A Clinical Data Manager reads a protocol for a clinical trial to test the efficacy and safety of a new blood thinner for prevention of secondary cardiac events. The stated endpoint is all-cause mortality at 1 year. Which data element would be required for the efficacy endpoint?

The study's primary efficacy endpoint is "all-cause mortality at 1 year." This is a time-to-event endpoint, which measures the time from a starting point (e.g., randomization) until the occurrence of an event (death). To perform the required survival analysis, it is essential to know both the event status (deceased) and the precise timing of that event. The "Date of death" is the critical data element that allows for the calculation of the survival time for each subject who experiences the event. This date determines whether the mortality event occurred within the specified one-year follow-up period, which is fundamental to evaluating the endpoint.

A. Drug level: This is a pharmacokinetic (PK) data point used to assess drug exposure, not the clinical outcome of mortality.

B. Coagulation time: This is a pharmacodynamic (PD) or surrogate marker that indicates the drug's biological effect, not the primary clinical endpoint itself.

C. Cause of death: This information is not required for an "all-cause mortality" endpoint, as the analysis includes deaths from any cause.

1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (1998). ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials E9. Section 5.6, "Data for Time-to-Event Analyses," specifies that such analyses require the date of the event and the date of censoring, making the date of death a required element for a mortality endpoint.

2. Friedman, L. M., Furberg, C. D., & DeMets, D. L. (2015). Fundamentals of Clinical Trials (5th ed.). Springer. In Chapter 8, "Choice of a Response Variable," the authors explain that for time-to-event outcomes, the analysis is based on comparing the time from study entry to the event. This fundamentally requires collecting the date of the event (p. 131).

3. Society for Clinical Data Management. (2023). Good Clinical Data Management Practices. Section 4.2, "Protocol and Study Documents Review," mandates that the Clinical Data Manager ensures the Case Report Form (CRF) is designed to capture all data necessary to support the study's endpoints. For a time-to-event endpoint, this explicitly includes the date the event occurred.

4. Pocock, S. J. (2013). Clinical Trials: A Practical Approach. Wiley. Chapter 10, "Outcome Measures," clarifies that for survival analysis, "For each patient, we need to know the time from entry into the study until the event occurs" (p. 136), which necessitates recording the date of death.