Safety signals

Levine JG, Tonning JM, Szarfman A. Reply The evaluation of data mining methods for the simultaneous and systematic detection of safety signals in large databases lessons to be learned. Br J Clin Pharmacol. 2006 61 105-13. 

Clearly, therefore, those involved in drug safety monitoring need to liase closely with both clinical research and medical information scientists. In addition, those responsible for clinical drug safety must undertake periodic safety update reports (PSURs) at predetermined intervals, in accordance with current International Conference on Harmonisation (ICH) guidelines. Such routine analyses can identify new safety signals as soon as they become detectable. 

IVT) studies (earlier depending on safety signal generation) can bring attrition earlier than preclinical development. HCA may be used on blood cells to detect cytotoxicity [37]... 

Compared to efficacy, safety is typically more multifactorial, as it is dependent on homeostasis of virtually all cellular processes. A wider number and diversity of potential molecular and cellular effects of compound interactions may affect safety than may affect efficacy or bioavailability. Accordingly, cytotoxicity assessment is less specific, more multi parametric and extrapolatable with less certainty, unless there are specific safety signals indicated by the chemical structure or by its precedents. Extrapolation of safety biomarker data needs a greater foundation of mechanistic understanding of both in vitro and in vivo pathogenesis of toxicities, as well as rigorous, empirical validation of models. 

Gordon AJ, editor. Benefit-risk balance for marketed drugs evaluating safety signals. Report of CIOMS Working Group IV. Geneva WHO Press 1998. 

Annual reports that contain well-developed and meaningful information will be an important tool for the Agency and the industry to assure postmarket safety and protect the public. When manufacturers prepare the type of analysis this guidance describes and provide this information to the FDA in annual reports, industry and the FDA will be better positioned to recognize and address possible safety signals. 

CIOMS Working Group IV. 1999. Benefit-Risk Balance for Marketed Drugs. Evaluating Safety Signals. CIOMS Geneva. 

In addition, there are some countries like the United States, which allow for consumers to report AEs, whereas other countries only allow healthcare professionals to make such AE reports. This can result in higher numbers of reports, though the information that is received may not be completely valuable or beneficial when searching for safety signals. Consumer reports can also be increased as a result of direct consumer advertising, especially when consumer hotlines are published. 

Once a safety signal is identified and analyzed, pharmacovigilence personnel must determine whether it signifies a shift in the relationship between risks and benefits. Weighing the risks and benefits of drug treatment is a... 

Hammond, I. W., Gibbs, T. G., Seifert, H. A, Rch, D. S. (2007 Nov). Database size and power to detect safety signals in pharma-covigilance. Expert Opinion on Drug Safety, 5(6), 713-721. 

Mahady, G., T. Low Dog, D.N. Sarma, and G.I. Giancaspro. 2009. Suspected black cohosh hepatotoxicity—Causality assessment versus safety signal. Maturitas 64(2) 139-140. 

Monitoring for safety presents statistically difficult problems. In looking for safety signals, the DMC searches for the unknown, the rare unexpected event. Problems of multiplicity abound—many outcomes and many looks conspire to muddle the sample space and therefore make probabilities ill defined. While one can, and should, specify precisely the number of outcomes to evaluate for efficacy, by definition one carmot specify the number of hypotheses relevant to safety. Instead, the DMC must remain alert to react to surprises, turning a fundamentally hypothesis-generating ("data dredging") exercise into somewhat of a hypothesis-testing framework. 

Xia HA, Ma H, Carlin BP. 2011. Bayesian hierarchical modeling for detecting safety signals in clinical trials. Journal of Biopharmaceutical Statistics 21(5) 1006-1029. 

Process for Safety Signal Detection, Assessment, and Management...98... 

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