50 pc efficacy in phase 3 trials needed for COVID-19 vaccine approval: Drug authority's draft guidelines

A COVID-19 vaccine candidate should show at least 50 per cent efficacy during phase III of clinical trials for it to be widely deployed, according to a draft guidance document for vaccine developers issued by the central drug authority.

However, adequate data informing about the potential risk of vaccine-associated Enhanced Respiratory Disease (ERD) will need to be generated, the Central Drugs Standard Control Organisation (CDSCO) said in its draft 'Regulatory Guidelines for Development of Vaccines with Special Consideration for COVID-19 Vaccine'.

It said people with a history or laboratory evidence of prior novel coronavirus infection should be allowed to participate in trials if they did not have acute COVID-19 or other acute infectious illness.

The draft guidelines have been uploaded on the CDSCO's website. It is seeking comments and feedback from the public until October 12.

"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 per cent...," the guidelines said.

Considering the urgent need for a safe and effective vaccine for the prevention of COVID-19, clinical development programs of COVID-19 vaccine may proceed through an adaptive and seamless approach.

"However, as applicable for any vaccine, regardless of whether clinical development programs proceed in discrete phases with separate studies or via a more seamless approach, an adequate data, including data to inform the potential risk of vaccine-associated Enhanced Respiratory Disease (ERD) will be needed," they said.

Consideration may be needed for conducting more than one vaccine efficacy trial in case different subtypes of a pathogen are involved, the guidelines underlined.

In such cases, the efficacy trials may be required to be conducted in different regions where certain subtypes are known to predominate.

It is anticipated that adequately powered efficacy trials for COVID-19 vaccines will be of sufficient size to provide an acceptable safety database for younger adult and elderly populations, provided that no significant safety concerns arise during clinical development that would warrant further pre-licensure evaluation.

Speaking at a press conference on Tuesday, Dr Balram Bhargava, director-general, Indian Council of Medical Research, said all vaccines for respiratory viruses are not 100 per cent effective.

"There are three things for a vaccine -- first the safety, second the immunogenicity and third the efficacy. The WHO says that if we can get more than 50 per cent efficacy that is an accepted vaccine. For respiratory viruses, we never get 100 per cent efficacy. We are aiming for 100 per cent efficacy but may get 50-100 per cent." According to the CDSCO guidelines, as it is possible that a COVID-19 vaccine "might be much more effective in preventing moderate to severe versus mild COVID-19", consideration should be given for powering efficacy trials for formal hypothesis testing on a severe COVID-19 endpoint.

Regardless, moderate to severe COVID-19 should be evaluated as a secondary endpoint (with or without formal hypothesis testing) if not evaluated as a primary endpoint, the guidelines said.

Establishing vaccine safety and efficacy in SARS-CoV-2 naïve individuals is critical, they added.

Vaccine safety and COVID-19 outcomes in individuals with prior SARS-CoV-2 infection who might have been asymptomatic are also important to examine because pre-vaccination screening for prior infection may not be feasible in practice when the COVID-19 vaccine is approved and introduced in the market.

"Therefore, subjects with history or laboratory evidence of prior COVID-19 infection should not be excluded from the COVID-19 vaccine trial. However, subjects with acute COVID-19 or other acute infectious illness should be excluded from such trials," the guidelines said.

Evaluation of vaccine safety and efficacy in phase III clinical trial in adults should include adequate representation of elderly individuals and individuals with comorbidities, they said.

Further, productive and developmental toxicity data should be there as per the requirements specified in the New Drugs and Clinical Trials Rules, 2019 to support the inclusion of pregnant women and women of childbearing potential, they added.

It is important for COVID-19 vaccines to plan for pediatric assessments of safety and effectiveness considering the pandemic in accordance with the New Drugs and Clinical Trials Rules, 2019.

After approval of a vaccine, it is essential to monitor vaccine safety in routine use, the guidelines underscored.

They also recommended the use of an independent Data Safety Monitoring Board (DSMB) for vaccine-associated ERD and other safety signal monitoring, especially during the later stage development.

In general, all vaccines, including those against coronavirus infection manufactured or imported into the country, are required to comply with the requirements and guidelines for chemistry, manufacturing and controls (CMC) specified in the Drugs and Cosmetics Rules, 1945 and New Drugs and Clinical Trials Rules, 2019.

All vaccines are required to be characterised and manufactured in compliance with good manufacturing practices as prescribed in the rules.