Preventive HIV type 1 vaccine clinical trials: a regulatory perspective.

The clinical development of a human immunodeficiency virus (HIV) vaccine should be planned so that adequate safety and efficacy data can be obtained in an efficient manner to permit a risk/benefit assessment. Phase 1 and 2 studies should support the selection of an appropriate vaccine formulation, dose and schedule for evaluation in efficacy trials. Evaluation of the immune response(s) elicited by an HIV vaccine has an important role, even early in clinical development. Immune assay results and viral detection/quantitation technology may be used to identify and characterize HIV infections occurring during the trials. Thus, information about the performance parameters of these assays is important. Considerable research and development may be needed in this regard, especially when multiple endemic HIV-1 subtypes (clades) are expected. Prior to initiating an efficacy trial, background epidemiological information (e.g., recent seroincidence, endemic clades), as well as safety and immunogenicity data with the candidate vaccine, should be obtained in the intended efficacy trial population. The effects of antiretroviral therapy use and sensitive viral detection assays on the evaluation of the primary efficacy end point (as well as secondary end points) are important considerations. The detailed statistical plan for an efficacy trial should consider the 95% confidence limits on the estimate of vaccine efficacy; this may be of exceptional importance when relatively low point estimates of efficacy are expected.

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies.

OBJECTIVE: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate. DESIGN: Meta-analysis. SETTING: Studies from 1966 to present. SUBJECTS: Studies were located with Medline, Embase, Reprotox, and from references of textbooks, reviews, and included articles. Included studies were original, concurrently controlled studies in any language. INTERVENTIONS: Data extraction and quality assessment were done independently and in duplicate. MAIN OUTCOME MEASURES: Maternal exposure to benzodiazepines in at least the first trimester; incidence of major malformations or oral cleft alone, measured as odds ratios and 95% confidence intervals with a random effects model. RESULTS: Of over 1400 studies reviewed, 74 were retrieved and 23 included. In the analysis of cohort studies fetal exposure to benzodiazepine was not associated with major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1. 35) or oral cleft (1.19; 0.34 to 4.15). Analysis of case-control studies showed an association between exposure to benzodiazepines and development of major malformations (3.01; 1.32 to 6.84) or oral cleft alone (1.79; 1.13 to 2.82). CONCLUSIONS: Pooled data from cohort studies showed no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft. On the basis of pooled data from case-control studies, however, there was a significant increased risk for major malformations or oral cleft alone. Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip.