The critics are pointing to the small size of the clinical trial, exemption of Phase-3 trial, use of the drug as off-label for COVID-19, and making claims to the press before data is published in a peer-reviewed journal.
Biocon's Itolizumab, which was approved to treat COVID-19, has sparked a controversy. The drug was approved on July 11 by the Drug Controller General of India (DCGI) for restricted emergency use for treating moderate to severe coronavirus disease (COVID-19) cases.
Itolizumab isn't a new drug. The drug was approved in 2013 for treating psoriasis, and is now repurposed for treating COVID-19. The drug was positioned as an affordable option to Tocilizumab, an IL-6 inhibitor drug marketed by Roche and its Indian partner Cipla, which is also used for treating COVID-19 patients.
Indian Council of Medical Research (ICMR) Director-General Balram Bhargava said there is not enough evidence from clinical trials that the drugs Itolizumab and Tocilizumab reduce mortality in COVID-19 patients.
Itolizumab, meanwhile, is drawing sharp scrutiny. The critics are pointing to the small size of the clinical trial, exemption of Phase-3 trial, use of the drug as off-label for COVID-19, and making claims to the press before data is published in a peer-reviewed journal. People are seeking more transparency from the Indian drug regulator on checks and balances that are being adopted while approving the drug.
To be sure, there are eminent doctors who are vouching for the drug. Some of them have used the drug as off-label, where an approved drug is used for a disease that it is not approved to treat. Kiran Mazumadar-Shaw, the outspoken Chairperson of Biocon, is taking certain naysayers of Itolizumab on Twitter head on, but some conversations have turned unsavoury.
Here are the main questions raised on the drug
Is the trial underpowered?
The Itolizumab trial is a randomised, controlled, open-label study at four hospitals in India, enrolling a total of 30 hospitalised COVID-19 patients with moderate to severe ARDS. Twenty patients were randomised to receive Itolizumab plus supportive care, while 10 patients in the control group received supportive care alone. The primary endpoint was mortality at one month.
Biocon said the small study was a feasibility study to see any benefit and were pleasantly surprised to find mortality benefit.
The company said that in the Itolizumab arm there were no deaths and all patients have recovered; in the control arm three patients died and the remaining have recovered.
But critics wonder if the trial is underpowered due to small sample size to pick a real effect of reducing the mortality.
Biocon's Chief Medical Officer Sandeep Athalye says this a label extension of an already approved product, and if they are able to show the magnitude of effect in a small trial, which is statistically significant, even a small trial would suffice.
Why no phase-3 trial?
Phase-3 is a large, multi-centre trial where the drug is tested on patients to demonstrate efficacy on treating the intended disease compared to placebo or regular standard of treatment.
The DCGI has waived Biocon’s need to conduct phase 3 clinical trials, and allowed the company to conduct post-marketing surveillance, also called Phase 4. But some experts say that given the complex nature of the COVID-19 disease, phase-3 ought to be done.
"If a disease is uniformly fatal then a small sample size is enough to establish whether or not a drug works. If death is, say under 10-20 percent, then you need to study a lot of patients to be sure the study's conclusions are valid. This is statistical theory at its finest," tweets Jammi N Rao, a public health physician with expertise in statistics and epidemiology,Biocon said several doctors have used the drug off-label on 150 patients since May on compassionate grounds in Maharashtra, Gujarat and Delhi and all have been cured of COVID-19.
In an interview to IANS, Mazumdar-Shaw defended that if they did a 100-patient trial on Itolizumab, it would have taken three months, even as patients were dying from COVID-19.
Peer-reviewed journal or press release?
Some experts have criticised the way the company went to the media before publishing the data in a reputed journal, that would have allowed independent experts to assess the claims threadbare.
Biocon said it will be publishing the trial data as well as real-world data to further strengthen the body of evidence for Itolizumab.
Has the regulator followed due process?
Some critics have questioned the DCGI for waiving phase-3 trial. They sought the regulator to make the minutes of the subject expert committee (SEC) that decided to approve the drug to be made public. Some even went to the extent of seeking disclosure of the names and professional details of SEC members to verify if they have any conflict of interest.
Biocon defended saying that the process followed has been extremely robust. “The kind of scientific discussions that we had, have been of a very high order,” Mazumdar-Shaw said.