New Delhi: The use of placebo controls in clinical trials remains controversial and researchers are increasingly questioning its role for testing Covid-19 vaccines.
Placebo is an inactive drug used in a clinical trial and is sometimes referred to as a “sugar pill”.
In placebo-controlled trials (PCTs), the results of one group, which is administered a therapy, is compared to the results of a control group that does not receive the therapy.
The World Health Organization’s Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation may have advocated for the continued use of blinded placebo-controlled studies for “reliable evidence” last December, but the scientific community thinks otherwise.
Indian Journal of Medical Ethics (IJME) has published two articles last week and is set to come out with more arguments against the use of placebo-controlled trials in Covid-19 vaccine development, primarily because of its effects on access to vaccines by low-and-middle-income countries.
“We want to critique it (the WHO ad hoc group’s position), we do not agree with such a kind of position. Long back in 1990s, when the HIV epidemic was prevalent in different countries, this issue was settled, there are informational guidelines, and the Helsinki declaration that says that if you have an effective vaccine available, you cannot use placebo-controlled trials,” Dr Amar Jesani, the editor of IJME, told ThePrint.
“Those countries that are having more money are cornering more vaccines, at the same time they are saying that the countries that do not have as many vaccines must make more sacrifices by allowing these placebo-controlled trials,” he added.
The World Medical Association came up with the Declaration of Helsinki as a statement of ethical principles for research involving human subjects. The latest version of the declaration from 2013 advocates that placebo-controlled trials only be used “where no proven intervention exists”.
Arguments against placebo-controlled trials
In one of the IJME articles, titled ‘Problematic Covid-19 vaccine trials in times of vaccine nationalism’ published on 3 March, the author pointed out that “placebo-controlled trials are generally justified when equipoise exists — that is, a genuine uncertainty exists within the expert medical community about the preferred treatment”.
This, the article said, was the situation in 2020, but is no longer the case now.
The author, Raffaella Ravinetto — a researcher at Belgium’s Institute of Tropical Medicine — stated that “calling upon equipoise between placebo and the local standard, for justifying placebo-controlled studies in settings where vaccines are not yet available due to vaccine nationalism and lack of equity, would be unethical”.
In another article published on 4 March, author Gustavo Ortiz-Millán — a researcher at the National Autonomous University of Mexico — also talked about how it will further skew the balance between high-income countries and low-income countries in terms of access to vaccines.
“It is not only going to be ethically objectionable, it is also going to be very hard for any pharmaceutical company to get participants in high-income countries, where people are starting to get rapidly vaccinated…”
“So whoever insists on conducting a PCT for vaccine development should know that these trials would have to be conducted in low-and middle-income countries,” Ortiz-Millán added.
Along with the Declaration of Helsinki, the Indian Council of Medical Research’s (ICMR) ‘National Ethical Guidelines For Biomedical and Health Research Involving Human Participants also states, “When an available therapy is effective in preventing serious harm, such as death or irreversible morbidity in the clinical trial population, it is inappropriate to use a placebo control.”
ThePrint reached the head of Bioethics Unit of ICMR through email for a comment on the matter, but there was no response until the time of publishing of this report.
Some scientists said placebo-controlled trials are not “morally acceptable”, while some said it would be ethical to give a choice of vaccination on priority to those who got placebo in clinical trials.
“When both these vaccines — Covaxin and Covishield — were undergoing phase 3 trials in India, they were two independent research efforts; one set of researchers did not have complete knowledge of the other’s formulation… Then, we had no choice but to do studies with placebo being used for control groups,” said Mala Ramanathan, professor at Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, and working editor of IJME.
“We can say that medical professionals have learnt to manage Covid-19, the mortality rates are going down… and, therefore, placebo-controlled trials, which use a lesser sample size, are possible. But how fair is it when death is a possibility due to Covid-19? It is not morally acceptable.”
Shahid Jameel, a noted virologist, however, said that he would have opposed PCTs only if the vaccines would have been fully approved in India.
“In India, both vaccines are being used under Emergency Use Authorisation, which means that they are being used to deliver the specific goal of protecting healthcare and frontline workers and people with increased risk of severe disease. Neither vaccine is licensed for full use in India just yet,” he said.
“What must, however, be done is to identify those who got placebo in clinical trials and give them the choice of getting vaccinated on priority. That would be the ethical thing to do,” he added.
About alternative means of testing Covid vaccines, scientists said the new vaccines should just prove their efficacy against the existing ones.
“It can be said that the sample size requirements are less for placebo control and, therefore, the results will be available faster. But what we have to prove now is that a new vaccine is more efficacious than at least the 81 per cent that Covaxin has proved to be. Why do we need to do placebo-controlled RCTs (random-controlled trials) now?” Ramanathan said.
The paper by Gustavo Ortiz-Millán has also suggested that RCTs be done through active-controlled trials, which would be more ethical in the current scenario.
RCTs are trials where subjects are randomly assigned to either of two groups, receiving different treatments. In active-controlled trials, one group receives the treatment under study and the second group receives a comparable standard treatment.
Jameel, however, pointed out, “Active-controlled trials that compare two vaccines for the same disease against each other will only say how much better (or worse) vaccine A is compared to vaccine B. The endpoints would also have to be revised otherwise it would be a very long trial.”
Ruth Macklin, Professor Emerita at the US-based Albert Einstein College of Medicine, who is co-editing the IJME issue with the series of articles on PCTs, told ThePrint, “It is clear that a study with an active control would take longer than one using a placebo control, and would also cost more.”
“But what we need to know at this point is whether a new candidate vaccine is better or worse than existing vaccines. Why do we need to know whether a new vaccine is better than nothing (i.e. placebo)?”
She added, “It is clear that vaccine sponsors and possibly also the researchers would like the most efficient studies — quicker and cheaper. That’s why they are arguing for placebo controls. But the ethical question is whether it is acceptable to give participants a placebo when all these other vaccines are now being rolled out for use.”
This report has been updated to reflect the correct name of Indian Journal of Medical Ethics.