Adverse Events Distribution

The Adverse Events Distribution report summarizes subject counts and percents for adverse events by MedDRA term. The report displays a frequency-sorted bar chart and table to help quickly identify the most commonly occurring adverse events (AEs). In addition, the report can be used to drill down into specific event types, such as switching from all adverse events to treatment emergent adverse events only. By default, the report displays adverse events by treatment groups, but options are available for further exploration by sex, race, country, study site identifier, or any combination of variables from the demographics domain. The report is also useful for exploring the distribution of the events by severity, seriousness, and other adverse event characteristics. Finally, the report can be filtered using adverse event variables to create focused displays, such as adverse events with an occurrence reate of at least 5%.

Click below to view a video summary of this report or scroll to read detailed descriptions of the report results and options.

Methodology

The report subsets the data based on the event type, additional filter criteria, and a unique occurrence algorithm. For event type, if a type other than all events is selected, the report filters the AE domain by comparing adverse event start dates with treatment start and end dates. For additional filters, the report compares the AE domain against the selected criteria and retains only those records that meet the specified conditions. The record displayed for each event is determined by sorting the data by Unique Subject Identifier (USUBJID), group level, term level, seriousness (AESER), severity (AETOXGR/AESEV), and event start date (AESTDY), and then selecting the first record for each term level. After the data have been subset accordingly, counts and percentages are calculated for each adverse event.

Note: Records marked as not occurring (xxOCCUR = N) are excluded from this analysis.

Usage and Interpretation

The Adverse Events Distribution report was run using the Nicardipine sample data set under several scenarios to demonstrate the usage and interpretation of the results.

Note: Click on the figures below to enlarge.

Example 1: Treatment-emergent AEs that occur in 5% or more of subjects, displayed by severity.

In this example, the report options were set as shown in the following table:

Option Settings
Option Type Option Setting  
Data Term and Group Level Dictionary-Derived Term, ungrouped
Event Type Treatment-emergent events
Stack by Serious Event
Show Counts or Percents Percents
Display Overall Percent Occurrence Lower bound set to 5 percent
All other options are set to default.

This report summarizes the adverse events that were categorized as Treatment Emergent and had an occurrence rate of at least 5% during the study period. It enables us to identify the most prevalent AEs and evaluate their occurrence rates across treatment groups, as well assess the severity of these events. Although no statistical testing is performed, observations can be made regarding differences between treatment groups and the severity of the AEs.

Figure 1: Bar Chart and Tabular Summaries

The Bar Chart and Tabulate summaries show that, based on the Dictionary-Derived Term, there were 26 different treatment-emergent AEs with an overall occurrence rate of at least 5% during the trial. These events are listed in order of prevalence, from Vasoconstriction, the most prevalent, to Hypernatraemia, the least prevalent. Because multiple occurrences of events in the same subject are counted once in this report, we can see that 407 subjects (45.1%) experienced Vasoconstriction as a treatment-emergent event during the trial. From the bar chart, we see that Vasoconstriction had a higher prevalence in the Placebo treatment group than in the Nic .15 treatment group. Selecting one or more bars in the bar chart highlights the corresponding cells in the table.

The bar chart also suggests that the severity of adverse events did not differ greatly between treatment groups, except for Vasoconstriction, which was more likely to be classified as serious in subjects in the placebo group (15.4%) than in subjects in the Nicardipine group (5.8%). To show only the serious events, select the Serious Event = Y in the Display Report Filter. The bar chart and tabulate summaries will be filtered accordingly, as shown below:

Figure 2: Serious Event =Y

Example 2: Adverse Events with an occurrenc rate greater than 1% in any race group, limited to pretreatment events with a Moderate or Severe toxicity grade

In this example, report options were set as shown in the following table:

Option Settings
Option Type Option Setting  
Data Demographic Grouping Race
Event Type Pre treatment events
Show Counts or Percents Percents
Display Percent Occurrence in Any Treatment or Comparison Variable Lower bound set to 1 percent
Toxicity Grade/Severity Moderate or Severe
All other options are set to default.

This report example summarizes pretreatment adverse events categorized as moderate or severe and grouped by body system or organ class and Dictionary-Derived Term. Included are events with an occurrence rate of at least 1% in any race group. The report enables us to identify pretreatment imbalances in moderate and serious adverse events across race groups. Although no statistical testing is performed, observations can be made regarding the differences between race groups for these specific pretreatment adverse events.

Figure 3: Bar Chart and Tabular Summaries

The bar chart and tabulate summarize adverse events that occurred at a rate greater than 1% in at least one race group. Included are summaries for pre-treatment adverse events by race based on their Dictionary-Derived Term. The tabulate displays events according to their Body System/Organ Class classification and is sorted from the most frequent to the least frequent event. The bar chart shows the events in descending order of prevalence by Dictionary-Derived term. From either the chart or tabulate display, we observe that Vasoconstriction was the most frequent pretreatment event, occurring in 12.5% of the patients overall. Hydrocephalus was the second most prevalent event occurring, in 11.4% of subjects.

From the bar chart we see that, during pretreatment, Vasoconstriction was more prevalent among subjects in the Asian race group. Subjects in this group also had a relatively higher prevalence of “Intracranial pressure increased” compared with the other race groups. However, only 15 Asian subjects were included in the trial; therefore, these pretreatment race differences may be attributable to the smaller sample size and may not indicate significant difference in pretreatment events. Differences in sample size across race groups are evident from the tabulate column N’s and is easily seen in the bar chart display by selecting “Counts” instead of “Percentages” in the Show Counts or Percentages option, as shown below.

Figure 4: Viewing counts instead of percentages

Example 3: Serious adverse events with an outcome of death that were related or possibly related to treatment, summarized by race and action taken with study treatment

In this example, report options were set as shown in the following table:

Option Settings
Option Type Option Setting  
Data By Variables Race (RACE)
Term and Group Level Reported Term for the Adverse Event, ungrouped
Stack by Action Taken with Study Treatment
Additional Filters Select Domain ADAE, Column AEREL, values of “Possibly Related” and Related ( :AEREL == "POSSIBLY RELATED")
Display Serious Event Y
Toxicity Grade/Severity Moderate or Severe
Outcome of Adverse Event Fatal
All other options are set to default.

This report summarizes serious adverse events based on the Reported Term for events with a fatal outcome that were classified as either "Related" or “Possibly related” to study treatment. Although no statistical testing is performed, this report provides a visualization of these fatal events and the actions taken with study treatment, summarized by treatment group and race. This information might be important to regulators and others responsible for overseeing study conduct and subject safety.

Figure 5: Bar Chart and Tabular Summaries

The bar chart and tabulate summarize these serious adverse events by treatment group, race, and action taken with study treatment. From the tabulate, we observe that a total of six subjects experienced these events. Because there are more than six rows, we know that some subjects experienced more than one serious adverse event. This report counts multiple occurrences of the same reported term only once per subject. The bar chart shows that the dose was modified or the drug was withdrawn in response to all but three of these events.

We observe that, for one subject in the NIC.15 group who experienced a Respiratory disorder event, the dose was not changed. By selecting the corresponding bar in the bar chart or cell in the tabulate, we can then select the Review Subject Filter button to subset the report to that subject's data. This is shown below, revealing that the subject had Peripheral Oedema, Anoxia, and Atrial Flutter, as well as Respiratory disorder.

Figure 6: Filtered Bar Chart and Tabulate

Options

Data

Treatment or Comparison Variable

Specifies the variable used to define the groups to be compared in the report. This variable is typically a planned or actual treatment variable, such as ARM, ACTARM, TRTxxA, or TRTxxP, but it can also be another variable that defines meaningful comparison groups, such as SEX or RACE.

Select None to display the data without grouping by a treatment or comparison variable.

Include missing Treatment or Comparison Variable values

Check this option to add a Missing category for any missing values in the specified Treatment or Comparison variable. If missing values are detected, a Missing section will be added to the graph and columns for Missing will be added to the tabulate.

By Variables

Use this field to specify one or more By variables from ADSL to use in your analysis.

Selecting a By variable will split the bar chart and tabulate by the grouping variables selected in this option as well as by the variable selected for the comparison or treatment variable.

By Variables

By variables are optional (in most reports)variable specifications whose values define groups of observations, such as hour, month, or year. By variables can enable analyses to be performed separately on different groups as defined by that variable. Choosing a By variable such as gender (ADSL variable = SEX), for example, groups the subjects by gender and conducts two separate analyses: one for males and one for females.

Alternatively, specifying a By variable enables you to animate an image so that you can see how response values change according to some grouping, like over time.

To Specify One or More By Variables:
8 Click to open the Add window (shown below) that lists each variable contained in domain and SUPPxx (if merged) specific to this report

Note: In Demographics Distribution only, variables are taken from ADSL, in addition to the report-specific DS and SUPPPDS (if available) data sets.

8 Select the variables you want to include in the analysis and click to add those variables to the text box.

In this example, AGE Group 1, RACE, and SEX were selected and added.

Note: If no By variables are specified, the analysis is conducted across all the subjects

Term and Group Level

This option allows for changing between MedDRA terms with the option to choose a single MedDRA term or a grouping of two MedDRA terms like Dictionary-Derived Term grouped by Body System or Organ Class. Switching this option swaps out the term plotted on the x-axis of the graph as well as the term in the first column of the tabulate.

Dictionary-Derived Term, grouped by Body System or Organ Class is selected by default.

Possible term and group levels are listed in the following table:

Term and Group Level

Corresponding Variable

Function

Body System or Organ Class

AEBODSYS in AE
• Uses Body System or Organ Class level of adverse events as categories.

High Level Group Term (HLGT)

AEHLGT in AE
• A superordinate descriptor for multiple higher level terms (HLTs)

High Level Term (HLT)

AEHLT in AE
• A superordinate descriptor for multiple preferred terms (PTs).

Dictionary-Derived Term

AEDECOD in AE
• Uses Dictionary-Derived Term level of adverse events as categories.

Reported Term for the Adverse Event

AETERM in AE
• Uses Reported Term for the Adverse Event level of adverse events as categories.

Event Type

Use this feature to specify the inclusion of particular events in the analysis. The selection limits the report to only adverse events of that type.

By default, all events are included in the analysis.

Available options are listed in the following table:

Option:

Select when you want to:

All event types

• Include all events.

Pre treatment events

• Include events that occur before dosing for treated subjects.

Treatment emergent adverse events

• Include events that occur on or after the first dose of study drug.

Note: For information about how treatment emergent-adverse events (TEAEs) are defined, please refer to How does JMP Clinical determine whether an Event Is a Treatment Emergent Adverse Event?.

On treatment events

• Include 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). The date of last dosing is normally taken from EXENDTC. If EXENDTC does not exist, the date is taken from EXSTDTC instead.

Off treatment follow up events

• Include events that occur after the last dose of drug (+ the offset). The date of last dosing is normally taken from EXENDTC. If EXENDTC does not exist, the date is taken from EXSTDTC instead.

Note: When crossover is detected, only those events that occur within the specified treatment period dates are shown. This is true even when All Event Types has been selected. For example, pre-treatment events are not assigned to a treatment and therefore not shown in the report.

Ignore available treatment emergent flags

This option applies only if the selected event type specifies treatment-emergent events. If this option is not checked, then the report will check for existing treatment emergent flags in the data and subset based on those flags. If the option is checked, then the Algorithm JMP Clinical uses to define treatment emergence will be applied.

Stack

Use this widget to distinguish different levels within each of the adverse events summarized by the bars in the plots.

By default, this option is set to None, but can be changed to seriousness, severity, and other adverse event characteristics. When something other than None is selected, the bars in the bar chart will be stacked by the selected variable, and the tabulate will split each demographic grouping column by the stack variable.

Potential options are listed in the following table:

Option:

Select when you want to:

None

Display all of the occurrences of each adverse event with no indications of levels within each class.

Serious Event

Display each adverse event bar in two colors: one that represents serious events and one that represents non-serious events.

Toxicity/Severity

Display each adverse event bar in three colors: one that represents mild events, one that represents severe events, and one that represents moderate events

Outcome of the Adverse Event

Display each adverse event bar in six colors. Colors represent the following: Recovered/Resolved, Recovered/Resolved with Sequelae, Recovering/Resolving, Not Recovering/Not Resolved, Fatal, and Unknown.

Causality

Display each adverse event bar in four colors. Colors represent the following events: not related to the treatment, unlikely related to the treatment, possibly related to the treatment, and related to the treatment
Action Taken with Study Treatment Display each adverse event bar in five colors. Colors represent the following events: Dose Not Changed, Not Applicable, Unknown, Dose Modified, and Drug Withdrawn.
Period

This option is displayed only when multiple treatment periods have been detected and displayed. Pretreatment is been assigned to period=0. Displayed counts indicate the number of subjects experiencing an event in each period.

Note: This is selected by default when crossover data is detected.

Note: The options available are dependent on the presence of the relevant variables in the data. For example, Severity is listed only when AESEV is present in the data tables.

Show Counts or Percents

This option enables you to specify whether to view the result in terms of total counts or as percentages of the total. This option only impacts the bar chart. Selecting counts will display subject counts on the left side y-axis of the bar chart and selecting percents will swap the axis out for percentages.

Additional Filters - Adverse Events

The Adverse Events field is an optional parameter that enables you to filter rows from the AE data set to choose the appropriate records to subset to adverse events of interest. Risk indicators are calculated using this subset of adverse events only.

This filter uses JMP WHERE clauses to Select Rows that meet the specified criteria. To use this filter, you must enter the JSL (JMP Scripting Language) expressions that constitute the WHERE clause in the appropriate text box for specific filtering of AEs. Note: This is an advanced concept that not only requires some basic knowledge of the JSL WHERE clause syntax (similar to, but different from, SQL), but also an understanding of the exact variables in the tables in the study.

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.

To specify an Adverse Events filter:
8 Click to open the WHERE Clause Builder to construct the desired filter.
8 Click to clear the filter.

Display

Report Data Filters

The report filter limits the bar chart and the tabulate to only those records that meet the filter selection. For example, if the lower bound of the Overall Percent Occurrence is set to 5, then only adverse events occurring in at least 5% of all subjects will be displayed. The filter builds upon itself, so if Serious Event equals Y and Outcome of Event equals Fatal are both selected, then only serious events that were fatal will be displayed.

Refer to Data Filter for more information.

Note: Filter specifications are reapplied when any widget options are changed.

Action Buttons

Action buttons provide an easy way for you to drill down into your data. The following action buttons are generated by this report:

• Click to re-run 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 that contains 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.
• Select one or more subjects and then click to apply the Review Subject Filter and filter all reports in the review builder on the selected subjects.
• Select a group of subjects and click to specify Derived Population Flags that enable you to distinguish the selected group of subjects from the general population.

Note: For information about how treatment emergent adverse events (TEAEs) are defined in JMP Clinical, please refer to How does JMP Clinical determine whether an Event Is a Treatment Emergent Adverse Event?.

Default Settings

Refer to Set Study Preferences for default Subject Level settings.