Inadequate diversity of information resources searched in US-affiliated systematic reviews and meta-analyses: 2005-2016.

OBJECTIVE: Systematic reviews and meta-analyses (SRMAs) rely upon comprehensive searches into diverse resources that catalog primary studies. However, since what constitutes a comprehensive search is unclear, we examined trends in databases searched from 2005-2016, surrounding the publication of search guidelines in 2013, and associations between resources searched and evidence of publication bias in SRMAs involving human subjects. STUDY DESIGN: To ensure comparability of included SRMAs over the 12 years in the face of a near 100-fold increase of international SRMAs (mainly genetic studies from China) during this period, we focused on USA-affiliated SRMAs, manually reviewing 100 randomly selected SRMAs from those published in each year. After excluding articles (mainly for inadequate detail or out-of-scope methods), we identified factors associated with the databases searched, used network analysis to see which resources were simultaneously searched, and used logistic regression to link information sources searched with a lower chance of finding publication bias. RESULTS: Among 817 SRMA articles studied, the common resources used were Medline (95%), EMBASE (44%), and Cochrane (41%). Methods journal SRMAs were most likely to use registries and grey literature resources. We found substantial co-searching of resources with only published materials, and not complemented by searches of registries and the grey literature. The 2013 guideline did not substantially increase searching of registries and grey literature resources to retrieve primary studies for the SRMAs. When used to augment Medline, Scopus (in all SRMAs) and ClinicalTrials.gov (in SRMAs with safety outcomes) were negatively associated with publication bias. CONCLUSIONS: Even SRMAs that search multiple sources tend to search similar resources. Our study supports searching Scopus and CTG in addition to Medline to reduce the chance of publication bias.

Ketoconazole-Associated Liver Injury in Drug-Drug Interaction Studies in Healthy Volunteers.

Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure. All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support restriction of ketoconazole as an index CYP3A inhibitor in DDI studies involving healthy volunteers.