Authors: Genpro Biostatistics Team
After all the tensions and confusion, mankind conquered COVID-19 disease through the development of effective vaccine. When you are going through the development history of vaccines, you will come across these terms; ITT Analysis, Toxicity Monitoring, Interim analysis, Immunogenicity, noninferiority, Vaccine efficacy, etc. Yes, these terms are relevant in a novel vaccine development trial. This blog will take you to the biostatistical aspects of vaccine trials.
The duration and efficacy of the clinical trials for COVID-19 vaccine are the most considerable factors for the inventors. These two factors are focused based on statistical decisions. The statistical decisions are very helpful for the pharmaceuticals to get their roles quickly and more effectively. The following statistical areas played an important role in getting the COVID-19 vaccine trails quick and effective.
The proper selection of the trial design will give a better accurate quick invention. As per WHO, Phase IIB/III efficacy trials should be randomized, blinded, and placebo-controlled or active-controlled. An individually randomized controlled trial with 1:1 or 2:1 randomization between vaccine and placebo groups is usually the most efficient study design for demonstrating vaccine efficacy. Other types of randomization, such as cluster randomization, may be acceptable if there is evidence that potential biases have been avoided.
During the development of study, the data will be monitored and analyzed based on the safety and efficacy endpoint using current actual data. If interim Analysis of the data suggests that the vaccine is safe and effective, then the study can be reliably moving forward. Apart from the prediction of the outcome, this analysis should be primarily focused on cost reduction. Sample Sizes and Interim analysis time will be depending on the results coming from the primary and secondary analyses and the realistic nature of the outcomes from the subjects. During the interim analyses, data should be analyzed statistically as same as in the final analysis.
Immune Response and subgroup analyses
Immune response are correlated with demographic factors including gender and age groups or other groups of interest. So, the clinical trial should include adequate assessment of these populations on the immune response.
Toxicity Monitoring and group sequential design
Toxicity monitoring is the recommended part of the vaccine trial designs. Toxicity will be monitored on a risk group basis. This group will be based on the ordinal scale recommended by WHO (Patients in Stages 3, 4, and 5 are categorized as the intermediate-risk group, while patients in Stages 6 and 7 are categorized as the high-risk group). Subjects with high risk can be done with a group sequential design with stratification without toxicity monitoring Since the goal should be to reduce the mortality rate as much as possible. Subjects with Low risk can be done with a group sequential design with stratification with toxicity monitoring to ensure the intervention and efficacy.
Since large number of patients are randomized, the intervention and control groups will be balanced with respect to both measured and unmeasured baseline covariates, hence, ITT analysis is preferred for the COVID-19 vaccine trials. Here all participants will be analyzed in the intervention group to which they were randomly assigned. ITT analyses may capture early side effects of vaccine resulting in incomplete vaccination. By the same measure, ITT analyses may also capture post-exposure prophylactic effects of the vaccine if present.
Immunogenicity assessment is an important statistical area in vaccine trials. Immunogenicity is the capacity of a vaccine to elicit a measurable immune response. It is the ability of the vaccine to generate an immune response in an individual. Immunogenicity is different from efficacy. Vaccine Efficacy measures are the percentage reduction of disease in the vaccinated group compared to the placebo group. One of the objectives of COVID-19 vaccine trials includes the non-inferiority evaluation of immune response to the test vaccine in participants. Non-inferiority trials are designed to check the test vaccine is not worse than the placebo by more than a small pre-specified amount (Non-inferiority margin). The noninferiority margin is the crucial one because the whole result is illustrated based on this value. The immunogenicity analysis will include the bioassay endpoint (Antibody concentrations) and the metric analyzed (geometric mean concentration, proportion of fold -response). Biostatistics plays a huge role in vaccine trials because these measures are calculated using statistical theories.
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