This article is written by Arundhati Roy, from RTI Cell, iPleaders and the article is edited by Khushi Sharma (Trainee Associate, Blog iPleaders).
Table of Contents
Introduction
One of the critical pillars in controlling and managing certain diseases is vaccination. According to The Centers for Disease Control and Prevention (CDC), vaccinations should be taken throughout your life as it protects against many infections. The scientists say that the vaccines consist of either killed or weakened viruses which makes it almost impossible to get a disease from vaccination.
The outbreak of Coronavirus disease or COVID-19 was first identified in Wuhan City, Hubei Province, China as a result of an upsurge of cases of respiratory illness in the year 2019. In the first instance, it was reported to the World Health Organization (WHO) on 31st December 2019. As there was a proliferation of COVID-19 patients all over the world, the WHO declared it a global pandemic. With the onset of the COVID-19 pandemic, there was a race to prevent and cure the patients inflicted with the diseases. However, discovering and developing a vaccine is a long, complex process, often lasting 10-15 years, including the involvement of public and private authorities. The 20th Century has witnessed the stages of vaccine development going through a strict, standardized procedure such as developing, testing, and regulating vaccines before getting approval as a cure for a certain disease. As a result of the outbreak of the COVID-19 pandemic, India also came to the forefront to develop and manufacture a COVID-19 vaccine with three other international vaccine developers. To enable the development of vaccines at a fast pace, the Indian Government has undertaken various initiatives to affirm regulatory steps and ease out the regulatory process to develop a vaccine. Currently, two vaccines have received Emergency Use Authorization (EUA) from the National Regulator (Drugs Controller General of India), which are “Covaxin” by Bharat Biotech International Limited (BBIL) and “Covishield” by Serum Institute of India. Since the labs have started developing vaccines to contain the spread of the disease, granting Emergency Use Authorization has become the talk of the town. Till the writing of this article, three more anti-Covid vaccines have been given EUA by the Drug Regulatory Authority in India, the latest ones being Russian Sputnik V and DBT-BIRAC supported ZyKov-D developed by Zydus Cadila.
Surprisingly, “New Drugs and Clinical Trials Rules, 2019” governing clinical trials introduced in 2019 would serve as the primary regulatory framework for testing proposed COVID-19 vaccines. The impugned question is how the Drug Regulator Authority can grant any vaccine emergency use authorization and on what basis. It further raises many questions on the effectiveness of a vaccine, which is still on the clinical trial face. These vaccines, after receiving EUA, are being administered to people from children to adults. The present article studies the concept of Emergency Use Authorization of the vaccine in India and digs into the laws that allow such vaccines authorization.
What is vaccination?
As per World Health Organization (WHO), vaccination is a simple, safe, and effective way of protecting an individual against harmful diseases before they come in contact with them. The vaccination process is such that it uses an individual’s natural defences to build resistance to specific infections and makes the immune system stronger of the person vaccinated.
Interestingly, the COVID-19 vaccines use a version of a spike-like structure on the surface of the COVID-19 virus called Spike protein or S protein. The primary COVID-19 vaccines which are being made include the mRNA vaccine as one of its types. Most vaccines that are made consist of a weakened or dead bacteria or virus, however, the mRNA vaccine uses a molecule called messenger RNA or mRNA rather than part of an actual bacteria or virus.
WHO further explains that vaccines train an individual’s immune system to create antibodies, just as the body does when exposed to a disease. However, they say that vaccines contain only killed or weakened germs like viruses or bacteria, which do not cause the disease or put the vaccinated individuals at risk of its complications.
What is Emergency Use Authorization (EUA)?
The FDA defines an Emergency Use Authorization (EUA) as a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID-19 pandemic. Once a vaccine is submitted for EUA, the FDA will evaluate a EUA request to determine whether the relevant statutory criteria have been met while considering the totality of scientific evidence about the vaccine available to the FDA.
It is discretionary upon FDA under EUA, to allow the use of unapproved medical products, or uses of approved medical products in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions when certain statutory requisites have been fulfilled, including that there are no adequate, approved, and available alternatives.
The Food and Drug Administration (FDA) is an agency that provides scientific and regulatory advice to developers of vaccines and undertakes the task of rigorously evaluating the scientific information through all phases of clinical trials, which continues after a vaccine receives approval from the FDA or is authorized for emergency use.
Emergency Use Authorization (EUA) in India
Taking into account the current pandemic situation, it is impossible to collect all the evidence that a drug regulator would require in the normal circumstances to give approval to a drug, vaccine, device or test. In India, the Drug Controller General of India (DCGI) is the regulator to take decisions in determining the efficacy and safety of a drug that is not fully tested before releasing it for the general public in the situation of a declared emergency. On having evidence that suggests that a drug or vaccine may benefit patients, then the regulator has the authority to issue an emergency use authorization to a vaccine, drug or any other medical product to make it widely available for use.
It is to be noted that vaccines to medicines, diagnostic tests and even medical devices need the approval of a regulatory authority before they can be administered. The Central Drugs Standard Control Organization (CDSCO) is the National Regulatory Authority (NRI) in India. Before any vaccine or medicine is approved, an assessment is carried out with respect to their safety and effectiveness, from the data collected from their clinical trials.
When EUA is granted?
Owing to the global pandemic situation, it is essential to prevent the pathogen from spreading at the earliest. In general circumstances, several years go in processing and developing a vaccine wherein a good amount of time is taken in carrying out trials so as to demonstrate the safety and efficacy of a vaccine. But as the situation prevailing is of a COVID-19 pandemic, it may not be possible to go through each and every step of vaccine development and hence, emergency use authorization is being seen as a basic thumb rule, that empowers the drug regulators to approve a vaccine or a drug if the known and potential benefits outweigh the known potential risks.
When the vaccine developers apply for Emergency Use Authorization (EUA), their application is only considered when they provide sufficient efficacy data from phase 3 trials. It is to be noted that data generated from phase 1 or phase 2 trials do not suffice to fulfil the criteria for obtaining EUA. But phase 1 and phase 2 trials are required to show that the product is safe enough to go further for phase 3 trials. This means that when applying for EUA, the vaccine or medicine should not omit any of the essential safety trials. The Regulatory Authority examines and satisfies themselves that the product obtained from the trials meets the reasonable threshold limits for safety purposes and is effective in use, before approving it.
In the US, the FDA, which has the authority to grant EUA, has specified for Covid vaccines, that only those applications for EUA would be considered whose phase 3 data manifested that it was at least 50% effective in preventing the disease. The essential condition is to generate this data from over 3000 trial participants, who are required to be followed up for any serious adverse effects for at least a period of one month after all dosages were administered to them.
What happens in Phase 1 and Phase 2 Trials?
In order to evaluate the safety of vaccines at higher doses, it is administered to a limited sample set of healthy people during the Phase 1 trials. Further, it is observed whether Phase 1 trials throw up any safety concern, if it doesn’t then Phase 2 trials are undertaken. Phase 2 is carried out on a larger set of people consisting of hundreds of people who have dissimilar health conditions and belong to different demographic groups. This entire process is done to appraise the efficacy as well as side effects of the vaccine or medicine. Thereafter, the trial moves further to Phase 3, wherein a much larger sample of people i.e. thousands of people representing the population is involved to determine effectiveness and safety. Phase 3 trials aid in generating critical information on efficacy and additional important safety data. Also, additional information is procured about the immune response in people who receive the vaccine in comparison to those who receive a control, such as a placebo.
Process of obtaining EUA in India
The concept of Emergency Use Authorization is an entirely new phenomenon for India, despite it having a place in US FDA regulations which is explicit about the conditions and process for receiving a EUA. Nonetheless, the scenario is vague in India, as the experts say that there are no explicit provisions for granting EUA in India’s Drug Regulations, nor the procedure is stated as to how it can be received. However, during this COVID-19 emergency, the CDSCO has been permitting emergency or restricted emergency approvals to not only COVID-19 vaccines but medicines as well. These vaccines and medicines to receive emergency approvals are Covishield, Covaxin- the first two vaccines to receive approval in January 2021, Remdesivir and favipiravir in June 2020, and itolizumab in July 2020. Surprisingly, there is neither any data on how these drugs received approval nor any clinical data published anywhere pertaining to the grounds for giving such approvals. Even after perusing the entire legislation on Drugs Control, there is no such clause that allows or permits such emergency use of medical products.
The National Expert Group on Vaccine Administration for COVID-19 (NEGVAC) in its 23rd meeting which was held on 11th April 2021, took up the matter of augmenting the COVID-19 vaccines which are available for fighting the pandemic as well as to accelerate the pace of domestic vaccine programme and then after comprehensive contemplation made a recommendation. The NEGVAC recommended that the vaccines for COVID-19, which have been developed & are being manufactured in foreign countries & which have been granted emergency approval for restricted use by USFDA, EMA, UK MHRA, PMDA Japan or which are listed in WHO (Emergency Use Listing) may be granted emergency use approval in India, mandating, the requirement of post-approval parallel bridging clinical trial in place of conduct of local clinical trial as per the provisions prescribed under the Second Schedule of the New Drugs & Clinical Trial Rules, 2019. Further, the first 100 beneficiaries of such vaccines shall be assessed for 7 days for safety outcomes, before it is rolled out for further immunization programmes. This recommendation of the NEGVAC was eventually accepted by the Union Government after deliberation.
What is WHO’s Emergency Use Listing (EUL)?
The World Health Organization listed the Pfizer/BioNTech vaccine for emergency use, making it the first vaccine which received emergency validation from WHO.
WHO’s emergency use listing (EUL) procedure evaluates the suitability of novel health products during public health emergencies. To address the situation of emergency, the EUL works with the aim of making medicines, vaccines and diagnostics available as expeditiously as possible while adhering to the uncompromising criteria of safety, efficacy and quality. The threat posed by the emergency as well as the benefit that would accrue from the use of the product against any potential risks is weighed in the evaluation process.
There is an involvement of rigorous assessment of late Phase 2 and Phase 3 clinical trial data as well as substantial additional data on safety, efficacy, quality and a risk management plan in the EUL pathway. The data obtained are then reviewed not just by independent experts but also by WHO teams who take into contemplation the current body of evidence on the vaccine under consideration, the plans for monitoring its use, and plans for further studies. As part of the EUL process, the company manufacturing the vaccine makes a commitment to continue to generate data in order to get full licensure and WHO prequalification of the vaccine.
The WHO’s Emergency Use Listing (EUL) facilitates the countries to accelerate their own regulatory approval processes to import and administer the vaccine. Under EUL, UNICEF and the Pan-American Health Organization are enabled to procure the vaccine for distribution to countries in need.
Regulatory laws for vaccine development and EUA in India
“New Drugs and Clinical Trials Rules, 2019” which deals with clinical trials would constitute the main regulatory framework for testing of proposed COVID-19 vaccines. These Rules lay down the provisions with respect to clinical trials and various aspects associated with a new drug. All potential COVID-19 vaccines will be a “new drug” as per the definition given under the New Drugs and Clinical Trials Rules. Thus, these rules shall regulate the import and manufacturing of all such vaccines either for clinical trials or for sale and distribution. However, the chief regulatory approvals under the Rules are to be required to be taken from the Drug Controller, India which is within the Central Drugs Standard Control Organization (CDSCO), the national regulatory body for drugs and medical devices.
It is pertinent to note that, it is nowhere stated in the New Drugs and Clinical Trial Rules, 2019 about the emergency use authorization or any such term as EUA as these terms have found a place in the legislation of countries like the US, UK, and such other developed countries. Nonetheless, the regulatory system in India has laid down provisions for a “special situation.” These rules prescribe the provision for an “accelerated approval process” which depends upon the situation. These provisions do match the need of the current pandemic situation. It further states that during such a situation, the ‘product’ (medicine, vaccine) needs to have a “meaningful therapeutic benefit.” The Rules provides that if needed for the treatment of life-threatening diseases like the COVID-19 pandemic which is currently being faced by the world, a new drug, the vaccine can be granted approval provided that the new drug or vaccine manifest “remarkable efficacy” during the Phase 2 human trials. But this approval will be given for temporary use and whose validity shall not exceed a period of one year as per the IE Report.
How much risk is involved in using a product that has only been granted a EUA?
The US FDA states that the general public should be informed so that they have knowledge that the product has only been granted Emergency Use Authorization and has not yet received complete approval from the Authorities. For instance, when mass administration of COVID-19 vaccine is being carried out, they should be well-versed with the potential benefits and risks of the vaccine, and the extent to which such benefits or risks are unknown.” And most importantly knowing the potential risks and benefits, they should have a right to refuse the vaccine.
However, the question of whether a person has a right to refuse vaccination or not is a debatable question. Despite that, no country has made vaccination compulsory, yet the guidelines issued by the Government to deal with the COVID-19 pandemic situation includes for many purposes such as travelling, entering restaurants, malls, etc., compulsory vaccination, otherwise, they shall not be allowed to do so. This is however subject to terms and conditions but the right to refuse vaccine/medicine is somehow curtailed.
Which medicine and vaccine received the EUA in India?
As per the RTI reply received from the Central Drugs Standard Control Organisation(CDSCO), considering the emergency and unmet medical need for COVID-19 disease, CDSCO has approved Restricted Emergency Use of Remdesivir Injectable Formulations for treatment of patients with severe COVID-19 infection subject to various conditions and restrictions on 01.06.20 for import and marketing the drug in the country.
CDSCO has granted permission to manufacture and market the same injectable formulations of the drug to the indigenous 05 manufacturers for the same indication, restriction and conditions for use as stipulated for the innovator’s product.
Favipiravir 200mg tablets on 19.06.2020 for treatment of patients with mild to moderate COVID-19 disease subject to the above conditions, as part of the accelerated approval process for restricted emergency use in the country. Further, drugs are
1. Itolizumab Injection 25mg/5 ml solution for intravenous infusion.
2. Casirivimab (r-DNA origin; 120 mg/ml) and Imdevimab (r-DNA origin; 120 mg/ml).
3. Bamlanivimab (r-DNA origin 700mg per container) and Etesevimab (r-DNA origin 700mg per container).
4. Pegylated Interferon alfa-2b for Injection (r-DNA origin) 50 µg/0.5ml, 80µg/0.5ml, 100 µg/0.5ml, 120 µg/0.5ml and 150 µg/0.5ml powder for concentrate for solution for infusion in a single-use vial (lyophilized vial for subcutaneous).
5. Tocilizumab Injection (r-DNA Origin 80 mg/4 mL, 200 mg/10 mL and 400 mg/20 mL.
Further, the RTI reply states that as per the provisions of New Drugs and Clinical Trials Rules, 2019 under Drugs and Cosmetics Act, 1940, based on the recommendations of Subject Expert Committee (SEC) comprising of experts from Microbiology, Pulmonology, Immunology, Paediatrics, Internal medicine etc. and as per office order dated 15.04.2021 and 01.06.2021, Six COVID-19 vaccines are approved for restricted use in an emergency situation for prevention of COVID-19 in the country. Further, the list including details of permissions of approved COVID-19 vaccines are publically available on the CDSCO website www.cdsco.gov.in. on the following link: https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NzY2OQ==
In addition to this, New Drugs including vaccines are regulated under the New Drugs and Clinical Trials Rules, 2019 of the Drugs and Cosmetics Act, 1940.
Efficacy of COVID-19 vaccines/medicines in India
It is to be noted that Covaxin has currently been granted approval for emergency restricted use, while Covishield has been allowed for restricted use in emergency situations that can potentially prevent coronavirus infection in people aged 18 years and above. Further, Covaxin has commenced its clinical trial in children belonging to the age group above two years. Reports suggest that the efficacy of Covishield is 90% and Covaxin is 81% as per the interim 3rd Phase trial. However, both of the vaccines have not yet received WHO’s approval, nor has been given a place in WHO’s Emergency Use Listing (EUL), despite having applied for the same. This raises another cause of concern which directs us to ask, “Do these vaccines have enough clinical trial data to prove efficacy and safety to prevent the spread of coronavirus?”
Other drugs to receive EUA for treatment of COVID-19 are Remdesivir and Favipiravir. Even though these drugs have existed as approved drugs for other ailments prior to being granted the EUA for treating COVID-19 patients, they could not be administered to COVID-19 patients in the absence of restriction, as there have been no such extensive clinical trials that could prove its potential risks and benefits to the fullest. However, they received authorization only because they displayed some positive results in limited testing in a given specified condition. In a way, they were “repurposed” through EUAs for COVID-19 patients. Now, here the impugned question is, “How the Drug Controller in India approves a medicine for emergencies when the law is silent on that part?”
Conclusion
It is pertinent to mention that the concept of Emergency Use Authorization (EUA) is relatively a recent phenomenon. The first EUA was granted to Tamiflu drug by the FDA in 2009 for the civilian population for infants and young children for the treatment of H1N1 influenza. So, even though EUAs have been granted for various medicines, diagnostics, and equipment like ventilators or even PPEs, it has never been granted for a vaccine. Noteworthy to say that only when a health emergency crisis arises EUA can be granted. Prior to the current pandemic situation, EUAs came during the spread of the Zika Virus, Ebola Virus, and MERS coronavirus. Although the concept of EUA is known to the world, it is surprising that the term EUA has found no place in the Indian legislation.
The public has the right to know on what data these vaccines have been granted emergency approval by the Indian Government, on what grounds, and how the law justifies them in the absence of any such provision. Not only should people be well-versed with what medicine/vaccine they are being given, but they should also have a right to refuse the vaccine/medicine without being unsatisfied as to its safety and efficacy.
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