Approval for Bharat Biotech's COVID-19 vaccine Covaxin lacks scientific basis

The decision to approve a major vaccine without consideration of its efficacy in itself is rather extraordinary to the point of being termed unscientific.

Published : Jan 23, 2021 06:00 IST

A dry run  for the COVID-19 vaccine delivery at Northern Railways Hospital in New Delhi on January 8.

A dry run for the COVID-19 vaccine delivery at Northern Railways Hospital in New Delhi on January 8.

The COVID-19 pandemic has been a disaster of unprecedented proportions worldwide and specifically in India. India has had some of the highest figures of infection due to the virus with attendant high mortality. It hit the country around mid-March 2020. Since then, the crisis has led to several challenges disrupting life in all aspects, especially socially, economically and medically.

As of January 6, the official number of infected cases was 1.27 crore, with 96.36 per cent discharged or recovered, 2.19 per cent (2.27 lakh) active and 1.45 per cent (1.5 lakh) dead (

One of the strategies to combat the onslaught of the pandemic worldwide, and in India too, has been the development of effective vaccines. The Government of India has encouraged development of vaccines in multiple ways. As a result, several indigenous vaccines are in the pipeline—developed with or without technology from outside India. This is certainly a proud moment, especially for those who have seen India being dependent on imported foods and medicines.

The requirements for approval in India for manufacturing and/or marketing vaccines are laid out in the Drugs and Cosmetics Act, and especially the New Clinical Trial Rules, March 2019.

Indigenously developed vaccines : After initial laboratory and animal trials, Phase 1, 2 and 3 trials on human beings are to be conducted. Completed Phase 1 to 3 trial data are scrutinised at each stage by a Subject Expert Committee (SEC). The SEC looks at the Phase 3 data and, if satisfied, makes recommendations to the Drugs Controller General of India (DCGI) for licensing the vaccine for marketing and manufacturing.

Vaccines imported from abroad : If the vaccine is already approved in a country with good regulatory systems, requirements for clinical trials can be waived or abbreviated in India. Often as a precaution, a bridging trial is required to be done with the imported vaccine—a trial performed in India to confirm that the imported vaccine works as effectively with comparable safety, efficacy and immunogenicity on different genetic populations obtaining in India.

Also read: COVER STORY | Politics drives India's fight against the COVID-19 pandemic even as questions over DCGI's approvals for vaccines persist

The Covishield vaccine developed by the Serum Institute of India (SII) was granted permission for restricted emergency use on January 2, 2020, after considering, among other things, safety and immunogenicity data generated with Indian trial participants.

Covishield has been manufactured in India at the SII’s manufacturing premises in Pune with transfer of technology from Oxford University and AstraZeneca of their vaccine; therefore the latter is also called Oxford-AstraZeneca vaccine. So we can say the SII’s Covishield and the Oxford-AstraZeneca vaccine are the same, with the difference that Covishield is manufactured in Pune, India.

The second vaccine at an advanced stage of trial is Covaxin, jointly developed by the Indian Council of Medical Research-National Institute of Virology (ICMR-NIV), Pune, and Bharat Biotech International Limited, Hyderabad, and manufactured by Bharat Biotech. As of writing this, Phase 1 and 2 trials have been completed for Covaxin. The Phase 2 trial of Covaxin was determined by the SEC as having accepted safety and immunogenicity. However, trials will continue to monitor participants and collect data for the study duration.

Normally after Phase 2, the company would be asked to start the Phase 3 trial. In this case Bharat Biotech has approval for conducting Phase 3 trials with Covaxin with 25,800 participants.

Subject Expert Committee meetings

The Subject Expert Committee met during December 30, 2020-January 2, 2021, to consider the data of both the bridging study of SII’s Covishield vaccine and of the Phase 1-2 trials of Bharat Biotech’s Covaxin. While some informed observers appeared to have reservations with respect to even Covishield, or the manner of its data generation, the SEC recommended that permission be granted for restricted emergency use.

It is the decisions of the SEC with respect to Bharat Biotech that cause even greater concern. According to the All India Drug Action Network (AIDAN), in a statement made on January 5, 2021:

“A reading of the SEC minutes published on January 5, 2021, demonstrates the process through which the SEC deliberated and reviewed evidence for Covaxin between December 30, 2020, and January 2, 2021. Over the course of meetings over four days, the hesitation of the SEC in granting REU (Restricted Emergency Use) approval in the absence of any efficacy data had been documented.

“On December 30, 2020, the SEC asked Bharat Biotech to provide efficacy data, in addition to safety and immunogenicity data, for further consideration of its application. At the next meeting on January 1, the SEC noted that efficacy is yet to be demonstrated through clinical trials and appealed that the company should try to expedite Phase 3 trial recruitment and may perform interim efficacy analysis for further consideration of its application. The minutes say that on January 2, the firm presented further data and notably ‘requested for consideration of their proposal in the wake of incidence of new mutated coronavirus infection’. At this stage, the SEC appears to have relented on its insistence for efficacy data and recommended grant of restricted use in emergency situation in clinical trial mode . At the same time, the committee also observed that the vaccine candidate has ‘potential to target mutated coronavirus strains’ (emphasis added, throughout).

“One is perplexed at the abrupt change in thinking of the SEC from the first two meetings to the third day on which the approval was recommended while apparently discounting the need for efficacy data as the condition of the approval.”

Issues of concern

The decision to approve a major vaccine in a pandemic and without consideration of efficacy in itself is rather extraordinary to the point of being termed unscientific. Dr Gagandeep Kang, FRS, one of the leading experts in vaccinology in India, said in a video interview with The : “…without efficacy data no vaccine should be cleared and agreed that this means the clearance given to Bharat Biotech’s Covaxin without efficacy data has been done on the wrong basis. She said she found the limited approval given to the Bharat Biotech vaccine without Phase 3 trial efficacy ‘extremely confusing’” .

Again, The Wire reports : “In an interview with TheTimes of India , [Gagandeep] Kang, who is the vice-chair of the board of Coalition for Epidemic Preparedness Innovations and a professor at the Wellcome Trust Research Laboratory at the Christian Medical College at Vellore, has said that she is quite confused by both the approvals…. While controversy has surrounded the Bharat Biotech vaccine since it was first announced, [Gagandeep] Kang says that even the process of approval followed for the AstraZeneca-Oxford vaccine is confusing.… She also said that approval for a vaccine (in this case, Covaxin) in a ‘clinical trial mode’ is something she has not seen before in a career spanning several decades ”.

The issues of concern following this shocking and unscientific decision with respect to Covaxin are:

1) What is the legal basis for issuing an approval for restricted use in emergency situation in clinical trial mode?

2) What does it mean to approve a drug under the “clinical trial mode”?

Legal basis for Covaxin approval: Issues

Compliance with New Drugs and Clinical Trials Rules, 2019?

Let us turn our attention to the first question flagged above. The relevant part of the Drugs and Cosmetics Act and Rules are the New Drugs and Clinical Trials Rules, 2019.

Rule 80 (7) says:

The local clinical trial may not be required to be submitted along with the application referred to in sub-rule (1) if,

(i) the new drug is approved and marketed in countries specified by the Central Licensing Authority under Rule 101 and if no major unexpected serious adverse events have been reported; or

(ii) there is no probability or evidence, on the basis of existing knowledge, of difference in Indian population of the enzymes or gene involved in the metabolism of the new drug or any factor affecting pharmacokinetics and pharmacodynamics, safety and efficacy of the new drug; and

(iii) the applicant has given an undertaking in writing to conduct Phase 4 clinical trial to establish safety and effectiveness of such new drug as per design approved by the Central Licensing Authority:

Provided that the Central Licensing Authority may relax this condition, where the drug is indicated in life-threatening or serious diseases or diseases of special relevance to Indian health scenario or for a condition which is unmet need in India such as XDR tuberculosis, hepatitis C, H1N1, dengue, malaria, HIV, or for the rare diseases for which drugs are not available or available at a high cost or if it is an orphan drug.

Second Schedule

These rules have to be read together with the Second Schedule: “Requirements and Guidelines for Permission to import or Manufacture of New Drug for Sale or to Undertake Clinical Trial”.

Under the Second Schedule, we look at “Special situations for a new drug where relaxation, abbreviations, omission or deferment of data may be considered” wherein there is a subsection on “Accelerated Approval Process” for extraordinary COVID pandemic like situations “provided that there is a prima facie case of the product being of meaningful therapeutic benefit over the existing treatment”. One would say a COVID-19 vaccine is such a potential product deserving of accelerated approval process, but the prima facie case mentioned above had not been demonstrated for Covaxin when Bharat Biotech met the SEC in December 30-January 2. Phase 3 trials on efficacy are essentially meant to make such a prima facie case. And then for final approval of the product, Phase 3 data are to be evaluated with Phase 2 data on acceptable immunogenicity and safety. Phase 3 also has secondary endpoint generating further safety data.

Please note that it is not either efficacy or safety but both. In the case of a vaccine, immunogenicity too is important—the ability to induce immune response in the body. Immunogenicity was found to be acceptable in the Phase 2 data produced for Covaxin. However, immunogenicity per se does not guarantee efficacy—think HIV. Immunogenicity is a necessary but not a sufficient requirement for demonstrating efficacy.

Also read: COVID vaccination poses both a challenge and an opportunity

“Remarkable efficacy”

The subsection on “Accelerated Approval Process” has subclauses (a) to (e) to be read together. Specifically, subclause (d) says: If the (sic) remarkable efficacy is observed with a defined dose in the Phase 2 clinical trial of investigational new drug for the unmet medical needs of serious and life-threatening diseases in the country, it may be considered for grant of marketing approval by the Central Licensing Authority based on Phase 2 clinical trial data. In such cases, additional post-licensure studies may be required to be conducted after approval to generate the data on larger population to further verify and describe the clinical benefits, as per the protocol approved by the Central Licensing Authority.

Remarkable efficacy—it may be noted—has to be observed, that is demonstrated, even if approval is given with only Phase 2 data. In the current Covaxin case any kind of efficacy, let alone remarkable efficacy, has been shown. The SEC minutes has this to say: “… firm [Bharat Biotech] has presented the safety and efficacy data from non-human primate challenge study where the vaccine has been found to be safe and effective”.

Quick or expeditious review process

Further below the subsection on “Accelerated Approval Process”, there is a section titled “Situations where quick or expeditious review process can be sought for approval of a new drug after clinical development: for situation (sic) where the evidence for clinical safety and efficacy have been established even if the drug has not completed the all or normal clinical trial phases , the sponsor or applicant may apply to the licensing authority for expedited review process wherein the licensing authority will examine and satisfy the following conditions:

(a) it is for a drug that is intended to treat a serious or life-threatening or rare disease or condition;

(b) if approved, the drug would provide a significant advantage in terms of safety or efficacy;

(c) there is substantial reduction of a treatment-limiting adverse reaction and enhancement of patient compliance that is expected to lead to an improvement in serious outcomes;

(ii) the sponsor or applicant may also apply to the licensing authority for expedited review.”

Again it may be noted that safety and efficacy have to be established. There is no escape from demonstrating efficacy along with safety for final approval.

Restricted use in emergency situation in ‘clinical trial mode’

The eventual restricted use approval given by the government to Covaxin was under a so-called clinical trial mode. It is not clear what is meant by this new term, which is not to be found in the Drugs and Cosmetics Act or any related literature. Senior government authorities, many of them doctors and scientists, concerned with COVID-19 management and policies, have been active trying to explain what this means.

One explanation was that it is a clinical trial-like situation with close monitoring, emergency user after user, but without a placebo or a control arm. Informed consent of the patient or the user will be taken. But then will other requirements of clinical trial like a trial protocol, Clinical Trials Registry-India (CTRI) registration or an ethics committee apply? Will compensation in case of serious adverse effects apply as in normal clinical trials?

Or is clinical trial mode an open label single arm study? One does not know. It is also argued that Covaxin is a whole cell vaccine, and is capable of tackling mutant strains of the virus including the notorious UK strain. This, however, is a hypothesis whose proof needs to be demonstrated.

Also read: Oxford vaccine enjoys advantages in race to beat COVID-19

Other functionaries of the government have said this peculiar mode of approval is for backup in case of sudden upsurge when actually the incidence of cases is decreasing. Even if a sudden surge did occur because of a mutant strain, current reports show that it is not clear whether the Covishield like vaccine will be totally useless, but we have enough stocks in both companies, assuming not everybody will be affected by the mutant strain.

Anyway, why cannot we wait for three months when we will have the final Phase 3 results of Covaxin? Or at least wait for some interim efficacy results of Phase 3 trial of Covaxin?

Please note that a May 2020 amendment to the Clinical Trial Rules gives the permission to manufacture a vaccine, but not market it, before completion of clinical trial rules. To be fair, one should laud both companies for stockpiling their vaccines before completion of clinical trials. It is an enormous financial risk by any standards. But what is plausible risk taking for a company cannot be sensible risk taking by regulators.

The upshot is that the rather unprecedented decision of a “clinical trial mode” approval, a lexicographic legerdemain, has perplexed serious scientists and painted the actions of our regulatory authorities as much as the SEC as arbitrary, inexplicable and possibly inscrutable. This when nine pharmaceutical companies in the United States issued a joint pledge in September 2020 that they would “stand with science” and not put forward a vaccine until it had been thoroughly vetted for safety and efficacy and that they have “a united commitment to uphold the integrity of the scientific process” ( anies-pledge-coronavirus-vaccine.html).

One wishes the SEC, the DCGI and our own vaccine companies felt a similar urgency to uphold the integrity of the scientific process.

S. Srinivasan is affiliated with All-India Drug Action Network as co-convener and with LOCOST, Vadodara.

(Acknowledgments: Advocate Tanya Agarwal for confirming my reading of the law; and Malini Aisola and Siddharth Das for corrections. Usual disclaimers apply.)

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