By Warren Howard | February 27, 2026| 0 Comments

Adverse Event Calculator: IR vs EAIR

Input Data

What You Need to Know

Understanding these metrics is crucial for evaluating drug safety:

  • IR (Incidence Rate) Percentage of patients who experienced the event, regardless of treatment duration
  • EAIR (Exposure-Adjusted Incidence Rate) Events per 100 patient-years, accounting for varying treatment lengths
  • Patient-Year One person exposed for one year (365.25 days)
Important: The FDA requires EAIR for drug safety assessments when treatment durations vary significantly between groups.

Results

Incidence Rate (IR)

IR = (Number of events / Total patients) × 100
0.00%
This is the raw percentage of patients who experienced the adverse event

Exposure-Adjusted Incidence Rate (EAIR)

EAIR = (Number of events / Total patient-years) × 100
0.00 per 100 patient-years
This shows the rate per 100 patient-years of exposure
Why this matters: A 15% IR might seem high, but if patients were only on the drug for 3 weeks, the actual risk is much lower than a 15% rate over 2 years.
Key insight: When treatment durations vary significantly, EAIR provides a more accurate assessment of true safety risks than raw percentages.

When a new drug enters clinical trials, regulators and doctors don’t just look at how well it works-they also need to know how safe it is. But here’s the problem: adverse event rates aren’t as simple as saying "15% of patients had nausea." If one group took the drug for 3 months and another for 2 years, comparing raw percentages can mislead you. That’s why experts now rely on more precise methods like exposure-adjusted incidence rate (EAIR) to get the real picture.

Why Raw Percentages Lie About Risk

The simplest way to report adverse events is called incidence rate (IR). It’s just: number of people who had the side effect divided by total people in the study. So if 15 out of 100 patients got a headache, you say "15% experienced headache." But this ignores something critical: time. Imagine two groups in a trial. Group A takes the drug for 30 days. Group B takes it for 730 days-two full years. If 10 people in Group A get a rash, that’s 10%. In Group B, 20 people get a rash. At first glance, it looks worse. But if you think about it, Group B had way more time to develop side effects. The raw percentage doesn’t tell you if the drug is actually riskier, or if people just had more time to react.

A 2010 analysis cited by Amgen statisticians found that using IR alone can underestimate true event rates by 18% to 37% when treatment lengths vary. That’s not a small error-it’s enough to make a drug look safer than it really is, or worse, to wrongly scare people away from a beneficial treatment.

Enter Patient-Years: The EIR Method

To fix this, researchers use event incidence rate adjusted by patient-years (EIR). Instead of counting people, you count time. One patient-year means one person was exposed to the drug for one full year. If five people took the drug for 6 months each, that’s 2.5 patient-years.

The formula is simple: number of events divided by total patient-years. Then you scale it to "per 100 patient-years" to make it easier to read. So if 15 events happened over 200 patient-years, the EIR is 7.5 per 100 patient-years.

This method works better for recurring events. Say a patient gets diarrhea twice in 18 months. IR counts them as one person with diarrhea. EIR counts two events over 1.5 patient-years-giving you a clearer sense of how often the problem actually happens. JMP Clinical and other regulatory software now use EIR as a standard output, pulling dates from trial records (TRTSDTM and TRTEDTM) to calculate exposure automatically.

The FDA’s Push for EAIR: What Changed in 2023

In 2023, the FDA made a major move. They requested that a company submitting a supplemental biologics license application (sBLA) switch from IR to exposure-adjusted incidence rate (EAIR). This wasn’t a suggestion-it was a requirement. And it signaled a turning point.

EAIR doesn’t just count events per time. It accounts for recurrence and variable exposure in a way EIR doesn’t. For example, if a patient stops the drug for 3 weeks due to side effects, then restarts, EAIR adjusts for that gap. EIR might still count them as continuously exposed. EAIR doesn’t.

MSD’s safety team found that switching to EAIR revealed previously hidden safety signals in 12% of their chronic therapy programs. One drug looked fine with IR. But when they used EAIR, they noticed a spike in liver enzyme elevations in patients who took the drug for over 18 months-something IR had buried.

The European Medicines Agency (EMA) still allows both IR and EAIR, but requires justification. The FDA, however, is moving toward EAIR as the new baseline. Dr. Gary Koch, former biostatistics professor at UNC, called ignoring exposure time a "fundamental statistical error." He wasn’t exaggerating.

Calendar with patient treatment gaps, illustrating accurate patient-year calculation

How Competing Risks Change Everything

Here’s where things get even trickier. In cancer trials or elderly populations, patients often die before they can experience a side effect. If someone dies from heart failure after 6 months, you never see if they’d have developed kidney damage at month 12.

Traditional methods like the Kaplan-Meier estimator-commonly used in survival analysis-treat death as a "censored" event. But that’s wrong. Death isn’t just missing data-it’s a competing event. It removes the patient from the pool of people who could experience the adverse event.

A 2025 study in Frontiers in Applied Mathematics and Statistics showed that using Kaplan-Meier in these cases leads to inflated risk estimates. Instead, they recommend cumulative hazard ratio estimation, which breaks down risk into separate pathways: one for death, one for the adverse event. Simulations showed this method was 22% more accurate when competing events occurred in more than 15% of patients.

Real-World Challenges in Implementation

Switching from IR to EAIR sounds great-but it’s not easy. A 2024 PhUSE survey found that programming EAIR in SAS takes 3.2 times longer than IR. Median time: 14.7 hours vs. 4.5 hours. Common mistakes? Incorrect date handling (28% of cases), not accounting for treatment interruptions (19%), and inconsistent patient-year calculations (23%).

Roche reported that 35% of their medical reviewers initially misread EAIR results. One reviewer thought a rate of 8.5 per 100 patient-years meant "8.5% of patients had the event." It doesn’t. It means "in every 100 people followed for one year, you’d expect 8.5 events." That’s not the same thing.

CDISC’s Oncology Therapeutic Area Guide (v3.0, 2023) now requires both IR and EAIR for serious adverse events. The FDA’s Biostatistics Review Template now includes checklists asking: "How was exposure time calculated?" and "Was treatment interruption accounted for?"

The PhUSE team released open-source SAS macros for EAIR calculation in March 2023. They’ve been downloaded over 1,800 times. Users report an 83% drop in programming errors after using them. Still, adoption is slow. Only 47% of regulatory submissions in 2023 included exposure-adjusted metrics-up from 12% in 2020, but far from universal.

Transparent human body showing competing risks of death and side effects in clinical trials

What You Need to Know Today

If you’re reading clinical trial data-whether you’re a doctor, researcher, or patient-you need to ask three questions:

  1. Is the adverse event rate reported as a percentage (IR) or as events per 100 patient-years (EIR/EAIR)?
  2. What’s the average treatment duration in each group? If it’s more than 6 months, raw percentages are unreliable.
  3. Was exposure time adjusted for treatment interruptions? If not, the numbers may be misleading.

The global clinical trial safety software market hit $1.84 billion in 2023, growing at 22.7% yearly-mostly because regulators are demanding better methods. The ICH E9(R1) guidelines from 2020 already require that safety analyses consider exposure time. The FDA’s 2024 draft guidance on exposure-adjusted analysis is just codifying what smart statisticians have known for years.

By 2027, experts predict 92% of Phase 3 drug submissions will include EAIR alongside IR. The future of drug safety isn’t about counting people-it’s about counting time, events, and real-world behavior.

What’s the difference between incidence rate (IR) and exposure-adjusted incidence rate (EAIR)?

Incidence rate (IR) is the percentage of patients who experienced an adverse event, regardless of how long they were on the drug. Exposure-adjusted incidence rate (EAIR) counts the number of events per unit of exposure time (usually per 100 patient-years), and adjusts for treatment interruptions, restarts, and varying durations between groups. EAIR gives a more accurate picture of how often side effects occur over time.

Why does the FDA prefer EAIR now?

The FDA prefers EAIR because raw percentages can hide real safety risks when treatment durations differ between groups. For example, a drug given for two years might naturally cause more side effects than one given for three weeks-but IR would make them look equally risky. EAIR accounts for time and recurrence, giving regulators a clearer, fairer view of true safety profiles. In 2023, the FDA required EAIR in an sBLA submission, marking a major regulatory shift.

Can I trust a study that only reports IR?

Be cautious. If the study has varying treatment lengths-especially over six months-IR alone is misleading. Always check whether exposure time was considered. A 2010 analysis showed IR can underestimate true event rates by up to 37% in trials with heterogeneous durations. Look for EAIR or EIR in safety tables. If it’s not there, the safety data may be incomplete.

What’s patient-year and how is it calculated?

A patient-year is one person exposed to a drug for one full year (365.25 days). To calculate it, you take the time between first and last dose for each patient, subtract any gaps where treatment was stopped, and divide by 365.25. For example: a patient on treatment for 18 months with a 2-week break = 1.5 years minus 0.04 years = 1.46 patient-years. Tools like JMP Clinical and SAS automate this using trial dates.

Do all regulatory agencies require EAIR?

No. The FDA is pushing hard for EAIR and now requires it in certain submissions. The European Medicines Agency (EMA) accepts both IR and EAIR but demands justification for the choice. The International Council for Harmonisation (ICH) E9(R1) guidelines require that safety analyses account for exposure time, but don’t mandate one specific method. Still, the industry trend is clearly moving toward EAIR as the gold standard.

What Comes Next

The FDA’s Sentinel Initiative is testing machine learning models that use EAIR data to automatically flag safety signals. Early tests showed a 38% improvement in detecting problems before they become widespread. Meanwhile, the PhUSE team is preparing an R-based reference implementation for EAIR, due in early 2025. As these tools become standard, the days of reporting simple percentages will be over.

If you’re reviewing a clinical trial, don’t just look at the headline number. Ask: How much time did people spend on the drug? Were interruptions accounted for? Was recurrence measured? Because in drug safety, time isn’t just a factor-it’s everything.