About the author: Dr. Sai Krishna Gudi is a Ph.D. student at the College of Pharmacy, Rady Faculty of Health Sciences, University…
Author: T V Padma is a science journalist based in New Delhi, with special interest in public health and research ethics
Ten days after it rolled out two vaccines in mid-January, one of which was mired in controversy, India has vaccinated more than 2.3 million people. The country, one of the world’s largest vaccine suppliers, and battling the second highest number of Covid-19 infections in the world, with more than 10 million cases[i], rolled out one the biggest immunization programs against the disease on 16 January. In doing so, it has inadvertently added to the growing number of niggling questions over blurring of lines between the urgency of a vaccine during a pandemic and the need to conform to clinical research and regulatory protocols without taking short-cuts. The Covid-19 pandemic has brought to the fore the remarkable progress of vaccine science that has, in less than year, turned out 236 candidate vaccines so far, 63 of which are in clinical phase and 173 in pre-clinical phase.[ii] International and national health agencies responded with alacrity to the pandemic to ensure speedy vaccine research and trials against a new infection.
Welcome as the speed is, it has thrown open some vexatious issues in research ethics. An open letter in Wellcome Open Research notes[iii] that while there is a “dire need” for a safe and effective vaccine “as quickly as possible”, the need for speed has “thus far resulted in significant deviations from standard approaches to vaccine research and regulatory approval. For instance, Russia, China, and the United Arab Emirates have each authorized COVID-19 vaccination outside of clinical trials, and the US Food and Drug Administration has expressed its willingness to consider granting emergency authorization for a COVID-19 vaccine before phase three trials are completed,” the letter says. Examples of dilemmas include whether one should allow human challenge studies to infect healthy volunteers in Covid-19 trials[iv], or should one continue with a placebo once interim results of a clinical trial demonstrate efficacy and safety. Another dilemma is about grant of approval — scientists from the Department of Bioethics, and the Fogarty International Center at the National Institutes of Health (NIH) Bethesda, point out in Science[v] that “a single finding of safety and efficacy may not be sufficient for a vaccine candidate to receive FDA approval” and that depending on the strength of the data, it may be important to conduct additional research to become more confident of the vaccine candidate, before offering it to millions of people. They also point out that “FDA frequently requires a finding of efficacy in two phase 3 trials before approving medical interventions for marketing to the public.”
Now, India finds itself raising another tricky question – can one speed up vaccine approval without efficacy data from phase 3 trails in public domain, or even before completion of phase 3 trials? The Covid-19 vaccine roll-out in India had an initial target of 10 million healthcare workers and 20 million frontline workers.[vi] And these are just the initial priority lot in a country with 1.3 billion people – another 270 million are to be vaccinated in the coming months. For this massive vaccination program against Covid-19, India on 3 January granted emergency conditional approval to two vaccines. The first vaccine is the Indian version of Oxford-AstraZeneca’s Covishield developed by Serum Institute of India, Pune. The second is Covaxin, made by the Indian Council of Medical Research – National Institute of Virology and Hyderabad-based Bharat Biotech.
The latter vaccine, which uses a weakened virus was approved for restricted emergency use, “in a clinical trial mode” before the completion of phase III trials that commenced in November 2020, and without even interim phase III efficacy data in public domain at the time of approval. The country’s regulator said the “the vaccine has been found to be safe as per the data available till date”. An expert committee reviewed the data and on safety and immunogenicity of the Indian vaccine and recommended “restricted use in emergency situation in public interest as an abundant precaution, in clinical trial mode,” The Drugs Controller General of India Venugopal Somani assured, “We’ll never approve anything if there is slightest of safety concern. The vaccines are 110 per cent safe.”
The company, meanwhile, said that the evaluation of the vaccine “has resulted in several unique product characteristics and persistence of immune responses to multiple viral proteins, as opposed to only a spike protein.” It has also shown “broad-spectrum neutralizing capability with heterologous SARS-CoV2 strains”, which potentially reduces or eliminates escape mutants.
But the hasty approval has triggered a controversy that neither the country with a reputation of one the world’s leading vaccine suppliers nor Bharat Biotech with its impressive track record of affordable vaccines that include hepatitis-B, polio, rotavirus, Japanese encephalitis and Zika, needed, and could have avoided.
Indian scientists point out that no one doubts the safety of Covaxin, but there is no adequate, convincing data on high efficacy at the time of approval. “The point, therefore, is that we are flying blind, hoping to land safely,” says India’s leading virologist Shahid Jameel, Director, Trivedi School of Biosciences, Ashoka University near Delhi.
“Also it could lead to precedence where future applicants could also want to leverage such approaches for approval,” points out Anant Bhan, adjunct professor at Yenepoya Medical College, Mangaluru, and former president of the International Association of Bioethics. “We will be launching a program with vaccines where we still are awaiting data points, and potentially might have to make amendments in the program once such data, at the completion of ongoing studies, becomes available.”
The meaning of “use in a clinical trial mode” is unclear — will it be offered as a candidate vaccine in a clinical trial, with informed consent? Or as Jameel points out, “volunteers in a clinical trial are subject to exclusion and inclusion criteria, and are covered by a trial insurance. It was later clarified that it simply means that those who get the vaccine would be followed up as those in a clinical trial.”
India’s most recent New Drugs and Clinical Trials Rules, 2019[vii] offers some leeway by allowing the regulator to take decisions during emergency situations. “But, there is no clear language to my knowledge around “restricted emergency use” or “emergency use approval”, and clinical trial mode,” says Bhan. “We are all still waiting to learn what it could actually mean in detail, though some elements like the need for informed consent, a formal protocol, adverse event form are apparent based on publicly available information.”
Do the exigencies of a raging pandemic justify the blurring of lines and a rush to approve and roll out for millions of people?
As Angus Dawson, professor of bioethics from the University of Sydney, argues in Research Ethics, “whilst there is some opportunity to expedite the research process in developing a SARS-CoV-2 vaccine, we should not rush to drop key phases of the traditional stepped approach to research trials including during the development of new vaccines.” Dawson argues, “we have good reason to retain the current mechanisms for research, given what we know from our previous experience with vaccines, and we should resist the appeal for ‘shortcuts’ on the grounds of speed.”
“While expediting processes in times of a pandemic is important, we cannot move away from the fundamental facets of science, including for clinical trials,” says Bhan. “It would be ideal to have a well-rounded understanding of all aspects of a trial vaccine—safety, immunogenicity, and efficacy before making a decision. Even if it is based on early interim data, at least we need some element of data on all of these aspects, and ensure these are also communicated in the public domain.”
“Decisions can and should be done with shorter turnaround times during a pandemic, but they should also be well considered and involve transparency and clear rationale and scientific arguments,” points out Bhan. “Haste in the absence of these could create issues.”
For there are dangers that short-cuts to research and approval will only weaken the public’s confidence at a time when vaccine science rose the challenge. “We have a historic moment to quell a pandemic with vaccines,” says Jameel. “But we also have to ensure that the deployed vaccines have the ability to do so. Science has done remarkably well to produce so many vaccines in such a short time. It is important to have the transparency by way of evidence to show that the deployed vaccines are effective. Data and transparency will build confidence.”
An “all’s well that ends well” approach should not brush under the carpet some questions of research and regulation ethics that the global vaccine roll outs have raised.
Photo Courtesy: Press Information Bureau of the Indian government
[iii] Smith MJ, Emanuel EJ, Thomé B and Upshur REG. Ethical conditions for accelerating COVID-19 vaccine
[iv] BMJ 2020;371:m4258
[v] Science 11 Dec 2020: Vol. 370, Issue 6522, pp. 1277-1279 DOI: 10.1126/science.abf5084
[vii] New Drugs and Clinical Trials Rules, 2019 — CDSCO