A vaccine manufacturer having conducted pre-clinical studies on animals has to submit a detailed protocol to the Drug Controller General of India (DCGI) to get permission for the first phase of human trials. This protocol includes details of the vaccine--the raw material used, proportion of each component, status of the preclinical studies. Along with this the details of clinical test sites, candidates for the human trial have to be provided such as the number of persons, their age group, health background, whether they are insured against any adverse reaction etc. The vaccine candidate also has to set up an ethics committee which includes both internal and external members. This committee too has to be approved by the regulator. If a company does not have its own ethics committee, it can ‘borrow’ one from established universities or any of the institutes affiliated with the Indian Council of Medical Research (ICMR). These protocols are established by the ICMR.
Based on the findings of the phase-1 trial and after establishing safety criteria, the regulator gives permission for the second phase to study the side-effects of the vaccine on patients. A similar process is followed for the third phase, which is a large-scale trial spread over a longer duration and on a much larger number of participants. The third phase is the most crucial as it establishes the efficacy of the vaccine--its ability to prevent clinical disease--and requires a long-term follow-up of the subject. The government may, in some cases, allow the company to club two phases of trials.
After studying and inspecting the findings of the phase three trials and ensuring safety and efficacy through extensive data DCGI may allow a vaccine to be registered.
In many studies, vaccine developers also conduct a phase-4 trial after the vaccine is approved and licensed.
What are the requirements for the review of the ethics committee?
This review is done by the principal investigator to study the duration of the trial, funding details - self, institutional or by a funding agency. It needs details of clinical trial sites - in India and globally, number of subjects in the control and the study group along with a justification for the sample size. Details of participants including whether they are receiving any incentive for the study have to be taken into account. Their informed consent along with a risk-benefit assessment such as whether there are any anticipated physical, social, psychological discomforts, risk to participants is also taken into account.
What are the safety protocols put in place?
The vaccine maker has to provide detailed findings of the trial to get the permission for the next stage. These findings are inspected by the regulator to ensure the safety of the drug. The Central Drugs Standard Control Organisation has laid down clear guidelines recently for coronavirus
vaccine, for the safety assessments throughout the clinical development of the vaccine. These include solicited local and systemic adverse events (expected reactions such as fever, sore arm etc) for at least 7 days after each study vaccination in an adequate number of study participants and any unsolicited adverse events 21-28 days days after the vaccination. Any serious adverse effects have to be assessed in the participants six months after all study vaccination.
Covid-19 vaccine trials have to periodically monitor for unfavorable imbalances between vaccine and control groups in Covid-19 disease outcomes, in particular for cases of moderate to severe Covid-19 that may be a signal for vaccine-associated enhanced respiratory disease (ERD).
The vaccine study has to establish criteria for halting the trial in such an event. In the late stage development of the vaccine, the CDSCO guidelines recommend setting up a data safety monitoring board to vaccine related adverse reactions.