not hundreds" of studies using the two drugs. Dr.Mills, an expert on clinical trials. finds this profoundly disturbing. In that other trials were studying the medicines as treatments for out-patients in a milder phase of the disease or as a 'prophylaxis' in the prevention of the infection to begin with, and as far as these studies were concerned, the impact on very ill patients -- the focus of the U.K. trial -- was irrelevant to the work involved in these trials.

A bottle and pill of Hydroxychloroquine  AFP via Getty Images

Misinterpretation of trial data has become a critical problem resulting in 'disastrous' outcomes for other studies in the COVID-19 pandemic, argue Dr.Mills and his colleagues in a medical journal commentary recently published in Lancet Global Health. Scientific oversight boards fail frequently to recognize distinct phases to COVID-19 sickness, they argue, and that what may work at one point in the disease's progress may be of no use at another stage -- or vice versa. 

Oxford University professor Nick White was able to convince U.K. authorities to reverse their decision to shut down his own planned study of hydroxychloroquine as a preventive as a result of the RECOVERY findings, but acknowledged in a journal paper of his own that trials such as his own now face similar threats of discontinuance as funding is removed under the influence of the RECOVERY conclusion. The result is that it will remain unknown whether drugs like hydroxychloroquine could be useful as preventives or in early illness usefulness.

The problem, as far as he is concerned, can be traced to the unprecedented manner in which science is being communicated throughout the global pandemic. Rather than sober, informed exchanges of peer-reviewed journal papers, research now is frequently published on 'pre-print' websites or through news releases absent review, then journalists report them and the results spread through social media platforms as though science has given its last word on the subject.

According to Dr.Mills' paper, experts who rule on funding requests and ethics approvals may lack awareness that other distinct phases of COVID-19 exist, so that a drug with possible anti-viral capabilities like hydroxychloroquine may help a patient suffering early stages of the disease against the threat of the virus, while a patient severely ill in the intensive-care unit is unlikely to be helped by the drug because an exaggerated immune response and inflammation cannot respond positively to its application.

One study of Remdesivir was found to have little benefit when initiated 11 days following the start of symptoms, but it has become a modest success among COVID treatments used at an earlier date; it hastened recovery when administered a mere two days earlier. Only hospitalized patients were studied in the RECOVERY trial. Washington University was set to study hydroxychloroquine use as a prophylaxis for 40,000 front-line health workers until researchers were informed the study would be discontinued as a result of RECOVERY's findings, and the trust placed in them as the last word on the subject.

In South Africa, an ethics board stopped a trial using lopinavir on COVID outpatients in view of RECOVERY's hospital patient results until investigators persuaded the board to amend its ruling. In the interim, eight critical weeks was lost until the issue was resolved. Dr.Mills' concern is that a satisfactory understanding on how best to treat people who become ill from the SARS-CoV-2 virus will fail to eventuate in good time before people end up in hospital.

The Recovery trial’s multi-armed adaptive design and its fast-twitch release of results into the world have opened up an unusual pathway of absorption into the body of accepted scientific knowledge.  Photograph: Mariusz Burcz/Alamy