Module 3
Alerting Users About Risks -
General Considerations
Demonstrating professionalism and consistency in generating, presenting, and timing of appropriate safety information for medicine users, and demonstrating a thorough understanding of applicable labeling regulations, guidelines, and regulatory expectations, is paramount for establishing trust and confidence with regulatory authorities. The art and craft of providing effective and timely safety alerts is not simply a facet of the art and science of safety signal detection and evaluation. At any time during an ongoing evaluation of emerging safety information, professionals need to be prepared to – and able to – decide whether to communicate to medicine users, what to communicate, and how to communicate (and whether to communicate through labeling).
Core labeling and local labeling both are expected to be "scientific" and to exclude speculative elements while at the same time alerting users about potential risks at a point in time where there might be significant uncertainty about a causal association between observed events and the use of a medicine. In each case, authors of labeling have to find the "right balance" between level of certainty about a causal association and the "timeliness" of an alert, and they can always be criticized in retrospect for any decision to not yet modify labeling.
This module reviews regulatory and other terms used to describe the threshold for alerting about potential adverse reactions and interactions, using a "common-sense approach to alerting users about risks" as a reference backdrop. It also reviews the sources and effects of subjectivity on the timing of alerts and discusses the appropriateness of projecting the level of subjective confidence on a probability scale.
Topics of this module include:
- Review of concepts: Possible, likely, unlikely, proof, well established
- Review of concepts: Reasonable possibility, reasonable causal association, reasonable evidence of causal association, some basis to believe, reasonable suspicion
- Review of concepts: Speculation, inability to rule out
- Sources and consequences of subjectivity and inter-decider variability in decision making on safety alerts
- To what extent and how we can reduce inter-decider variability
- The value of investigator causality assessment and "causality scales," and the role of the sponsor and regulatory agency