Indian samples of global Covid-19 vaccines need to be larger: Experts

Indian players like Bharat Biotech and Zydus Cadila ready for large-scale phase-3 trials

After global vaccine candidates faced hurdles in their phase-3 trials, experts point out that the sample sizes for clinical trials here for these candidates are too small to establish safety and efficacy. Moreover, leading Indian vaccine candidates are themselves gearing up for large-scale phase-3 trials next year. 

Sources in the Central Drugs Standard Control Organisation (CDSCO) said that the Indian regulator will be very careful now when allowing foreign candidates to conduct clinical trials on Indian population.

In fact, the Indian regulator has recently rejected the proposal of Dr Reddy's Laboratories to conduct a phase-3 clinical trial of Russia's Sputnik V saying that the data submitted was generated through a 'small' sample size. "We have not yet asked Serum Institute to increase sample size. It has approval for phase II and III studies and is following that design. But, yes, we will be very cautious about future approvals," said a source. 

Meanwhile, domestic players such as Zydus Cadila and Bharat Biotech are readying for large-scale efficacy trials in phase 3. According to sources, Bharat Biotech's Covaxin would be tested on 30,000 people, while Zydus' ZyCoV D may be tested on 12,000-14,000 people. 

On Monday Johnson & Johnson's (J&J) Covid19 vaccine candidate was put on hold after it reportedly had an adverse effect on a participant. "We have temporarily paused further dosing in all our Covid-19 vaccine candidate clinical trials, including the  Phase 3 ENSEMBLE trial, due to an unexplained illness in a study participant," the company said in a statement. This implies that the online enrollment system for 60,000 volunteers too has been closed now while the independent safety committee reviews the situation. Earlier, AstraZeneca-University of Oxford vaccine was also put on hold and then resumed in UK and India after a volunteer developed severe neurological symptoms that are similar to a disease called transverse myelitis, a rare inflammation of the spinal cord. The US regulator, in fact, is yet to give its nod to AstraZeneca to restart its trials in UK. 

In the above context, experts like senior virologist Jacob John and even indigenous vaccine makers point out that the trial size for the clinical trials that are happening in India for AstraZeneca vaccine are too small. Serum Institute of India (SII) is conducting a phase 3 clinical trial over 1600 people here in India for the AstraZeneca candidate. 

"The sample size of 1600 is not big enough as the placebo arm should have a reasonable number of disease cases. We need a certain number of cases in the placebo arm to compare with the vaccine arm to know that the vaccine arm has considerably less number of disease cases. The sample size has to be fairly large," John said. 

While domestic vaccine makers do admit that adverse events routinely crop up during large scale trials, they claim that the sample size has to be larger to know what kind of reactions can happen in the Indian population. 

"Especially, the cohort of the entire 40,000 people is happening in the UK. We are allowing the trials on few thousand people. Such a trial can only check immunogenicity (the capability of a vaccine to generate immune response or antibodies), it cannot check efficacy (comparing the rates of diseases in vaccinated and non-vaccinated people)," said the owner of a vaccine maker here who are also developing a Covid19 vaccine candidate. 

"We have to see the source of infection and what is the endemicity in the population. The sample sizes are determined based on that. If we are doing a superiority trial over placebo, then the sample size will depend on efficacy target. If we accept a 50 percent efficacy vaccine, then we need to take a larger sample. If I say that 80 percent of people will not get the disease if vaccinated as against a placebo, then my sample size can be smaller," he explained. The basic point is that the lesser risk the vaccine maker takes to establish efficacy, the larger the sample size. Endemicity means natural to or characteristic of a particular place, people. 

If 50 per cent people given the vaccine don't get the disease, and the regulator accepts that (which is the case for Covid19 vaccine), then the risk of establishing the candidate's efficacy is less and thus the sample needs to be larger. 

Mahima Datla, managing director of Biological E had told Business Standard in an earlier interaction that Indian players have never done efficacy studies of vaccines as there have not been new vaccine discoveries here. "We have followed up already discovered vaccines and done backward engineering. The innovator ends up doing the efficacy studies to prove the vaccine works. No one in India has done this scale of efficacy studies," she had said. 

Interestingly, Biological E is the Indian partner of J&J for manufacturing 500 mn doses of their vaccine. It did not respond on the recent halt of trials in US.

TESTING TIMES

• Smaller samples can only establish immune response, and not efficacy in Indian population
• Larger trials may also throw up underlying issues in vaccines specific to Indian population
• Indian players gearing up for large-scale efficacy studies on sizes of 12,000 to 30,000 people for domestic vaccines
• AstraZeneca vaccine trial now to take place on 1,600 people here 
• US FDA has not allowed AstraZeneca to resume trials after adverse events were reported
• India rejected DRL’s phase 3 trial design of Russian vaccine as data submitted was on ‘small’ sample