Three vaccines have knocked on the Indian drug regulator's door for an emergency use authorisation, let's dive into the rulebook to understand how vaccines are approved in India.The updated clinical rules that govern both drugs and vaccines provide for certain provisions to be used under health emergencies or for unmet needs for life-threatening diseases. The DCGI in a webinar last week had alluded to these rules saying that while in a normal situation reviews of clinical trial data are done when all the phases are completed – currently during the pandemic the regulator has adopted ‘rolling reviews’ – which leads to adaptive clinical trial design where different phases of the trials are allowed to run in parallel. Data from individual trials are reviewed as they are generated and based on these “interim analysis” vaccines or drugs are allowed to move to the next phase of trials. We’ve seen these been used in vaccines and even drugs like Favipiravir, Remdesivir.When it comes to approvals – the new rules allow for phase 3 trials to waived – which is otherwise the most crucial to test efficacy and safety – if ‘remarkable efficacy’ is observed with a defined dose in the Phase II trials – however only for situations of ‘unmet medical needs of serious and life-threatening diseases'Biocon's drug Itolizumab was given a Phase 3 trial waiver for treatment of serious COVID-19 patients.Experts, however, say this cannot and should not be directly adapted for vaccines as the rules specify “treatment of serious diseases” and not refers to prevention.Additional post-marketing surveillance studies to look at long term effect and safety will be required if a waiver is given.For approvals, regulators look at trial data generated in India – either full or bridge trial data. If trials are not done in India completely – in emergency regulator may look at approving drugs or vaccines based on trial data generated globally but ones that have been reviewed and approved by regulators specified by DCGI – like USFDA, UK MHRA, Japan etc. This of course if no major unexpected serious adverse events reportedWhile DCGI has been granting approvals for “emergency restricted use”, such terminology similar to USFDA or EU does not exist in India rules.Now let's see where do the 3 vaccines stand viz-a-viz these rules as per their submissionsPfizer the first one to apply in India has submitted global trials data and is seeking a waiver for bridge trials in IndiaThe data submitted in India has been cleared and vaccine approved for restricted emergency use by both Bahrain and MHRA, UK – a regulator India follows.Pfizer fits the accelerated review criteria.. but logistics, pricing may be a dampener and since this is a new mRNA vaccine technology – India may require a bridging trial.Serum Institute made its move fast and applied also with global trials data from 4 trials in the UK and Brazil.The difference here is the data has yet not been submitted to or reviewed and approved by any global regulator as yet – so it skips that criteria,Besides, the India bridge trials have still not been completed and immunogenicity data are expected the third week of December. For efficacy, global data will be reviewed and DCGI may wait for a global regulator to clear the vaccine first before making a move.Now the latest in the race is Covaxin by Bharat Biotech where the transparency on what data is submitted is the least.Phase 3 trials have just started on Nov 17 – this is a complete phase 3 trials with 26,500 participants in India and no foreign trials – trials will assess the efficacy of the vaccine along with safety. This is a two-dose vaccine – to be administered 28 days apart. Bharat Biotech has said it is designed for efficacy when both doses are taken and 14 days after the 2nd dose; so 42 days from 1st dose.This essentially means from no efficacy data has been generated so far in Phase 3 trials.Now the company can submit Phase 1 and Phase 2 data on immunogenicity and safety for review -- however, vaccine experts have indicated just identifying that a vaccine elicits an immune response is not enough unless we know it prevents the disease, severe disease and especially in a high-risk population. And all of this data is generated in phase 3 trials.Bharat Biotech has so far not disclosed or published or released any data from Phase 1 or 2 as yet. Besides, no efficacy data on any other inactivated vaccines are available globally for reference in this case.So all in all – for Bharat Biotech a lot of unanswered questions. The regulator may ask for the trials to be completed before reviewing the vaccine for approval.Also, experts point out that with fast declining cases, low mortality with Sars-Cov2 and high recovery rate – India is certainly in a better position versus the US or the UK to complete vaccine trials, at least Phase 3 and approve a vaccine based on complete, solid data. After all, a vaccine is just one of the tools to help arrest COVID-19.