Safety analyses multiplicity issues

There are several important questions in drug safety evaluation How to detect unexpected adverse drug reactions while handling the multiplicity issue properly How to s)mthesize data from different trials, or even different sources How to deal with rare events How to evaluate multidimensional, complex safety information as a whole Can we monitor a potential safety issue in a continuous manner during a trial so that patients can be better protected These questions lead to some unique statistical challenges in quantitative safety analysis including low power due to rare events, multiplicity. 

Safety analyses in pharmaceutical clinical trials tend to be largely descriptive because there are so many adverse events (AEs) and other safety parameters evaluated, and analysis of them leads to issues of multiplicity (see Section 8.9). As... 

Some of the issues have already been touched on in Chapters 3 and 7 others will be dealt with when we come to consider multiplicity in Chapter 10, and also safety of treatments in Chapter 23. (In particular, some matters regarding survival analysis will be touched on in that chapter.) Other remarks and issues to do with measurement will be found in various chapters on more particular specialist matters for example. Chapter 21 which deals with pharmacokinetics and Chapter 24 which deals with pharmaco-economics. In this chapter we shall cover those important Issues which remain. 

It is often argued that formal analyses of safety data are inappropriate, usually because pre-specified hypotheses are not available. This raises the issues of multiplicity and intentions (in designing the experiment) for a frequentist analysis. For a Bayesian analysis the equivalent problem is raised of having to establish prior distributions after the data are in. Neither mode of inference deals well with carrying out post-hoc analyses. 

Use of multiple SIS Multiple Safety Instrumented Systems are sometimes used to provide a higher SIL capability, e.g., the use of two SILl systems to possibly satisfy the needs for a SIL2 system. Generally this will not work. When using multiple SIS a careful analysis is required to ensure that maintenance, common cause issues are properly analyzed. There is also the issue of "SIL capability." When a PLC is certified, it must follow a rigorous quality process according to the SIL level (see Chapter 7). A SIL 1 PLC will not likely have the quality needed for SIL 2. A SIL 2 PLC will not likely have the quality needed for SIL 3. 

Beside the main use of SysML in the design and modeling of complex systems, numerous publications describe the use of SysML for system analysis regarding safety our security issues. David et al. (2010) describe a method to assess how the functional design process is linked to reliability techniques with automated model analysis of the SysML model. Grunske and Joyce (2008) used SysML to provide a quantitative security evaluation for component based systems. They created modular attack trees for the components in the system and also transferable attack probabilities between the components to explore vulnerabilities in multiple system components. 

Part 3 discusses road safety issues of vulnerable road users pedestrians, cyclists, young drivers and PTWs. Decision makers will find the analysis of PTW mobility and safety in the OECD countries useful, which concludes in a number of measures integrated with the development of a safe system approach. Research methodologies are proposed to track multiple people in crowds of pedestrians. Finally, analysis of... 

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