With its robust domestic vaccine industry and strong fundamentals of the Universal Immunisation Programme, India is now embarking on the world’s largest COVID-19 vaccination programme , on January 16, 2021. This represents the forging of a novel public-private collaboration wherein the vaccine supply is under the responsibility of Indian pharma companies and the Ministry of Health and Family Welfare for the implementation of the vaccination programme.
The vaccine development programme has received unstinted support from the government, and two vaccines (Covishield and Covaxin) have been granted permission for restricted use in an emergency situation subject to certain regulatory conditions. The clinical trial ongoing within the country by the firms will continue. These vaccines are thus deemed to be market ready while regulatory processes and logistic requirements are being laid out.
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The expedited development was guided by the “adaptive and seamless” approach advocated by the World Health Organization (WHO) for public health emergencies and promoted by the Central Drugs Standard Control Organisation, and some of the current discourse of regulatory issues is focused on the authorisation process.
Traditional clinical trials follow a straightforward but mandatory three-step approach: designing, conducting and analysing the collected data, according to a pre-specified analysis plan. Seamless adaptive designs add a ‘review-adapt’ loop to the linear design-conduct-analysis sequence, with a pre-defined one primary endpoint and several secondary endpoints. An adaptation is referred to a change made to the trial procedure, such as eligibility criteria, study dose, treatment duration or study endpoints, and/or statistical procedures such as randomisation, study design, study hypothesis or statistical analysis plan, while a clinical trial is at the design stage. These are a priori planned adaptations and should be based on data collected from the study itself, and different from unplanned ad hoc modifications that are common in traditional trials.
Impact of modifications
In the current situation, where the clinical trial of both vaccines shall continue, community engagement is critical to establish community acceptability of control arms, placebo, and blinding and should adhere to WHO’s guidelines on good participatory practice (GPP). Acceptability may impact whether trials are individually or cluster randomised, blinded or unblinded, and have use of a placebo or other comparator. Unique cultural considerations such as drawing of blood may impact the study design, and in turn the choice of endpoints collected in the study.
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There are some key regulatory concerns and the challenge of communicating them to the users and beneficiaries of research including policymakers. What is the level of adaptation that is agreed to by the regulatory agencies? What are the regulatory standards for the review and approval process of data obtained from adaptive trials with different levels of modifications? And, most critically, has the trial become a totally different trial after the modifications for addressing the study objectives of the originally planned clinical trial?
Need for more caution
The European Medicines Agency cautions that while the increased flexibility of this option may well fit the needs in early phases of drug development, their use in late Phase II or confirmatory Phase III trials deserves a more cautionary approach. Pharmacology experts thus opine that “not every trial can be rescued by adaptation and adaptive designs... these should not be a cure for poor planning”. While adaptive designs do have a risk of introducing bias in a trial, that is not to be construed as a reason for staying away from these designs. The challenge is to minimise operational bias by rigorous planning and transparency. There is also a need to build and sustain trust through clear and comprehensive sharing of the adaptive design protocols in scientific journals for peer guidance, particularly in projects with major translational relevance. These challenges are as critical to the regulators as to those designing communication strategies and messages, with obvious implications for vaccine confidence.
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Given the conditions under which the vaccines are being rolled out, there is considerable debate among scientists, the medical community and the public at large. Among these diverse constituencies, there are optimists and sceptics about the effectiveness and safety of the vaccines. According to WHO, vaccine confidence encompasses trust in the effectiveness and safety of the vaccine as much as in the system that delivers.
Adequacy of processes
An important aspect is also the perceived motivations of policymakers making decisions about the vaccine. Given the fact that data are still awaited on the effectiveness and safety of the vaccine, the rollout decisions may well add to the scepticism. In addition, there is a need for imaginative social and behavioural research that takes on board the scientific uncertainties and helps to build trust in the health service system and the community. Trust-building in the vaccine and its rollout is important for a robust communication strategy. The lack of this does not augur well for programme implementation even while efforts are being made to promote and sustain vaccine demand.
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Therefore, it is critical at this stage for the government and establishment scientists to communicate how the regulatory processes and authorisation are adequate and appropriate. Are we, as a community of researchers and policymakers, making adequate and appropriate efforts to communicate these uncertainties? Communicating uncertainty entails identifying facts that are specifically relevant to potential vaccinees, characterising the relevant uncertainties, assessing their magnitude, drafting possible messages and evaluating their success. Underlying the vaccine optimism is the search for a strong signal that the evidence is certain enough and how far the predictions of valued outcomes can be relied upon.
Needed, openness
Scientists are trained and professionalised in dealing with doubt and uncertainty, given that all scientific knowledge is uncertain. To quote Richard Feynman, “... to solve any problem that has never been solved before, you have to leave the door to the unknown ajar. You have to permit the possibility that you do not have it exactly right. Otherwise, if you have made up your mind already, you might not solve it.” The task, particularly in the current context, is to be able to communicate scientific uncertainty — both to policymakers and the public at large. This requires a climate of transparency and data sharing that allows for public scrutiny and a healthy debate.
Rajib Dasgupta and Rama V. Baru are professors at the Centre of Social Medicine and Community Health, Jawaharlal Nehru University, New Delhi. The views expressed are personal
