Vaccine development today becomes especially important against the COVID-19 pandemic. Pharmaceutical companies have activated the general fight against the coronavirus. In this article, we will describe the peculiarities of clinical trials of vaccines.
The widespread use of vaccines necessitates monitoring the quality and efficacy of immunizations, which is an integral part of the epidemiological surveillance of infectious diseases. The effectiveness of immunization depends on several reasons due to the complexity of their production technology, the variety of mechanisms of action on the human body, as well as the need for special oversight over the quality of drugs and the rules of their use. For this purpose, special attention should be paid to clinical trials of vaccine preparations with subsequent expertise of all stages according to regulatory documents.
According to the 78 Decision of the EAEU, to register a vaccine it is necessary to conduct the following studies:
1. Reports of pharmacodynamic studies
2. Efficacy and safety research reports
3. Post-authorization experience reports
Phase I studies are conducted on a small (20 to 100 people) group of healthy volunteers. During the phase, I clinical trials, safety, and reactogenicity parameters are determined, as well as preliminary data on the immunogenicity of the vaccine, if possible. Based on these parameters, the dose and route of administration of the vaccine are selected. Phase I studies are designed to study the tolerability and safety of the vaccine in a limited population of healthy volunteers.
After obtaining the results confirming the preliminary safety of the vaccine in Phase I trials, extended vaccine trials are conducted with a larger number of volunteers (100-500 people) to confirm the safety and efficacy of the vaccine, i.e. Phase II clinical trials.
Phase II clinical trials must necessarily be conducted with a core group (those receiving the study drug) and a control group, in which volunteers are administered either a placebo or a comparison drug. Volunteers included in the main and control groups must be randomized by sex, age, etc. The efficacy (immunogenicity, therapeutic or prophylactic efficacy) and tolerability of the newly developed drug (submitted for registration) are compared either to a placebo or to a comparison drug (a unidirectional drug registered in a country with already characterized safety and efficacy indicators).
Note that EMEA/CHMP/VWP/164653/2005 states that it is important to evaluate the immunological response for different age subgroups and to carefully collect safety information after each vaccine dose is administered.
If the new vaccine contains an antigen that has not yet been used in any registered vaccine, de-escalation of the dose will be required. The gradual inclusion of populations of different ages is suggested, starting with the oldest: older than 18 years, 13-18 years, 6-12 years, 2-5 years, 1-2 years, then children under the age of 1 year. Children participate in studies only with written parental consent. If, however, a new antigen is already used in a registered vaccine, it is possible to consider including all safety data for the age subgroups obtained in a study of an already registered vaccine. Also, if different dosage forms of the same vaccine are intended to be used for children of different ages, age de-escalation studies should be conducted. Thus, further tactics will depend on whether the vaccine under development contains a new antigen or whether this antigen is already used in registered vaccines.
Phase III clinical trials include evaluation of prophylactic and/or therapeutic efficacy. Randomized controlled trials are conducted with large numbers of volunteers (from 300 to several thousand people). These are large-scale clinical trials designed to obtain efficacy and safety data on the vaccine. When organizing and conducting this phase of research, it is necessary to provide for the participation of specialists-epidemiologists and infectious disease doctors. In this connection, the trial sites responsible for conducting this type of clinical trials should include both the clinical institutions of The Ministry of Health of the Russian Federation and the institutions of The Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing.
The next step is to learn about possible vaccine-related adverse events and to evaluate the effect of immunizations on reducing disease-that is the effectiveness of vaccines. This work is ongoing and provides complete information on the evaluation of the new drug.
After three successful phases of clinical trials, the vaccine under study undergoes a registration process, upon completion of which its efficacy and safety are monitored under conditions of practical use, i.e., phase IV trials. The tasks of post-registration trials include: identifying rare side effects from the use of drugs; expanding the indications for drug administration; developing epidemiologically substantiated tactics for vaccine use; evaluating the cost-effectiveness of the drug, specifying the regimen of administration. The protocol for post-registration testing of vaccines must be developed taking into account the peculiarities of the epidemiology of the disease, its distribution in different territories, peculiarities of the age structure, etc. Also, one of the goals of post-registration studies is to identify rare or unanticipated events that may not have been established by phase II or III studies. Vaccine safety data are obtained through active and passive data collection.
For example, from observational studies of vaccine use, a huge amount of statistical information is collected from which to judge vaccine quality and to compare efficacy with counterparts produced by other manufacturers.
The process of clinical trials of vaccines is very time-consuming. Not only do the studies have to produce a positive vaccine effect, but they also have to identify any adverse reactions. The results of these clinical studies must guarantee that the vaccine is safe and actually able to prevent the development of the disease or significantly reduce the adverse effects of the disease.