On July 2, ICMR had sent a threatening letter sent to principal investigators at 12 sites to complete the Phase-1/phase-2 trail of India’s first indigenous COVID-19 vaccine by August 15. This despite participant enrolment not having begun. The letter warns that non-compliance will be viewed very seriously.

In a letter sent to principal investigators in 12 institutions who would be conducting India’s first indigenous COVID-19 vaccine (BBV152 COVID Vaccine) trial, Dr Balram Bhargava, Director-General the Indian Council of Medical Research (ICMR) has clearly stated that it wants to make the vaccine available for public use latest by August 15 this year. The letter is dated July 2.

The vaccine has been developed by the Hyderabad-based Bharat Biotech in collaboration with ICMR. Bharat Biotech has only completed the animal studies.

The letter says: “It is envisaged to launch the vaccine for public health use latest by August 15, 2020, after completion of all clinical trials. BBIL [Bharat Biotech] is working expeditiously to meet the target, however, final outcome will depend on the cooperation of all clinical trial sites involved in this project.”

Apparently, this is a letter sent to the principal investigators at the 12 sites to inform them that their institution has been chosen as a trial site. The letter notes: “You have been chosen as a clinical trial site of the BBV152 COVID vaccine. ln view of the public health emergency due to COVID-19 pandemic and urgency to launch the vaccine, you are strictly advised to fast track all approvals related to initiation of the clinical trial and ensure that the subject enrolment initiated no later than 7th July 2020.”

The letter makes it abundantly clear that even patient enrolment for Phase-1 trial has not begun as on July 2, but yet the ICMR wants the vaccine to become available for public use latest by August 15.

What makes the letter more alarming is the clear threat to all 12 investigators. The letter warns: “Kindly note that non-compliance will be viewed very seriously [emphasis in the letter]. Therefore, you are advised to treat this project on highest priority and meet the given timelines without any lapse”.

The letter states: “This is the first indigenous vaccine being developed by India and is one of the top priority projects which is being monitored at the topmost level of the Government.”

Dr. Rajni Kant from ICMR had in a WhatsApp group stated that the “letter is genuine and request has been made to fast-track the vaccine trials.”

“To my knowledge, such an accelerated development pathway has not been done ever for any kind of vaccine, even for the ones being tried out in other countries. Even with accelerated timelines, this seems really rushed, and hence with potential risks, inadequate attention to process,” says Dr. Anant Bhan, a researcher in global health and bioethics in a tweet.

Bharat Biotech got the necessary permission to conduct the Phase-1 and Phase-2 trial only a few days ago. The permission was based on the safety and efficacy results of studies carried out on mice, rats and rabbits.

The letter clearly states that even the preclinical development of the vaccine is not yet complete. The letter says: “ICMR and Bharat Biotech are jointly working for the preclinical as well as clinical development of this vaccine.”

“For a vaccine for which pre-clinical development is still ongoing, as per the letter itself, how can clinical trial recruitment be starting on July 7? And that the vaccine will be launched on August 15? A vaccine trial completed in little over a month, efficacy pre-decided?” asks Dr. Bhan in a tweet.

The letter unwittingly reveals from where the orders to complete the trial latest by August 15 has come from. It says: “This is the first indigenous vaccine being developed by India and is one of the top Priority projects which is being monitored at the topmost level of the Government [emphasis added].”

Dr. Krishna Ella, Chairman and Managing Director of Bharat Biotech had earlier messaged me saying that the vaccine will altogether be tested on 1,125 volunteers in Phase-1 and Phase-2. He had also said that it would take 28 days to complete the Phase-1 trial. The details provided in the clinical trial registry site too mentions 1,125 participants will be enrolled in the Phase-1/Phase-2 trial.

What the clinical trial registry details say

According to information provided at the clinical trial registry, three formulations are to be tested and two doses of the vaccine are to be administered on days 0 and 14. Follow-up of the vaccinated participants for a few days/weeks can begin only after the second dose of the vaccine is administered.

According to the clinical trial registry, enrolment was supposed to begin from July 13, and the duration of the trial was supposed to be 15 months. The trial was registered on July 1.

Informed consent

Besides enrolling 1,125 volunteers, informed consent has to be taken from each of the 1,125 healthy volunteers, and they should be tested using RT-PCR to ensure that they are not infected with novel coronavirus. Ethics committee in each of the institution has to approve the trial before the trial can begin. The trial results have been analysed, which again will take at least a couple of days. Each one of these steps requires time and cannot be hurried up.

Informed consent is central to the trial and has to be taken from each participant before enrolling participants. This process alone can take weeks. By hurrying up the trial, will the consent of participants ever be taken, and even if taken, how informed will the informed consent be? How can the nodal agency itself encourage such unethical clinical trial practices?

Can the trial be rushed?

Phase-1 trial tests for safety of the vaccine and is carried out a small number of participants. Phase-2 trial can begin only when the safety of the vaccine has been guaranteed. “This is novel virus and a novel vaccine. So, Phase-2 trial can begin only when the safety of the vaccine is known,” says Dr. Bhan.

While Phase-2 (which tests for safety, dosage and efficacy) and Phase-3 trial (that looks at safety and efficacy) can be combined, Phase-1 has to be independently carried out.

According to information provided in the clinical trial registry, immunogenicity and  safety data will be reviewed by the Data safety and monitoring board after completion of seven days post second dose vaccination and day 28. Based on the results, the data safety and monitoring board will recommend progression towards the next Phase of the trial.

The registry adds: “The interim report will contain a detailed analysis of the data based on the primary and secondary objectives of all visits through Day 28 (Immunogenicity & Safety).”

Thus it becomes abundantly clear that follow-up till day 28 is needed and results of the Phase-1 trial analysed before it can progress to Phase-2. In Phase-2, each participant has to be administered two doses of the vaccine on day 0 and day 14. Though details on duration of follow-up are not mentioned in the registry, one can expect the follow-up to last at least a couple of weeks.

How then can ICMR expect the vaccine to become available for public use by August 15.

Since Bharat Biotech has so far not got the necessary permission to conduct a Phase-3 trial, one wonders whether ICMR will do away with Phase-3 trial and make the vaccine available based on Phase-2 trial results or rush the Phase-3 trial too in the next six weeks. After all, the letter reads: “ It is envisaged to launch the vaccine for public health use latest by 15th August 2020 after completion of all clinical trials” [emphasis added].

Problems with the trial and the threat

“The letter orders the ethics committee to sign on the dotted lines and approve the trial. Clinical trials can be conducted only in teaching hospitals or academic institutions. Some of the sites chosen are small private hospitals. It is not clear if private hospitals have an institution ethics committee. Do they have a drug safety and monitoring board to monitor for serious adverse events and stop the trial if the vaccine is harming the volunteers?” asks Prof. S.P. Kalantri from the Mahatma Gandhi Institute of Medical Sciences, Wardha, Maharashtra.

“Which of the institutions in the list are going to run phase 1 studies — safety studies — which require a lot of precautions/risk management,” wonders Dr. Bhan.

“ICMR has a conflict of interest as it also involved in developing and testing the vaccine and also sends out this letter to the principal investigators giving them a deadline to complete the trial,” says Dr. Bhan.

How reliable will the trial data be

Since the trial will has to be hurried up to meet the pre-determined date of completion, and since most of the trial sites are small private hospitals, how reliable will the trial results be. This will be the most egregious human clinical trial in Indian history if ICMR is intent on completing the trial in about 43 days and makes the vaccine available to the public latest by August 15.

Even China has permitted CanSino Biologics COVID-19 vaccine (Ad5-nCoV) for use only by the military for a period of one year. The vaccine has not been approved for use by the public. And China took the decision based on the data of Phase-1 and Phase-2. Here, even enrolment of participants for Phase-1 trial is yet to begin, ethical clearance from 12 sites not available, informed consent not obtained but yet ICMR wants to make the vaccine available to the public in six weeks so it can be announced on Independence Day.

Dr. Balarm Bhargava said he will get back to me, while Dr. Krishna Ella of Bharat Biotech could not be reached.

Do us a favour

“Do me a favor, speed it up, speed it up,” U.S. President Donald Trump told the National Association of Counties Legislative Conference about speeding up the development of a vaccine for novel coronavirus. In an Editorial in the journal Science, H. Holden Thorp after saying that it might take 12-18 months or more to get a vaccine, added: “But do us a favour, Mr. President. If you want something, start treating science and its principles with respect.”

What Thorp said about Trump holds true here too.

Where the trial will take place

King George Hospital Vishakhapatnam, University of Health Science, Rohtak; AIIMS Ansari, Nagpur; AIIMS Phulwarisarif, Patna; Jeevan Rekha Hospital, Dr BR Ambedkar Road, Opp. Civil Hospital, Belagavi, Karnataka; Gillukar Multispeciality Hospital, Nagpur; Rana Hospital, Rail Vihar Medical College Road, Gorakhpur; SRM Medical College Hospital and Research Centre, Kattankulathur, Tamilnadu; Nizam Institute of Medical Science. Pungutta, Hyderabad; Dr E Venkata Rao, B 704, Palm Heights Shampur, Orissa; Prakhar Hospital, Kanpur, Uttar Pradesh; and Dr Sagar Vivek Redkar, Consultant Physician, Mumbai.

UPDATE – 11.50 pm, July 3

The Indian Scientists’ Response to COVID-19 (Indscicovid) has issued a statement condemning ICMR for accelerating the trial when even animal trials are not completed.

It says: “This recent circular from Indian Council of Medical Research, New Delhi proposes an accelerated development pathway for the BBV152 COVID vaccine. It is clear from the letter that the preclinical development of the vaccine is not complete as yet; and even patient enrolment for Phase-1 trial has not taken place. Phase-2 trial can begin only when the safety of the vaccine has been assured. Talk of launching the vaccine on a date presumes success of clinical trials as well. Considering these, ISRC views the acceleration with grave concern and urges ICMR to follow the standard norms for safe vaccine development.”