Bioequivalence of Nomegestrol Acetate (NOMAC) and Estradiol (E2) in Commercial Versus Phase 3 Pivotal Clinical Batches of NOMAC-E2 Tablets (P06328): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bioequivalence of Nomegestrol Acetate (NOMAC) and Estradiol (E2) in Commercial Versus Phase 3 Pivotal Clinical Batches of NOMAC-E2 Tablets (P06328) (NCT01345786), a randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration of NOMAC (Cmax of NOMAC).

2. Clinical Question

3. Trial Design

This was a randomized, open-label, single-dose, four-way, replicate crossover study conducted in two parallel parts at two sites, with one site for each part. It was registered as a Phase 1 trial and is recorded as completed. The reported start was 2009-11 and primary completion was 2010-06.

In a crossover design, participants receive more than one treatment condition at different times, so comparisons can be made within a participant rather than relying only on comparisons between separate groups. The replicate feature indicates that the study included repeated dosing periods for the products. The registry describes sequence-dependent assignment of commercial and Phase 3 batches across Period 1, Period 2, Period 3, and Period 4. Further details about sequence allocation and the interval between doses are not reported in the registry record.

Part 1 compared commercial NOMAC-E2 with Phase 3 Batch A. Part 2 compared commercial NOMAC-E2 with Phase 3 Batch B. Both products were given as a single oral dose of 2.5 mg NOMAC and 1.5 mg E2. The registry describes randomization but no masking; the study was open-label.

Although enrollment was 158, the number of pharmacokinetic profiles used for analysis varied by part and product. The registry notes that profile counts reflect the single-dose administration periods actually completed, because some participants discontinued before completing all four periods. It also notes that Part 1 excluded certain data from participants who were misdosed. The detailed analysis population for each endpoint and the full reasons for exclusions are not reported in the registry record.

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 # of plasma profiles analyzed is based on the # of single-dose administration periods actually completed (some participants discontinued without completing all 4 dosing periods). Part 1 analyses also excluded certain data from participants who were misdosed, and Part 2 analyses excluded participants who did not receive drug.

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.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration of NOMAC (Cmax of NOMAC), measured over 0 hours to time of maximum observed plasma concentration of NOMAC (tmax of NOMAC) (blood samples were collected for NOMAC evaluation up to 144 hours postdose).

The highlighted primary endpoint is maximum observed plasma concentration of NOMAC, commonly abbreviated Cmax. It records the highest measured NOMAC concentration in plasma over the sampling period. Concentration is reported in ng/mL, and the listed timeframe extends from dosing to the time of maximum observed concentration. Blood samples for NOMAC evaluation were collected through 144 hours after dosing.

Cmax is used in pharmacokinetic comparisons because it describes the peak concentration reached after a dose. In a bioequivalence study, peak concentration is considered alongside measures of overall exposure, such as area under the concentration-time curve. The registry’s description says that the primary bioequivalence assessment included Cmax and AUC measures for NOMAC and E2. The posted primary endpoint results summarized in the record concern NOMAC Cmax; numerical results for the other stated primary pharmacokinetic measures are not reported in the registry record.

The registry gives the group means and full ranges for the posted Cmax endpoint, as well as a sponsor-reported ratio and 90% confidence interval for each part’s comparison. These are different summaries: the range describes the spread of observed values within an arm, while the ratio and confidence interval address the relative concentration estimate between products. The registry record does not state the prespecified bioequivalence limits, so the reported intervals alone do not establish whether a formal bioequivalence criterion was met.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a randomized crossover design and sponsor-reported ratio estimates for the primary NOMAC concentration comparison. It does not report the full statistical model, the prespecified bioequivalence limits, or the detailed handling of all analysis populations. The concepts below explain how these kinds of statistics are generally interpreted; they do not assert that a particular unreported method was used.

What does a crossover comparison use?

In general, a crossover study compares treatments within the same participants across separate dosing periods. This can account for stable differences between people, because each participant contributes measurements under more than one product condition. Repeated treatment periods can also help characterize within-person variability. The registry describes four-way replicate crossover dosing, but the full model, period effects, sequence effects, carryover handling, and washout details are not reported in the registry record.

The analysis population for a pharmacokinetic endpoint may be based on completed dosing periods rather than every enrolled participant. That distinction matters in a crossover study: a participant who does not complete all periods may still contribute data for periods completed, depending on the analysis rules. The registry says profile counts were based on single-dose administration periods actually completed and notes some Part 1 misdosing exclusions. Detailed endpoint-specific rules are not reported in the registry record.

What does the ratio estimate mean?

A ratio compares an estimated concentration measure for one product with the corresponding estimate for the other product. It expresses the relative estimate on a common scale. The sponsor-reported results use the label Ratio (Test/Ref %) and give a 90% confidence interval. The registry does not define the test and reference labels in the results description, so the reported ratios are best cited as posted rather than assigned a direction beyond that label.

In general, a confidence interval represents a range of values compatible with the data under the analysis assumptions and method. A narrower interval indicates more precision than a wider interval, but interpretation also depends on the decision limits defined in the protocol. For bioequivalence, the interval is ordinarily judged against prespecified acceptance bounds. Those bounds and the statistical plan are not reported in the registry record. It is therefore not possible to infer the formal decision rule from the ratio and interval alone.

The arm means and full ranges are descriptive summaries, whereas the ratio and its interval are inferential summaries. A full range gives the minimum and maximum observed values in an arm. It does not show the precision of the group mean, and it can be influenced by extreme observations. The ratio analysis may use a model and scale different from the descriptive arithmetic means; the record does not provide enough detail to reconstruct the sponsor’s model from those summaries.

How should recalculated confidence intervals be read?

For the posted secondary clearance and volume measures, the recalculated comparisons use unadjusted mean differences from arm-level summary statistics. These are simple, unadjusted recalculations and do not recreate the crossover model. The mean difference is expressed in the outcome’s original units, and its confidence interval describes uncertainty around that difference under the recalculation’s assumptions.

When a confidence interval for a difference includes zero, the data are compatible with no difference as well as with differences in either direction at the interval’s stated level. When it does not include zero, that is evidence against a zero difference under that calculation, but it does not establish clinical importance or resolve multiplicity. The record’s secondary recalculations are not adjusted for multiple comparisons. They should not be treated as confirmatory findings or as evidence about the primary bioequivalence decision.

An unadjusted p-value describes how unusual data at least as incompatible with a null hypothesis would be under the assumptions of the particular test. It does not measure the probability that the null hypothesis is true, and it does not convey the size or practical importance of an estimate. In this study, the recalculated p-values are unadjusted comparisons based on posted summary statistics, not the sponsor’s reported crossover analysis.

Why does variability matter?

Pharmacokinetic measurements can vary between participants and between dosing periods. Greater variability generally makes estimates less precise unless there is enough information to offset it. The posted Cmax full ranges illustrate that observed concentrations varied within each arm, but range values alone cannot separate between-person variation from within-person variation or identify the source of variability.

General statistical methods sometimes account for over-dispersion, which means the observed variation is greater than a model expects. Allowing for that extra variation can prevent uncertainty from being understated. The registry record does not report whether over-dispersion was assessed or how variability was modeled. A reader should therefore avoid assuming a specific variance structure from the summary statistics alone.

What do planning illustrations mean?

Any sample-size illustrations based on observed effects are planning scenarios, not observed power and not evidence that the trial had a particular chance of detecting an effect. They use assumptions stated with the illustration, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. The trial’s own sample-size justification and design assumptions are not reported in the registry record. Such scenarios can show how required sample size changes when a smaller effect is targeted, but they cannot replace the original protocol’s rationale or establish that a study was adequately powered for its intended bioequivalence question.

10. Analyses Reported by the Sponsor

The sponsor’s reported primary results are the ratio estimates and 90% confidence intervals for NOMAC Cmax in the two part-specific comparisons. These estimates arise from the sponsor’s primary analysis as recorded in the registry. The statistical model and its full assumptions are not reported in the registry record, so the analysis cannot be independently reconstructed from the posted arm summaries alone.

The recalculated results concern secondary clearance and volume measures. They are unadjusted mean-difference calculations from summary statistics, not recalculations of the sponsor’s Cmax ratios. They therefore do not directly confirm, contradict, or replace the sponsor’s primary analysis. The registry does not identify a discrepancy between sponsor-reported and recalculated results.

For interpretation of the primary endpoint, the sponsor’s own analysis takes precedence over a simple calculation from summary data. Even so, the ratio estimates should be considered together with the confidence intervals and the missing protocol details. In particular, the prespecified bioequivalence limits and complete statistical plan are not reported in the registry record. Without those details, the posted numbers can be described precisely, but the formal decision rule cannot be independently evaluated.

11. Multiplicity, Missing Data and Analysis Populations

The registry does not report whether the statistical plan adjusted for multiple testing across the primary pharmacokinetic measures, secondary outcomes, or the two study parts. This matters because the study description names several primary parameters for NOMAC and E2, while the registry also lists secondary pharmacokinetic outcomes. If many comparisons are considered, an unadjusted finding can be less persuasive than a result from a prespecified, multiplicity-controlled analysis.

The reported 90% confidence intervals belong to the sponsor’s primary ratio analyses. The registry record does not report the prespecified equivalence margins or explain how the interval estimates were used to reach the formal bioequivalence decision. It also does not report a complete statistical analysis plan, so the sequence of testing, any hierarchy among outcomes, and the handling of multiplicity cannot be established from the posted information.

Missingness and analysis populations require particular attention in a replicate crossover study. The registry notes that profile counts depend on completed single-dose periods and that some participants discontinued before completing all four dosing periods. It also says Part 1 analyses excluded certain data from misdosed participants. The detailed reasons for discontinuation, number of missing profiles, endpoint-specific inclusion rules, and Part 2 exclusion details are not reported in the registry record.

Those omissions limit assessment of whether missing data could have affected the estimates. In general, incomplete crossover participation may reduce the information available for within-participant comparisons; if missingness is related to treatment, period, or measured concentrations, estimates can also be affected. Whether such mechanisms were present or addressed in this trial is not reported in the registry record.

The registry does not report interim analyses, and no interim-analysis plan should be inferred. The sample-size justification for the original study is also not reported in the registry record. Planning illustrations based on observed effects are separate from the trial’s design rationale and are not observed power.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The registry reports no serious adverse events in the listed safety groups: 0 of 80 participants at risk for commercial NOMAC-E2 in Part 1, 0 of 77 for Phase 3 Batch A in Part 1, 0 of 72 for commercial NOMAC-E2 in Part 2, and 0 of 72 for Phase 3 Batch B in Part 2. These counts describe the groups and events recorded in the registry; they do not establish that serious events are impossible or that the products have equivalent safety.

The numbers at risk for safety reporting are not identical to the pharmacokinetic profile counts, because the safety groups and pharmacokinetic analysis populations are different summaries. The record also lists other adverse events affecting participants in each group. Those events are separate from serious adverse events and should not be conflated with them.

Death counts are not reported in the registry record. The trial involved a single-dose pharmacokinetic assessment in healthy postmenopausal females, so the safety counts should be interpreted within that study setting and exposure design. The registry figures alone do not support broader conclusions about safety in other populations or with different patterns of use.

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

The results describe relative pharmacokinetic measurements after a single dose of the commercial NOMAC-E2 tablet and the corresponding Phase 3 batch. For the posted primary NOMAC Cmax comparisons, the sponsor reported a ratio and 90% confidence interval for each study part. Those estimates quantify the observed concentration comparison and its uncertainty under the sponsor’s analysis.

They do not, by themselves, establish whether the formal bioequivalence criterion was met. A bioequivalence conclusion depends on prespecified margins and a defined analysis plan, neither of which is reported in the registry record. The result also cannot be generalized into a claim about contraceptive effectiveness, long-term use, or clinical outcomes, because this study measured pharmacokinetics after single doses.

The study addressed two distinct batch comparisons rather than a direct comparison between Batch A and Batch B. Differences between the two parts could reflect differences between the batches, the participants or study settings, or other factors; the registry does not report an analysis designed to separate those possibilities. A cross-part contrast should not be interpreted as randomized evidence comparing the Phase 3 batches with each other.

Likewise, the secondary recalculations are not substitutes for the sponsor’s primary analysis. They describe unadjusted mean differences in selected calculated pharmacokinetic measures and do not account for the full crossover structure. Their p-values and intervals should be treated as exploratory, particularly because the multiplicity plan is not reported.

The safety record shows zero serious adverse events in each listed group, with the stated numbers at risk. That is a useful description of what was recorded during the study, but it does not demonstrate absence of risk. Taken together, the posted data provide a bounded account of measured exposure and recorded safety events in this particular trial design; they do not answer broader clinical or long-term questions.

14. Why This Trial Matters Statistically

This trial illustrates a statistical distinction that is central to bioequivalence work: a reported ratio and confidence interval must be interpreted against a prespecified decision margin. The estimate alone is not the decision. When the margin and full analysis plan are unavailable, readers can describe the relative concentration estimate and its precision, but cannot independently verify the formal conclusion.

The replicate crossover design also highlights the importance of analysis populations. Participants may contribute some completed dosing periods without completing every period, and the registry explicitly notes that profile counts were based on completed administrations. That makes the link between enrollment and endpoint-specific sample size important. A single enrollment figure does not describe how much information contributed to each pharmacokinetic comparison.

Comparisons are separated into parts because each part evaluates a different Phase 3 batch against the commercial process. That structure means that the evidence should be read as two batch-specific comparisons, not as one pooled estimate or a direct comparison between the Phase 3 batches. The design and reporting therefore shape the questions that can be answered.

Finally, the secondary calculations show why statistical significance, magnitude, and precision should be considered separately. An unadjusted p-value is not a measure of practical importance, and exploratory results across several outcomes can be difficult to interpret without a stated multiplicity strategy. The registry supports a careful reading of the observed pharmacokinetic summaries while leaving important design and analysis details unresolved.

15. 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.

The registry record does not provide the prespecified bioequivalence limits, complete statistical analysis plan, or full crossover model. It therefore does not allow an independent reconstruction of the sponsor’s primary analysis or evaluation of the exact formal decision rule. The reported ratio estimates remain interpretable as posted, but the underlying model assumptions and testing hierarchy are not reported.

The primary objective describes several pharmacokinetic parameters for NOMAC and E2, but the numerical results available in the registry record do not include all of those stated parameters. The posted primary result is NOMAC Cmax. Results for the other stated primary AUC measures are not reported in the registry record. This limits assessment of the full pharmacokinetic evidence supporting the study objectives.

The two parts compare commercial product with different Phase 3 batches, and each part took place at a separate site. The record does not report a direct randomized comparison of Batch A with Batch B. Accordingly, cross-part differences cannot be attributed solely to batch formulation. Further details about site-level comparability, period effects, washout, and sequence balance are not reported in the registry record.

Some participants did not complete all four dosing periods, and the record notes a misdosing-related exclusion in Part 1. Detailed reasons for discontinuation, endpoint-specific analysis populations, and the handling of incomplete profiles are not reported. This makes it harder to judge how closely the analyzed profiles represent all enrolled participants and whether missingness could have influenced the estimates.

Finally, secondary recalculations use summary statistics and do not reproduce the crossover analysis. They are unadjusted for multiplicity and should be regarded as exploratory. The single-dose pharmacokinetic setting and healthy postmenopausal population also constrain what can be inferred about other populations, repeated use, clinical outcomes, or longer-term safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Bioequivalence of Nomegestrol Acetate (NOMAC) and Estradiol (E2) in Commercial Versus Phase 3 Pivotal Clinical Batches of NOMAC-E2 Tablets (P06328) — NCT01345786.
• Registry record last updated 2022-02-09; status last verified 2022-02.
• Results first posted 2011-08-29.
• 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.

19. Record Summary

NCT01345786 was a completed Phase 1 randomized, open-label, replicate crossover study of commercial NOMAC-E2 and Phase 3 batches A and B. It enrolled 158 healthy postmenopausal females and was conducted in two parts at two sites. Participants received a single oral dose of 2.5 mg NOMAC and 1.5 mg E2.

The primary objective was to assess bioequivalence between the commercial product and the relevant Phase 3 batch in each part. For NOMAC Cmax, the registry reports sponsor-derived ratio estimates with 90% confidence intervals. It also records selected secondary pharmacokinetic results and adverse-event counts. The registry does not report the full analysis plan, equivalence margins, or numerical results for all stated primary parameters.