Bengaluru: July 2 turned out to be an unexpectedly tumultuous day for the Indian medical community. Director general of the Indian Council of Medical Research (ICMR) Balram Bhargava sent a letter to various institutions around the country asking them to begin human clinical trials for a COVID-19 vaccine named COVAXIN, to be manufactured by Hyderabad-based drugmaker Bharat Biotech (BB).
BB had announced on June 29 via a press release that it had received permission from the Drugs Controller General of India (DCGI) to begin these trials, as well as touted a claim that COVAXIN was India’s first indigenous COVID-19 vaccine. In his July 2 letter, Dr Bhargava urged the institutions – specifically, 12 hospitals and research centres around the country – to begin enrolling participants for the clinical trial no later than July 7, and to have the vaccine ready for “public health use”, which presumably means use by doctors, by August 15.
This was by all standards less a rapid vaccine development process and more an improper one. Many observers quickly raised multiple questions about whether such a trial could even be considered legitimate.
Randomised controlled clinical trials are the gold-standard of modern medicine tests. Researchers perform them to evaluate whether a specific drug or combination of drugs is both efficacious and safe. Since a vaccine’s entry into the healthcare system depends on the results of these trials, researchers usually perform them with large cohorts of participants – typically in the thousands – and over many months, allowing themselves room to check for rare and/or delayed side-effects as well.
This is why Dr Bhargava’s, and by proxy ICMR’s, decision to conduct human clinical trials as well as manufacture the vaccine in a span of five weeks on the assumption that the vaccine will work without any modifications raised questions about whether science is in command or politics.
Dr Bhargava’s announcement that the company had DCGI approval to proceed with human clinical trials for COVAXIN is also suspect. As Prem Anand Murugan wrote in The Wire, the company had received an inactivated strain of the novel coronavirus only on May 9. It’s not clear how the company could have completed animal trials, prepared the reports and had them vetted by the DCGI’s office all in the 50 days until June 29. No other information, including the trial results and the reports, is available in the public domain.
Seeking to nip any controversy in the bud, ANI on Friday published a clarification from ICMR on Dr Bhargava’s July 2 letter:
It is worth noting that earlier a letter from the ICMR DG to Bharat Biotech leaked out claimed that the vaccine would be ready by August 15. However, when asked ICMR clarified that the purpose of the letter was to expedite trials so that results could be available by August 15, the vaccine would need more time for public use.
It seems either Dr Bhargava originally intended for the vaccine to be ready for public use by August 15 but later changed his mind or that his letter on July 2 was not precisely worded.
Either way, trying to complete human clinical trials for a vaccine, which in turn is targeted at a new virus – a life form that hasn’t been around on Earth for more than a year – that in turn is spreading through a population with tremendous genetic, biological and circumstantial diversity in five weeks seems unrealistic, and is unlikely to inspire confidence in the people who will ultimately be tasked with using it.
Especially since, as Dr Bhargava’s letter itself notes, work on the preclinical and clinical development of the vaccine has not yet been completed (“ICMR and BBIL are jointly working for the preclinical as well as clinical development of this vaccine.”)
Aveek Jayant, a clinical professor of cardiac anaesthesiology and ICU services at the Amrita Institute of Medical Sciences and Research Centre, told The Wire Science that “the first code of clinical decision-making” is primum non nocere, Latin for ‘first, do no harm’. And this, he said, “applies to vaccines even more probably than those of drugs [because] here the risks arise not only from a failure to protect … but also vaccine-induced disease or the phenomenon of antibody-mediated enhancement that could [enhance] the spectre of disease.”
And given the short span of the trial, Dr Jayant said “any subject enrolled after July 15 will not be studied enough from the immune-response point of view” – regarding harm and benefit – “within the short period of four weeks that follow. The human immune system is immune to the naïvety of our political masters and the complete spinelessness of our medical elite!”
Nonetheless, ICMR seems keen on meeting the deadline. Dr Bhargava said in his letter that while “BBIL is working expeditiously to meet the target,” the “final outcome will depend on the cooperation of all clinical trial sites involved in this project,” so should any of the 12 institutes specified in the letter fail to comply, “non-compliance will be viewed very seriously”, emphasised in bold text.
At the same time, the trial’s design itself indicates that the full results may not be available up to seven months after, if not longer, and the trial’s targeted duration is specified as 15 months. Thus, there is a troubling difference between what is being done and what has been communicated.
According to the trial’s registration on the Clinical Trials Registry of India, 0.5 ml of three formulations of the vaccine – dubbed BBV152A, BBV152B and BBV152C – will be administered to participants (in the control group) via intramuscular injection, across two sets in two phases. The target sample size is 1,125 participants.
The vaccine works, like all vaccines, by introducing an inactivated pathogen (or a part of it) into the body and provoking the sort of immune response that the body will remember. So the next time an active form of the same pathogen invades the body, the body will know exactly what to do to eliminate it. The strength of provocation is called the immunogenicity. The time taken between the body to develop a specific antibody and for that antibody to show up in the blood is called the seroconversion rate.
The trial progression is as follows (quoted verbatim, edited for brevity and style):
Phase 1 – Group 1
A total of 125 subjects will be enrolled in Group 1 and will receive two intramuscular doses of BBV152A and control vaccine in 4:1 ratio. The two doses will be administered 14 days apart. Upon completion of seven days post-vaccination of the 50 participants in Group 1 (either test or control), a data safety monitoring board (DSMB) will review all the data and recommend progression to the next cohort. Thereafter, participants will be further enrolled into the higher dose cohort (Groups 2 and 3), with the continuation of the remaining participants of Group 1.
A total of 125 subjects will be enrolled in Group 2 and will receive two intramuscular doses of BBV152B and control vaccine in 4:1 ratio. The two doses will be administered 14 days apart.
Group 3: A total of 125 subjects will be enrolled in Group 3 and will receive two intramuscular doses of BBV152C and control vaccine in 4:1 ratio. The two doses will be administered 14 days apart.
After completing 7 days after the second dose of vaccination as well as after day 28, immunogenicity and safety in Groups 1, 2, 3 will be reviewed by DSMB, and it will recommend progression towards the next phase of the trial.
An interim report based on the safety and immunogenicity of the three formulations from Group 1, Group 2 and Group 3 will be notified to the Central Drugs Standard Control Organisation (CDSCO) for further progression of the clinical development of the vaccine. This interim report will contain a detailed analysis of the data based on the primary and secondary objectives of all visits through day 28 (immunogenicity and safety).
The ultimate goal is the selection of a safe, well-tolerated, and immunogenic intramuscular vaccine, which will be further, evaluated in the phase 2 study.
A total of 750 healthy volunteers of age between 12 to 65 years will be enrolled in the study and vaccinated on day 0 and day 14 with a selected formulation (X1 and X2) based on the endpoints of Phase 1 study. Since the age group differs from Phase 1, upon completion of the enrolment and vaccination of 50 participants in cohort 1 (X1) and cohort 2 (X2), as per randomisation, safety assessment will be conducted seven days after vaccination. If the study product is deemed safe based on the DSMB review, participants will be further enrolled.
The researchers conducting the trial will ultimately have to track two sets of outcomes over two periods, for three formulations, across the control group and the placebo group. The total number of data points, and subsequently interpretations, is thus very large.
The two primary outcomes are as follows: researchers conducting the trial will have to check for adverse side-effects within two hours, seven days and 14 days of administering the vaccine, and the immunogenicity and seroconversion within 14 days, 28 days, 104 days and 194 days. For the secondary outcomes, researchers will have to check the immunogenicity and the seroconversion rate of the antibodies within 14 days, 28 days, 104 days and 194 days.
The 12 trial sites are: AIIMS Patna; AIIMS Delhi; Gillukar Multispecialty Hospital, Nagpur; Institute of Medical Sciences and SUM Hospital, Jajapur; Jeevan Rekha Hospital, Belgaum; King George Hospital, Visakhapatnam; Nizam’s Institute of Medical Sciences, Hyderabad; PGIMS Rohtak; Prakhar Hospital, Kanpur; Rana Hospital and Trauma Centre, Gorakhpur; Redkar Hospital, Goa; SRM Hospital and Research Centre, Kancheepuram.
Anant Bhan, a bioethics expert based in Bhopal, pointed out on Twitter that there is no clarity on how “the clinical trial sites mentioned in the [letter’s] appendix were chosen” and how they were deemed eligible. “Was this selection done by ICMR or by [BB]? Some of these seem to be small nursing homes and hospitals; are they the apt place to run a pandemic vaccine trial?”
All together, the implication is that any decision-making that happens after a five-week period is likely to be arbitrary, if not unethical. In fact, another ethical consideration that has already reared its head is that according to the registration, of the 12 institutional ethics committees’ approvals required, only five are marked ‘approved’. The status of the remaining seven is ‘submitted/under review’.
So it’s not clear how Dr Bhargava can insist that the institutes selected to conduct the trials begin participant enrolment “no later than July 7” or why the deadline of August 15 was chosen. The latter in particular seems arbitrary except for the fact that it is also India’s independence day.
In his independence day address last year, Prime Minister Narendra Modi announced India’s human spaceflight mission even before the Indian Space Research Organisation had. Will he attempt to do the same this year with a supposedly indigenous COVID-19 vaccine even before ICMR has concluded its clinical trials?
Note: This article was updated at 7 pm on July 3, 2020, to include comments by Aveek Jayant and to include a copy of Balram Bhargava’s letter.