Exposure adjusted event rate (EAER) and exposure adjusted incidence rate (EAIR)

In clinical trials, analyses of the adverse events (AEs) including serious adverse events, mortality, and adverse event of special interests (AESI) are the center piece of the safety analyses. The default approach is to calculate the incidence of AEs (the number of subjects with one specific type of AE divided by the number of patients in the specific group). The presentation of the AE profiles is usually based on the incidence of AEs. For example, in an example table below, the incidence of AEs was presented for each preferred term by treatment group. The numerator is the number of subjects with one specific AE (preferred term) and the denominator is the total number of subjects in each treatment groups (109 for Drug-X group and 110 for Placebo group). 

Comparing the incidence of AEs between treatment groups is valid and fair if the length of exposure is balanced between two treatment groups. If the treatment exposure in one group is significantly longer than another group, the incidence of AEs may give a biased comparison. 

Ii the average duration of exposure differs significantly between treatment groups within a trial or between trials included in an analysis due to differential drop-out rates or study design, such incidence of AEs will need some adjustment to make the comparison meaningful. In the situation that the treatment exposures between treatment groups are not balanced, the exposure adjusted event rate (EAER) or exposure adjusted incidence rate (EAIR) may be calculated where the denominator for the calculation is the exposure duration expressed in person-time such as person-year or patient-year.

In FDA CDER's MAPP "Good Review Practice: Clinical Review Template", it mentioned the following: 

"An analysis of the overall rate of serious events and the rate of specific serious events for each treatment group in critical subgroups (e.g., demographic, disease severity, excretory function, concomitant therapy) and by dose. The median duration of exposure should be examined across treatment groups. If there is a substantial difference in exposure across treatment groups, incidence rates should be calculated using person-time exposure in the denominator, rather than number of subjects in the denominator,...by treatment group"

"Analyses should be corrected for differences in drug exposure using person-time in the denominator to calculate mortality rates. If person-time exposure is not included in the submission (ideally, it should be requested at the pre-NDA/pre-BLA meeting), it should be requested as soon as the need is recognized..."

When the incidence rate of AEs (or exposure adjusted incidence rate) needs to be calculated, the denominator is for sure the person-time, but the numerator for the calculation can be confusing. Should the numerator be the number of events or the number of subjects with at least one event? 

If the event can occur only once for each subject, the number of events and the number of subjects with at least one event will be the same (each subject can die only once!). Therefore, the exposure adjusted mortality rate will be same no matter which numerator is used. 

If the same subject experience multiple occurrences of the same AE during the study period, the incidence of AEs will be different depending on which numerator is used in calculation. In a previous post, Incidence Rate (IR) – How could this be wrongly calculated?, I stated that the number of events should be used as the numerator for incidence rate calculation and criticized the use of the number of subjects with events as the numerator. In most situations, it is better and more accurate to count more than one event to the numerator if the subject experience multiple occurrences of the same event during the study period. 

In FDA guidance "Safety, Efficacy, and PharmacokineticStudies to Support Marketing ofImmune Globulin Intravenous(Human) as Replacement Therapy forPrimary Humoral Immunodeficiency", the serious bacterial infection is the primary interest. The serious bacterial infection can occur more than one in a specific patient. The guidance said the following: 

"We recommend that you provide in the BLA descriptive statistics for the number of serious infection episodes per person-year during the period of study observation. Additional information important to our review includes a frequency table giving the number of subjects with 0, 1, 2… serious infections, a description of each serious infection, and summary statistics for the length of observation of each subject."

"Based on our examination of historical data, we believe that a statistical demonstration of a serious infection rate per person-year less than 1.0 is adequate to provide substantial evidence of efficacy. You may test the null hypothesis that the serious infection rate is greater than or equal to 1.0 per person-year at the 0.01 level of significance or, equivalently, the upper one-sided 99% confidence limit would be less than 1.0."

MACE (Major Adverse Cardiac Event) is the most frequently used endpoint in cardiovascular outcome studies. Incidence rate for MACE should be calculated with number of events as the numerator and the person-year as the denominator. This can be exemplified in FDA's Briefing Document for Cardiovascular and Renal Drugs Advisory Committee Meeting for GSK's drug Daprodustat for for the treatment of anemia due to chronic kidney disease (CKD). The same patient can have more than one MACE event (from the non-fatal events to fatal event). 

However, in practice, the number of subjects has often been used as the numerator in incidence rate calculation. It turned out both the number of events and the number of subjects can be used in the calculation depending on how the denominator of exposure (person-time) is calculated.  

PSUSE published a document "Analysis and Displays Associated with Safety Topics of Interest: Focus on Phase II to IV Clinical Trials". In the document, two different terms were proposed: exposure adjusted event rate (EAER) and exposure adjusted incidence rate (EAIR). EAER is calculated using the number of events as the numerator and EAIR is calculated using the number of subjects as the numerator.

Exposure-adjusted event rate (EAER): The number of events (if a patient has more than one occurrence of the same event, all occurrences are counted) divided by the total time exposed. This is sometimes referred to as person-time absolute rate. Total time exposed is calculated as the sum of each patient’s time in the interval, whether or not the patient experienced the event. The time unit used can be changed (e.g. if the original units are events per person-year, this can easily be converted to events per 100 person-years by multiplying by 100). The exposure time should be based on the same time interval in which any events that occur would be counted.

Exposure-adjusted incidence rate (EAIR): The number of patients with an event divided by the total time at risk for the event. Total time at risk will be calculated as the sum of time from the first dose (or randomisation) to first event for patients who experienced the event and the time during the entire assessment interval for patients who do not experience the event. This is sometimes referred to as the incidence rate or person-time incidence rate . As noted above, we believe the addition of “exposure-adjusted” or “person-time” is beneficial for clarity.

Notice that for EAIR calculation, the exposure duration (the person-time) is from the first dose to the first event, not the entire exposure duration (from the first dose to the last dose). 

In practice, EAER and EAIR were not specifically distinguished, the numerator and the denominator may be mismatched with the intended use. The numerator can be either the number of events or the number of subjects as long as the exposure or person-time is correctly calculated. 

For recurrent events or composite events where the same patient can have more than one event, if the exposure (denominator, person-time) is calculated for the entire duration, the numerator should be the number of events so that all events (not the first event) are counted in the calculation. If the exposure (denominator, person-time) is calculated from the first dose to the occurrence of the first event (or the entire exposure duration if the subject does not have any event), the numerator should then be the number of subjects. For example, in a paper "Exposure-adjusted incidence rates (EAIRs) of adverse events (AEs) from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in HR+/HER2- metastatic breast cancer (MBC)", how the denominator of exposure time is calculation was explicitly spelled out. 

Time-at-risk EAIR considers patient’ exposure of a specific AE in quantifying the risk of AE, defined as the number of pts who experienced at least 1 specific AE, divided by the total exposure time (patient-year of exposure [PYE]) in each arm. For patients who experienced specific AEs, exposure time was calculated from first dose date up to the first AE onset, and for patients who did not, from first dose up to data cutoff (if still on study treatment) or up to last dose (if discontinued study treatment).

In some cases, both EAER and EAIR may be calculate, for example, in FDA's clinical review for NDA 211675Orig1s000, both EAER and EAIR were calculated. In a statistical analysis plan by 

UCB, the details about the calculations of both EAER and ERIR were provided. 

Whether or not the EAER or EAIR is calculated may or may not change the conclusion of the safety assessment, however, it is worth noting the differences in the numerator and denominator used in the calculations. 

In summary, the AE analyses can be adjusted for the exposure duration. If the numerator is the number of events, the denominator should be the total exposure duration or person time (from the first dose to the last dose) and the calculated parameter is "Exposure adjusted event rate (EAER)". If the numerator is the number of subjects, the denominator should be the exposure duration or person time where the exposure duration is calculated from the first dose to the time of the first event for subjects with event(s) and from the first dose to the last dose for subjects who do not have any event. The calculated parameter is "exposure adjusted incidence rate (EAIR).