By Dr Lalit Kant
World over the regulatory agencies 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 use of a vaccine before it qualifies for full license, they would be prepared to authorize emergency use approval on grounds of public health. The condition is that the balance of risk and benefit justifies temporary supply of the vaccine. A favourable benefit-risk determination can be made for vaccines that offer more than modest benefit or for those with sufficient data to assess safety profile.
An emergency use authorization (EUA) route is being adopted by many countries to facilitate availability of Covid-19 medicines and vaccine(s) to priority population groups. Though each country is free to adopt criterion for such an authorization, there are some guiding principles.
It is important to ensure that community gets safe and effective products expeditiously, and the testing and regulation must be fast tracked and rigorous. Under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA), regulators have been discussing COVID-19 vaccine development and the necessary evidence required for regulatory decision-making that meets the needs of regulators around the globe. This is critical for speeding-up and streamlining global development and authorisation of vaccines against COVID-19. In November 2020, ICMRA and the World Health Organization (WHO) committed to working together to ensure that patients have access to safe and effective medicines against COVID-19 as early as possible, while the existing rigorous scientific standards for the evaluation and safety monitoring of treatments and vaccines are maintained at all times.
In late November 2020, the WHO finalized its ‘consideration for evaluation of Covid-19 vaccines’ that indicates both the process and the criteria that it will use to evaluate COVID-19 vaccines that are submitted either for prequalification (PQ) or for Emergency Use Listing (EUL). 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%. It also mentions that only vaccines that have undergone phase IIb or phase III studies and have been submitted to the National Regulatory Authority of record would be reviewed. It would also need data of adverse events of special interest, related or possibly related serious adverse events and medically attended adverse events after vaccination in all vaccinees with a minimum of 3 months, preferably up to 12 months, of follow-up after completion of administration of all doses in the vaccination schedule.
Let’s look at the processes adopted by the five countries which are amongst the firsts 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.
While according Emergency Use Authorization to Covid-19 vaccines of Pfizer-BioNTech and Moderna the US FDA has followed this process and requirements. Similar is the case with UK’s MRHA while reviewing applications for Pfizer-BioNTech and AstraZaneca/Oxford vaccine.
China started work on Covid-19 vaccines in January 2020. A vaccine based on adenovirus delivery system was approved for limited use in June, 2020 on conclusion of Phase II trials. By end of November between 40 000 and 50 000 army men have been vaccinated by 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 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 – 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 11th of August, Russia announced that its regulators have approved for limited roll out its Covid-19 vaccine, named Sputnik V. At the time when the Russian vaccine was approved by its national authorities, it had data for Phase I/II and none had been published.
In India, the Central Drug Standard Control Organization (CDSCO) is the apex regulatory authority to approve for 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 approvals 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 for 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. The Rules provide a relaxation for skipping Phase III clinical trials if ‘remarkable efficacy’ is 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 bench mark set by World Health Organization and others, the Central Drugs Standard Control Organization (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 of COVID-19 virus vaccine of Serum Institute of India (AstraZaneca/Oxford vaccine named Covishield) and Bharat Biotech (inactivated vaccine called Covaxin).
The SII vaccine had submitted the interim safety and immunogenicity data generated from trial in India and the data was found comparable with the data from the overseas clinical studies.
The SEC took cognizance of Bharat Biotech’s vaccine Phase I and Phase II clinical trials. It also noted that the Phase III efficacy trial was initiated in India in 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 SEC recommended for grant of permission for restricted use in emergency situation 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 ongoing within the country by the firm will continue. Based on these recommendations, the Drugs Controller General of India, accorded emergency use authorization, 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 recognized 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. Meaning that these regulatory bodies are uncompromising. This is relevant to countries which do not have a regulatory authority or have a weak one, that 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 scrutinized.
The Russian, Chinese or the Indian regulatory authorities do not figure in the list.
The writer is Dr Lalit Kant ,Infectious Disease Epidemiologist.
