Two COVID-19 vaccines that have been approved for restricted use and daily fresh cases dropping since mid-September, which suggest slowing of the virus spread in India, will make recruitment for trials more challenging. Hence, many people who would have volunteered would not see the urgency now as earlier.
On January 1, the Pune-based Serum Institute’s Covishield vaccine was granted permission for restricted use, while Bharat Biotech’s Covaxin got a similar approval the next day with certain other riders. With two vaccines now being greenlighted for restricted use, the four high-risk priority groups, beginning with frontline health-care workers, will soon begin getting vaccinated. Nearly 300 million people belonging to the four priority groups are to be vaccinated with either of the two vaccines for free.
The Ahmedabad-based Zydus Cadilla only recently got the regulatory permission to carry out phase-3 trial and has to begin the recruitment, while the Hyderabad-based Biological E is yet to reach that stage. It is unclear if Dr. Reddy’s Laboratory has completed enrollment for phase-3.
In a webinar hosted by DBT on December 31, Krishna Mohan, Executive Director of Bharat Biotech, had mentioned about the challenges in recruiting participants for phase-3 trial as many felt they had only a 50% chance of getting the candidate vaccine. And the news about vaccines soon becoming available made the recruitment even more challenging.
Pankaj Patel, Chairman of Zydus Cadilla said during the webinar that he anticipates difficulties in quick recruitment of volunteers but not with recruitment per se. “There are enough people committed to helping clinical studies. It might take longer but there won’t be a challenge with recruitment,” he said.
Now, with two vaccines approved for restricted use, how much more challenging will it be to enrol participants for clinical trials, particularly phase-3 trials that need 25,000-30,000 people? “I think it would be more challenging than earlier for this reason,” says virologist Dr. Shahid Jameel, Director of the Trivedi School of Biosciences at Ashoka University.
Neurovirologist Dr. V. Ravi formerly with NIMHANS too agrees that it would be challenging to recruit participants now. But says that DBT is addressing this through a call for research proposals for enhancing capacity for conduct of clinical trials for COVID-19 vaccine candidates.
Dr. Jameel also points out other challenges in recruiting participants now. “With the daily cases coming down, many people who would have volunteered would not see the urgency now as earlier. Also, with increasing numbers of infected people, there would be a reduced pool of susceptible people. Prior infection is an exclusion criterion,” he says.
Issues with slow spread
With the number of daily fresh cases slowing down since mid-September despite winter and festival season, the spread of the virus appears to be slowing down. This raises an altogether different challenge in carrying out phase-3 trials where the efficacy of the vaccine is measured by comparing the number of COVID-19 cases and the kind of protection offered in participants in the vaccine arm vis-à-vis the placebo arm. China had to rely on other countries to carry out phase-3 trials of its vaccines as the virus spread had slowed sharply.
“It is going to be a challenge, mostly because of the requirement of certain cases to develop in the trial after vaccine administration to understand efficacy,” says Dr. Giridhara Babu, epidemiologist at the Public Health Foundation of India, Bengaluru. “It is best to recruit participants based on an antibody test, and have two distinct groups of people to participate (both infected and susceptible) in trials to understand the efficacy in both groups. This will ensure reaching the sample size efficiently.”
Professor of Microbiology at CMC Vellore, Dr. Gagandeep Kang says vaccine manufacturers can carry out phase-3 trials outside India and efficacy results from such trials would be accepted by the Indian regulator for vaccine approval.
Health-care workers are relatively better informed of clinical trials and are more likely to participate in trials. However, with the government vaccinating them on priority, this section of potential participants will now hesitate to take part in COVID-19 trials. Dr. Jameel sees another reason why health-care workers would hesitate to participate in trials when they have been prioritised to get the vaccine. He says: “Why would health-care workers participate if they are at high risk of infection, in line of vaccination, but have only a 50% chance of getting a vaccine?”
Testing in younger people
Older people are particularly at risk of developing severe disease and even dying compared with younger people. That is precisely the reason why people over 50 years are one of the four high-risk groups to get the vaccine on priority. And since vaccines would become available in the market only after the government finishes vaccinating the priority groups, which would take many months, will trials be able to recruit only younger people?
Only in an ideal situation will 100% of older people get vaccinated on priority. There will always be a certain percentage of older people who might be missed. Enrolling such people then depends on individual trial sites, says Dr. Ravi.
Dr. Jameel says: “Yes, younger people can be induced to participate in phase-3 trials. But the vaccine will then only be tested largely in a young and generally healthy group, unlike the population it would target when approved.”
Serum Institute suing a Covieshield trial participant for Rs.100 crores has surely not helped in encouraging people to participate in trials. “That was a PR disaster. The picture that emerged was a company abandoning and threatening a trial participant who volunteered initially for no monetary gain,” says Dr. Jameel. Dr. Babu says the behaviour of the company was akin to intimidating the participant. “It would have been ideal for the manufacturer, data safety and monitoring board or regulator to speak about this incident to enthuse confidence in potential participants,” Dr. Babu says.
Trust issues not addressed
Ignoring the special challenges that companies now face in conducting COVID-19 vaccine trials in India, participation in trials has not been a high priority for people in India. “People still view participating in clinical trials as being guinea pigs and we have done nothing to address the trust issues relating to clinical research. We are now seeing significant problems in recruitment in Phase-3 trials because our communication strategies about clinical research tend to be very limited,” Dr. Kang said during the webinar.
“I think the problem is in ensuring proper communication regarding the trials. We need good communicators, who are as good or even better than the scientists who do the trials,” says Dr. Babu.
Dr. Ravi too agrees saying that lack of awareness is the main reason for hesitancy. “Well designed communication strategies providing correct information and engagement with all stakeholders in the community is what is needed to address this challenge,” says Dr. Ravi.