Understanding the Relationship between Causality Assessment and Drug Labeling Practices: An Evaluation of US Regulations and FDA Policy Documents

The United States Prescribing Information (USPI), also known as the Food and Drug Administration (FDA) drug label, serves as a primary source of information for healthcare professionals to access reliable information on drug benefits and risks. Within the drug label, adverse events are listed across varying sections (e.g., Contraindications, Warnings and Precautions, Adverse Reactions). However, at present it is unclear what evidentiary thresholds FDA applies before including specific adverse event types in various sections of the drug label. To examine this question, we conducted an analysis of United States (US) regulations, guidance documents, standard operating procedures and policies published by FDA pertaining to the assessment of adverse events and drug labeling.

This study examines how causality assessments shape decisions regarding the inclusion and placement of adverse events in the US drug label.

We analyzed US regulations and policy documents published by FDA up to June 2024. Sources included the electronic Code of Federal Regulations, FDA policy documents (e.g., guidance documents, standard operating procedures, and policies) identified through searches of the FDA website and Westlaw legal database. Documents were analyzed using ATLAS.ti to extract and compare causality-related language across drug labeling sections.

Our analysis identified heterogeneous and sometimes contradictory causality assessment evidentiary thresholds across US drug label sections. We found no predefined or standardized causality thresholds specified in FDA regulations, allowing interpretive flexibility that may contribute to variability and opacity in labeling decisions. For example, the Adverse Reactions section requires "some basis to believe" a causal relationship, while the Warnings and Precautions section states that "reasonable evidence" of causality is needed for serious events.

We recommend greater standardization of causality-related terminology and public documentation of evidentiary rationales supporting labeling decisions. Improved clarity regarding evidence certainty would better support prescribers and patients in understanding drug-related harms and strengthen public trust in regulatory drug safety assessments.