An abridged version of this piece appeared in The Telegraph on July 27, 2020.

In a break from regular procedure to approve new drugs, the Drugs Controller General of India (DCGI) recently granted an approval to Biocon Ltd. without the mandatory Phase III clinical trial. According to the company, it conducted a Phase II study on a cohort of 30 patients. This therapeutic candidate, Itolizumab is an anti-CD6 monoclonal antibody that was previously approved by the DCGI for the treatment of psoriasis, which is a skin disease. The status of this drug in foreign markets is unclear.

After receiving the DCGI approval, Biocon’s top brass promoted the drug through social media channels and television interviews. Spokespeople for the drug manufacturer used adjectives like “breakthrough drug”, “compelling outcome”, “life-saving”, “unique” to tout the efficacy of this drug in treating COVID-19 during their promotional campaign. It was left to Indian Council of Medical Research (ICMR) to dispute some of these statements in a press conference where its Director General said that there was no evidence from clinical studies to show that this drug reduced mortality amongst severely ill COVID-19 patients.

The DCGI’s actions have raised eyebrows in the public health community because this is one of the few times that the Indian Regulator has approved a drug for a specific indication before the regulatory authorities in the US or the EU and has waived the conduct of Phase III confirmatory studies. Medical doctors, clinical scientists and those who have experience in drug development and public health have asked questions about this approval because a waiver of Phase III clinical trials is unheard of in the medical community even during public health emergencies. There is an unease that this approval will be used as a precedent by others seeking to circumvent the mandatory requirement of rigorous Phase III clinical trials to demonstrate an acceptable benefit-risk profile for any therapeutic candidate.

It is important to understand the role of a properly designed and conducted a Phase III clinical study in drug development. Unlike a Phase II study, which is the subject of this controversy, a large, properly randomized Phase III study helps us answer what truly is the therapeutic efficacy of the experimental drug while considering its risks (side effects). It is also the riskiest phase of drug development as a large percentage of drug candidates that make it through Phase II fail during a Phase III study. Such a study often demands a patient cohort of hundreds and often thousands of subjects in order to show meaningful statistical differentiation from a random chance of recovery from the disease. For example, the dexamethasone studies that recently demonstrated a significant reduction in deaths of COVID-19 patients recruited 6,400 patients of whom 2,100 received dexamethasone, while the remaining received standard care. Phase III clinical trials for Remdesivir were carried out in two stages, the first involving 397 patients and the second which began with 600 patients and was later expanded to 1,000 patients. The results of these trials for both dexamethasone and Remdesivir were published in reputable peer reviewed journals while their approval was being considered by regulatory bodies. Biocon in contrast got the approval from the DCGI based on a clinical trial which had a cohort of just 30 patients and we are yet to see any studies published in a reputed peer reviewed journal.  Epidemiologist and public health physician Jammi Nagaraj Rao explained the true size of patient cohort needed to demonstrate if the study were to meet its primary endpoints for reduction in mortality rate or to have compelling data.

Given these well-founded concerns over the waiver of Phase III study for this approval, it is necessary to understand how drug approvals in India have reached this slippery slope where pivotal Phase III trials can be waived based on such small Phase II studies. The only publicly available information about this drug’s approval, due to the inherent opacity of India’s drug regulatory framework, are the minutes of the Subject Expert Committee (SEC) which advises the DCGI on new drug approvals. The minutes for the SEC meeting where Biocon’s drug was approved do not even reveal the names of the experts who participated in the meeting and reviewed the data from Biocon. The minutes also do not list any clinical or statistical reasons for waiver of Phase III studies. Rather, they note that Biocon’s drug was being approved for ‘Restricted Emergency Use’. However the New Drugs & Clinical Trials Rules, 2019 under which Biocon’s drug was approved does not have any clause like its American counterpart, where drugs can be authorized for ‘Restricted Emergency Use’ under section 564 of the Federal Food, Drugs and Cosmetics Act.

Under Indian law, there are two other alternative pathways for approval of drug candidates that have not been evaluated in Phase III clinical trials. The first is the ‘accelerated approval’ procedure in the Second Schedule of the New Drugs & Clinical Trials Rules, 2019. To secure an approval under this pathway, pharmaceutical companies have to show that their experimental drug candidate demonstrated ‘remarkable efficacy’ during the Phase II trials for a disease that lacks alternative treatments and that there is a prima facie case of meaningful therapeutic benefit over the existing treatments. Given the small patient cohort for this study, it would be important to understand how the SEC determined “remarkable efficacy” of this drug candidate if it was approved using this pathway. To our knowledge, this pathway has never been used earlier in India. In the U.S., even when a drug gets ‘accelerated approval’ its manufacturer is still required to conduct Phase III studies to evaluate the drug candidate’s benefit-risk ratio – there is no question of a waiver.

The second regulatory pathway is laid down in Rule 91 where an ‘unapproved drug’ maybe manufactured in India for treatment of patients with life-threatening diseases. There is no discussion of waiver of Phase III trials under this provision. Therefore, it is not clear under which of these two provisions did the SEC and the DCGI grant “Restricted Emergency Use” for Biocon’s drug candidate and the DCGI is doing little to clear the confusion.

Observational data (Phase IV studies) is no substitute for properly designed and controlled Phase III studies.

The lack of transparency and the ease with which the basic norms of evidence-based approval of drugs are being thrown to the wind by the DCGI is worrying because India has had a troubling history of new drug approvals. The 59^th report of the Parliamentary Standing Committee on Health had exposed many scandals in how new drugs were approved – this included the approval of drugs that had not been approved in the Western world. There is then the report of the Mohapatra Committee which was constituted to inquire into the questionable approvals pointed out by the Parliamentary Standing Committee. It took us two long years, a rather trying process to get a copy of the report that singles out three former DCGIs by name for granting these approvals which have no scientific or clinical rationale.

This pandemic has exposed the dysfunction in the country’s regulatory system that has always thrived on the patronage of the pharmaceutical/ayush industry and brought its true nature into sharp focus to a much wider audience than is often interested in how the Ministry and the Drug Regulator function. The past few weeks have witnessed a gross violation of the Drugs and Magic Remedies Act by the makers of Coronil with little to no consequence and the approval of Favipiravir based on sparse clinical data. As concerned citizens we are well within our right to ask questions of the DCGI about its new approval without being accused of undermining national interest and we hope the government will respond constructively to our concerns.