August 15 deadline for Covaxin impossible to achieve, say trial sites

This, even after India clubs phase 1 & 2 of vaccine trials: Experts

India’s Covid-19 vaccine story took an unexpected turn after the Indian Council of Medical Research’s (ICMR’s) chief wrote to investigators of the clinical trial sites chosen for Covaxin — being developed by Bharat Biotech in partnership with the National Institute of Virology — informing them of the launch date coinciding with India’s Independence Day (August 15). 

The clinical trial sites are divided in their opinion on the timelines as well as the protocols to be followed for the trials — some say phase 1 and 2 will be conducted together and the trials can end within a month, while many feel that it is impossible to stick to the deadline. 

Interestingly, recruitment of participants will begin from July 7, and the sites claim that they have not yet even received the vaccine. The trials will be conducted on 1,125 people, of which 375 volunteers will participate in phase 1. Sources said after the phase 2 ends, the Central Drugs Standard Control Organisation is likely to take a call on whether to launch the vaccine on compassionate use grounds, at least for health-care workers.

Dr Chandrasekhar Gillurkar of Gillurkar Multispeciality Hospital  in Nagpur, one of the 12 sites, confirmed they have not got the vaccine and haven’t started the recruitment yet. “We will start screening patients (to see if they have Covid-19) from Tuesday. Their samples will be sent to a Delhi laboratory and the report will come in three days. We will then recruit healthy volunteers,” he said.

Gillurkar added that after the vaccine is given (counted as Day Zero), the site will wait for 14 days or so. The second dose will be given before the 14th day. After the second dose, these volunteers will be checked again after 14 days to see if they have developed antibodies. 

Gillurkar clarified this is the speediest way — combining phase 1 and 2. If after Day zero, any adverse reaction happens, the second dose will not be given to the volunteer. He said in order to come to any conclusion, under this process, it would take at least a month or so after Day Zero. 

 

What is the usual process followed in phase 1 and phase 2 of any clinical trial? 
 

Dr T Jacob John, senior virologist, explained: “Vaccine trials start with pre-clinical toxicity studies on laboratory animals. Human trials begin with phase 1, which involves giving vaccines to volunteers with informed consent and then look for adverse effect. There are two kinds of adverse effects — if it has any toxic effect on any human body tissues (picked up by symptoms or biochemical parameters in blood), and check if one develops any adverse immune reactions.” 

John said the first week sees only direct toxicity of the injected material and then the researcher checks if there are any abnormal immune responses. “If nothing happens in 30 days then one can imagine that anything that happens beyond that cannot be attributed to the injected vaccine candidate,” he said. 

If any adverse reaction happens, the vaccine candidate is scrapped. 

John said cutting the process shorter is not a good idea.  

The phase 1 results are seen by the supervisory body, usually a data and safety monitoring board, they give a nod for the vaccine to go to phase 2. Phase 2 then checks the dosage and has two arms or more. In one, people are given a single dose and in the other people are given two doses. Sites confirmed that Bharat Biotech’s Covaxin candidate will have two arms. 

John said people will be followed up for 28 days. An investigator at a site in western India that has participated in Bharat Biotech trials earlier said this process of 28 days follow up cannot be shortened. “We cannot even reduce it even by one day. We cannot skip any single step of protocol. If the ICMR is saying that this is possible, then they are the best people to answer that question. Fast-tracking the process means they want the sites to be prepared and start working,” the doctor said. 

Other medical experts, too, expressed concern on the fast-tracking of the trial. 

Satyanarayana Mysore, head of Department of Interventional Pulmonology, Manipal Hospitals, said: “They should not be jumping the gun and they have probably not heard of immunological disasters. Intention might be very noble, but it is extremely important to stick to the norms... Cut the red tape but not the steps involved in the process.”

He added that even if they merge everything, how will we know whether the vaccine will protect against Covid-19? “Only timeline will tell if it is effective,” Mysore said. 
 

The ICMR on Saturday issued a statement saying that they are only trying to cut the red tape in the process of clinical trials and fast-tracking the process of the trials was in line with global practices. 

John further highlighted that if some sites involved in the trials do not get positive results from phase 1, the entire trial cannot proceed to phase 2. “It would take a minimum of three months to complete phase 1 and phase 2, if one does not lose a single day in between. By October we can have the vaccine cleared for phase 3. So August 15 is nowhere in the scene,” John said emphatically. 

Medical experts further said ICMR chief has, in a way, vitiated the process by writing to investigators giving a deadline. “The vaccine is a collaboration between Bharat Biotech and the ICMR. Now if one of the partners tries to set a deadline before the trials can even begin, assuming the candidate’s efficacy, it is odd. In fact, it has threatened action in case of delay and involvement of ‘top-most’ people in the government. Some ethics expert in the site ethics committees can raise concerns about this and not give a nod,” he said. 

A Mumbai-based medico-legal expert, however, said there was nothing particularly illegal in giving a deadline to finish the trials. “What is odd is to say it as a launch date. This assumes the efficacy. However, the most important point here is that the ICMR or the government or any clinical trial sponsor cannot influence the decision of the ethics committee. The independent committee will only give nod when it is satisfied,” he said. 

This process too is now under the cloud as one of the sites said they are being told that once the phase 1 trials start, the go-ahead for the phase 2 will come immediately. 

Industry sources said Bharat Biotech had approached the ICMR to help with the virus strain and thus the collaboration began between the two. One of the sites said they and Bharat Biotech are under a lot of pressure now. “Our aim is to have a safe and effective vaccine. Bharat Biotech has developed the vaccine, and now we have to see if it is effective. Now, we are under a lot of pressure.”

In fact, Krishna Ella, chairman and managing director of Bharat Biotech, has noted in earlier interviews that the vaccine could be available for mass use by early 2021. Bharat Biotech refused to comment for this story. 

Industry sources further said there was a possibility of the vaccine being launched for the public after phase 2 and the phase 3 trials being conducted simultaneously. “The drug regulator, however, will take a very cautious view on this,” said the source. This could not be verified from the CDSO.