Regulatory agencies around the world are under intense pressure to grant approvals for the new Covid-19 vaccine(s). Several developed countries have indicated that if there is a compelling case for the use of a vaccine before it qualifies for full licence, they would be prepared to authorise emergency use approval on grounds of public health. The condition is that the balance of risk and benefit must justify temporary supply of the vaccine. A favourable benefit-risk determination can be made for vaccines that offer more than a modest benefit or for those with sufficient data to assess its safety profile.
An emergency use authorisation (EUA) route is being adopted by many countries to facilitate the availability of Covid-19 medicines and vaccines to priority population groups. Though each country is free to adopt criterion for such an authorisation, there are some guiding principles.
Let’s look at the processes adopted by the five countries which are amongst the first to give EUA to Covid-19 vaccines—the ‘Lighthouse countries’.
The US FDA, in its October 2020 guidance entitled Emergency Use Authorization for Vaccines to Prevent Covid-19, explains that, for a Covid-19 vaccine among others, issuance of an EUA would require that the vaccine’s benefits outweigh its risks, based on data from at least one well designed Phase 3 clinical trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner.
Further, at the time of the submission of the application, the Phase 3 study should have already enrolled at least 3,000 vaccine recipients and shown sufficient information to support a low-risk for vaccine-induced respiratory disease. To ensure that a widely deployed Covid-19 vaccine is effective, the primary efficacy endpoint point estimate for a placebo-controlled efficacy trial should be at least 50%.
The European Medicines Agency and the UK’s Medicines and Healthcare products Regulatory Agency have adopted a similar approach. According to the Emergency Use Authorization granted to Covid-19 vaccines by Pfizer-BioNTech and Moderna, the US FDA has followed this process and requirements. Similar is the case with the UK’s MRHA while reviewing applications for the Pfizer-BioNTech and AstraZeneca/Oxford vaccines.
China started work on Covid-19 vaccines in January 2020. A vaccine based on the adenovirus delivery system was approved for limited use in June 2020 on the conclusion of Phase II trials. By the end of November, between 40,000 and 50,000 army men were vaccinated with this vaccine. Two inactivated vaccines had been approved for limited use in China to vaccinate high risk groups (including healthcare workers) since July 2020, following encouraging the results of Phase I and II clinical trials. Chinese regulators appear to be satisfied with the data of animal studies and the safety and immunogenicity data from Phase I and II trials. According to reports, hundreds of thousands of people in China have received these vaccines, which include healthcare workers, pandemic prevention personnel, border inspection personnel, etc.
Russia had launched clinical trials on its adenovirus-based Covid-19 vaccine in June 2020. On the 11th of August, Russia announced that its regulators have approved a limited roll out of its Covid-19 vaccine, named Sputnik V. At the time, when the Russian vaccine had been approved by its national authorities, it had data for Phase I/II but none had been published.
In India, the Central Drug Standard Control Organisation (CDSCO) is the apex regulatory authority to approve public use medicines, diagnostics tests, devices, vaccines, etc. The New Drugs and Clinical Trials Rules, 2019, framed under the Drugs and Cosmetics Act, 1940, lists the multiple provisions to be followed for review and approval of new drugs, clinical trials and vaccines. In these rules, there is also a provision to accelerate the approval of a new drug intended for use against diseases of special relevance to India or for filling an unmet medical need in India, especially for a disaster or special defence use. In such a situation, marketing approval could be granted based on Phase II clinical data if remarkable efficacy had been observed with a defined dose in the Phase II clinical trial of the new drug. The regulator can then also grant market approval for the new drug or vaccine based on Phase II data to meet what the rules define as ‘unmet medical needs of serious and life- threatening diseases in the country’.
Like the benchmark set by the WHO and others, the Central Drugs Standard Control Organisation (CDSCO) indicated in its draft ‘regulatory guidelines for vaccine development, with special consideration for Covid-19 vaccine’ that “to ensure that a widely deployed Covid-19 vaccine is effective, the primary efficacy endpoint point estimate for a placebo-controlled efficacy trial should be at least 50%”.
In the first week of January 2021, based on the recommendations of the Subject Expert Committee of Central Drugs Standard Control Organisation (CDSCO), the DCGI accorded Restricted Emergency Approval to the Covid-19 virus vaccine by Serum Institute of India (AstraZeneca/Oxford vaccine, named Covishield) and Bharat Biotech (inactivated vaccine, called Covaxin).
The SII vaccine had submitted interim safety and immunogenicity data generated from trials in India and the data was found comparable with the data from the overseas clinical studies.
The SEC took cognisance of Bharat Biotech’s vaccine’s Phase I and Phase II clinical trials. It also noted that the Phase III efficacy trial was initiated in India among 25,800 volunteers and till date about 22,500 participants have been vaccinated across the country and the vaccine has been found to be safe, as per the data provided. The data on safety and immunogenicity of the vaccine was reviewed and the SEC recommended granting permission for restricted use in emergency situations in public interest as an abundant precaution, in clinical trial mode, to have more options for vaccinations, especially in case of infection by mutant strains. The clinical trial being carried within the country by the firm will continue. Based on these recommendations, the Drugs Controller General of India has accorded emergency use authorisation, with conditions, to the two vaccines.
The WHO has developed a concept of Stringent Regulatory Authority (SRA) to guide medicine procurement decisions and is now recognised by the international regulatory and procurement community. Based on a laid down criteria, the WHO considers regulatory authorities of 35 countries (as of November 2020) stringent, which means that these regulatory bodies are uncompromising. This is relevant to countries which do not have a regulatory authority or have a weak one because they can adopt an approval given by one of the stringent regulatory authorities for a medicine (including vaccines) on the faith that it would have been well scrutinised. The Russian, Chinese or the Indian regulatory authorities do not figure on the list.
The writer is an infectious disease epidemiologist.
