To be continued from Part One:
(1) The human clinical trial is divided into four phases: namely, phase I, phase II, phase III and phase IV.
The phase I focuses on safety and the subjects should be healthy, usually adults.
The purpose of the Phase II assay is to observe or evaluate whether the vaccine will achieve the desired effect (usually referred to as immunogenicity) and general safety information in the target population.
The purpose of the Phase III assay is to comprehensively evaluate the protective effect and safety of the vaccine, which is the basis for obtaining approval for registration.
The phase IV clinical assay is a comprehensive evaluation of the safety and effectiveness of the vaccine population after the vaccine is registered and marketed.
(2) Pre-clinical research and laboratory evaluation of vaccines
1). The preclinical study results of the vaccine confirmed that the test vaccine is suitable for human trials.
2). The nature of the test vaccine should be determined, including safety and immunogenicity indicators in appropriate animal models; efficacy and immunogenic data should be provided to establish and improve vaccine immunogenicity (eg, seroconversion, antibody titer, cellular immunity, etc.) And indicators of effectiveness and methods of detection.
(1) Vaccine production and quality control materials should be provided; test vaccines and placebos should be produced in accordance with GMP requirements and passed national tests.
(2) The bacterial strains and/or cell batches of the vaccines used in clinical trials should be consistent with the generations after registration. Vaccines used in clinical trials should have complete batch manufacturing and verification records and maintain a consistent process.
(3) The quality standard of clinical trial vaccine should be consistent with the marketed vaccine; the clinical trial data should reflect the stability and consistency of vaccine quality.
(4) Since the commonly used drug toxicity test may not be suitable for vaccines, the lack of suitable animal models and animal model response patterns are different from those of the human body, and researchers should fully consider the design of vaccine safety evaluation.
(5) A variety of research data such as vaccine different immunization procedures, doses, and pathways should be provided.
(6) DNA vaccines, recombinant vaccines, and synthetic peptide vaccines should be carried out according to the corresponding production, quality control and pre-clinical evaluation requirements; the compatibility and compatibility of adjuvants, new additives and vaccines should be demonstrated. The combined vaccine should be subjected to appropriate immunogenicity studies on animal models to assess the reactivity of individual antigens. Live attenuated vaccines should provide research data on virulence, ancestral transmission, and genetic information exchange with wild strains.
(7) Epidemiological and related infectious disease surveillance data should be provided for the intended population of vaccines, with the aim of determining the incidence of the disease, the proportion of infections and morbidity, clinical manifestations, diagnostic criteria, high-risk groups (age, gender, ethnicity or population, geography), social characteristics and seasonal factors, etc.). On this basis, determine the number of samples and clinical trial time for the population required for the assay.
(8) Pharmacokinetic studies are generally not required for injectable vaccines because they do not provide useful information for determining the appropriate recommended dose, but should be considered when administered by other routes.
The monitoring of its effectiveness, safety and quality when the vaccine is used after marketing is called Phase IV clinical assay.
(A) The purpose of the Phase IV clinical trial is to monitor the various conditions of the vaccine in the normal use of a large number of target populations in order to identify adverse reactions and monitor effectiveness/effectiveness. A more accurate assessment of adverse effects and effectiveness can be obtained by actively monitoring and carefully counting data from Phase IV clinical trials. For sporadic and rare diseases, the entire population needs to be investigated to ensure statistical credibility, but general research is often limited to groupings.
(B) In most cases, phase IV clinical trials were conducted in a case-control or observational cohort study.
(C) Post-marketing monitoring and research mainly focus on the following aspects
(D) In order to ensure post-marketing monitoring, the applicant is obliged to submit the post-marketing monitoring plan when applying for registration. The monitoring results (effectiveness, adverse reactions and quality) should be reported to the State Food and Drug Administration. Post-marketing surveillance projects should be commensurate with disease epidemiology, infrastructure and target areas. Before starting to implement post-marketing monitoring projects, the basic standards of effectiveness, safety and quality should be clearly defined.
(E) The following aspects should be evaluated in the Phase IV clinical assay plan:
Reference
[1] Newman M J, Wu J Y, Coughlin R T, et al. Immunogenicity and toxicity testing of an experimental HIV-1 vaccine in nonhuman primates.[J]. Aids Research & Human Retroviruses, 1992, 8(8):1413-1418.
[2] Verdier F, Barrow P C, Burge J. Reproductive toxicity testing of vaccines.[J]. Toxicology, 2003, 185(3):213-219.
[3] Farrington C P. Relative incidence estimation from case series for vaccine safety evaluation.[J]. Biometrics, 1995, 51(1):228-235.
[4] Farrington C P. Control without separate controls: evaluation of vaccine safety using case-only methods[J]. Vaccine, 2004, 22(15):2064-2070.
[5] Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.[J]. Proceedings of the National Academy of Sciences of the United States of America, 1993, 90(8):3539-3543.
