Adverse Events Time to Event
Adverse Event Time to Event generates analyses for studies with one or more treatment arms and computes treatment differences between all treatments for studies with two or more treatment arms.
Most analyses of adverse events (AEs) compare the proportion of patients experiencing an AE across treatments. This analysis is limited in that it does not consider the time at which an event occurs. For example, two treatments could have the same number of patients experiencing events, but the patients on one treatment could experience their events much earlier than the other treatment. Experiencing an event early implies that there is ample opportunity to experience the event additional times over the course of follow up.
This analysis does not consider each and every AE experienced by the patient (see the Adverse Events Recurrence for this type of analysis), only the first experienced. For each type of AE, the analysis computes the time until the first event for patients experiencing the event. Patients who do not experience the event are censored at their last available follow-up.
When using CDISC standards, the AE or ADAE data sets summarize the events that were experienced by patients in the study, but more information is needed. In order to conduct a recurrence analysis, dates representing the start and end of an appropriate follow-up period need to be defined for all patients, not just those who experience a particular AE. Further, the derivation of the appropriate follow-up dates will depend on the types of AEs of interest for analysis (see below).
The figure above displays start and end dates appropriate for different types of events. Dates used to define follow up period are described below, and they are considered in the order of presentation.
Note: Visit End Date is equivalent to Visit Start Date if it is not available.
All Events include any AEs that may occur on study once informed consent is signed until the patient ends study participation.
| • | Start date: Consent Date or Enrollment Date or Earliest Visit Start Date |
| • | End date: End of Participation or End of Study or Maximum of (Latest Visit End Date, Latest date for Disposition Events from the DS domain) |
Treatment Emergent Events include any AEs that may occur on or after the first dose of study therapy determined by the treatment arm.
| • | Start date: First Treatment Date |
| • | End date: End of Participation or End of Study or Maximum of (Latest Visit EndDate, Latest date for Disposition Events from the DS domain) |
On Treatment Events include any AEs that may occur on or after the first dose of study therapy and before or at the last dose of study therapy.
| • | Start date: First Treatment Date |
| • | End date: Last Treatment Date |
Pre-Treatment Events include any AEs that may occur prior to the first dose of study therapy.
| • | Start date: Consent Date or Enrollment Date or Earliest Visit Start Date |
| • | End date: First Treatment Date |
Off Treatment Events include any AEs that may occur after the last dose of study therapy.
| • | Start date: Last Treatment Date |
| • | End date: End of Participation or End of Study or Maximum of (Latest Visit End Date, Latest date for Disposition Events from the DS domain) |
For Screen Failures, the following changes apply:
All Events
| • | No changes |
Pre-Treatment Events
| • | Any events are considered to have occurred before treatment since treatment was never received |
| • | End date: End of Participation or End of Study or Maximum of (Latest Visit End Date, Latest date for Disposition Events from the DS domain) |
Excluded from Treatment Emergent, On treatment, and Off Treatment events since no treatment was received.
Note: This report is not valid for crossover studies due to the limitations of the statistical methods in computing treatment differences (which assumes treatment arms are independent).
Report Results Description
Running this report with the Nicardipine sample setting generates the tabbed Results shown below (click image to enlarge). Output from the report is organized into sections. Each section contains one or more plots, data panels, data filters, or other elements that facilitate your analysis.
The Adverse Events Time to Events report generates analyses for studies with one or more treatment arms and computes treatment differences between all treatments for studies with two or more treatment arms.
The Report contains the following elements:
Results Summary
Double-Dot Plot
For studies with two or more treatment arms, differences between the treatment arms are compared at the minimum of the maximum follow-up times for the treatments. Here, the minimum follow-up time is 111 days.
This plot above (click image to enlarge) is a modification to the more common dot-forest plot that is provided in other reports, as confidence intervals between the difference in probabilities estimated from two Kaplan-Meier curves are generally not available. The left panel presents the probability of a patient experiencing an event at the end of the study (here, 125 days). The right panel presents the difference in probabilities between the two treatments (here, Nicardipine minus Placebo, though this can be modified using the Treatment Differences are With selector). The y-axis is sorted so that events with greatest risk for Nicardipine are at the top of the figure with those with greatest risk on placebo are on the bottom. This highlights events that may be of interest to examine further. Note that for a single arm study, a dot-forest is provided with 95% confidence intervals provided around the individual estimate of event probability.
The limitation of the dot-forest plot, however, is that it only communicates the risk between treatments at a single point in time. For two or more treatments, an alternative to screen events across the entirety of follow-up, the max difference plot, shown below, can be utilized.
Data Filter
The data filter has variables to subset the dot-forest plot by the overall event total, the maximum by treatment event total, or the Failure, though other variables may be added.
Max Difference Plot
This plot above (click image to enlarge) computes the difference in Kaplan-Meier curves across the duration of follow up. When more than 2 treatments are available, the difference between the maximum probability and the minimum probability are summarized. For two treatments, the direction of the treatment differences are considered to show which of the two treatments has greater risk. For example, the above figure shows greater risk for nicardipine for phlebitis, hypotension, and isosthenuria, while placebo shows elevated risk for vasoconstriction and hypertension. Note that this plot is filtered to those events were limited to those with at least a difference of 9.57% observed at least once along follow up.
Plots by Adverse Event
The remaining plots are specific to an individual AE which can be selected by the Data Filter. By default, the event at the top of the double-dot plot is selected (here, phlebitis). Event plots are presented below (click image to enlarge).
Event Plots
The plot of the left is a patient-level event plot which summarizes the follow-up for each patient with the first event highlighted on the plot. If multiple events were experienced on that same date, this would be denoted by differing bubble size. Though difficult to see for all patients, once a patient experiences an event becomes dashed so that it is easier to distinguish follow up that occurs after the first event. This helps the user determine whether particular events lead to patient discontinuation after the first event. The right plot is a treatment-level event plot where all events are presented along a line which represents the maximum follow up experienced on the treatment arm. As visible from either plot, patients experience their first phlebitis event within 15 days, and the nicardipine arm had far more patients experience events.
Time to Adverse Event
This plot (click image to enlarge) is a failure-type Kaplan-Meier plot, which starts at 0 (no one has the event) with increasing probability to communicate the cumulative proportion of patients who have experienced a phlebitis event. Based on the tests and narrow confidence intervals, one can conclude there is a difference in phlebitis events between the two treatments.
The Number at Risk table, displayed at the bottom of the figure when All Patients is selected using the Number at Risk display option, communicates the number of patients who have yet to have an event or be censored. When Cumulative Events is selected using the Number at Risk display option, the total number of patients with events up to and including a particular time are presented in the risk table, which has now been renamed Cumulative Events. Numbers are presented every 30 days and at the last day of follow up.
Options
Data
Term Level
Term Levels are determined by the coding dictionary for the Event domain of interest, typically these levels follow the MedDRA dictionary. Use this widget to specify how each adverse event is named and the level at which the event is considered. For example, selecting Reported Term for the Adverse Event reports the event specified by the actual event term as reported in the AE domain. Refer to Term Level for more information.
Include serious adverse events only
By default, all events are included in the analysis. However, you can opt to include only those considered serious. Checking the Include serious adverse events only widget restricts the analysis to those adverse events defined as Serious under FDA guidelines.
Event Type
Analysis can consider all events or only those that emerge at specific times before, during, or after the trial period. For example, selecting On treatment events as the Event Type includes only those events that occur on or after the first dose of study drug and at or before the last dose of drug (+ the offset for end of dosing).
Ignore available treatment emergent flags
If you choose to ignore available treatment emergent flags, the analysis includes all adverse events that occur on or after day 1 of the study.
Collapse Events
Checking this option, when combined with available filters groups events meeting the filter criteria into a single user-defined set of events. The first event in this set, no matter what it may be, is used to compute the time to the set of events.
Number at Risk Interval (days)
Enter the number of days comprising the block of time between study days where the number of subjects remaining in the study are reported.
Color Risk Table by Treatment
Use this option to color the numbers in the Risk Table by treatment.
Additional Filters - Adverse Events
This filter lets you restrict your analysis to only those subjects that meet specific criteria at the AE domain level. See Adverse Events for more information.
Note: To filter subjects with a specific event or finding, one could also use the Subpopulation Builder on any domain of interest. For example, filter to all subjects that exhibit cardiac failure ( :Customized Query 01 Name == "Cardiac failure" ) and run all reports on those.
Display
Number at Risk
Use this option to specify whether to calculate risk for all subjects or just those experiencing cumulative events. All Patients, which is set by default, displays the number of patients currently at risk in the analysis (i.e., those who have yet to have an event or be censored). Cumulative Events displays the number of patients who have experienced an event by the given time point.
Add Intervals
Check this option to show the 95% pointwise confidence bands for the Kaplan-Meier survival functions in the Survival Plot and the Failure Plot. Meeker and Escobar (1998, ch. 3) discuss pointwise and simultaneous confidence intervals and the motivation for simultaneous confidence intervals in survival analysis.
Add Simultaneous Intervals
Check this option to show the 95% simultaneous confidence bands for the Kaplan-Meier survival functions in the Survival Plot and the Failure Plot. Meeker and Escobar (1998, ch. 3) discuss pointwise and simultaneous confidence intervals and the motivation for simultaneous confidence intervals in survival analysis.
Add Tests
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General and Drill Down Buttons
Action buttons provide you with an easy way to drill down into your data. The following action buttons are generated by this report:
| • | Click  to rerun the report using default settings. |
| • | Click  to view the associated data tables. Refer to Show Tables for more information. |
| • | Click  to generate a standardized pdf- or rtf-formatted report containing the plots and charts of selected sections. |
| • | Click  to generate a JMP Live report. Refer to Create Live Report for more information. |
| • | Click  to take notes, and store them in a central location. Refer to Add Notes for more information. |
| • | Click  to read user-generated notes. Refer to View Notes for more information. |
Default Settings
Refer to Set Study Preferences for default Subject Level settings.
Methodology
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References
Meeker, W. Q., and Escobar, L. A. (1998). Statistical Methods for Reliability Data. New York: John Wiley & Sons.