Safety reporting in developing country vaccine clinical trials—A systematic review

With more vaccines becoming available worldwide, vaccine research is on the rise in developing countries. To gain a better understanding of safety reporting from vaccine clinical research in developing countries, we conducted a systematic review in Medline and Embase (1989–2011) of published randomized clinical trials (RCTs) reporting safety outcomes with ≥50% developing country participation (PROSPERO systematic review registration number: CRD42012002025). Developing country vaccine RCTs were analyzed with respect to the number of participants, age groups studied, inclusion of safety information, number of reported adverse events following immunization (AEFI), type and duration of safety follow-up, use of standardized AEFI case definitions, grading of AEFI severity, and the reporting of levels of diagnostic certainty for AEFI.The systematic search yielded a total number of 50 randomized vaccine clinical trials investigating 12 different vaccines, most commonly rotavirus and malaria vaccines. In these trials, 94,459 AEFI were reported from 446,908 participants receiving 735,920 vaccine doses. All 50 RCTs mentioned safety outcomes with 70% using definitions for at least one AEFI. The most commonly defined AEFI was fever (27), followed by local (16) and systemic reactions (14). Logistic regression analysis revealed a positive correlation between the implementation of a fever case definition and the reporting rate for fever as an AEFI (p = 0.027). Overall, 16 different definitions for fever and 7 different definitions for erythema were applied. Predefined AEFI case definitions by the Brighton Collaboration were used in only two out of 50 RCTs.The search was limited to RCTs published in English or German and may be missing studies published locally. The reported systematic review suggests room for improvement with respect to the harmonization of safety reporting from developing country vaccine clinical trials and the implementation of standardized case definitions.

► All 50 vaccine RCTs measured safety outcomes, 35 of which used AEFI definitions.
► Up to 16 different definitions were used for common AEFI, such as fever.
► Use of fever case definitions increased reporting rates for fever as an AEFI.
► Brighton Collaboration case definitions were used in only 2/50 vaccine RCTs.
► The maximum duration of follow-up (active in 90%) ranged from 3 days to 2 years.