The story so far: On June 23, the claim by Patanjali Ayurved [Haridwar, Uttarakhand] that its preparations, ‘Coronil’ and ‘Swasari’, would cure COVID-19 in only seven days, was met with robust disbelief in some quarters, even as it hogged media space soon after the announcement. Ramdev, the yoga guru, and who is associated with the company, claimed that a randomised controlled trial (RCT) among COVID-19 positive patients had proved favourable results. The government, through the Ministry of AYUSH (Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homoeopathy) responding a short while later, told the company to stop advertising the drug as a cure for COVID-19, pointing out that it would attract provisions of Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954
What has the government said?
The Ministry, in a statement (https://bit.ly/2Zgbfco), said the details of the study were not known to it and it has asked Patanjali Ayurved “to provide at the earliest details of the name and composition of the medicines being claimed for COVID treatment; site(s)/hospital(s), where the research study was conducted for COVID-19; protocol, sample size, Institutional Ethics Committee clearance, CTRI registration and results data of the study (ies) and stop advertising/publicizing such claims till the issue is duly examined”. The Ministry has also “requested the State Licensing Authority of the Uttarakhand government to provide copies of the licence and product approval details of the Ayurvedic medicines being claimed for the treatment of COVID-19”.
It is learnt from media reports on the yet-to-be published RCT conducted on behalf of the company, that 100 patients who had tested positive were given the medicine (five dropped out midway). The clinical trial tested the drug on 45 people and another 50 were given a placebo. The claim was that 69% (31 persons) of those on the drug tested negative on the third day, and 25 of those on the placebo arm of the trial had also tested negative.
What is the place of RCTs place in clinical trials?
As per definition, a randomised controlled trial, or RCT, is a study in which people are allocated at random, entirely by chance, to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be standard practice/treatment options, a placebo (a drug without an active substance, or a ‘sugar pill’), or no intervention at all. The idea is to measure and compare the outcomes against the control after the participants receive the treatment.
Prof. Madhukar Pai, director, McGill Global Health Programs, McGill University, Canada, teaching an online course on epidemiology for journalists with Suno India portal, explains that RCTs are based on multiple factors, including type of interventions being evaluated, and number of participants. In single-blind trials, the participants, or the investigators do not know who is assigned what; in double-blind trials, both participants and investigators do not know; and triple and quadruple-blind trials, where three or four of the relevant groups are not aware of the treatment assignment.
Is an RCT a good tool to employ during the throes of an epidemic? Why do we need RCTs?
“No other design can get us close to the ‘counterfactual’ comparison we need to see if an intervention is causally linked to a particular outcome,” says Prof. Pai.
Nancy Cartwright, writing in one of the Springer journals, in October 2009 (https://rdcu.be/b5hbx), argues that RCTs are widely taken as the gold standard for establishing causal conclusions.
S.P. Kalantri, professor of medicine, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Maharashtra, answers this question with a resounding yes. He says, “We need studies that get data that we can trust.” This means, clear and robust evidence about benefits and risks. A good RCT (for COVID-19) should enrol enough numbers, define clinical endpoints, including mortality and morbidity, also whether intubation was needed and days of stay in hospital. He adds: The hurry, hype and marketing for drugs (Ayurveda and Favipiravir) even before results were published were ‘just not science’.
“The priority is to have safe, efficacious drugs that can be used in the real world setting,” he explains. “We get the best evidence from an RCT, while other strategies have huge limitations. The problem with simple descriptive studies, for instance, is that there are no comparisons.”
In well-designed RCTs, researchers, after random assignment of participants, assess whether randomisation was done sufficiently to eliminate the influence of confounding factors, and avoid selection bias. Researchers follow the groups over days, weeks, years and observe major clinical end points. In the end, all other things being equal, it will be possible to measure what benefit a particular group X got, in comparison to Y group. It is possible to estimate if there were any differences between the two groups, say, in mortality, and if this was because of strategic effect of the cause, or due to pure chance. RCTs remove the impact of chance in cause and effect relationships, says Dr. Kalantri.
But ethically, an RCT can only be employed when researchers think/hope that the interventions will offer benefits. Participants can be enrolled in a randomised controlled trial that is expected to leave them better off. The dexamethasone study where mortality was reduced by a third, is a classic example here.
The Solidarity and RECOVERY (or Randomised Evaluation of COVid-19 thERapY) trials are examples of large-scale RCTs done with multiple partners at many locations, bang in the middle of an epidemic. They have already been instrumental in setting the standard of care — for instance, hydroxychloroquine was hyped up as a drug but studies conclusively proved no ameliorative effect in using it. The Remdesivir study, on the other hand, showed some improvement in reducing intensive care unit stay, while there was no great impact on mortality, says Dr. Kalantri.
What is the future?
Strident science should be the basis of any interventions in therapeutics or vaccinology, experts emphasise. The over 200 projects in the pipeline, listed in the Clinical Trials Registry of India, might produce results over time, but as in the case of Patanjali Ayurved, the regulator’s immediate and scientific response to unpublished claims will be essential, they urge.
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