Safety issues over mass production of COVID vaccines: A techno-legal perspective

It has been more than a year-long struggle now with restrictions, efforts, recovery and fight by nations around the world against the virus but the pandemic is showing no signs of abating. Just when the world starts to settle down, resuming normalcy in some sense, the next wave hits us with new strains of virus again infecting masses and pushing nations towards yet another lockdown situation.

People were just reviving from the first outbreak of the pandemic, but then the second and third wave of the virus struck causing even more fatal and grimmer situations across the world. Since the vaccine is the only silver lining, everyone is looking towards select pharmaceutical companies to produce millions of doses of vaccines within a span of days and months.

However, it has been seen that the larger portion of doses are being supplied and reserved for developed countries as they are home to these select pharma companies, leaving poor and developing countries for want of vaccine supply. At the same time, vaccine companies are seen working towards speeding up production to best meet the global requirement. One of the biggest manufacturing deals have been locked by AstraZeneca-University of Oxford. The developer contracted 25 firms across 15 countries for manufacturing 2.9 billion vaccine doses[1]. The largest partnership was with the Serum Institute of India in Pune in June 2020 to produce one billion doses of the AstraZeneca vaccine.

Since India is the largest vaccine producer worldwide, it accounts for more than 60 per cent of the COVID-19 vaccine supply to the United Nations International Children’s Emergency Fund (UNICEF). Several Indian pharma companies are also continuing their efforts to develop a vaccine and testing its safety and immunogenicity in the Indian population. Not only industry, but the academia, regulatory bodies and Indian governments are working together to fight against the pandemic. To further this combined effort, some noticeable changes are being made in the Indian legal framework towards vaccine development and availability.

National legal framework to regulate COVID-19 vaccine

The Central Drugs Standard Control Organization (CDSCO) has been authorised to grant approval for conducting non-clinical and clinical trials, to grant manufacturing, imports, sale and distribution license to the manufacturer for medicinal and biological products, diagnostic tests and medical devices therein. Since a vaccine is categorised as a new drug under D&C Act, it also needs to abide by the requirements for conducting clinical trials under the New Drugs & Clinical Trials (NDCT) Rules, 2019.

Accelerated approval process 

The Review Committee on Genetic Manipulation of the Department of Biotechnology, together with CDSCO, has formulated an accelerated regulatory approval policy and also formed an empowered committee, which could undertake review and examination of vaccine and drugs applications for COVID on priority without compromising on safety aspects. The accelerated approval process does not mandate a bridging study to be performed on the local population which is generally required under D&C Act. The accelerated approval of a new drug rather requires significant safety and efficacy data including details of the potential risk of vaccine-associated Enhanced Respiratory Disease (ERD) generated from its parallel ongoing/completed non-clinical/clinical experiments in other countries. For example, ZydusCadila (ZyCoV-D), Serum Institute of India (Covishield) and Bharat Biotech (COVAXIN) have received approval for their vaccines under the accelerated process.

Non-clinical and clinical study of COVID-19 vaccine

A new COVID-19 vaccine seeking approval from CDSCO for a first-in-human clinical trial will be required to submit non-clinical safety studies to substantiate its safety report. Moreover, the companies, while seeking approval over the new vaccine, will also need the test/manufacturing license from CDSCO if they wish to manufacture the vaccine for conducting clinical trials; the same is subject to a joint inspection by Central and State Licensing Authorities.

In September 2020, the CDSCO granted test license permission to manufacture COVID-19 vaccine for pre-clinical testing to seven Indian vaccine manufacturers namely, Serum Institute of India, Pune; Cadila Healthcare, Ahmedabad; Bharat Biotech International, Hyderabad; Biological E, Hyderabad; Reliance Life Sciences, Mumbai; Aurbindo Pharma, Hyderabad and Gennova Biopharmaceuticals, Pune.

Regulation of approved COVID-19 vaccine

In addition to approving and regulating the clinical trials, CDSCO also evaluates the licensed vaccines throughout its product development cycle under independent batch release testing conducted by Central Drugs Testing Laboratory. Further, as per NDCT Rules, 2019, the approved vaccines are also subject to post-marketing studies to generate direct evidence of efficacy and safety data against further infections, if any, (such as SARS-CoV-2). The said post-marketing studies can be any of the below:

• Phase IV (post-marketing trial)

• Post-marketing surveillance or observational or non-interventional study for active surveillance;

• Post-marketing surveillance including assessment of Adverse Events Following Immunisation (AEFI) and Adverse Events of Special Interest (AESI).

Regulated use of vaccine during emergency 

To tackle the emergency, Indian Regulators have introduced a provision of ‘Restricted Use at Emergency Situation’ which is similar to USFDA’s and UK’s ‘Emergency Use Authorization (EUA)’. CDSCO has already approved two vaccines Covishield and COVAXIN under “Restricted Use at Emergency Situation” to Serum Institute of India and Bharat Biotech respectively.

Further, the Drug Controller General of India (DCGI), together with the National Expert Group on Vaccine Administration on COVID-19 (NEGVAC), clarifies that the medical products already approved by USFDA, EMA, UK MHRA, PMDA Japan or which are listed in WHO Emergency Use Listing (EUL) for management of COVID-19 infection may be granted Emergency Approval under ‘Restricted Use at Emergency Situation’ in India. It further prescribes, “that foreign-produced vaccines for Covid-19, which have been granted emergency approval for restricted use by US FDA, EMA, UK MHRA, PMDA Japan or which are listed in the WHO Emergency Use Listing (EUL) may be granted emergency 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 and Clinical Trial Rules, 2019.Further, the first 100 beneficiaries of such vaccines shall be assessed for seven days for safety outcomes, before it is rolled out for further immunization programme. This will facilitate imports, including bulk importation, fill-finish capacity, etc. which will help to expedite vaccine manufacturing capacity and vaccine availability for domestic use to significantly increase base and coverage of vaccination.”[2]

Accelerated approval framework and dangers if any in these pandemic times?

In the past, there have been instances of accelerated approval by Indian Regulatory Authorities which are questionable, to say the least, for example-the approval of Itolizumab (Alzumab) to Biocon Pharmaceuticals for treatment of cytokine release syndrome in patients with moderate-to-severe COVID-19 and acute respiratory distress syndrome was questioned by the experts. Itolizumab (Alzumab) is an anti-CD6 monoclonal antibody already authorised for the treatment of psoriasis. CDSCO had waived the confirmatory Phase III trial which otherwise is required in usual cases.

Since the drug got approval for repurposed indication, the requirement of Phase III clinical trial should be necessary to substantiate safety and efficacy parameters of Itolizumab in patients with moderate-to-severe COVID-19 and acute respiratory distress syndrome.

Considering all the above pointers, one can conclude that despite all efforts and exceptions created by the Government to accelerate the approvals and manufacturing relating to vaccines, the gap between the exponentially rising demand for vaccine and the supply thereof is still large. There is a high burden on vaccine manufacturers as still only a few of them are capable to produce and supply the vaccines at the requisite rates. Mass production and abreast supply of medical products are required to counter this global pandemic. However, the recent move from CDCSO to grant emergency approval for restricted use to already approved vaccines from USFDA, EMA, UK MHRA, PMDA and listed under WHO Emergency Use Listing (EUL) could be instrumental for vaccine producers from other countries to make available and market their vaccines in India.

COVID vaccines are being developed and distributed to market within a much shorter period against an estimated eight to 11 years for a usual candidate drug/vaccine to reach the market; thus, the need of the hour is a rapid and strict vigilance over post-marketing studies with real-time feedback from monitoring of safety and efficacy of the new vaccines. One such step is the confirmation of the quality of vaccines for every batch via ‘independent batch release testing’ conducted by Central Drugs Testing Laboratories before it goes to the market. Just like any emergent situation, large quantities, timely delivery and high quality are all of the prime essence. Governments will have to keep striving to increase the momentum of production and distribution of vaccines, along with proper checks and balances in place for quality and corrections if there need be.

[1]https://www.astrazeneca.com/what-science-can-do/topics/technologies/innovating-production-and-manufacture-to-meet-the-challenge-of-covid-19.html

[2]https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/notice15april21.pdf