The pandemic has not only exposed the dire situation of the public health infrastructure, but also the opacity with which drug/medical device approvals are granted in India. We have had many controversies over the last few months: the use of hydroxychloroquine for treating COVID-19 patients, grant of licences for diagnostic kits for COVID-19, and the specificity of serological tests for detecting antibodies against the virus. Another controversy is brewing due to the opacity surrounding the regulatory approval granted to Favipiravir for the treatment of COVID-19 patients with mild or moderate symptoms.
No scientific consensus
The Drugs Controller General of India (DCGI) has approved Glenmark Pharmaceuticals, an Indian pharmaceutical company, to sell generic versions of Favipiravir for the treatment of COVID-19 . This drug, originally invented by a Japanese company, was meant to treat influenza. After the outbreak of COVID-19, doctors in China and Russia started using it to treat COVID-19 patients although there is no scientific consensus on the efficacy of the drug.
As per Glenmark’s filing with the Bombay Stock Exchange, the company has received “accelerated approval” from the DCGI for “restricted emergency use in India”. On what basis did the DCGI grant approval? Will the underlying data be made publicly available to the medical community? While the New Drugs and Clinical Trial Rules, 2019 allow the DCGI to grant approvals for the use of certain drugs based on approvals granted overseas, they do not absolve it from making their rationale for such decisions public.
There is no information on the DCGI’s website explaining the scientific basis of its approval of Favipiravir for COVID-19. Evidence-based medicine requires the testing of pharmaceutical drugs through randomised clinical trials (RCT) wherein one set of patients get a placebo (or an alternate therapy) and the other set of patients gets the investigational drug. Neither the doctors nor the patients know who gets what drug. If the set of patients that gets the investigational drug shows a better outcome, it can be presumed that the drug has a demonstrable therapeutic effect on the disease in comparison to the comparator. This is the gold standard for demonstrating the efficacy of a drug in treating a particular disease. The data collected from such clinical trials are usually published in a peer-reviewed journal where they are subject to scientific scrutiny. This system has worked during this pandemic to disprove claims that hydroxychloroquine was useful in treating COVID-19.
With regard to Favipiravir, we know that Glenmark was conducting a clinical trial for this drug in India. According to the Clinical Trials Registry of India (CTRI), Glenmark’s study was meant to be carried out on 150 patients at 12 different hospitals in Chhattisgarh, Gujarat, Maharashtra and Delhi with the aim of comparing Favipiravir with “standard care” provided to patients with mild or moderate COVID-19 . The decision to enrol patients with “mild” COVID-19 is baffling given that virtually all these “mild” cases often resolve themselves without any intervention. Further, the CTRI does not explain the nature of the “standard care” being provided to the patients. It is important to disclose this information from a scientific and ethical viewpoint. If we do not know the treatment with which Favipiravir is being compared, how do we know if it is any better than perhaps a placebo?
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The Japanese regulator, which approved this drug for influenza, mandated a warning to be printed on the packaging of this drug for early embryo toxicity and teratogenicity, specifically cautioning its use in women in the early stages of pregnancy. The exclusion criteria listed on the CTRI list pregnant and lactating women, which is not necessarily the same thing. The protocol on CTRI also specifies that the 150 patients enrolled in the study will be randomised 1:1. This patient cohort is not adequate to substantiate statistically either the primary or the secondary endpoint of the study.
Flaws in observational studies
Glenmark claims in a letter to the Bombay Stock Exchange that it was granted approval based on evaluation of data and expert opinion. We tried to retrieve the scientific studies that have tested the effectiveness and safety of this drug among mildly ill COVID-19 patients. PubMed, a database that contains more than 30 million citations and abstracts of biomedical literature, lists a single study published in a journal called Engineering . It shows that a group of Chinese investigators did an observational study on 80 patients and concluded that those who got the drug tended to have faster disappearance of virus and quicker improvement of shadows in their chest x-rays. The study was not a randomised controlled trial and therefore, small size apart, had two serious flaws — bias (the sample studied is not representative of the population it was drawn from or the population at large) and confounders (unable to control for all other factors that might differ between the two groups). The only way to eliminate these is to design a prospective randomised controlled study. We are unable to find well-designed robust scientific studies on the effectiveness and safety of this drug in COVID-19 patients. Therefore, the explanation that the grant was approved based on “evaluation of data” does not seem tenable.
Subsequent to a scandal in 2012, the DCGI instituted a system of review by a Subject Expert Committee (SEC) to decide whether a new drug should be approved for the Indian market. The SEC was meant to have external experts who were specialists in the field of therapy being considered. After a SEC approval, the DCGI is required to take the final call on whether to approve a drug. Thereafter the information on which such decisions were made was required to be disclosed because the Right to Information Act requires such a disclosure. However, in this case, the minutes of the meetings, the composition of the SEC and the clinical trial results submitted to the SEC/DCGI are not available on the DCGI’s website. A representative of Glenmark disclosed on a channel that the approval for restricted use was based on an “early readout” from the study; the study is expected to be completed in the coming weeks and months. So, on what basis did the DCGI approve restricted use of this drug?
Also read | Registration of Ethics Committee to approve clinical trials made mandatory now
A culture of secrecy around drug approvals serves no purpose except to benefit pharmaceutical companies. At ₹103 a tablet, the manufacturer stands to make a fortune once there are bulk orders for this drug. However, if the drug does not work as advertised, the DCGI could end up promoting widespread misuse of this drug and a false sense of security amongst the population. The regulator would be responsible for promoting irrational medicine as it has been on previous occasions. We would caution our countrymen against any such purchases until the DCGI makes public the clinical information on the basis of which the accelerated approval has been granted along with the minutes of the SEC meeting where this drug was approved.
S.P. Kalantri is Professor of Medicine at the Mahatma Gandhi Institute of Medical Sciences and Medical Superintendent of Kasturba Hospital, Sevagram, Maharashtra; Dinesh Thakur is a public health activist
