On July 14, the Indian Council of Medical Research (ICMR) has announced the initiation of the human clinical trials phase for the two indigenously developed Covid-vaccine candidates. Approximately 1,000 voluntary participants are to be identified for each of the vaccine candidates entering the phase I/II clinical trials at different sites across the country.
“They are trying to do early clinical testing for these two candidate vaccines. There are pre-clinical experiments as well for other vaccines being done at the National Institute of Virology (NIV) in Pune. Experts are working day and night to do these experiments and it is their moral duty to develop vaccines as fast as possible as more than half a million people have succumbed to COVID-19 across the world. So ‘fast-tracking’ the development of COVID vaccines is more important,” mentioned the Director-General of ICMR Dr Balaram Bhargava in a press briefing.
While the development carries the potential of inventing vaccines against the contagion, the idea of fast-tracking medical trials has created flutters among the medical community. Before jumping to conclusions, let us look at the vaccine landscape in a holistic manner.
The Indian Vaccine Candidates
As of now, there are two indigenously developed Indian vaccine candidates among the six Indian companies who have been pursuing the vaccine development.
The Hyderabad-based Bharat Biotech had claimed to have developed India’s first Covid-19 vaccine, Covaxin, in collaboration with the Indian Council of Medical Research (ICMR) and National Institute of Virology (NIV). Another vaccine candidate ZyCoV-D, developed by Ahmadabad-based Zydus Cadila, has also claimed considerable success rates during its pre-clinical trial phases.
The vaccine candidates Covaxin and ZyCoV-D were cleared by the Drugs Controller General of India (DCGI) for the beginning of the first and second phases of the human trial on June 29 and July 3, respectively. “The researchers explained that SARS-CoV-2 uses the receptor-binding domain (RBD) on its spike protein to bind to the host cell-surface receptor, ACE2, and infect human cells”, reports LiveMint.
The scientists at ICMR and NIV had isolated the strains of Sars-CoV-2 and transported 11 such isolated and cultured strains to Bharat Biotech in May to further the development of Covaxin. After the successful completion of comprehensive pre-clinical studies continuing two months, Bharat Biotech had claimed these studies to have borne promising results with extensive safety and effective immune responses.
The company, Zydus Cadila, on the other hand, has adopted two different approaches towards the development of the vaccine candidate, ZyCoV-D. “The first one being the development of a DNA vaccine by using the viral protein of the virus, which would, in turn, trigger the body’s immune system against the coronavirus. The other approach included producing the vaccine candidate using live attenuated recombinant measles virus”, elaborates a report by the Times of India.
“In animal studies, the vaccine was found to elicit a strong immune response in multiple animal species like mice, rats, guinea pigs, and rabbits. The antibodies produced by the vaccine were able to completely neutralize the wild type virus in virus neutralization assay indicating the protective potential of the vaccine candidate,” Zydus Cadila Healthcare Ltd, mentioned in a statement to stock exchanges. The participant recruitment procedure for ZyCoV-D is yet to begin.
“There are two indigenous candidate vaccines and they have done successful toxicity studies in rats, mice, and rabbits. These data were submitted to the Drugs Controller General of India (DCGI) following which both these candidate vaccines got clearance to start the early phase of human trials,” informed the ICMR Director-General, Mr. Bhargava.
Apart from these two, Serum Institute of India (SII) is collaborating with US-biotech firm Codagenix and Austria’s Themis Bioscience and Oxford-AstraZeneca. Delhi’s Panacea Biotec has also been partnering with US-based Refana Inc.
The Bright Side
The development of effective vaccination against the deadly contamination of Covid-19 may turn out to be an immediate sigh of relief to many.
Terming India as the ‘pharmacy of the world’ where originates 60 percent of US medicines, Mr. Bhargava stressed the importance of India as a global pharmaceutical supplier.
“Any vaccine candidate that is produced or developed in any part of the world, will ultimately have to be scaled up by India or by China because these two are major producers of vaccines in the world and that every developed nation or everyone trying to develop a vaccine are aware of it and therefore, they are in communication with India for the vaccine distribution ultimately if it is developed”, said Mr. Bhargava.
Hence, if these human trials in India are proven to become successful, not only India will be able to keep a regulatory check on its prices in the Indian market but also enter the domain of competitive vaccine export all across the globe while its demands are at the peak. India may also be able to garner greater political and economic leverage as an influential global player by the means of vaccine exportation.
Reasons For Concern
1. The ICMR Dictated Timeline
ICMR Director-General Balram Bhargava came up with an extremely tight deadline in a letter to 12 hospitals, including AIIMS, chosen to be a part of the Covaxin studies. “It is envisaged to launch the vaccine for public health use latest by 15 August 2020 after completion of all clinical trials,” Bhargava wrote in the letter dated July 2.
“It is one of the top priority projects which is being monitored at the topmost level of the government”, he added. He not only asked the hospitals to fast-track the vaccine approval procedure but also directed the hospitals to enlist the participants by July 7 July. The letter also added sternly that “noncompliance will be viewed very seriously.”
“Faced with the unprecedented nature of the COVID-19 pandemic, and the consequent dislocation of the normal life, all other vaccine candidates across the globe have been similarly fast-tracked. ICMR’s process is exactly in accordance with the globally accepted norms to fast-track the vaccine development for diseases of pandemic potential wherein human and animal trials can continue in parallel”, claimed ICMR in a press release dated July 4.
“Just as red tape was not allowed to become a hindrance in the fast track approval of new indigenous testing kits or for introducing in the Indian market potential COVID-19 related drugs, the indigenous vaccine development process has also been sought to be insulated from slow file movement. The aim is to complete these phases at the earliest, so that population-based trials for efficacy could be initiated without delay”, the press release added the need to avert quintessential red-tapism.
2. Dearth of Ethical Committee Approval
To begin with, 7 out of the 12 institutes participating in the vaccine trial are yet to get the precursory approval from the respective independent ethics committees. Among the 5 institutes agreeing to the process of expediting, 4 are private hospitals who have already consented to the Covaxine trial on humans on June 30, a day after it was cleared by the DCGI.
“As a principal investigator, I would not move unless I get clearance, let it be anyone who is telling. It is not that I am being adamant, but I am humbly saying that we should follow the principles. And the first and the most important principle is: do no harm.” said Venkata Rao, the trial in charge of one of the designated sites at the Institute of Medical Sciences and SUM Hospital in Odisha. Similar is the opinion of the principal investigator of Lucknow’s King George Hospital, Dr. R. Vasudev.
3. The Hasty Timeline
The medical community and the virologists alike scoffed at such a hasty timeline allowing less than 2 months, envisioned by the ICMR for the completion of the vaccine trials on humans.
“In my knowledge, such an accelerated development pathway has never ever been done for any kind of vaccine. This seems really, really rushed,” says Anant Bhan, an independent ethics and policy researcher and former president of the International Association of Bioethics. In his opinion, the timeline “carries potential risks and provides inadequate attention to required safety procedures”.
After the pre-clinical trial studies, conducted on animals, bear fruits, the clinical trials are ideally conducted in three-phases. Phase I of it enrolls around 20 to 100 volunteers and may last from a few months up to a year. Phase II trials assign up to several hundred volunteers living with the symptoms and can continue from several months to a few years.
Phase III of it is the largest phase assigning thousands for it. After these three phases are over, another phase includes a post-marketing study which may ideally take several years to ascertain. There arose confusion regarding the Covaxin trial documentation which does not mention phase III of the trial and leaves enough room for misperceptions over the phases I and II sequencing.
“Clinical trials cannot be rushed. Even when expedited, phase I and phase II trials will take a minimum of 5 months. The duration of a phase III trial would depend on several factors, including the number of subjects enrolled and decisions by a data safety monitoring board, but would probably add at least another 6 months,” commented Indian virologist and expert vaccine researcher Thekkekara Jacob John. “ICMR’s intentions may be good but the processes have been vitiated and the risk is it can derail the vaccine,” he added.
4. The Rate of Success
“Normally, the probability of success for a vaccine in the preclinical phase is around 7%, rising to 15% to 20% for vaccines that reach clinical tests,” says Seth Berkley, CEO of Gavi, the Vaccine Alliance, cautioning India about the slim success rate of vaccine trials.
There have also been allegations of turning the vaccine into a tool of a political gimmick with the expectation of the Indian Prime Minister announcing its public use during his Independence Day speech on August 15.
“It’s not about getting there first but to be able to do it well and it is good that India has been able to come up with candidate vaccines, which is not a small achievement,” comments T. Sundararaman, the global coordinator of the People’s Health Movement.
The Vaccine Landscape Across The Globe
According to the draft landscape of COVID-19 candidate vaccines published by the World Health Organisation, as of July 15, there are 23 vaccines at the clinical evaluation phase while 140 others are at the pre-clinical phase.
The University of Oxford and AstraZeneca Plc.’s experimental vaccine, ChAdOx1-S, has become the first to enter the final stages of clinical trials on June 25. ChAdOx1-S, led by Oxford’s Sarah Gilbert, one of the prime forerunners among the vaccine candidates, is expected to be through human trials by September. AstraZeneca has already made agreements to produce 2 billion doses.
Chinese aided Sinovac and the US-based Moderna Inc., the firsts to have spearheaded the effort towards vaccine formulation, have also reached the third phase of the trial.
CanSino Biological Inc./Beijing Institute of Biotechnology, Anhui Zhifei Longcom Biopharmaceutical/ Institute of Microbiology (Chinese Academy of Sciences), Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm are some of the other prime collaborations, entering the first two phases of the clinical trial phase, led by China. Among other countries are also Japan.
It is true that amid the pandemic situation the process of vaccine trials may be expedited and red-tapism may be avoided, the creation of a timeline should be reasonable and tenable.
In 2017, the dengue vaccine, Dengvaxia, the fiasco in the Philippines resulted in disastrous results of committing unintentional homicide. Incidences of hasty trials going wrong are not few in the history of medical research and thus, maintenance of the due trial protocols are both necessary and significant in forestalling its callous usage on humans.
The haste and impatience amid the current crisis are understandable, though are not rational given the number of human lives to be impacted because of it. As we desperately hope to have effective Covid-19 vaccines in the near future, treating it as a model for humankind’s well-being should be the primary motive over competitive market rivalries.