New Delhi: Several hours after the Indian Council of Medical Research confirmed that its director general Dr Balram Bhargava had written to the principal investigators in the Covaxin trial asking for the vaccine against Covid-19 to be launched by 15 August, there was no clarity from the apex body about how the timeline would be shrunk.
Vaccine development timelines akin to those for Covid have not been met yet. The fastest vaccine that has been approved so far was for mumps in 1967, which took four years from virus isolation to vaccine licencing. The ebola vaccine has been the second fastest, with an expedited global response commencing in 2014 resulting in the vaccine being licenced after 5 years.
In its submission to the Clinical Trial Registry of India (CTRI), the developer of the vaccine candidate, Bharat Biotech International Limited (BBIL), has submitted that the duration of the trial is a year and three months. The trial protocol requires follow-ups on Day 14, Day 28, Day 104 and Day 194, which means over six months.
The date of first enrolment of trial participants is given as 13 July. In his letter to the principal investigators of the trial at 12 institutions across the country, Bhargava asked for enrolment to be “initiated no later than 7 July”.
Bhargava also wrote: “It is envisaged to launch the vaccine for public health use latest by 15 August 2020 after completion of all clinical trials. BBIL is working expeditiously to meet the target. However, the final outcome will depend on the cooperation of all clinical trial sites involved in this project.”
The letter has not only been criticised by the health community, but has also met with contradictory and conflicting responses from the principal investigators it is addressed to. Several of the investigators ThePrint spoke to also offered data inconsistent with what is mentioned in the letter and the registered study protocol.
Calls and messages to Bhargava and the government’s Principal Scientific Adviser Dr K. VijayRaghavan about the modalities to be adopted to shrink the trial duration did not elicit a response.
Meanwhile, BBIL chairman and managing director Krishna Ella told ThePrint: “Enrolment of the cohort for the phase 1 is underway. Right now, we are awaiting the approval for human clinical trial vaccine batches from the regulator; parallelly, we are also awaiting ethical committee approvals from various institutions, some of which have already come.
“Inactivated vaccines have a well-proven and accepted track record, with no potential to infect or replicate. It just serves the immune system as a dead virus and mounts an antibody response towards the virus. Conventionally, inactivated vaccines have been around for decades.”
Clinical trial registry document
According to information submitted to the CTRI, the trial plans to enrol subjects in three groups of 125 each for Phase 1, in which after 28 days, the safety and immunogenicity of the vaccine candidate — that is, whether it is capable of generating an immune response in the body — will be seen.
Following this, an interim report is to be submitted to the Central Drugs and Standards Control Organisation.
Phase 2 is to be a randomised double-blind study. This means subjects will be randomly assigned to two groups, one of which will receive the vaccine candidate and one won’t, and neither group will be told what they are receiving.
“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 based on the endpoints of Phase 1 study. Since the age group differs from the Phase 1, upon completion of the enrolment and vaccination of 50 participants in Cohort 1 and Cohort 2 as per randomisation, safety assessment will be conducted seven days after vaccination,” reads the trial registration document.
The evaluation of immunogenicity in Phase 2 is to be done on Day 14, Day 28, Day 104 and Day 194 in the two cohorts (groups). The total sample size is 1,125.
The vaccine candidate
Bharat Biotech’s vaccine candidate has been developed from a SARS-CoV-2 strain isolated by the National Institute of Virology in Pune. The firm is working with the ICMR and the NIV for its development.
The vaccine got approval on 29 June for Phase 1 and Phase 2 trials from CDSCO. It is made from a dead virus, so that it retains its unique identifying features for the immune system of the body to recognise it and produce antibodies, but cannot spread infection.
It is currently in pre-clinical stages, which means its action outside the body, or ‘in-vitro’, is being tested. Its reaction is also being studied among animals.
Pre-clinical trials were also conducted on guinea pigs and mice to ascertain whether Covaxin is safe for use.
Experts and investigators concerned
Anant Bhan, a researcher in global health and bioethics, expressed concern about the crunched timeline.
“Obtaining and processing data from just Phase 1 & 2 takes time. This timeline is very aggressive. The trial has not begun recruiting participants yet, but they seem to be predicting that the results will be obtained, processed, and released in just over a month. This is a cause for concern,” Bhan said.
“It is unclear whether they have would have examined data adequately from the planned Phase 1 & 2 studies, and also have done efficacy because they seem to have already announced a timeline for releasing the vaccine. It is also unclear how the institutes were selected for this and whether they are well equipped to handle vaccine trials, which require a high degree of safety,” he added.
Does this mean all these 'institutions' have to follow all due processes to enable this trial to be run within 5 days from the letter? Including ethics committee approvals? Is that not undue pressure on the institution and committees?
— Anant Bhan (@AnantBhan) July 3, 2020
A report by ANI stated that ICMR had clarified that the purpose of the letter was to simply expedite the trial process, so that data would be available by 15 August.
However, an ICMR official told ThePrint that the letter is a demi-official communication, and agreed that “the aim is to complete the trial before 15 August”. The official added: “It is envisaged to launch the vaccine for public health use latest by 15 August 2020 after completion of all clinical trials. BBIL is working expeditiously to meet the target, but final outcome will depend on the cooperation of all clinical trial sites involved in this project.”
Many principal investigators mentioned in the letter expressed apprehensions about ICMR’s timeline.
“You can’t rush the scientific process” said an investigator at one of the institutes when asked if they were under pressure to meet the deadline.
Admitting that the institutes had received the letter, the investigator said: “Nothing changes, we have already fast tracked the process but we cannot risk someone’s life.”
The investigator’s institute is waiting for the vaccine, as are most other institutions. Seven of the 12 hospitals haven’t even received approvals from their respective ethics committees yet.
Venkata Rao of the Institute of Medical Sciences and SUM Hospital, Odisha, said the trial would inevitably deviate from the 15 August deadline.
“Like us, several sites are still awaiting approval from the ethics committee, which could take days. Recruitment will follow, and then observation for 28 days. All sites will not start their trials simultaneously, so there will be a lag between each site’s cycle,” Rao explained.
“It’s designed to go from phase 1 to phase 2, and we will get an indication if it’s working after phase 1,” he said.
Prabhakar Reddy of the clinical pharmacology department of the Nizam’s Institute of Medical Sciences in Hyderabad added: “It will only be possible to get the results of the first phase of the trial by 15 August 15.” Reddy said this deadline is still achievable, if all 12 centres finish recruitment of the participants by 20 July and get the data by 5 August. His institute has also not received its ethics committee clearance.
(This report has been updated with reactions from BBIL, health experts and investigators part of the trial)