Abstract
In drug or vaccine development, some adverse events (AEs) of interest may occur infrequently. Because of their clinical importance, those AEs may be studied in a clinical trial with large sample size, long-term follow-up, or in meta-analysis of combined data from multiple trials. The conventional summary and analysis methods based on frequency of first occurrence and comparing the proportion difference between treatment groups may not be the best approach because (1) the drug exposure information is not considered in the frequency summary and analysis and (2) any recurrence of an event in the long-term follow-up is not accounted for. When recurrence events are considered, issues on the analysis such as intra-subject correlation among the recurrence events, over-dispersion, and zero inflation may need to be considered. In this paper, we review several approaches for summary and analysis of safety data in these settings. Considerations are given on the assumptions of the risk function, adjustment for differential follow-up, and handling of over-dispersion and excessive zero for low incidence events. Applications to drug and vaccine clinical trials will be used for demonstration.
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References
Almenoff J, Tonning JM, Gould AL, Szarfman A, Hauben M, Ouellet-Hellstrom R, Ball R, Hornbuckle K, Walsh L, Yee C, Sacks ST, Yuen N, Patadia V, Blum M, Johnston M, Gerrits C, Seifert H and LaCroix K (2005). Perspectives on the use of data mining in pharmacovigilance. Drug Safety, 2005: 981-1007.
Bae S, Famoye F, Wulu JT, Bartolucci AA and Singh KP (2005). A rich family of generalized poisson regression models with applications. Mathematics and Computers in Simulation 69: 4-11.
Barker C (2010). Exploratory method for summarizing concomitant medication data – the mean cumulative function. Pharmaceutical Statistics 9: 331-336.
Chan ISF and Zhang Z (1999). Test-based exact confidence intervals for the difference of two binomial proportions. Biometrics 55: 1202-1209.
Chen X (2002). A quasi-exact method for the confidence intervals of the difference of two independent binomial proportions in small sample cases. Statistics in Medicine 21: 943-956.
Chuang-Stein C (1998). Safety analysis in controlled clinical trials. Drug Information J. 32:1363S–1372S.
Keene ON, Jones MRK, Lane PW and Anderson J (2007). Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study. Pharmaceut. Statist. 2007: 89–97.
Li XM, Mehrotra DV and Barnard J (2006). Analysis of incomplete longitudinal binary data using multiple imputation. Statistics in Medicine 25: 2107-24.
Liu G, Wang J, Liu K and Snavely DB (2006). Confidence Intervals for an Exposure Adjusted Incidence Rate Difference with Applications to Clinical Trials. Statistics in Medicine 25:1275-1286.
Liu G (2012). A note on effective sample size for constructing confidence intervals for the difference of two proportions. Pharmaceut. Statist. 11: 163–169.
Miettinen O and Nurminen M (1985). Comparative analysis of two rates. Statistics in Medicine 4:213-226.
Newcombe RG (1998). Two-sided confidence intervals for the single proportion: comparison of seven methods. Statistics in Medicine 17: 857-872.
Siddiqui O (2009). Statistical Methods to Analyze Adverse Events Data of Randomized Clinical Trials. Journal of Biopharmaceutical Statistics 19:889-899.
Yang J, Li X and Liu G (2012). Analysis of zero-inflated count data from clinical trials with potential dropouts. Stat in Biopharm Research. 4: 273-283.
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Liu, G.F. (2013). On Analysis of Low Incidence Adverse Events in Clinical Trials. In: Hu, M., Liu, Y., Lin, J. (eds) Topics in Applied Statistics. Springer Proceedings in Mathematics & Statistics, vol 55. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7846-1_22
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DOI: https://doi.org/10.1007/978-1-4614-7846-1_22
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