When the standard of care is available only to a section of the population, the priority groups at the moment, then it is not standard of care for the rest of the population. Therefore, it is ethical to continue with a placebo in the population outside the priority groups, as long as that non-priority status is maintained.
On February 3, 2021, the Subject Expert Committee of the Indian drug regulator approved the Pune-based Serum Institute to conduct a phase-2/3 trial of CovoVax COVID-19 vaccine that was originally developed by Novavax Inc headquartered in the U.S. The Novavax vaccine was found to have over 89% efficacy in a phase-3 trial carried out in the U.K. In mid-January Dr. Reddy’s lab was allowed to carry out a phase-3 trial of Sputnik V vaccine. There are other vaccines which too will begin human clinical trials in India.
In both these cases, the SEC allowed the vaccine manufacturers to use a placebo in the control arm even as two vaccines — Covishield and Covaxin — have been granted restricted use approval. Though the two vaccines (here and here) have only a restricted use approval, is it correct to test the efficacy of new COVID-19 vaccines by comparing it with a placebo and not use either Covishield or Covaxin in the control arm?
“There are two ways to think about this,” Dr. Gagandeep Kang, Professor of Microbiology at CMC Vellore says in an email. “Usually, ‘restricted use’ or ‘emergency use’ is not considered as equivalent to licensure. Taking a regulatory point of view, if a product is not licensed and available for use, then the availability of a product for ‘restricted use’ does not preclude any standard study design, including the use of placebo.”
Dr. Kang then adds: “We can also think about this from an ethical perspective. All persons in a control arm should receive, at a minimum, the standard of care. If the vaccine under ‘restricted use’ is considered the standard of care, then all controls will need to be given the ‘restricted use’ vaccine.”
Dr. Anant Bhan, a Bhopal-based researcher in global health and bioethics, says in an email: “The regulator should have specified what their criteria for allowing placebo-controlled trials to still be given permissions are, and whether a revised standard of care will only apply when full licensure if given (and not just approved for restricted use). It circles back to the need for more transparency, and clear detailed justifications with regards to regulatory decisions in the country.”
No clear guidelines
But at the moment, we do not have any written guidance on the path that will be taken by the regulatory authorities, says Dr. Kang. But in the case of CovoVax vaccine, the drug regulator has allowed Serum Institute to use a placebo under the condition that the participants randomised to the placebo arm could be unblinded 60 days after the second dose upon request of the participant and offered the candidate vaccine.
“Ethically, all clinical trial participants, both in the current trials and future studies have to be informed about the availability of vaccines for priority populations in the country after restricted use approval from the regulator,” emphasises Dr. Bhan. “What would be the ethical obligation to minimise risk in those receiving a placebo? And what kind of information would be provided to them so that they make an informed decision about participation?”
Why placebos can be used
Dr. Kang sees one more reason why the drug regulator might not be wrong in allowing companies to use a placebo in the control group. “When the standard of care is available only to a section of the population, the ‘priority groups’ at the moment, then it is not standard of care for the rest of the population. Therefore, it is ethical to continue with a placebo in the population outside the priority groups, as long as that non-priority status is maintained,” she explains.
Dr. Kang highlights further subtleties in allowing vaccine companies to use a placebo and not insist that they use either Covishield or Covaxin in the control arm. “If the regulators had insisted on using any of the restricted use vaccines, that would create another complication — how would the company with the new vaccine get access to the ‘restricted use’ vaccine since it is not approved for sale in the open market?” she wonders.
Difficulty in recruiting volunteers
While the U.S., which has less than one fourth of India’s population, conducted at least six clinical trials with more than 30,000 participants each, Bharat Biotech faced difficulty in recruiting nearly 26,000 participants for the phase-3 trial of Covaxin. The use of a placebo in the control arm might make volunteer recruitment even more difficult especially when vaccination of the remaining priority groups — those older than 50 years, and younger people with comorbidities — begins soon.
Given the larger sample size requirements when an approved vaccine is used in the control arm, and also because the concerns around seriousness of COVID-19 seems to have gone down in public perception given the falling number of COVID-19 cases in India, recruitment of the numbers required could be challenging. These trials could also take longer, and be costlier to run, Dr. Bhan says.
“I think volunteer recruitment might become more difficult unless younger people, who stand no chance of getting a vaccine in the near future, opt in,” says virologist Dr. Shahid Jameel Director of the Trivedi School of Biosciences at Ashoka University. “But that would raise the issue of the vaccine trial population skewed towards a younger population without sufficient numbers of older volunteers. Since younger people predominantly get asymptomatic infection, they may also not volunteer.”
Acknowledging the challenges faced by vaccine companies in recruiting volunteers even before restricted use approval was granted to the two vaccines, Dr. Kang is optimistic that volunteer recruitment is not an insurmountable task. “I think recruitment of volunteers is always about clear communication. With the right kind of communication, a lot of people are willing to participate in advancing science, as long as they understand the study process, risk and benefit and know that the study staff are always available to them,” she says.
Challenges in conducting non-inferiority trial
Testing the efficacy of a new vaccine by comparing it with an already approved vaccine in the control arm is called a non-inferiority trial. The non-inferiority trial attempts to show that the new vaccine is not an unacceptably worse alternative to the already approved ones.
“If a comparator is to be used among vaccines with restricted use approval, it should be ideally the vaccine for which safety, immunogenicity and efficacy data is available, at least globally, if not in India,” says Dr. Bhan.
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