Thursday, November 6, 2014

Should we do Ebola trials using placebos?

I wrote this letter in response to an article in the medical journal the Lancet saying that it was unethical to use placebos in trials of treatments for Ebola. It wasn't accepted for publication (they published a similar but better written letter from someone else which you can read here- so i've decided to put it online.

Adebamowo et al write that randomised controlled trials (RCT) of treatments for ebola virus disease (EVD) are unethical1. I disagree. Their first objection is that randomisation is unethical based on a lack of equipoise. Equipoise exists when there is a lack of evidence of efficacy for an intervention and is disrupted only when data are collected. They have presented no data to suggest a disruption of equipoise and it must therefore remain. Any proposed treatment for EVD with no evidence of efficacy but a scientific basis for its use might cause harm just as easily as benefit and there are a multitude of examples from the history of evidence based medicine to remind us of this.

The authors state that none of them would have agreed to participate in an RCT of the investigational product zMapp. As a healthcare worker who is about to travel to West Africa and is therefore at some risk of infection I take the opposite view. I would refuse to take part in a trial of an unproven investigational product, either as a patient or investigator, unless it was as part of an RCT as I believe it would be unethical to do so. There was a limited supply of zMapp but if we had used 5 doses and performed a 10 patient RCT which dropped the death rate from 60% to 30%, we would have had a 42% chance of detecting the drug’s effectiveness. Instead we have missed that opportunity by giving it in an uncontrolled way. We now have no idea whether to move to mass production of zMapp as soon as possible or to push on with an RCT, and all the while people are dying.

The authors state that we use drugs with barely proven efficacy on cancer patients with a poor prognosis. This is indeed ethical if there is some limited evidence of efficacy and the prognosis is very poor. We can see a parallel in extremely drug resistant tuberculosis (XDR-TB) which has a similar if not worse prognosis than EVD2. While there are a number of drugs with phase 1 trial data, none are being given to patients outside of a trial setting. Only drugs with phase 2 evidence of efficacy such as bedaqualine are being used on a compassionate basis outside of RCTs.

The authors suggest that randomisation would be impractical and that patients could not be expected to offer informed consent. This is a patronising view of the people of West Africa. Informed consent based on the explicit knowledge that the doctors have no idea whether the treatment might be beneficial or harmful is definitely possible. Moreover it is very unlikely that any new treatment would be available in sufficient quantities to treat more than a tiny fraction of those affected by EVD. When a small supply of a novel drug becomes available how will it distributed? One hopes that it will not merely be offered to privileged foreign healthcare workers but be given to local patients in West Africa. An equitable and ethical way to distribute the drugs would be to offer entry to an RCT.

EVD is not so devastating that we should abandon RCT’s, in fact the opposite is true. We are duty bound to perform them whenever we can so that scarce resources can be channelled in appropriate directions once data arrives. Not to do so would be the unethical choice.

(1) Adebamowo C, Bah-Sow O, Binka F, Bruzzone R, Caplan A, Delfraissy J, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014 Oct 18;384(9952):1423-1424. (2) Pietersen E, Ignatius E, Streicher EM, Mastrapa B, Padanilam X, Pooran A, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet 2014 Apr 5;383(9924):1230-1239.

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