Trial biostatistics toolkit

SIMBE01 PK and Bioequivalence Results

Synthetic 2x2 crossover worked example: results report

Synthetic data only: simulated for this worked example; not real trial data and not a regulatory deliverable. Every number below is computed by study/run_all.R from code in this repository.

Summary

Bioequivalence of the test tablet (T) to the reference tablet (R) was shown for both primary parameters in 38 participants (bioequivalence set). The ratio of geometric means T/R was 101.07% for Cmax (90% CI 98.89% to 103.30%) and 103.99% for AUC(0-t) (90% CI 98.52% to 109.75%), both within 80.00% to 125.00% (ICH M13A). The supportive AUC(0-inf) ratio was 104.62% (98.63% to 110.97%) in the 37 participants whose AUC(0-inf) met the SAP parameter rules in both periods.

The within-participant CV was 5.6% for Cmax and 14.0% for AUC(0-t), below the 25% assumed in the sample size, so both intervals are narrower than planned. In this simulation Cmax varies little within a participant because the simulator’s occasion-to-occasion variability acts on clearance.

Analysis sets and exclusions

Analysis set Participants
Enrolled (randomized) 40
Safety 40
PK concentration 40
PK parameter 40
Bioequivalence 38
Periods with an exclusion rule triggered or a measurable pre-dose concentration
Participant Period Treatment Pre-dose (% of Cmax) Decision
008 2 Test 2.5 kept (below the 5% rule)
029 2 Test 0.0 emesis within 2 h of dosing

The simulated scenarios and what the SAP rules did with each (read from ADSL and the evaluated exclusion rules):

Documented scenarios (03_adam/sdtm/scenarios.json)
Participant Scenario Period excluded Bioequivalence set
017 withdraws consent after Period 1 (no Period 2 dose) no no
029 vomits 45 minutes after the Period 2 dose emesis within 2 h of dosing no
008 measurable Period 2 pre-dose concentration at 2.5% of that period's Cmax (below the 5% rule) no yes
035 12 h sample in Period 1 not collected no yes
012 4 h sample in Period 1 drawn 25 minutes late no yes
024 6 h sample in Period 2 reported below the LLOQ between quantifiable samples (a simulated sample-handling problem; no reassay) no yes

A withdrawn participant keeps the profiles they have in the PK summaries but has no data for the other product, so leaves the bioequivalence set. A missed sample is omitted and nothing is imputed.

NCA

PKNCA 0.12.1 on actual sampling times (pre-dose samples at time 0), AUC by linear-up/log-down (linear when a concentration is 0), values below the LLOQ set to 0 wherever they fall and left out of the lambda z fit (conc.blq = list(first = "keep", middle = "keep", last = "keep")), lambda z from at least 3 points after tmax chosen by adjusted R-squared. The SAP parameter rules are applied with PKNCA exclude(): AUC(0-inf) is not summarized or analyzed when more than 20% is extrapolated, and lambda z-based parameters when the adjusted R-squared is below 0.90; the values stay in ADPP with NCAEXRSN set.

What the ICH M13A BLQ setting changes: the same NCA with the PKNCA default (a BLQ value between quantifiable samples dropped). Only values that differ are listed.
Participant Period Treatment Parameter BLQ kept as 0 (ICH M13A, used) PKNCA default (BLQ dropped) Difference (%)
024 2 Reference AUCIFO 1443.75 1564.60 -7.7
024 2 Reference AUCLST 1312.11 1432.96 -8.4
ICH M13A acceptability checks (executed)
Check Result Rule Met
Participants with evaluable data for both products (bioequivalence set) 38 of 40 (95.0%) ICH M13A 2.2.3.1: at least 12 yes
Profiles with AUC(0-t)/AUC(0-inf) below 80% 2 of 78 (2.6%) ICH M13A 2.2.2.2: discuss validity if more than 20% of profiles yes
Profiles with fewer than 3 points in the terminal phase 0 of 78 (0.0%) SAP and ICH M13A: at least 3 points yes
Profiles whose AUC(0-inf) is more than 20% extrapolated (AUC(0-inf) not summarized or analyzed) 2 of 78 (2.6%) SAP parameter rule: value kept in ADPP (NCAEXRSN), not summarized yes
Profiles with adjusted R-squared below 0.90 (lambda z-based parameters not summarized or analyzed) 0 of 78 (0.0%) SAP parameter rule: values kept in ADPP (NCAEXRSN), not summarized yes
Profiles with Cmax at the first post-dose sample 2 of 78 (2.6%) ICH M13A 2.1.8.1: discuss robustness; supplementary analysis 2 removes 2 participant(s) of the bioequivalence set yes
Periods excluded for emesis within 2 h of dosing 1 of 79 (1.3%) SAP rule: documented before bioanalysis (ICH M13A 2.2.1) yes
Periods excluded for a pre-dose concentration above 5% of Cmax 0 of 79 (0.0%) ICH M13A 2.2.3.3: exclude the period (applied to the bioanalytical results) yes
Periods with AUC(0-t) below 5% of the product geometric mean (without the participant) 0 of 79 (0.0%) ICH M13A 2.2.1.1: may exclude, at most 1 participant (applied to the bioanalytical results) yes

Concentrations

Mean (SD) plasma concentrations of the test and reference products against nominal time after dose, 0 to 48 hours, on a linear scale. Synthetic data.

Mean concentrations (linear), nominal times

The same mean concentration profiles of the test and reference products on a semi-log scale against nominal time. Synthetic data.

Mean concentrations (semi-log), nominal times

Each participant's concentration profile for the test and reference products on a semi-log scale against actual sampling time. Synthetic data.

Individual concentrations (semi-log), actual times

Table 14.4.1.1 Summary of Plasma SIMDRUG Concentrations (ng/mL) by Nominal Time

PK concentration set

Study SIMBE01 (synthetic)

Test Reference
(N=39) (N=39)
Nominal time (h)
0 (pre-dose)
n (n BLQ) 39 (38) 39 (39)
Mean (SD) 0.05 (0.29) 0.00 (0.00)
CV% 624.5 NE
Median 0.00 0.00
Min - Max 0.00 - 1.84 0.00 - 0.00
0.25
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 73.58 (35.52) 72.76 (35.81)
CV% 48.3 49.2
Median 66.30 63.80
Min - Max 20.90 - 180.00 16.10 - 177.00
0.5
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 94.93 (41.29) 93.58 (40.79)
CV% 43.5 43.6
Median 83.10 87.20
Min - Max 30.90 - 211.00 27.50 - 217.00
1
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 101.25 (37.23) 100.62 (37.04)
CV% 36.8 36.8
Median 86.30 92.80
Min - Max 40.40 - 205.00 39.60 - 198.00
1.5
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 97.33 (33.41) 99.15 (34.17)
CV% 34.3 34.5
Median 90.60 94.10
Min - Max 45.70 - 194.00 40.40 - 183.00
2
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 96.10 (31.80) 97.00 (36.28)
CV% 33.1 37.4
Median 92.60 89.90
Min - Max 46.70 - 178.00 45.20 - 212.00
3
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 85.46 (24.31) 82.97 (25.95)
CV% 28.4 31.3
Median 83.10 80.10
Min - Max 44.90 - 152.00 42.50 - 176.00
4
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 77.39 (21.94) 76.45 (22.61)
CV% 28.3 29.6
Median 74.10 73.60
Min - Max 44.70 - 141.00 42.00 - 156.00
6
n (n BLQ) 39 (0) 39 (1)
Mean (SD) 63.49 (16.59) 61.00 (21.01)
CV% 26.1 34.4
Median 63.60 59.40
Min - Max 37.40 - 113.00 0.00 - 138.00
8
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 52.42 (17.22) 51.84 (16.50)
CV% 32.8 31.8
Median 47.00 48.40
Min - Max 29.20 - 104.00 28.80 - 116.00
12
n (n BLQ) 38 (0) 39 (0)
Mean (SD) 36.56 (12.98) 36.75 (16.48)
CV% 35.5 44.8
Median 36.35 34.50
Min - Max 16.10 - 60.70 11.30 - 96.40
16
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 27.93 (13.47) 27.29 (13.49)
CV% 48.2 49.4
Median 24.60 28.00
Min - Max 7.08 - 52.40 4.51 - 62.40
24
n (n BLQ) 39 (0) 39 (0)
Mean (SD) 15.06 (10.05) 14.42 (9.90)
CV% 66.7 68.7
Median 13.10 13.60
Min - Max 1.00 - 37.90 0.57 - 39.00
36
n (n BLQ) 39 (5) 39 (6)
Mean (SD) 6.90 (6.41) 6.54 (5.93)
CV% 92.9 90.8
Median 5.29 4.90
Min - Max 0.00 - 25.40 0.00 - 25.50
48
n (n BLQ) 39 (11) 39 (12)
Mean (SD) 3.45 (4.11) 3.17 (3.90)
CV% 119.1 123.0
Median 1.87 2.12
Min - Max 0.00 - 16.00 0.00 - 19.50

BLQ (below 0.50 ng/mL) set to 0 (ICH M13A); n BLQ in parentheses. NE = not estimable.

Periods excluded under the SAP rules are not summarized (ADPC.ANL02FL).

Synthetic data; not a regulatory deliverable.


Program: study/04_analysis/03_tlf.R; data cut-off 2026-05-29 (synthetic).

PK parameters

Table 14.4.4.1 Summary of Plasma SIMDRUG PK Parameters

PK parameter set

Study SIMBE01 (synthetic)

Test Reference
(N=39) (N=39)
Maximum concentration (Cmax) (ng/mL)
n 39 39
Mean (SD) 108.8 (39.4) 107.6 (39.7)
CV% 36.3 36.9
Geometric mean 102.4 101.2
Geometric CV% 36.1 36.2
Median 94.1 101.0
Min - Max 49.2 - 211.0 46.4 - 217.0
AUC to last quantifiable conc, AUC(0-t) (h*ng/mL)
n 39 39
Mean (SD) 1261.7 (405.1) 1234.0 (414.9)
CV% 32.1 33.6
Geometric mean 1199.1 1172.4
Geometric CV% 33.5 33.2
Median 1188.4 1156.7
Min - Max 653.6 - 2111.8 609.0 - 2774.5
AUC to infinity, AUC(0-inf) (h*ng/mL)
n 38 38
Mean (SD) 1313.7 (457.7) 1268.1 (437.7)
CV% 34.8 34.5
Geometric mean 1238.7 1200.8
Geometric CV% 36.0 34.4
Median 1205.2 1177.5
Min - Max 662.0 - 2319.5 617.0 - 2838.2
AUC(0-inf) extrapolated (%)
n 39 39
Mean (SD) 4.50 (5.57) 4.15 (5.55)
CV% 123.8 133.9
Geometric mean 2.48 2.23
Geometric CV% 154.2 164.6
Median 2.35 2.07
Min - Max 0.39 - 25.85 0.23 - 30.82
Terminal half-life, t1/2 (h)
n 39 39
Mean (SD) 9.37 (4.83) 8.95 (4.91)
CV% 51.5 54.9
Geometric mean 8.28 7.85
Geometric CV% 54.5 56.1
Median 8.84 8.28
Min - Max 2.92 - 25.28 2.73 - 29.03
Terminal rate constant, lambda z (1/h)
n 39 39
Mean (SD) 0.0951 (0.0509) 0.1010 (0.0557)
CV% 53.5 55.1
Geometric mean 0.0837 0.0883
Geometric CV% 54.5 56.1
Median 0.0784 0.0837
Min - Max 0.0274 - 0.2378 0.0239 - 0.2535
Time of Cmax, tmax (h)
n 39 39
Median 1.05 1.03
Min - Max 0.25 - 4.17 0.27 - 2.05

NCA with PKNCA 0.12.1 on actual sampling times; AUC by linear-up/log-down; BLQ = 0 and omitted from lambda z (ICH M13A).

Geometric mean = exp(mean(log x)); geometric CV% = 100*sqrt(exp(s^2) - 1) on the log scale.

Periods excluded under the SAP rules are not summarized (ADPP.ANL01FL).

AUC(0-inf) is not summarized when more than 20% is extrapolated (2 profiles); lambda z-based parameters are not summarized when the adjusted R-squared is below 0.90 (0 profiles). Values kept in ADPP (NCAEXRSN).

Synthetic data; not a regulatory deliverable.


Program: study/04_analysis/03_tlf.R; data cut-off 2026-05-29 (synthetic).

Bioequivalence

Table 14.4.3.1 Bioequivalence Analysis: Ratio of Geometric Means (Test/Reference) and 90% CI

Bioequivalence set

Study SIMBE01 (synthetic)

n Adjusted geometric mean, Test Adjusted geometric mean, Reference Ratio T/R (%) 90% CI (%) Within-participant CV% Within 80.00 to 125.00%
Cmax (ng/mL) 38 103.3 102.2 101.07 98.89, 103.30 5.6 Yes
AUC(0-t) (h*ng/mL) 38 1204.9 1158.7 103.99 98.52, 109.75 14.0 Yes
AUC(0-inf) (h*ng/mL), supportive 37 1243.3 1188.4 104.62 98.63, 110.97 15.1 Yes

General linear model on ln(parameter): sequence, participant(sequence), period, formulation (fixed effects; ICH M13A).

Adjusted geometric mean = exp(least-squares mean). Ratio and 90% CI back-transformed from the T - R difference; decision on unrounded limits.

Within-participant CV% = 100*sqrt(exp(MSE) - 1).

AUC(0-inf): participants whose AUC(0-inf) passes the SAP parameter rules (at most 20% extrapolated, adjusted R-squared at least 0.90) in both periods.

Synthetic data; not a regulatory deliverable.


Program: study/04_analysis/02_be.R and 03_tlf.R; data cut-off 2026-05-29 (synthetic).

Table 14.4.3.2 ANOVA Effects for ln(Cmax) and ln(AUC(0-t))

Bioequivalence set

Study SIMBE01 (synthetic)

DF Sum of squares Mean square F Error term p-value
ln(Cmax): Sequence 1 0.0058 0.0058 0.02 Participant(sequence) 0.8797
ln(Cmax): Participant(sequence) 36 8.9749 0.2493 78.49 Residual <0.0001
ln(Cmax): Period 1 0.0064 0.0064 2.00 Residual 0.1657
ln(Cmax): Formulation 1 0.0022 0.0022 0.68 Residual 0.4156
ln(Cmax): Residual 36 0.1143 0.0032
ln(AUC(0-t)): Sequence 1 0.0656 0.0656 0.34 Participant(sequence) 0.5651
ln(AUC(0-t)): Participant(sequence) 36 7.0093 0.1947 10.02 Residual <0.0001
ln(AUC(0-t)): Period 1 0.0040 0.0040 0.21 Residual 0.6526
ln(AUC(0-t)): Formulation 1 0.0290 0.0290 1.49 Residual 0.2295
ln(AUC(0-t)): Residual 36 0.6993 0.0194

Sequence is tested against participant(sequence); the other effects against the residual mean square.

Sequence and participant(sequence) sums of squares are sequential; period and formulation are adjusted for all other terms.

No test for carry-over (ICH M13A).

Synthetic data; not a regulatory deliverable.


Program: study/04_analysis/02_be.R and 03_tlf.R; data cut-off 2026-05-29 (synthetic).

Profiles with Cmax at the first post-dose sample (ICH M13A 2.1.8.1): the true Cmax may have come earlier
Participant Period Treatment First post-dose sample, nominal (h) tmax, actual (h) Bioequivalence set
013 1 Reference 0.25 0.267 yes
030 1 Test 0.25 0.250 yes
Supplementary analyses: (1) excluded periods put back for participants with both periods; (2) the bioequivalence set without the participants with Cmax at the first post-dose sample
Analysis Parameter n Ratio T/R (%) 90% CI (%) Within limits
Excluded periods put back Cmax 39 99.46 96.03, 103.00 Yes
Excluded periods put back AUC(0-t) 39 102.48 96.67, 108.63 Yes
Excluded periods put back AUC(0-inf) 37 104.62 98.63, 110.97 Yes
Without participants with Cmax at the first post-dose sample (ICH M13A 2.1.8.1) Cmax 36 100.57 98.40, 102.80 Yes
Without participants with Cmax at the first post-dose sample (ICH M13A 2.1.8.1) AUC(0-t) 36 103.35 97.74, 109.28 Yes
Without participants with Cmax at the first post-dose sample (ICH M13A 2.1.8.1) AUC(0-inf) 35 103.95 97.79, 110.50 Yes

Safety

Table 14.1.2 Demographic and Baseline Characteristics

Safety set

Study SIMBE01 (synthetic)

TR RT Total
(N=20) (N=20) (N=40)
Age (years)
n 20 20 40
Mean (SD) 43.8 (7.6) 43.8 (7.6) 43.8 (7.5)
Median 44.5 43.0 44.0
Min - Max 32.0 - 59.0 34.0 - 58.0 32.0 - 59.0
Height (cm)
n 20 20 40
Mean (SD) 168.3 (9.6) 172.3 (7.6) 170.3 (8.8)
Median 166.7 174.8 171.9
Min - Max 151.9 - 186.5 156.7 - 182.1 151.9 - 186.5
Weight (kg)
n 20 20 40
Mean (SD) 72.3 (15.0) 73.2 (12.1) 72.7 (13.5)
Median 68.2 74.7 71.6
Min - Max 51.3 - 106.6 54.3 - 92.7 51.3 - 106.6
BMI (kg/m2)
n 20 20 40
Mean (SD) 25.7 (5.7) 24.8 (4.9) 25.2 (5.2)
Median 24.6 24.0 24.6
Min - Max 18.0 - 35.4 18.9 - 36.2 18.0 - 36.2
Sex, n (%)
n 20 20 40
Female 12 (60.0%) 9 (45.0%) 21 (52.5%)
Male 8 (40.0%) 11 (55.0%) 19 (47.5%)
Race, n (%)
n 20 20 40
Asian 1 (5.0%) 4 (20.0%) 5 (12.5%)
Black or African American 7 (35.0%) 4 (20.0%) 11 (27.5%)
Multiple 1 (5.0%) 0 (0.0%) 1 (2.5%)
White 11 (55.0%) 12 (60.0%) 23 (57.5%)
Ethnicity, n (%)
n 20 20 40
Hispanic or Latino 5 (25.0%) 2 (10.0%) 7 (17.5%)
Not Hispanic or Latino 15 (75.0%) 18 (90.0%) 33 (82.5%)
Not reported 0 (0.0%) 0 (0.0%) 0 (0.0%)

Percentages use the number of participants in the column.

Synthetic data; not a regulatory deliverable.


Program: study/04_analysis/03_tlf.R; data cut-off 2026-05-29 (synthetic).

Table 14.3.1.1 Overview of Treatment-Emergent Adverse Events

Safety set

Study SIMBE01 (synthetic)

Test Reference
(N=40) (N=39)
Participants with at least one TEAE 9 (22.5%) 10 (25.6%)
Total number of TEAEs 13 19
Participants with a related TEAE 8 (20.0%) 6 (15.4%)
Participants with a severe TEAE 0 1 (2.6%)
Participants with a serious TEAE 0 0
Participants with a TEAE leading to withdrawal 0 0
Participants with a TEAE leading to death 0 0

TEAE = adverse event with onset on or after the first dose, assigned to the treatment taken most recently before onset.

Each participant counts once per row; N = participants dosed with that treatment.

No total column: in a crossover a participant contributes to both columns. MedDRA v28.1 (synthetic coding).

Synthetic data; not a regulatory deliverable.


Program: study/04_analysis/03_tlf.R; data cut-off 2026-05-29 (synthetic).

What this report is and is not

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