IMPORTANCE: Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern. OBJECTIVE: To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs. DESIGN, SETTING, AND PARTICIPANTS: This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021. EXPOSURE: The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine). MAIN OUTCOMES AND MEASURES: The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality. RESULTS: Among 1?183?999 individuals in 11 databases, 909?168 individuals (mean age, 56.1 years; 507?316 [55.8%] women) were identified as new users of ranitidine, and 274?831 individuals (mean age, 58.0 years; 145?935 [53.1%] women) were identified as new users of other H2RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration. CONCLUSIONS AND RELEVANCE: In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.

IntroductionVaccine safety surveillance commonly includes a serial testing approach with a sensitive method for ‘signal generation’ and specific method for ‘signal validation.’ The extent to which serial testing in real-world studies improves or hinders overall performance in terms of sensitivity and specificity remains unknown.MethodsWe assessed the overall performance of serial testing using three administrative claims and one electronic health record database. We compared type I and II errors before and after empirical calibration for historical comparator, self-controlled case series (SCCS), and the serial combination of those designs against six vaccine exposure groups with 93 negative control and 279 imputed positive control outcomes.ResultsThe historical comparator design mostly had fewer type II errors than SCCS. SCCS had fewer type I errors than the historical comparator. Before empirical calibration, the serial combination increased specificity and decreased sensitivity. Type II errors mostly exceeded 50%. After empirical calibration, type I errors returned to nominal; sensitivity was lowest when the methods were combined.ConclusionWhile serial combination produced fewer false-positive signals compared with the most specific method, it generated more false-negative signals compared with the most sensitive method. Using a historical comparator design followed by an SCCS analysis yielded decreased sensitivity in evaluating safety signals relative to a one-stage SCCS approach. While the current use of serial testing in vaccine surveillance may provide a practical paradigm for signal identification and triage, single epidemiological designs should be explored as valuable approaches to detecting signals.