Multicenter Study for Pediatric Subjects Evaluating Pharmacokinetics and Safety of EXPAREL: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Multicenter Study for Pediatric Subjects Evaluating Pharmacokinetics and Safety of EXPAREL (NCT03682302), a randomized phase 3 study. The primary outcome is Area Under the Plasma Concentration-versus-time Curve (AUC) 0 to Infinity.

2. Clinical Question

3. Trial Design

The registry describes a completed Phase 3, randomized, open-label, sequential study sponsored by Pacira Pharmaceuticals, Inc. Enrollment was 98. The study start date was 2019-04-02, and primary completion was 2019-08-30. Its stated objectives were to evaluate EXPAREL pharmacokinetics and safety in pediatric subjects aged 6 to less than 17 years undergoing various types of surgery.

The treatment groups were organized by both age and surgery. In subjects aged 12 to less than 17 years undergoing spine surgery, EXPAREL was compared with bupivacaine HCl. In subjects aged 6 to less than 12 years, the registry describes EXPAREL groups undergoing spine surgery and cardiac surgery. It does not list a bupivacaine group for the younger age range. The regimen descriptions specify a single local-infiltration dose at the end of surgery, with dose limits that differ between EXPAREL and bupivacaine HCl.

Although the study is identified as randomized, the registry record does not report the allocation procedure, the sequence of enrollment or treatment, or how randomization related to the different age and surgery groups. Masking is listed as none, so the study was open-label. Further details of the protocol, such as the planned timing of analyses and the rationale for the group structure, are not reported in the registry record.

The primary pharmacokinetic analysis included subjects who received study drug and had at least 1 quantifiable plasma concentration, analyzed according to actual treatment received. The analysis counts reported for the primary endpoint are 16 and 15 in the older spine groups, 2 in the younger spine EXPAREL group, and 21 in the younger cardiac EXPAREL group. The safety counts use different at-risk group sizes, so the posted populations for these outcomes should not be treated as interchangeable.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The pharmacokinetic population consisted of subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Safety population The Safety population consisted of all subjects who underwent the planned surgery and received study treatment, with analysis by actual treatment received.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Plasma Concentration-versus-time Curve (AUC) 0 to Infinity, measured over 15, 30, 45 min, 1-1.25h, 2-4h, 10-18h, 24-36h, 42-60h (spine surgery) or 15, 30, 45 min, 1-1.25, 15-25, 20-40, 45-55, 64-72h (cardiac surgery).

The primary endpoint is the mean area under the plasma concentration-versus-time curve from zero to infinity, reported in ng*h/mL. Area under the curve, often abbreviated AUC, combines measured plasma concentrations over time into a measure of overall drug exposure. The registry lists blood-sampling times extending from minutes after surgery through later time windows, with schedules differing for spine and cardiac surgery.

As a general pharmacokinetic concept, AUC is used to describe the extent of systemic exposure rather than a single concentration at one moment. That is useful because concentrations change over time, and a single measurement can miss differences in the concentration profile. The endpoint is a continuous measure, and the registry reports group means with standard deviations.

The endpoint is not itself a direct measure of pain relief, duration of analgesia, or a clinical benefit. The stated primary objective was pharmacokinetic evaluation, while safety was a secondary objective. The registry record does not explain how values below quantification, missing samples, or the extrapolation from observed concentrations to infinity were handled, so those details are not reported in the registry record.

7. Results Posted in the Registry

• Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine: mean 5,709 versus 14,246 on control; difference -8,537 (95% CI -13,304 to -3,770), standardized effect d = -1.23; z-test p = <0.001.
• Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL: mean 26,164 versus 14,246 on control; difference 11,918 (95% CI -879.44 to 24,715), standardized effect d = 0.54; z-test p = 0.068.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: it is a mean AUC value, measured in ng*h/mL. A continuous endpoint can take a range of values rather than representing a yes-or-no event. The registry reports a mean and standard deviation for each analysis group. The mean summarizes the center of the observed values, while the standard deviation describes their spread around that mean. As a general statistical explanation, the mean is informative about average exposure, but it does not show the shape of the distribution or how much individual values overlap between groups.

What does a mean difference describe?

A mean difference expresses the distance between two group means on the endpoint's original measurement scale. The posted comparison of bupivacaine HCl with the older spine EXPAREL group is -8537 ng*h/mL. The negative direction corresponds to a lower posted mean in the bupivacaine HCl group than in the EXPAREL reference group. The comparison of the younger cardiac EXPAREL group with the older spine EXPAREL group is 11920 ng*h/mL, in the direction of a higher posted mean in the cardiac group. These are differences in AUC, not differences in a clinical pain outcome.

The direction and meaning of a contrast depend on which group is used as the reference. A difference is not automatically a causal treatment effect: interpretation as a treatment effect requires groups that are comparable apart from treatment, along with a valid analysis. In the comparison involving younger cardiac subjects and older spine subjects, age and surgery type differ as well as group membership. The posted contrast cannot isolate those influences. The older spine comparison is between the EXPAREL and bupivacaine HCl groups in the same stated age and surgery category, but further details about randomization and analysis are not reported in the registry record.

How should the confidence interval be read?

A confidence interval conveys uncertainty around an estimated contrast. In general, it gives a range of values reasonably compatible with the data and the method's assumptions; it is not a guarantee that the true value lies in that range. For the bupivacaine HCl comparison, the interval runs from -13300 to -3770 ng*h/mL and does not include zero. For the cardiac comparison, the interval runs from -879.4 to 24720 ng*h/mL and includes zero. The latter interval is broad, so the estimate is imprecise and supports a range of possible directions and magnitudes.

A p-value assesses how compatible the data are with a specified null model, commonly a zero difference, under the analysis assumptions. The posted unadjusted p-values are <0.001 and 0.068 for the two listed comparisons. A p-value does not measure the probability that the null hypothesis is true, the size of an effect, or its clinical importance. Nor does a threshold-based label replace attention to the estimate and interval. The cardiac comparison's interval illustrates why a result that does not meet a conventional significance threshold should not be interpreted as proof that the groups are identical.

Why does variability matter?

As a general statistical concept, greater variability makes a group mean harder to estimate precisely, all else equal. The posted standard deviations are 9119 for older spine EXPAREL, 3282 for older spine bupivacaine HCl, 7306 for younger spine EXPAREL, and 28040 for younger cardiac EXPAREL. The cardiac group's spread is large relative to its mean, and its confidence interval for the posted contrast is wide. This pattern cautions against treating the point estimate as a precise description of the broader population.

Pharmacokinetic observations can be unevenly distributed, with some values much higher than others. As general statistical context, a mean-based analysis can be sensitive to such values, and normal-approximation methods may be less reliable when samples are very small or distributions depart from model assumptions. The registry record does not report diagnostic checks, transformations, robust methods, or distributional assumptions for the trial's own analysis. The recalculated comparison summaries are unadjusted re-calculations from posted summary statistics, not replacements for a sponsor analysis. The record does not flag a discrepancy between the posted figures and these recalculations.

What is the role of the analysis population?

The pharmacokinetic population was defined as subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received. This definition means that inclusion depended on receiving study drug and having a quantifiable measurement. It is not necessarily identical to the population originally randomized. General statistical interpretation should keep the analysis population in view, because excluding subjects without qualifying measurements can affect how representative the analyzed groups are. The registry does not report the number excluded from pharmacokinetic analysis, reasons for missing or unquantifiable measurements, or a sensitivity analysis addressing those cases.

Overall, the posted calculations use group means and standard deviations to describe exposure and summarize two contrasts. They provide evidence about the observed pharmacokinetic data under the stated population definition, but their uncertainty, group structure, and lack of reported analysis details constrain broader conclusions.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data locate an estimated quantity. The posted confidence interval for the bupivacaine HCl versus older spine EXPAREL contrast extends from -13300 to -3770 ng*h/mL. It lies on one side of zero, but it still covers a range of possible mean differences. The estimate is therefore not exact, even though the interval does not include zero.

For the younger cardiac EXPAREL versus older spine EXPAREL contrast, the 95% confidence interval extends from -879.4 to 24720 ng*h/mL. It includes zero and is broad, encompassing both a modest negative difference and a substantially positive one. The interval indicates that the data do not pin down the contrast precisely. Because the comparison also combines different age and surgery groups, its uncertainty is not the only interpretive limitation.

The confidence intervals are reported for the two listed comparisons, not for every group mean. The registry does not report confidence intervals for the individual group means or the mean in the younger spine EXPAREL group. That group's analysis count is 2, which limits the amount of information available to characterize its mean and variability. The registry record also does not report the interval method or any adjustments for multiple comparisons.

As a general explanation, a confidence interval reflects sampling uncertainty conditional on the statistical method and its assumptions. It does not account automatically for every possible source of bias, missing data, measurement error, or differences between groups. In this study, variation in observed AUC, small analysis groups, and the distinction between surgery types all matter when judging how precisely the posted estimates answer a clinical question.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for 80% power and participants per arm for 90% power. They are not total event counts. The planning illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It uses the observed effect as a reference and considers detecting the full observed effect, 75% of the observed effect, or 50% of the observed effect.

For each effect-size scenario, the 80% power column gives the illustrative number of participants per arm for a design that would have an 80% chance of detecting an effect of that specified size if the assumptions hold and the effect is real. The 90% power column uses a higher chance of detection and therefore calls for more participants per arm than the corresponding 80% planning figure. These are design calculations based on observed estimates, not observed power.

Smaller effects are harder to distinguish from random variation, so planning for 75% or 50% of the observed effect requires more participants per arm than planning for the full observed effect. For the older spine contrast, the figures range from 11 participants per arm for 80% power and 14 for 90% power when planning for the full observed effect, to 42 and 56 when planning for 50% of the observed effect. For the cardiac comparison, the corresponding figures are 54 and 72 for the full observed effect, and 215 and 287 for 50% of the observed effect.

These figures are planning illustrations derived from the observed comparisons. They do not describe the trial's original sample-size rationale. The original design assumptions and justification are not reported in the registry record. Differences between the two sets of planning figures reflect the effect and variability estimates used in each posted comparison; they should not be read as evidence about the study's actual design process.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -8536.700; pooled standard deviation σ = 6943.301.
2. n = 2 × (1.96 + 0.842)² × 6943.301² / -8536.700² = 10.4, rounded up to 11 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -8536.7                      # observed difference in means
sigma <- 6943.30079637647                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(3682302)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 11 (80% power), 14 (90% power)
 75% of observed effect: n per arm = 19 (80% power), 25 (90% power)
 50% of observed effect: n per arm = 42 (80% power), 56 (90% power)
power.t.test: 11.4 
Simulated power at n = 11 per arm: 0.785 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, but it reports no secondary outcome analyses. The primary endpoint has two posted comparisons, and both listed p-values are unadjusted. The registry record does not report a multiplicity strategy, such as whether a particular comparison was designated as the main inferential test or whether any adjustment was planned across outcomes or comparisons.

Multiplicity is a general statistical concern that arises when several hypotheses are tested. As the number of tests grows, the chance of at least one apparently unusual result under a set of null hypotheses can increase. Adjustment procedures or a prespecified testing hierarchy can address this issue, but the registry record does not report whether such approaches were used. The reported unadjusted p-values should therefore be interpreted as applying to the individual comparisons, without assuming control of an overall error rate.

Missing-data handling is also not described in detail. The pharmacokinetic population required receipt of study drug and at least 1 quantifiable plasma concentration, and analysis followed actual treatment received. The registry record does not report how many subjects were excluded from that population, why measurements were unavailable or unquantifiable, how missing time points were handled, or whether sensitivity analyses were performed. It also does not report the methods used to estimate the portion of the AUC extending to infinity.

The registry identifies the study as randomized, but gives no detailed account of allocation or the randomization process. It does not report whether the primary comparisons followed assigned treatment or how deviations from assigned treatment were handled beyond stating that the pharmacokinetic population was analyzed by actual treatment received. The protocol's statistical analysis plan, any interim analyses, and the original sample-size justification are not reported in the registry record. These omissions limit assessment of prespecification, the treatment of incomplete data, and the full inferential context for the posted results.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: dyspnea (3.4%), vomiting (3.4%), wound infection fungal (3.4%).

The registry posts serious adverse event counts separately from other adverse events and deaths for each safety group. The serious-event at-risk counts are 31 for older spine EXPAREL, 30 for older spine bupivacaine HCl, 5 for younger spine EXPAREL, and 29 for younger cardiac EXPAREL. Serious adverse events were reported for 0, 0, 0, and 2 subjects in those groups, respectively. No deaths were reported in the listed groups.

Other adverse events were reported for 19 of 31 at risk in older spine EXPAREL, 22 of 30 in older spine bupivacaine HCl, 5 of 5 in younger spine EXPAREL, and 9 of 29 in younger cardiac EXPAREL. These are counts of subjects with reported events, not measures of event severity or duration. The registry's listed serious-event terms are Dyspnea, Vomiting, and Wound infection fungal, each at 3.4%; the record does not provide further context for those terms in the summary.

As a general caution, safety counts describe events recorded during the study and do not by themselves establish that a drug caused an event or compare risk reliably across groups. Group sizes and clinical settings differ, and the registry record does not report a detailed safety analysis or causal assessment.

15. What the Result Does, and Does Not, Mean

The posted results describe pharmacokinetic exposure after EXPAREL and bupivacaine HCl in pediatric surgical groups, along with reported safety events. In the older spine groups, the posted mean AUC was higher for EXPAREL than for bupivacaine HCl, and the unadjusted confidence interval for their mean contrast did not include zero. This is evidence of a difference in the measured exposure endpoint in that comparison under the posted analysis. A difference in exposure does not by itself establish a difference in analgesia, duration of pain control, or any other clinical outcome.

The younger cardiac EXPAREL group's mean AUC was higher than the older spine EXPAREL reference mean, but its confidence interval included zero and was broad. Since the groups differ in age and surgery, the contrast cannot be interpreted as an isolated age effect, surgery effect, or treatment effect. The younger spine EXPAREL group has a mean based on an analysis count of 2 and no posted comparison, limiting the conclusions that can be drawn about that group.

The registry describes the study as evaluating pharmacokinetics and safety. It does not report a primary endpoint measuring pain relief. Therefore, the posted AUC results should not be taken as proof that EXPAREL improves or fails to improve postoperative pain. Nor do the listed adverse event counts establish that treatment caused or prevented particular events. They are descriptive safety observations in groups with different sizes and clinical contexts.

More broadly, statistical evidence about an endpoint is not the same as clinical importance. A mean difference and p-value do not indicate whether an exposure difference matters to patients, and the registry record does not state a threshold for a clinically meaningful AUC difference. The uncertainty intervals, analysis population, differing group characteristics, and unreported analysis details all constrain interpretation. The results are best understood as a limited description of the posted pharmacokinetic and safety data, not as a stand-alone basis for a treatment decision.

16. Why This Trial Matters Statistically

This study highlights a central issue in clinical biostatistics: the meaning of an estimate depends on the population, outcome, and comparison that generated it. The endpoint is a pharmacokinetic measure of plasma exposure, not a patient-centered pain outcome. Keeping that distinction explicit prevents a statistically detectable exposure contrast from being mistaken for evidence about analgesic benefit.

The group structure also matters. Age range and surgery type define the posted groups, and not every group has a matched comparator. The older spine comparison is more directly aligned by the stated age and surgery category, while the younger cardiac comparison uses an older spine reference. The latter contrast therefore combines clinical differences with the endpoint comparison. This illustrates why interpreting a numerical contrast requires attention to study design, not just its direction or p-value.

Precision is another important lesson. The interval for the cardiac comparison is broad and includes zero, and the younger spine EXPAREL group has an analysis count of 2. A point estimate can look definite while the available data leave substantial uncertainty. Reporting variability and intervals alongside means helps readers see that distinction.

Finally, the registry record does not report multiplicity procedures, detailed missing-data handling, or the original sample-size justification. Such information is important for evaluating how the analyses were planned and how robustly the results address their intended questions. The case demonstrates why a careful reading separates descriptive data, inferential comparisons, and claims about clinical relevance.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations specific to this study constrain interpretation. The primary endpoint is pharmacokinetic exposure, and the registry record does not post a primary clinical pain outcome or secondary outcome analyses. The available results therefore do not answer whether pain relief differed between groups.

The groups vary by age and surgery type. Only the older spine-surgery group includes both EXPAREL and bupivacaine HCl. The younger spine group and younger cardiac group are listed as EXPAREL groups, without a corresponding bupivacaine group in those settings. The posted cardiac comparison uses the older spine EXPAREL group as reference, so differences in age and surgery accompany the comparison. Randomized status is recorded, but allocation details and the relationship of randomization to these groups are not reported.

Analysis counts for the primary endpoint are small in some groups, particularly the younger spine EXPAREL group, whose count is 2. The cardiac EXPAREL group has a large standard deviation relative to its mean. These features limit precision and make it important not to overinterpret group averages. The registry does not report confidence intervals for all group means.

The pharmacokinetic analysis population required study-drug receipt and at least 1 quantifiable plasma concentration. Exclusions, missing measurements, handling of incomplete concentration profiles, and sensitivity analyses are not reported in the registry record. Further, the record does not state the statistical analysis plan, the original sample-size rationale, or any multiplicity approach. Safety group counts differ from the pharmacokinetic analysis counts, and the registry does not explain their reconciliation. These reporting gaps make it difficult to assess the full analysis process or generalize beyond the posted groups.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Multicenter Study for Pediatric Subjects Evaluating Pharmacokinetics and Safety of EXPAREL — NCT03682302.
• Registry record last updated 2021-01-06; status last verified 2020-12.
• Results first posted 2021-01-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

The registry record describes NCT03682302, a completed Phase 3 randomized, open-label, sequential study of EXPAREL pharmacokinetics and safety in pediatric subjects aged 6 to less than 17 years undergoing surgery. Enrollment was 98. The study began on 2019-04-02 and reached primary completion on 2019-08-30.

The primary endpoint was mean AUC from zero to infinity, measured in ng*h/mL. The posted groups included older subjects undergoing spine surgery who received EXPAREL or bupivacaine HCl, younger subjects undergoing spine surgery who received EXPAREL, and younger subjects undergoing cardiac surgery who received EXPAREL. The registry posts two unadjusted mean comparisons and safety counts, but no secondary outcome analyses.

The results describe exposure and recorded adverse events. Interpretation is limited by group differences, small analysis counts in some groups, broad uncertainty in the cardiac comparison, and missing details about multiplicity, missing-data handling, and the original design assumptions.