Biocon Ltd’s psoriasis drug, Itolizumab , re-purposed for COVID-19 and headlined as “breakthrough drug” for treating the moderately sick and the severely ill, appears to have been tested on too few patients to reliably conclude on its benefits, according to a review by The Hindu of data presented by the company to the Drug Controller General and comments by independent experts,who’ve seen the data.
To test the drug’s efficacy at preventing deaths or improving health outcome, the company recruited 30 patients across four hospitals, 20 of whom were given it along with the “standard of care treatment’ and 10 were given only standard of care. In the set of patients that got the drug, nobody died. Of the 10 who didn’t get the drug, three died. That nobody on the drug died was significant proof of the its success, said company officials.
On July 11, Biocon announced that it had received the regulator’s approval to use the drug for emergency use in cases where the infection caused a cytokine storm, namely an uncontrolled attempt by the immune system to neutralise the virus that often ended up damaging the lungs and other organs and even death. Itolizumab will be manufactured and formulated as an intravenous injection at Biocon’s bio-manufacturing facility at Biocon Park, Bengaluru.
With such a small sample size it would be ‘unwise’ to conclude that it was indeed the drug that was saving the patients, said SP Kalantri, a physician at the Mahatma Gandhi Institute of Medical Sciences, Sevagram. “Given that it’s such a small sample, 10 here and 20 there, even if one patient had died in the set that got the drug, it would have changed the picture. So it isn’t yet valid to call the results statistically significant. We can’t rule out the effect of chance [basis this study].”
An official from Biocon said the trial was designed employing a method called the Simon’s Two-Stage Design, an approach in executing phase-2 clinical trials (where the efficacy of a drug is tested). “If we were able to show two or more deaths in the control arm [the group without the drug], then a trial as small as 30 patients could yield results that were clinically significant,” said Dr. Sandeep Athalye, Chief Medical Officer, Biocon Biologics.
Given that the drug had been in use since 2013 and tested on at least 500 for psoriasis, it’s safety was not in doubt. “The 20 who got the drug have been discharged and are at home today within 30 days. We reported this level of improvement to the regulator and that’s probably why this drug has been approved for emergency use.” Other criteria such as improvement in oxygen levels and reduced inflammation were also much significantly convincing to several doctors who used the drug on their patients, he said.
The evaluation also rests on Itolizumab being added to the “best standard of care” which Dr. Athalye said “slightly varied” across hospitals. “In general this consisted of hydroxychloroquine, ritonavir (antivirals), oxygen therapy, antibiotics, heparin [to avoid clotting] and some got methylpredisarone [a corticosteroid].”
Dr. Kalantri said given that HCQ and antivirals had been conclusively shown to not benefit patients with moderate or severe manifestations of the disease, and dexamethasone (a steroid) was conclusively shown to improve patient mortality in the recovery trial conducted in the U.K., the latter should have been used as comparator. “Given that the benefits of dexamethasone are now proven, it would be unethical to not give it to someone who needs it.”
Dr. Athalye countered that when the trial began, in May, the benefits of dexamethosone hadn’t been demonstrated (the results were published on June 16). Secondly, the said drug interacted with HCQ on which most patients were on. “So people avoided giving those two together. Because of this interaction, it’s generally employed in the later stages when on ventilator and not early.”
Good reasons to justify use
Two other scientists familiar with clinical trials and affiliated with government’s medical research bodies, and therefore who didn’t want to be identified, said while the number of patients recruited were inadequate to judge the efficacy, there were good reasons to justify it in emergency use conditions. “It’s unlikely a company can afford to conduct a large trial when it’s already done a safety assessment for psoriasis. Secondly it’s hard to recruit patients in critical care conditions, in a controlled trial, when doctors would try anything to save lives and families would grasp at any possible treatment. So that leeway has to be given.”
Another scientist said there were no hard rules on a minimum number of recruits. “For an orphan drug [used to treat rare diseases], the FDA approves small numbers. So it depends on the context. Secondly, it’s useful if we have an Indian drug that would be cheaper and be made more available.”