Multi-centre Study to Compare Efficacy and Safety of AFOLIA and Gonal-f in Women for Assisted Reproductive Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Multi-centre Study to Compare Efficacy and Safety of AFOLIA and Gonal-f in Women for Assisted Reproductive Treatment (NCT01121666), a randomized phase 3 study. The primary outcome is Number of Oocytes Retrieved (Per Protocol Population).

2. Clinical Question

The clinical question is framed around an outcome of ovarian stimulation: the count of oocytes retrieved after treatment and ovulation triggering. The trial sought to compare two formulations, with equivalence—not superiority of one formulation over the other—as the stated primary objective. The registry’s description says treatment was to stop if criteria for ovulation triggering could not be reached by stimulation on day 16. This gives context for the endpoint’s timing, but does not establish how many participants stopped treatment or how they were handled in the analysis.

The comparison is based on women receiving assisted reproductive treatment, but the registry record does not report further details about age, infertility diagnosis, prior treatment, or other eligibility characteristics. Those details would help assess how closely the analyzed population matches a particular clinical setting. The primary endpoint is explicitly identified as belonging to the per protocol population, so the reported summary does not by itself describe every enrolled participant or every participant treated.

3. Trial Design

The registry record describes a Phase III, randomized, assessor-blinded, parallel-group, multicentre study of AFOLIA and Gonal-f in women undergoing assisted reproductive treatment. Its status is completed. The record lists enrollment as 460 and gives the study start as 2010-06 and primary completion as 2011-12. These record-level details describe the trial’s planned and administrative framework; they do not establish how many participants contributed to each endpoint analysis.

The two arms are AFOLIA-150 (follitropin alfa) and Gonal-f® (follitropin alfa). Both are described as formulations of r-hFSH. Random allocation is intended to create groups that are comparable on average at the start of a study, while a parallel design means participants remain assigned to one study arm rather than crossing over between treatments. Assessor blinding means outcome assessment was intended to be masked; the registry lists masking as single. Further details about who was masked and how masking was maintained are not reported in the registry record.

The primary endpoint is the number of oocytes retrieved, analyzed in the per protocol population. The registry’s endpoint description places retrieval 34-36 hours after hCG administration and after a maximum of 16 days of r-hFSH treatment. It states that the equivalence test used a predetermined margin of +/- 2.9 oocytes. The specific original sample-size assumptions, including the effect and variability anticipated when the trial was designed, are not reported in the registry record. The planning illustrations associated with the posted data are not a substitute for those original design assumptions.

The registry lists 23 outcome measures and 7 analyses. It also lists secondary outcomes concerning follicles, hormone concentrations, stimulation dose and duration, oocyte and embryo characteristics, fertilisation, and cryopreserved material. The detail available for those outcomes varies. The record does not report a complete statistical analysis plan, the planned handling of missing outcomes, or the rationale for the choice of the per protocol population for the primary endpoint. These gaps limit reconstruction of the full design and analysis decisions from the registry record alone.

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.

Before assignment: Of 460 participants in this trial 88 were reported as screening failures prior the group assignment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per protocol population

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 Number of Oocytes Retrieved (Per Protocol Population), measured over 34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment.

The primary endpoint is the number of oocytes retrieved per participant in the per protocol population. The registry describes retrieval after hCG was administered to trigger ovulation, at 34-36 hours after administration and after a maximum of 16 days of r-hFSH treatment. If ovulation-triggering criteria could not be reached by day 16 of stimulation, treatment was to be stopped.

Oocyte count is used in this trial as a measure of the ovarian response to stimulation. It is a count outcome, but the registry reports it using means and standard deviations. The central study question was whether the two formulations produced sufficiently similar mean counts under the trial’s definition of equivalence. The registry states that the prespecified clinical equivalence margin was +/- 2.9 oocytes. In general, an equivalence margin sets the largest difference considered clinically acceptable for the question being tested; the margin needs to be chosen before results are known to provide a meaningful reference for interpreting uncertainty.

Interpretation depends not only on the observed average in each arm, but also on the analysis population, variability, and the equivalence test. A mean comparison can describe the group-level contrast, while an equivalence analysis asks whether the uncertainty around that contrast is sufficiently contained within the prespecified acceptable range. The endpoint summary does not describe the full distribution of oocyte counts, and a group mean cannot show how responses varied among individual participants. Details about how missing or unusable endpoint measurements were handled are not reported in the registry record.

7. Results Posted in the Registry

• Gonal-f® (Follitropin Alfa): mean 10.60 versus 10.80 on control; difference -0.20 (95% CI -1.51 to 1.11), standardized effect d = -0.04; z-test p = 0.764.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Total Dose of r-hFSH Administered

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Gonal-f® (Follitropin Alfa): mean 1,569 versus 1,556 on control; difference 13.50 (95% CI -45.00 to 72.00), standardized effect d = 0.05; z-test p = 0.651.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Gonal-f® (Follitropin Alfa) and the control. The interval gives the range of effects that remain compatible with the data.

Fertilisation Rate of Oocytes

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Gonal-f® (Follitropin Alfa): mean 64.00 versus 66.10 on control; difference -2.10 (95% CI -7.45 to 3.25), standardized effect d = -0.08; z-test p = 0.442.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Gonal-f® (Follitropin Alfa) and the control. The interval gives the range of effects that remain compatible with the data.

Embryo Quality: Mean Number of Blastomeres

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Gonal-f® (Follitropin Alfa): mean 6.40 versus 6.60 on control; difference -0.20 (95% CI -0.73 to 0.33), standardized effect d = -0.08; z-test p = 0.461.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Gonal-f® (Follitropin Alfa) and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes span measures of stimulation, hormone response, oocytes, fertilisation, and embryo development. The available numerical summaries cover total r-hFSH dose, fertilisation rate, and mean number of blastomeres, among the secondary outcomes listed in the record. Across these posted continuous outcomes, the recalculated mean contrasts are small relative to their reported uncertainty, and the reported confidence intervals include zero. This is a broad pattern in the posted summaries, not evidence that every secondary endpoint is equivalent or that all clinically relevant differences have been ruled out.

These measures complement the primary endpoint by describing other aspects of the treatment process and laboratory outcomes. They do not replace the primary question about the number of retrieved oocytes, and they do not independently establish the sponsor’s primary equivalence conclusion. Secondary results may help describe whether the primary finding appears alongside differences in stimulation requirements or subsequent measures, but their interpretation depends on the endpoint definitions, analysis populations, and statistical methods used.

The record lists 23 outcome measures and 7 analyses, while 21 secondary outcomes are posted. Testing many outcomes creates more opportunities for apparently notable results to occur by chance. Unless the analysis accounts for multiplicity, individual unadjusted p-values do not preserve a single overall error rate across all outcomes. A multiplicity adjustment or a prespecified hierarchy could address this concern, but such a plan is not reported in the registry record. Consequently, secondary findings generally carry less confirmatory weight than a prespecified primary analysis and should be treated as supportive or exploratory rather than as a collection of independent definitive tests.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number and Size of Follicles ≥ 12 mm at Day 8 of Stimulation
• E2 Concentration at Day 8 and at Day of hCG Administration
• Total Dose of r-hFSH Administered
• Quality of Oocytes Retrieved
• Fertilisation Rate of Oocytes
• Embryo Quality: Mean Number of Blastomeres
• Number of Participants With Cryopreserved 2PNs, Embryos/Blastocysts
• Number of Days of r-hFSH Stimulation

9. Statistical Interpretation

10. Statistical Methods Explained

The registry identifies the primary analysis as an equivalence question and reports the sponsor’s method as Shuirmann's TOST. The posted recalculation uses a difference between group means and an unadjusted confidence interval. These methods are related to the same endpoint but answer different statistical questions. Because the registry flags a discrepancy, the sponsor’s own analysis takes precedence when describing the trial’s reported equivalence result; the recalculation is best treated as a separate descriptive check based on posted summary statistics.

What does a mean difference describe?

A mean is the arithmetic average of the measured endpoint in a group. The reported primary means are 10.8 oocytes for AFOLIA-150 and 10.6 for Gonal-f®. The recalculated contrast is defined as the Gonal-f® mean minus the AFOLIA-150 mean, giving -0.2. The negative sign indicates that the Gonal-f® mean is lower under that stated subtraction order. The sign depends on which group is subtracted from which; it does not by itself indicate clinical importance or establish a treatment advantage.

A standard deviation describes how spread out individual observations are around a group mean. The reported standard deviations, 5.11 and 6.06, describe participant-level variability in the two groups. They are not confidence intervals for the means. A confidence interval for a difference instead reflects uncertainty about the group contrast, taking account of the observed variation and the amount of information contributing to the estimate.

What does the recalculated confidence interval mean?

The recalculated 95% confidence interval for the mean difference is -1.506 to 1.106. In general, a confidence interval is a range of values compatible with the data and the method used to construct it. Its endpoints are not guaranteed bounds on the true effect, and the interval does not assign a probability to each possible value after the data have been observed. The stated confidence level describes the long-run performance of the method under its assumptions.

Here, the interval includes zero, which is consistent with the unadjusted p-value of 0.764 for a conventional difference test. That test addresses whether the means differ, not whether the formulations are equivalent. The trial’s stated margin of +/- 2.9 oocytes supplies the separate clinical limits for the equivalence question. The recalculated interval is within those limits, but it remains a recalculation rather than the sponsor’s reported test.

How does an equivalence test differ?

Two one-sided tests, often abbreviated TOST, assess whether a treatment contrast is above the lower equivalence boundary and below the upper boundary. In general, both one-sided conditions must be supported to conclude equivalence under the chosen procedure. This differs from a conventional test whose null hypothesis is no difference. A conventional test that fails to detect a difference does not establish that any possible difference is small enough to be acceptable. Equivalence testing directly uses the prespecified margin to define what counts as sufficiently similar.

The registry reports a TOST p-value of < 0.001, but does not report the test’s confidence interval or all calculation details. The recalculated interval and p-value come from an unadjusted comparison of the posted means and standard deviations. They should not be treated as though they reproduce every element of the sponsor’s equivalence analysis. The discrepancy flag makes that distinction especially important.

What assumptions matter for the recalculation?

The posted recalculation is based on summary statistics and is described as unadjusted. In general, a mean-based comparison summarizes the contrast on the original outcome scale and relies on assumptions about how uncertainty is estimated. The registry’s reported summaries do not give individual participant data, so distributional features such as skewness, unusual values, or the frequency of particular counts cannot be checked from these means and standard deviations alone. The recalculation is not a substitute for a full analysis using the trial data and its prespecified methods.

In general, over-dispersion occurs when outcome variation is greater than a model assumes. For count outcomes, this can make a simple model’s uncertainty estimate too small if the model does not accommodate the extra variability. The primary endpoint is reported as a mean and standard deviation, but the registry record does not report a count-model analysis or a specific assessment of over-dispersion. It would therefore be inappropriate to claim that a particular model was used or that this issue changed the trial result.

Why does the analysis population matter?

The primary endpoint is explicitly assigned to the per protocol population. In general, a per protocol analysis focuses on participants who meet specified requirements for following the study protocol. For an equivalence question, exclusions or deviations can matter because they may make groups appear more similar; this is a general methodological concern, not a finding about this trial. The registry does not provide the detailed per protocol rules or a corresponding intention-to-treat result, so the effect of analysis-population choices cannot be evaluated from the record.

The registry also does not report details of missing-data handling, the exact statistical model behind the sponsor’s test, or a complete analysis plan. These omissions constrain independent verification. The results should therefore be described at the level the record supports: the posted group summaries, the recalculated unadjusted contrast and interval, and the sponsor’s reported TOST result.

11. Confidence Intervals and Precision

The recalculated 95% confidence interval for the primary mean difference, defined as Gonal-f® minus AFOLIA-150, runs from -1.506 to 1.106 oocytes. It includes zero, indicating that the recalculation does not isolate a single direction of difference with conventional statistical confidence. The interval also lies within the registry’s stated equivalence margin of +/- 2.9 oocytes. This comparison of interval limits with the margin is informative about the recalculation, but it does not replace the sponsor’s own equivalence analysis.

Precision concerns how narrowly an estimate is bounded by uncertainty. A narrow interval gives more precise information about the possible size of a contrast, while a wider interval leaves a broader range of values compatible with the data. The interval must be interpreted against the question being asked: whether there is a difference, whether the difference is clinically acceptable, or whether equivalence has been established by the planned test. Those interpretations are not interchangeable.

The means are close, but closeness of point estimates alone does not establish precision or equivalence. Variation in the outcome, the analysis population, and the statistical method all contribute to uncertainty. The primary summaries report standard deviations of 5.11 and 6.06. The record does not provide the sponsor’s equivalence confidence interval or enough detail to reproduce its analysis. The interval reported for the recalculation should therefore be attributed to that unadjusted calculation, not presented as the sponsor’s interval.

The registry’s TOST p-value is < 0.001. A p-value is not a measure of the size of an effect or the probability that a result is true. It describes how incompatible the observed data are with a specified null hypothesis under the method’s assumptions. Since the registry does not provide the sponsor’s full test output, precision for the sponsor’s analysis cannot be assessed as fully as for the recalculated contrast.

12. 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 sample-size figures are planning illustrations for a future study based on the observed effect, not the trial’s original design justification. They are stated as participants per arm for 80% power and participants per arm for 90% power. The assumptions listed are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The trial’s own original design assumptions are not reported in the registry record.

The rows describe planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For the primary endpoint, the corresponding figures for 80% power are 11,657, 20,723, and 46,627 participants per arm; the figures for 90% power are 15,605, 27,743, and 62,420 participants per arm. Smaller effects are harder to distinguish from random variation, so detecting a smaller effect under the same planning assumptions requires more participants. The increase from the 80% column to the 90% column reflects a higher target probability of detecting the specified effect under the assumptions.

Power is a design property: it is the probability that a planned analysis will detect a specified effect if that effect is present and the assumptions hold. These calculated figures are not observed power for the completed trial. They should not be read as evidence that the completed study was underpowered or that its original design used these assumptions. The curve presents the same general planning relationship visually; it is a planning aid, not a result from participants in the trial.

13. 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 = -0.200; pooled standard deviation σ = 5.450.
2. n = 2 × (1.96 + 0.842)² × 5.450² / -0.200² = 11,656.6, rounded up to 11,657 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 <- -0.200000000000001                      # observed difference in means
sigma <- 5.4500181822918                     # 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(1121666)
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 = 11,657 (80% power), 15,605 (90% power)
 75% of observed effect: n per arm = 20,723 (80% power), 27,743 (90% power)
 50% of observed effect: n per arm = 46,627 (80% power), 62,420 (90% power)
power.t.test: 11657.6 
Simulated power at n = 11,657 per arm: 0.797 (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.

14. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary equivalence analysis as Shuirmann's TOST, with p < 0.001. The trial’s stated equivalence margin is +/- 2.9 oocytes. This is the result to cite when describing the sponsor’s own analysis. The registry does not provide a numerical confidence interval or the full details of the sponsor’s calculation, so the analysis cannot be reconstructed completely from the posted record.

The recalculation uses the posted means and standard deviations to form an unadjusted mean difference and confidence interval. It reports a difference of -0.2 oocytes, a 95% confidence interval from -1.506 to 1.106, and p = 0.764. That conventional test asks about evidence of a mean difference; it is not the same procedure as the sponsor’s equivalence test. Although the recalculated interval falls within the stated margin, it should not be substituted for the sponsor’s test or treated as an independent confirmation of every feature of the sponsor’s analysis.

The registry marks a discrepancy between the sponsor analysis and the recalculation. In that situation, the sponsor’s own analysis takes precedence for the trial’s reported result. The recalculation remains useful as a transparent, unadjusted check on the posted summary statistics, with its assumptions and limits kept explicit. Neither result should be described as a treatment recommendation.

15. Multiplicity, Missing Data and Analysis Populations

The record lists 23 outcome measures and 7 analyses, and it identifies a primary endpoint plus a range of secondary outcomes. It does not report a multiplicity strategy, such as an adjustment of significance thresholds or a testing hierarchy for the outcomes. When several hypotheses are tested, the chance of at least one apparently positive result can increase. In general, multiplicity procedures control or manage that risk, but without a reported plan it is not possible to determine how the secondary findings were intended to be interpreted collectively.

The primary equivalence question has a prespecified margin of +/- 2.9 oocytes and a sponsor-reported TOST analysis. That does not establish how the sponsor handled multiplicity across secondary outcomes or other analyses. The registry does not report whether the secondary hypotheses were confirmatory, exploratory, or arranged in a formal sequence. Unadjusted secondary results therefore warrant cautious interpretation, especially when viewed individually.

The primary analysis population is the per protocol population. The registry does not report detailed inclusion and exclusion rules for that population or provide a parallel primary result for another analysis population. It also does not report how missing primary or secondary measurements were handled, whether any imputation was used, or whether sensitivity analyses assessed the effect of missing data. These are important details because the population analyzed and the treatment of missing outcomes can affect both the estimate and its uncertainty.

Although the registry gives enrollment as 460, that figure should not be treated as the number contributing to every analysis. The primary arm summaries are reported for the per protocol population, while secondary outcomes have their own reported arm counts. The registry record does not explain all differences among those analysis counts or link each count to a detailed participant flow. A full assessment of exclusions, protocol deviations, missingness, and analysis-population consistency is therefore not possible from the reported information.

16. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ovarian hyperstimulation syndrome (2.8%), syncope (0.8%), abdominal pain (0.8%), biliary colic (0.4%), ovarian haemorrhage (0.4%).

The registry lists serious adverse events among 249 participants at risk in the AFOLIA-150 group, with 12 affected, and among 123 participants at risk in the Gonal-f® group, with 3 affected. These are the registry’s group counts; they should be read in the context of the listed at-risk denominators and not treated as a randomized comparison adjusted for differences in participant characteristics or exposure. The record does not provide further detail about event timing, duration, relatedness, or individual-level overlap among events.

The serious-event terms listed include ovarian hyperstimulation syndrome at 2.8%, syncope at 0.8%, abdominal pain at 0.8%, biliary colic at 0.4%, ovarian haemorrhage at 0.4%, and body temparature increased at 0.4%. These are reported term-specific percentages, not a complete description of all safety outcomes. The record does not report deaths in the displayed safety information. General adverse-event counts are also listed, but an event count does not by itself indicate severity, causal relationship, or comparative risk.

Safety summaries are descriptive. The information reported does not establish that one formulation is safer than the other, nor does it exclude uncommon harms. Interpretation would require the study’s event definitions, follow-up, exposure information, and detailed safety analysis, some of which are not reported in the registry record.

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

The primary result addresses a specific statistical question: whether the number of oocytes retrieved differed between AFOLIA-150 and Gonal-f® in the per protocol population, and whether the formulations met the trial’s stated equivalence criterion. The registry reports a sponsor TOST p-value of < 0.001 and an equivalence margin of +/- 2.9 oocytes. The unadjusted recalculation gives a mean difference of -0.2 oocytes with a 95% confidence interval from -1.506 to 1.106. Because the registry flags a discrepancy, the sponsor’s own analysis takes precedence when describing the trial’s reported equivalence result.

These results do not establish that the formulations are identical. Equivalence is defined in relation to a prespecified margin and statistical procedure, and the sponsor’s full numerical output is not reported in the registry record. The result also does not establish that either formulation is superior. A conventional test that does not identify a difference and an equivalence test are not interchangeable, and the recalculation should not be represented as the sponsor’s primary analysis.

The endpoint is a group-level measure of ovarian response. It does not by itself summarize every aspect of assisted reproductive treatment, including later clinical outcomes, individual experience, or all safety considerations. The secondary measures add context but are subject to uncertainty and multiplicity concerns. The analysis population is per protocol, and detailed missing-data methods are not reported, limiting what can be inferred about all enrolled participants.

The registry reports adverse-event summaries, but those counts and terms are descriptive and do not establish a comparative safety conclusion. The record also does not provide enough detail to generalize the findings to populations or treatment settings beyond the women studied. Overall, the posted information supports a careful account of the reported primary equivalence analysis and the recalculated summary, while leaving important details about analysis conduct, missing data, and broader clinical outcomes unresolved.

18. Why This Trial Matters Statistically

This trial illustrates why the statistical question must be identified before interpreting a p-value. The primary objective was equivalence, with a stated margin of +/- 2.9 oocytes. The registry also reports an unadjusted recalculation designed as a conventional mean comparison. A non-significant difference test does not demonstrate equivalence; the equivalence question requires evaluating uncertainty against the prespecified limits using the planned method.

The record also illustrates the value and limitation of transparent recalculation. The posted means and standard deviations allow an independent, unadjusted comparison to be described, including its confidence interval. That calculation helps readers understand the scale and precision of the observed contrast. But it cannot reproduce an analysis whose details are not reported, and it should not displace the sponsor’s own analysis when the registry identifies a discrepancy. Clear separation between reported and recalculated results prevents the two methods from being conflated.

Equivalence margins are clinically meaningful design choices, not just statistical thresholds. A margin defines how large a difference can be while still satisfying the study’s operational definition of similarity. The registry reports the margin, but not the original design assumptions that motivated the trial’s sample size. That distinction matters when interpreting post hoc planning illustrations: they describe hypothetical planning based on the observed effect, not the rationale used when the study was designed.

Finally, secondary outcomes and safety summaries broaden the picture but do not automatically strengthen the primary conclusion. Multiple outcomes, incomplete reporting of analysis plans, and missing-data uncertainty all affect how confidently the record can be interpreted. The trial is statistically informative precisely when its stated question, analysis population, sponsor result, recalculation, and limitations are kept distinct.

19. 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 primary endpoint is reported for the per protocol population, but the registry record does not give the detailed rules defining that population or a corresponding result for another analysis population. This limits assessment of whether the primary finding is robust to analysis-population choices. Although enrollment is listed as 460, it is not the number reported in each endpoint summary, and the available record does not provide a full participant-flow explanation for the analysis counts.

The record identifies the sponsor’s equivalence method and p-value, but not the sponsor’s confidence interval or enough detail to reproduce the test. The registry flags a discrepancy with the unadjusted recalculation. The recalculated result is therefore useful as a check based on posted summary statistics, but it is not a substitute for the sponsor’s analysis. The original sample-size assumptions and the complete statistical analysis plan are not reported in the registry record.

Details about missing outcome data, imputation, sensitivity analyses, protocol deviations, and the exact methods for secondary endpoints are not reported. The record lists many outcomes and analyses but does not report a multiplicity strategy. This makes individual secondary findings less suitable for confirmatory interpretation. The summaries also do not show the full distributions of the continuous endpoints, so unusual values or distributional features cannot be assessed.

The safety information is limited to the posted at-risk and affected counts and selected serious-event terms. Further details about duration, relatedness, follow-up, and event-level data are not reported in the registry record. The available information also does not establish how applicable the results are to patient groups or treatment settings beyond the study population. These limitations constrain interpretation; they do not, by themselves, show that the reported analysis is invalid.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Multi-centre Study to Compare Efficacy and Safety of AFOLIA and Gonal-f in Women for Assisted Reproductive Treatment — NCT01121666.
• Registry record last updated 2016-04-15; status last verified 2016-03.
• Results first posted 2016-04-15.
• 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.

23. Record Summary

The registry describes a completed Phase III, randomized, assessor-blinded, parallel-group, multicentre comparison of AFOLIA-150 and Gonal-f® in women receiving assisted reproductive treatment. Enrollment is listed as 460, and the primary endpoint is the number of oocytes retrieved in the per protocol population. The stated equivalence margin is +/- 2.9 oocytes.

The sponsor’s Shuirmann's TOST analysis is reported with p < 0.001. An unadjusted recalculation gives a mean difference of -0.2 oocytes, with a 95% confidence interval from -1.506 to 1.106 and p = 0.764. The registry flags a discrepancy, so the sponsor’s own analysis takes precedence for the reported equivalence result. Secondary outcomes and safety summaries add context, but multiplicity, missing-data handling, and several analysis details are not reported in the registry record.