Statistical Design And Safety Analysis Issues In The Vaccine Clinical Trials

Preventive vaccine injection plays an important role in infectious disease prevention and control. Before vaccines are available in the market, preventive vaccine clinical trials are so important that scientific and rational trial design with comprehensive statistical analysis is required to ensure the widely and safely use of preventive vaccines in the large population. Preceding laws and regulations should be strictly followed during the design and implementation of preventive vaccine clinical trials, such as the Vaccine Clinical Trials Technical Guidelines and Vaccine Clinical Trials Quality Control Guidelines. In addition, some key technical issues need more in-depth discussions.In vaccine clinical trials, especially injection vaccine clinical trials, it occurs constantly that the vaccines break because of transportation or inappropriate storage. Therefore, a mount of spare vaccine should be provided to guarantee the competence of vaccination. Only the right choice of spare vaccine allocation protocol and the effetelyimplement of allocation concealment can avoid breaking blind and ensure the trials to go on wheels. In the design of trials, the accuracy of sample size estimation will affect the reliability of the tests’ conclusion. Safety analysis, as an important vaccine clinical trials endpoint, should be given more attention for the particularity of the vaccine itself and its recipients. The existing safety analyses couldn’t meet the requirements. Therefore, an in-depth and comprehensive safety assessment is essential.Based on a comprehensive review of preceding issues of clinical trial design and statistical analysis, we explored some technical issues about this topic according to the results from an EV71 phase III clinical trial in China.The main parts of this thesis and results are as follows:1. Provide indirect allocation concealment and online real-time allocation concealment methods of standby vaccine in the blind state in vaccine clinical trials. In contrast with traditional direct allocation concealment, online real-time allocation concealment methods can generate random numbers of spare vaccine; realize the sharing and substitution of spare vaccine sufficiently, which can lead to more flexible, economical and efficient allocation of spare vaccine.2. Conduct sample size estimations in vaccine clinical trials with different primary endpoints such as protective efficacy, immunogenicity and lots consistency. Taking the clinical trials whose endpoint is protective efficacy for example, in group sequential design, we can largely save the sample size by conducting an interim analysis when effect size reach 75% and achieve a suitable test power.3. Deeply analysis the comparison of the trend of single vaccine’s incidence rates of adverse events changing with age, factors effecting the severity of adverse events and incidence rates of adverse events between one dose and two doses safety set. Taking the EV71 vaccine from Diploid cells for example, the incidence rates of adverse events declined with the increasing of ages, while the needed depicted incidence rates of adverse events declined with the increasing of ages. The incidence rates andseverity of adverse events of recipients who complete the boost dose were lower than those of recipients who only complete the initial dose.4. We compared the safety analysis among different vaccines. Based on safety of three different EV71 vaccines, Logistic model considering interaction and Meta analysis were used to compare safety. All the safety were satisfied. Compared with Diploid cell-based, the incidence of adverse enents of Vero cell-based EV71 was low.5. ROC curve analysis was used to explore the effective antibody levels in vaccine clinical trials which choose the protective efficacy as the primary endpoint. Take Diplod cell-based EV71 vaccine as an example, when protective effect against HFMD was considered, the GMT of 1:16 was appropriate.The study, reviewing relative studies of drug and vaccine clinical trials at home and aboard, explored statistical design and statistical analysis issues of preventive vaccine clinical trials. It can also provide valuable reference for comprehensive and profound safety analysis and effectiveness exploration.