With Serum Institute of India, Bharat Biotech and Zydus Cadila progressing in the testing of their Covid-19 vaccine candidates, sites across India will be looking at enrolling volunteers for mid- to late-stage human trials. A look at who is chosen, how, and what else the trial process involves:
Who is a volunteer?
If a product is undergoing clinical trials, it means either that it has never been used before or that it has never been used to treat the condition for which the trials are being conducted. The trials aim to find out if it is safe and effective. In a vaccine trial, the aim is to check how well it will protect a population by building their immunity against a particular pathogen.
When healthy people who have not been exposed to a particular illness consent to be injected with doses of the vaccine, they are known as volunteers, participants or trial subjects. Researchers observe these volunteers to determine whether the vaccine is safe to be given to the community at large.
“The first and foremost benefit of having volunteers for these trials is that you help progress science,” said Dr Chirag Trivedi, president of the Indian Society for Clinical Research (ISCR). “But, remember, it is absolutely voluntary for the person to participate.” He said the volunteer can also choose to back out of the trial later, even after it is under way.
What are the eligibility criteria?
Each trial uses a specific set of criteria to determine if a person is eligible to participate, according to ISCR. This includes factors like age and illnesses. The criteria are modified as the trials progress, as the researchers try to understand whether the shots will also protect those more vulnerable.
For the first phase of the trials of their respective Covid-19 vaccine candidates, Bharat Biotech (Covaxin) and Zydus Cadila (ZyCov-D) were looking at enrolling people between ages 18-55. Researchers also excluded applicants based on whether they had diseases or conditions like asthma, allergies, high blood pressure, or diabetes.
What has been modified since?
With Covaxin, ZyCov-D and the Oxford vaccine candidate (Covishield) having moved to the second phase of testing in India, the age group of those who can participate has widened. ZyCov-D’s phase II trials are enrolling those aged 12 and above, Covaxin is enrolling those aged 12-65, while the Covishield trials will reportedly enrol those aged 18 and above.
“Phase-wise, we relax the range of the age groups tested because of the objective that is to be studied. In phase I, the main objective is to test the safety and side effects… but in phase II, immunogenicity becomes objective number one and side effects are the secondary objective,” said Dr E Venkata Rao, the principal investigator in one of these trials. “In phase III, it is the efficacy trials to check how useful it is in the community (vaccinated).”
People who have participated in one trial are not eligible for another, because it may lead to “cross contamination” by the medical products being tested, skew up the results and even be dangerous for the volunteer.
How does one enrol?
Once a site receives approval to conduct clinical trials, it can advertise for volunteers, provided the advertisement is cleared by ethics committees. Those keen on volunteering can also search independently on the Clinical Trial Registry of India, which lists out locations for a specific trial, along with contact numbers. In the past, some participants have also found trials to participate in by contacting bodies like ISCR, Trivedi said.
Locations such as the Institute of Medical Sciences and SUM Hospital-Odisha’s Department of Community Medicine have set up websites for prospective volunteers. “We also have a form that helps people check whether they are eligible to register for the trials,” said Rao.
What happens after they register?
The trial site may call in the volunteer as part of its enrolment process, which includes ensuring that they are consenting only after they have understood all details. “We explain to each volunteer separately that this is the purpose of the study, these are the advantages, these are the disadvantages and this is the procedure,” said Rao.
This is usually done over camera, where audio-visual informed consent is taken. The volunteer is then tested to see whether he or she is eligible for the trial. In the case of the Covid-19 vaccine trials, this would include tests to make sure the prospective volunteer hasn’t already been exposed to the virus — which would make them ineligible.
Do volunteers get paid?
Under Indian regulations, volunteers do not receive any remuneration for participating in trials. According to experts, there is a pre-approved standard operating procedure for each trial, which allows compensation for food and travel whenever the volunteer has to visit the site, but this is a nominal amount.
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“There are poor and needy people in India. If you are trying to give compensation to incentivise them to join, then, at the end of the day, there will be some kind of pressure (on them) to take a risk,” said Rao, adding this is “ethically incorrect”.
What are the risks involved?
According to clinical trial practitioners, human trials are usually not supposed to lead to extreme adverse reactions. This is because the product has already gone through a phase of testing on animals with genetic codes similar to humans and is being tested on humans only after regulatory scrutiny and approvals.
A Data and Safety Monitoring Board (DSMB) is set up for each trial to study the information collected throughout the process. It can even recommend that a trial be stopped if there is a major cause for concern.
Even after the trial is completed and the vaccine is marketed, clinical centres are supposed to “meticulously” observe the blood levels of those injected, the ability of the shot to produce an immune response and side effects, said Rao. Volunteers in most of the Covid-19 vaccine trials around the world have reported manageable side effects such as headaches, fevers, itching and swelling.
Can a clinical trial go wrong?
Despite pre-clinical testing and DSMB checks, trials can still go wrong. According to Health Ministry data, 1,443 people who had participated in clinical trials in India had died of serious adverse events between 2015 and 2018. At least 88 of these deaths were known to be due to serious adverse events related to the trials.
There is no clear information on what type of volunteers these were (while vaccine trials recruit healthy volunteers, people who are really sick also participate in certain types of trials). The deaths could include critically ill patients who are not responding to available treatment and are enrolled in trials for a new, potentially life-saving treatment.
Things can also go wrong if regulations meant to safeguard participants are not followed. In 2010, seven of 23,000 girls in India who were injected with a human papillomavirus (HPV) vaccine as part of a study had died. In 2013, a Parliamentary Standing Committee observed that those conducting the study attempted to circumvent the “arduous” and “strictly regulated” route of clinical trials by calling it a “demonstration project”.
What happens if it goes wrong?
India’s clinical trial rules provide for a formula to compensate participants who die or experience injuries, including disabilities, related to clinical trials.
Based on this formula, the compensation would range from Rs 2 lakh to as much as Rs 74 lakh, depending on factors like how likely the participant was to die if they hadn’t participated in the trials, according to Trivedi. If a healthy young volunteer dies, their next of kin would get the “maximum” compensation, he said.
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