Thread by @zchagla

I want to highlight the story of Hydroxychloroquine, as although the evidence is shifting against this drug being effective in COVID-19, it is a complete failure in the scientific method, and the way clinical research is allowed to function
Thread below 1/

As the seeds of a pandemic grew, invitro studies flourished. One such potent drug was chloroquine - which showed cytotoxic effects. Given this and hydroxychloroquine were oral, globally available, cheap, and had decades of safety, there was hope
nature.com/articles/s4142…
2/

What happened next was strange. Multiple people sent me "one pagers" on how to manage COVID from China, Italy, and the USA. CQ or HCQ was on all of these, often given with some sort of witchcraft concoction and indication. At the time there was no data supporting it's use. 3/

Research groups like @DrToddLee @boulware_dr put together RCT's as would be the process. Raoult's high flawed study was released suggesting a significant benefit, and the hype from President Trump took it from a few embers to a raging forest fire. 4/

An FDA EUA was granted. Now clinicians were prescribing it globally without any real data to suggest it was safe. Many on social media turned down the idea of an RCT saying it was akin to doing an RCT of parachutes working, ethically it didn't make sense to deny treatment 5/

Those who set up RCT's struggled to convince regulatory, ethics boards, research institutions to conduct their studies. However, internationally people were giving the drug to thousands with no oversight, ethics, or safety monitoring. 6/

A Brazilian study, no placebo, and simply gave people low dose vs high dose CQ showed a potential mortality signal in high dose. No clue about natural history here. However, this triggered from the FDA and HC to take care in prescribing the drug. 7/
jamanetwork.com/journals/jaman…

What happened to the RCT's? Immediate calls to reexamine safety in light of this data, and consider the feasibility to continue. So poorly constructed non placebo controlled data lead to more safety hurdles for well constructed placebo controlled trials 8/

NYC study compared ppl who HQ when it was "safe" to people who didn't get HQ (when it was "unsafe") - no difference. Clinicians who acted recklessly outside of a clinical trial and then realized their faults, put the data together, and got a publication 9/
nejm.org/doi/full/10.10…

What did that do the RCT's - more hurdles to complete. Then the surgisphere data showing a large mortality risk to the drug, again in people who decided to use it off label with no oversight. The data set was fraudulent - but nearly shut down the WHO HQ RCT in the process. 10/

And finally this week, two RCT's. One by @boulware_dr and colleagues, and another by the #recoverytrial group in the UK. No benefit to HQ as compared to placebo post exposure or in hospitalized. This, nearly 3.5 months after the invitro data, the first conclusive RCT's. 11/

What is learned here? A myriad of political and other factors lead to RCT's becoming more difficult than giving the drug off-label. That then lead to observational studies which made it more difficult to complete RCT's. A negative cycle leading to reverse the pyramid of EBM 12/

The lessons learned - ethics boards, drug regulatory agencies, research institutes all need to play their part in supporting the rapid and safe development of placebo controlled RCT's for this pandemic. Anything less is unacceptable. The story of HCQ is a failure on this part.