The Covaxin phase-3 clinical trial in Bhopal shows that nothing much has changed even more than a decade since the highly controversial HPV vaccine trial in Andhra Pradesh wherein 23,500 girls were vaccinated without a proper informed consent. There is evidence that the trial in Bhopal has serious ethical violations of informed consent and medical follow-up.
More than a decade since the human clinical trial of the human papilloma virus (HPV) vaccine — it was controversial and carried out without proper consent on nearly 23,500 girls in the 10-14 age group in Vadodara, Gujarat and Khammam district of Andhra Pradesh — and eight years after the Supreme Court of India slammed the government for slipping into “deep slumber” in addressing the “menace” of illegal clinical trials carried out in India by multinational countries, nothing much seems to have changed.
The phase-3 clinical trial of Bharat Biotech’s COVID-19 vaccine, Covaxin, by a private hospital in the Bhopal-based Peoples College of Medical Sciences & Research Centre appears to suffer from serious violations and as a result, closely resembles the HPV vaccine trial. The HPV vaccine trial was carried out by the Program for Appropriate Technology in Health (PATH), a non-governmental organisation, in collaboration with the governments of Andhra Pradesh and Gujarat and the Indian Council of Medical Research (ICMR). Incidentally, the ICMR, tasked with promulgating research ethics guidelines, is the co-sponsor of the Covaxin trial.
The informed consent process, the cornerstone of ethics in clinical trials, was grossly violated during the HPV trial in Andhra Pradesh; consent forms of nearly 2,800 child participants were signed by a hostel warden or headmaster and not the parents.
Consent is not informed
During a press conference on January 10 and even earlier to other media outlets, the Covaxin trial participants alleged that they were ignorant of what they were signing up to. If true, it amounts to the consent nowhere close to being a truly informed consent. According to them, no efforts were apparently taken to explain and inform them of the pros and cons of taking part in the trial, nor were they told that they would either get a vaccine candidate or a placebo. Instead, they were misled by the trial site to think they were getting a COVID-19 vaccine for free. The participants were not made aware of their rights to free medical care in case of any adverse events. They were not given any time or option to discuss with the family before signing the consent form, either. As documents show, at least in a few instances, the consent was taken after vaccination, which amounts to a serious violation. They also alleged that they were not given a copy of the consent form and other documents to prove their participation.
Following the October 2013 Supreme Court order, the Indian regulator had in 2019 made mandatory an audio-video recording of the informed consent process of each vulnerable individual participant before conducting clinical trials. And a written consent from the participant had to necessarily be taken before the audio-video recording of the informed consent process. Since many of the 700-odd participants are illiterate, an impartial witness should have been present during the entire informed consent process to append his/her signatures to the consent form. There is no evidence that this was followed, based on what the participants said during the press conference.
In the Covaxin trial in Bhopal, over a dozen of the 700 adults from three-four communities living close to the hospital have told the media that they were lured with monetary benefits of ₹750. Luring people to participate in clinical trials by offering money is unethical.
However, the company in a press release states that a decision was taken to reimburse all participants at the rate of ₹750 for each study visit. The company claims the reimbursement amount was approved by every institutional ethics committee at the study sites, and is not an inducement.
While reimbursement for actuals, such as lost wages and cost of transportation to the trial site, is permissible, it amounts to inducement when a payment of ₹750 is openly announced; during the press conference, the participants highlighted the payment announcement. It is unclear if the institutional ethics committee even approved street announcements to be made inviting people to the trial. Whether a site can advertise and even the content of such promotional material need prior approval from the institutional ethics committee.
Medical follow-up and care
While free medical care in case of any adverse event is a right of each trial participant, there have been at least a few documented instances of violation. In other cases, the participants, unaware that they were part of a clinical trial and hence entitled to free medical attention, had sought care from private practitioners. With at least some participants not possessing their own mobile phones, medical follow-up over phone, even if there was one, was not actually possible.
If the HPV vaccine trial was investigated by a Parliamentary Standing Committee, such an independent investigation becomes all the more necessary as the ICMR is the co-sponsor of the trial.
One of the participants at the Peoples College of Medical Sciences & Research Centre died on December 21. While Bharat Biotech claims that all due processes were followed following this development, it is unclear why no information about the death of the trial participant, who belongs to a tribe, was made public by the Indian regulator. In the case of serious adverse events following injection with AstraZeneca’s COVID-19 vaccine in a trial outside India, the information was made public, and the trial was halted at all sites while an investigation was under way. The Serum Institute was also ordered to halt the trial by the Indian regulator pending investigation.
No time to waste
Only a thorough and impartial probe will restore confidence in clinical trials. All the more as a couple of COVID-19 trials have already progressed to the phase-3 trial stage and few more are in the early stages of testing. With two vaccines already approved for restricted use and the virus spread slowing down, recruiting participants will prove to be all the more challenging. The conduct of a highly unethical trial, if not thoroughly and quickly investigated, can adversely impact the conduct of these studies already under way.