Kiran Mazumdar Shaw and Balram Bhargava. Photos: Reuters and YouTube.
Indian Council of Medical Research (ICMR) director-general Balram Bhargava has acknowledged that there is no evidence from clinical trials that the drugs Itolizumab and Tocilizumab, approved for emergency use in India last month, reduce mortality in COVID-19 patients, The Hindu reported.
Itolizumab is a monoclonal antibody developed by Biocon Limited, the Bangalore-based pharmaceutical company led by entrepreneur Kiran Mazumdar Shaw. Earlier this month, Biocon issued a press release but neither data nor a scientific paper from a phase 2 clinical trial the company conducted in three cities to check Itolizumab’s ability to suppress cytokine storms in patients with severe COVID-19.
Shaw in particular has been championing Itolizumab’s efficacy despite widespread criticism that the phase 2 trials only enrolled 31 patients. But as Dr Jammi Nagaraj Rao, a public health physician, independent researcher and epidemiologist in the UK, wrote for The Wire Science:
[Biocon’s] trial is seriously deficient in its design. Its defects – particularly the extremely small sample size – largely invalidate the claims made in the press release from Biocon … The researchers have also not published data that would allow independent experts to assess their claim in the press release, that “Itolizumab demonstrated statistically significant advantage over the control arm, in one month mortality rate”. With such data and without further larger trials, it is difficult to see how the company can fulfil its ambition to “take this therapy to other parts of the world impacted by the pandemic”. … The irony is that Itolizumab may well be a breakthrough. If it is and if its real effects can be shown conclusively in a large trial, then Biocon would be able to boast of an unbeatable product. As things stand, it is unlikely to make that breakthrough without much greater rigour in the science of clinical trials.
What little details Biocon’s press conference earlier this month carried or were presented in a press release uploaded to the Biocon website on July 13 also failed to convince independent scientists of the trial’s statistical methods or the reliability of its results. However, both Shaw and the press release have called the data “compelling” and said the drug reduces mortality in COVID-19 patients.
ICMR director-general Bhargava appears to be the first senior government member to openly contest these claims.
It was on the back of these results that India’s Central Drugs Standard Control Organisation granted an emergency use authorisation for Itolizumab. This authorisation allows doctors to administer the drug to patients with moderate to severe acute respiratory distress syndrome, which is the condition a life-threatening COVID-19 infection inflicts on the lungs.
The other drug whose efficacy Bhargava has called into question – Tocilizumab – also intends to achieve the same outcome as Itolizumab: to reduce the mortality of COVID-19 patients by reducing the risk of a cytokine storm.
Both Itolizumab and Tocilizumab are drugs that have been repurposed to address the needs of COVID-19 patients. Itolizumab carries previous approval, under the name ALZUMAb, to treat patients with moderate to severe psoriasis. Similarly Tocilizumab has approval to help treat rheumatoid arthritis.
According to The Hindu, Bhargava said at a press briefing on Tuesday:
There are two drugs which have been thought to be preventing the cytokine storm. One is Tocilizumab and the other is Itolizumab, which are being thought that they can prevent the cytokine storm. Having said that, they have not yet demonstrated mortality reduction by any trial and therefore, trials are wanting, and are happening in different parts of the world, to look at whether there is mortality reduction with these two drugs.
However, the Drug Controller General of India has waived Biocon’s need to conduct phase 3 clinical trials. And following a question on Twitter by The Hindu‘s science journalist Jacob Koshy, Shaw replied that “pivotal data does show mortality reduction but yes larger [phase 4 trial] needs to be done to support this”.
In phase 3 trials, typically conducted with hundreds or thousands of participants at multiple centres and over multiple months, researchers check how efficacious a drug is compared to the current ‘gold standard’.
In phase 4 trials, which are conducted after the drug has received marketing approval assuming the phase 3 trials produced favourable results, the drug’s makers monitor thousands or tens of thousands of people to check for side-effects, drug-drug interactions, etc.