One step backward two steps forward

The results of a large multi-centre ICMR-led plasma trial were released yesterday. It shows no benefit in terms of reduction of mortality or progression from moderate to severe disease. What is helpful in dealing with these disappointments is to realise that this is exactly how science has progressed.

Sanjay Nagral
Sept 11, 2020, Mumbai Mirror

Towards the end of the 19th century, Emil von Behring, a German scientist was experimenting on diphtheria and tetanus, both killer diseases at that time. He injected guinea pigs and horses with diphtheria toxin and then removed their serum, which he believed contained ‘antitoxin’. He used this as treatment for diphtheria patients. Behring was awarded the very first Nobel Prize in Medicine in 1901 for what was then called ‘serum’ therapy.

The idea of using blood, or more precisely its fluid part or ‘plasma’, of those who have recovered from a disease is not new. It is based on the assumption that the antibodies, produced as a defence against infection, remain in the blood for some time. During this time if blood is removed, the plasma separated and injected into someone with an active infection, the antibodies will neutralise the infective agent in that person.

Such ‘convalescent’ plasma was used even during the Spanish flu in the early 20th century and later in the Ebola and MERS epidemics with some success. Hence, when Covid struck, one treatment that immediately came up was the use of convalescent plasma. In Behring’s time, they used trial and error, intuition and creative thinking to come up with treatments. It was accepted once it showed some benefits. Modern scientific rigour now demands that just because an idea seems historically and intuitively sound, it still needs a study to prove that it works. For example, one is unsure about the amount and type of antibodies necessary to eliminate the virus, as also the side effects of the plasma. Hence the need for trials. Pending results, many countries, including India, allowed temporary use of plasma on ‘compassionate’ grounds.

Globally, the Chinese, Dutch and Americans, all conducted trials with plasma. The results were mixed but certainly not dramatic. The Dutch actually abandoned their trial midway as the results did not show any benefit. The American trial from the Mayo Clinic suggested that those who had higher levels of antibodies after early plasma transfusion did better. But the investigators were quick to accept the design limitations as there was no control group.

In India, plasma therapy became a part of the optics of Covid treatment early on. Trials were announced but ‘compassionate’ use of plasma became widespread. This was especially the case with the rich and the powerful. Delhi Health Minister Satyendra Jain got himself transferred from a government hospital to a private one for plasma therapy. Plasma banks were set up. Chief ministers personally inaugurated them. TV channels ran appeals for donors. Simultaneously, studies were launched by the ICMR and other agencies.

The results of a large multicentre ICMR-led trial were released yesterday in the form of a ‘pre-print’ before being published in a peer reviewed journal. It shows no benefit in terms of reduction of mortality or progression from moderate to severe disease.

This is an important trial with several strengths to its credit. In design it was a randomised controlled study, currently regarded as the highest quality evidence. It has a large number of participants. This improves the quality of a trial as it reduces bias inherent in small numbers. The numbers were achieved by pooling patients from 39 centres, most of them public hospitals. This is commendable as multicentre trials are challenging in India. Also, the trials conducted across public hospitals where in the ‘control’ arm no plasma was administered simulates real life conditions.

As with any trial, there are shortcomings. For example, the donor plasma was not tested to check whether it had adequate antibodies. Also, the ‘standard’ care applied to patients in the control arm is unlikely to be standard across 39 centres in the country.

One of the major challenges in conducting such trials in the developing world is the process of consenting trial participants. It would be a bit naïve to think that an average patient gasping for oxygen and anxious about the disease is really understanding nuances like ‘randomisation’ before giving ‘informed’ consent. But this is a difficulty across many trials.

The most remarkable thing about this trial is the fact that it was published! It’s not common for ‘negative’ trials to be published in India and that too something which goes against an established notion which has political support. With all its limitations, this is good science as it should be.

This is certainly not the last word on plasma therapy. There are other trials being conducted which may show something different. The question now thrown up is whether plasma therapy should still be continued in practice? And if it is indeed not clearly beneficial what should the patients be told? Should other trials with the same design be allowed to continue?

These are vexing questions. What is helpful in dealing with these disappointments is to realise that this is exactly how science has progressed. Not only by successes but also recognising failures and moving on. One step backward two steps forward.