Union health minister Dr Harsh Vardhan said that India could consider granting “emergency use” authorisation for a COVID-19 vaccine. This, Vardhan said, would be done to ensure that the vaccine can be made available for the elderly and frontline workers.
“Normally, the third trial [Phase 3] takes about six to nine months. But if the government decides, this period can be cut short by giving an emergency authorisation,” Vardhan said. “Any emergency authorisation is always done by adopting reinforced safeguard[s] so that people don’t worry about the safety. A high-level group has been formed to monitor the pace of the vaccine development under the direct guidance of Prime Minister Narendra Modi. There will be no shortcut on safety. Emergency authorisation will be given only if it meets the standards,” he said.
India, however, doesn't have a regulatory framework for granting emergency use authorisation for vaccines, though a system to do so is in place for drugs, top experts have said in an article published in the Indian Journal of Medical Research, the peer-reviewed in-house publication of the ICMR. “India’s New Drugs and Clinical Trial Rules, 2019, accommodates “special situations for a new drug where relaxation, abbreviations, omission or deferment of data may be considered”, but this does not explicitly include public health emergencies such as novel epidemics and pandemics, nor does it have the provision for granting emergency use authorisation (EUA), reads the article ‘Revisiting regulatory framework in India for accelerated vaccine development in pandemics with an evidence-based fast-tracking strategy'.
Authors of the piece, Dr Amit Kumar Dinda, department of pathology, AIIMS, Dr Santanu Kumar Tripathi, Calcutta school of Tropical Medicine and public health expert Dr Bobby John of Aequitas Consulting explain that while the US FDA can accelerate the availability of pharmaceutical products and vaccines by using the mechanism of emergency use authorization (EUA), the Indian regulator lacks a similar mechanism.
“Under an EUA, it is possible for US FDA to authorize the marketing of an unapproved product or the unapproved use of an approved product when a justifiable health emergency or a potential emergency exists,” they say.
In India, though, the drug regulator has responded by allowing ‘restricted emergency use’ permission for a few drugs, and put out a formal notification allowing for manufacture of novel vaccines for COVID-19, they point out.
Regardless, questions around how exactly vaccine trials need to be 'shortened', and a safe vaccine be made available to the vulnerable population—and eventually, to all—albeit without compromising safety, remain, not just in India, but across the world. Vaccines take long—trials proceed sequentially in Phase 1, 2, 3 and 4—and typically take years before a safe and effective product can be made available for public use. Public health emergencies such as COVID-19 require a different approach, though, to shorten these timelines, while ensuring all safeguards.
To tackle that challenge, Dinda, Tripathi and John propose a first-of-its-kind plan, where each phase incorporates parallel processes. For instance, phase 1 of human trials would not mean stopping animal studies, rather those studies would continue even after the vaccine candidate has moved on to human trials. Similarly, elements of phase 3 would be incorporated in phase 2, and phase 4 processes would be incorporated in phase 3, to further shorten the time frame.
“To optimise time in a public health emergency such as the current one, several or all of the clinical evaluation, production planning, distribution strategy and safety evaluation steps of the vaccine development continuum could be conducted in “parallel, rather than in a sequential manner,” the authors propose.
During the Phase 2 trials, for instance, aside of the regular safety, immunogenicity and efficacy studies, a limited efficacy and safety trial among a small number of volunteers with appropriate controls would be done, as is done in a conventional Phase 3 trial. “This telescoped design will enable an earlier submission of safety and efficacy data, allowing for potential regulatory approval for an EUA for the candidate vaccine,” they say.
Regulatory approvals for the manufacturer for early rollout of the vaccine, and in parallel, robust data systems and a data safety monitoring board would need to be put in place for this phase, so that post-administration follow up data are clearly tracked and safety issues flagged up early, they add.
During Phase 3 trials, by which time the vaccine would have already been rolled out post-EUA issuance by the regulator, evaluations would continue. “Use of emergency use authorized candidate vaccines will be subject to regulatory oversight, rigorous safety and adverse event monitoring and also to revoking of approval on the basis of serious adverse effects,” the plan reads.
“This phase will telescope the conventional Phases 3 and 4, with clustered randomization of control populations built into the rollout design, instead of having a separate control arm. From those receiving the emergency use authorized vaccine, defined end point measures of neutralizing antibody titres will be monitored among selected individuals, as also among those in the cluster control groups to continuously provide efficacy data,” the authors suggest.
This rollout design, with short efficacy data feedback loop along with safety reporting to the regulator and adverse events following immunization monitoring by statutory bodies set up at appropriate jurisdictional levels in India, will generate real-world evidence for the vaccine, its safety and efficacy, and set up the pathway for full market authorization by the regulator earlier than the conventional approach.
In case a situation arises where there are multiple vaccines emerging with EUAs—a situation that is likely now—the choice of a vaccine recommended to be rolled out would depend on the outcomes of an “iterative evaluation undertaken by the public health authority, in consultation with the regulator”, of relative safety and tolerability of the vaccine, duration of protection, the logistical ease for its administration and finally the costs of the vaccine, the authors suggest.
Regulatory authorities would need to anticipate a scenario where the possibility of different vaccines administered to the same person might arise due to the deployment of multiple vaccines with multiple dosing schedules across the country, Dinda, Tripathi and John say.