ICMR Says Biocon’s Drug Trial Not Good Enough to Prove Mortality Reduction

Indian Council of Medical Research (ICMR) Director-General Balram Bhargava has admitted that there is no proof from clinical trials that the drugs Itolizumab and Tocilizumab, approved for emergency use in India last month, minimize mortality in COVID-19 patients.

Itolizumab is a monoclonal antibody developed by Biocon Limited, a Bangalore-based pharmaceutical company headed by entrepreneur Kiran Mazumdar Shaw. Earlier this month, Biocon released a press release, but neither data nor a research paper from a Phase 2 clinical trial conducted by the company in three cities to check Itolizumab's ability to inhibit cytokine storms in patients with extreme COVID-19.

In particular, Shaw championed the effectiveness of Itolizumab amid intense criticism that only 31 patients were enrolled in phase 2 trials.

Dr Jammi Nagaraj Rao, a public health physician, independent researcher and epidemiologist in the UK, wrote for The Wire Science. According to him, The Biocon trial is severely deficient in its structure. Its defects, especially the extremely limited sample size, largely invalidate the claims made in Biocon's press release. The researchers also did not publish data that would require independent experts to test their argument in the press release that 'Itolizumab demonstrated a statistically significant advantage over the control arm in one-month mortality rate”. Despite these data and without more big trials, it is difficult to see how the company can meet its goal to "transfer this treatment to other areas of the world impacted by the pandemic." Interestingly, Itolizumab could well be a success. If that is the case, and if its actual results can be seen unequivocally in a large trial, Biocon will be able to boast of an unbeatable drug. When things stand, this achievement is unlikely to be accomplished without much greater rigor in the science of clinical trials.

What little information Biocon's press conference held earlier this month or given in a press release posted to the Biocon website on 13 July have failed to persuade independent scientists of the methodological methods used in the analysis or the reliability of its findings. However, both Shaw and the press release called the data "compelling" and confirmed that the medication decreases mortality in COVID-19 patients.

ICMR Director-General Bhargava appears to be the first senior member of the Government to publicly challenge such claims.

It was on the basis of these findings that the Central Drugs Quality Control Organization of India issued an emergency use authorisation for Itolizumab. This authorisation requires doctors to prescribe the medication to patients with mild to extreme acute respiratory distress syndrome, which is a life-threatening disease of COVID-19 infection in the lungs.

The other medication whose effectiveness has been called into question by Bhargava – Tocilizumab – also aims to achieve the same outcome as Itolizumab: that the mortality rate of COVID-19 patients by reducing the chance of a cytokine storm.

Both Itolizumab and Tocilizumab are medicines that have been re-used to meet the needs of COVID-19 patients. Itolizumab has been previously approved under the name ALZUMAb for the treatment of patients with moderate to extreme psoriasis. In the same way, Tocilizumab has clearance to better cure rheumatoid arthritis.

The Hindu reported Dr Bhargava’s says at a Press Release. According to Dr Bhargava there are two medications that were thought to prevent a cytokine outbreak. One is Tocilizumab and the other is Itolizumab, which is thought to prevent a cytokine outbreak. Having said that, there has been no proof of a decrease in mortality in any of the experiments, and thus, the experiments are trying to see if there is mortality reduction in various parts of the world.

However, Biocon's need to perform phase 3 clinical trials has been waived by the Drug Controller General of India. And following a query on Twitter from Hindu science journalist Jacob Koshy, Shaw said, "Pivotal data does indicate a reduction in mortality, but yes, a larger [phase 4 trial] needs to be conducted to confirm this."

In phase 3 trials, usually performed with hundreds or thousands of patients in several centres and over many months, researchers are looking at how successful a drug is relative to the current 'gold standard.'

In phase 4 trials, which are performed after the medication has gained marketing clearance, believing that phase 3 trials have achieved positive results, drug manufacturers track thousands or tens of thousands of people for side-effects, drug-drug interactions, etc.