To Demonstrate Similarity of Pharmacokinetics and Evaluate Safety of CT-P16, EU-Approved Avastin and US-licensed Avastin: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for To Demonstrate Similarity of Pharmacokinetics and Evaluate Safety of CT-P16, EU-Approved Avastin and US-licensed Avastin (NCT03247673), a randomized phase 1 study. The primary outcome is AUC0-inf.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, parallel-group study of three formulations of bevacizumab: CT-P16, EU-approved Avastin, and US-licensed Avastin. The registry lists the study as completed, with enrollment of 141. The recorded start date is 2017-08-07, and the primary completion date is 2017-12-22.

The study description and title call it double-blind, while the registry masking field records quadruple masking. The registry record does not explain which people were masked or how masking was maintained. Allocation is listed as randomized, but the method used to generate or conceal the allocation sequence is not reported in the registry record.

Each arm received a single IV infusion at 5mg/kg. The parallel-group structure means each participant was assigned to a study arm rather than receiving all three formulations in sequence. The record does not report the timing or procedures for randomization, stratification, or dose administration beyond the single-infusion descriptions.

The primary endpoint was AUC0-inf in the PK population. Blood sampling is described from pre-dose through 2,352 hours after start of infusion, with multiple scheduled collection times. The record also lists time to Cmax and anti-drug antibody positivity as secondary outcomes. It does not report the original sample-size justification, planned enrollment by arm, or whether any interim analyses were planned.

Arm-level primary outcome data are reported for 46 participants receiving CT-P16, 47 receiving EU-approved Avastin, and 48 receiving US-licensed Avastin. The registry record does not provide a detailed participant-flow account or explain any differences between enrolled, treated, and analyzed populations.

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: PK 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.

Population: Safety Population

6. Primary Endpoint

The registry lists the primary outcome as AUC0-inf, measured over pre-dose, end of infusion, 1 hour after EOI, 4, 8, 12, 24, 48, 72, 168, 336, 672, 1,008, 1,344, 1,680, 2,016, and 2,352 hours after SOI.

AUC0-inf is the area under the concentration-time curve from time zero to infinity. It summarizes drug exposure over time after administration. The registry reports the endpoint as a mean in the PK population, with standard deviations for each arm. The listed unit is h*ug/mL.

Pharmacokinetic measures are used to characterize how drug concentrations change over time. AUC captures overall exposure, while the separately listed time-to-Cmax outcome concerns when the maximum concentration is reached. In general, an exposure measure can help compare formulations under the conditions of a controlled study; it does not by itself describe clinical benefit or patient outcomes.

The AUC0-inf measurements followed a schedule that began before dosing and continued through 2,352 hours after start of infusion. The registry describes the endpoint but does not report details of the concentration assay, how values below measurement limits were handled, or the method used to estimate the portion of the curve extending to infinity.

The posted arm means are 42030.0 h*ug/mL for CT-P16, 40410.0 h*ug/mL for EU-approved Avastin, and 43020.0 h*ug/mL for US-licensed Avastin. These descriptive means show the observed exposure summaries in the analyzed groups. Their interpretation as evidence of similarity would require a prespecified decision framework; a similarity margin is not reported in the registry record.

7. Results Posted in the Registry

• EU-approved Avastin: mean 40,413 versus 42,035 on control; difference -1,621 (95% CI -3,887 to 643.80), standardized effect d = -0.29; z-test p = 0.161.
• US-licensed Avastin: mean 43,018 versus 42,035 on control; difference 983.05 (95% CI -1,416 to 3,382), standardized effect d = 0.17; z-test p = 0.422.

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.

Number of Participants With Anti-Drug Antibody Positive

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • EU-approved Avastin: 4.3% (2/47) versus 4.3% (2/46) on control; risk difference -0.1 percentage points (95% CI -8.3 to 8.2), risk ratio 0.98 (0.14–6.66); unadjusted two-proportion z-test p = 0.982.
  • US-licensed Avastin: 6.2% (3/48) versus 4.3% (2/46) on control; risk difference 1.9 percentage points (95% CI -7.1 to 10.9), risk ratio 1.44 (0.25–8.21); unadjusted two-proportion z-test p = 0.681.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between EU-approved Avastin and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between US-licensed Avastin and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists time to Cmax and anti-drug antibody positivity as secondary outcomes. Numerical results are available for anti-drug antibody positivity, with counts of 2 participants in the CT-P16 arm, 2 in the EU-approved Avastin arm, and 3 in the US-licensed Avastin arm. Numerical time-to-Cmax results are not reported in the registry record.

Across the posted outcomes, the primary endpoint concerns mean drug exposure, while anti-drug antibody positivity concerns a participant count over a follow-up period of up to 15 weeks. These endpoints address different aspects of the study and use different data types. The antibody counts do not replace or confirm the AUC0-inf comparison; they provide a separate descriptive view of an immunogenicity outcome.

The secondary comparison p-values are unadjusted, and the registry record reports no sponsor analyses for these outcomes. In general, when several outcomes or contrasts are considered, unadjusted results do not account for the possibility of chance findings across the collection of tests. The record does not report whether the secondary outcomes were planned in a hierarchy, whether multiplicity was controlled, or how much weight the study assigned to each outcome.

Small event counts also limit the precision of binary comparisons. The reported counts are close, but counts alone do not establish equivalence or absence of an immunogenicity difference. The record does not provide a prespecified margin for interpreting these differences. These secondary findings should therefore be considered alongside the primary PK result, while recognizing that they answer different questions and have no reported formal analysis framework in the registry.

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

• Additional Pharmacokinetics (Time to Cmax)
• Number of Participants With Anti-Drug Antibody Positive

9. Statistical Interpretation

10. Statistical Methods Explained

The posted primary comparisons are recalculated from the arm-level means, standard deviations, and participant counts. They are simple unadjusted comparisons of mean AUC0-inf. The registry record reports no sponsor analysis results for the primary endpoint, so the recalculated estimates should not be mistaken for an analysis reported by the study sponsor. The record does not describe a model, covariate adjustment, or other analysis procedure for the original trial.

What does a mean difference describe?

In general, a mean difference expresses the separation between the average outcome in two groups, in the original outcome units. Here, the comparisons are expressed in h*ug/mL and use CT-P16 as the reference. A negative estimate for a comparator means its posted mean is lower than the CT-P16 mean; a positive estimate means its posted mean is higher. The estimate describes the groups, not the expected difference for every individual.

The recalculated mean difference for EU-approved Avastin is -1621.0, and the estimate for US-licensed Avastin is 983.0. The corresponding intervals extend from -3887.0 to 643.8 and from -1416.0 to 3382.0. Both include zero. The unadjusted p-values are 0.161 and 0.422, respectively. These p-values summarize how the observed estimates relate to a test of no mean difference under the calculation used; the registry record does not report a sponsor analysis or a prespecified similarity test.

Why report standard deviations?

In general, a standard deviation describes how spread out individual measurements are around the group mean. It is not the uncertainty in the mean difference, and it is not a range containing all participant measurements. The posted standard deviations are 6071.0 for CT-P16, 5013.0 for EU-approved Avastin, and 5783.0 for US-licensed Avastin. The recalculated comparisons use pooled standard deviations of 5561.0 for the EU-approved comparison and 5925.0 for the US-licensed comparison.

In general, greater variability among individual measurements makes group averages less precise when other features of the data are held constant. The actual precision also depends on the number of participants and the analysis. Here, the arm sizes for the primary outcome are 46, 47, and 48. The record does not report whether the original analysis used any additional adjustments or assumptions about the distribution of AUC values.

How should an interval be read?

In general, a confidence interval gives a range of estimates compatible with the observed data under a specified statistical procedure. A narrower interval indicates greater precision than a wider interval, all else equal. These recalculated intervals include zero, meaning they encompass both a zero mean difference and some differences on either side of zero. The confidence level and method for the posted intervals are not reported in the registry record, so they should not be assigned a confidence level by inference.

An interval that includes zero does not show that the groups are equivalent. In general, equivalence or similarity assessment requires prespecified bounds defining differences considered sufficiently small, followed by an analysis designed to compare the interval with those bounds. Those bounds and a formal similarity analysis are not reported in the registry record. The unadjusted p-values likewise do not answer whether the products meet a similarity criterion.

What does unadjusted mean?

In general, an unadjusted p-value is calculated for a comparison without an adjustment for the number of other outcomes or comparisons being examined. This study has two primary arm-to-arm contrasts using CT-P16 as the reference, and additional outcomes are listed. The registry record does not report a multiplicity procedure. The p-values therefore should be read as individual, unadjusted summaries rather than as results controlled across all comparisons.

The same caution applies to the secondary anti-drug antibody comparison p-values. Those values are 0.982 for EU-approved Avastin versus CT-P16 and 0.681 for US-licensed Avastin versus CT-P16. The registry record lists no reported analyses for the secondary outcomes. The displayed comparisons are recalculated from the posted summary counts and should not be attributed to a sponsor-reported inferential analysis.

What is not specified?

The registry record does not report the original statistical analysis plan, missing-data methods, rules for excluding observations, or treatment of protocol deviations. It does not describe how the PK population was formed, how AUC0-inf was estimated, or how uncertainty intervals were constructed. The record also does not report a sample-size justification or a planned interim analysis. These omissions limit assessment of whether the recalculated summaries match the trial's original analysis strategy.

11. Confidence Intervals and Precision

The primary comparisons have intervals from -3887.0 to 643.8 for EU-approved Avastin versus CT-P16, and from -1416.0 to 3382.0 for US-licensed Avastin versus CT-P16. Each interval includes zero and also allows for mean differences in both directions. The intervals therefore convey uncertainty around the point estimates; neither comparison is pinned down to a single value by the posted data.

In general, an interval is useful because it shows a range of estimates compatible with the observed data under the calculation method. Its endpoints are not the smallest and largest individual participant outcomes. The interval method and confidence level are not reported in the registry record, so the endpoints should be interpreted as posted uncertainty ranges without assigning an unreported confidence level.

The mean estimates themselves are 42030.0 for CT-P16, 40410.0 for EU-approved Avastin, and 43020.0 for US-licensed Avastin. The recalculated mean differences are -1621.0 and 983.0. Point estimates alone do not capture the uncertainty reflected by the intervals. The within-arm standard deviations also show that individual measurements varied around the arm means.

Precision is distinct from similarity. In general, evidence of similarity depends on whether an appropriately constructed interval falls within prespecified bounds, not merely on whether it contains zero or on whether an unadjusted p-value is large. The registry record does not report similarity bounds or a formal sponsor analysis, so the posted intervals cannot establish that criterion.

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 planning figures are participants per arm, not total events. They are illustrations calculated from the observed effect, not the trial's original design assumptions. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The trial's own sample-size justification and original design assumptions are not reported in the registry record.

The 80% power column describes the number of participants per arm that the planning calculation estimates would be needed to detect the selected effect with 80% power under those assumptions. The 90% power column gives the corresponding planning count for 90% power. In general, higher target power requires more participants when the other assumptions are held constant. Smaller effects also require more participants to detect than larger effects.

For the EU-approved Avastin primary comparison, planning for 100% of the observed effect gives 185 participants per arm for 80% power and 248 for 90% power. Planning for 50% of the observed effect gives 739 and 989 participants per arm, respectively. For the US-licensed Avastin comparison, the corresponding figures are 571 and 764 for 100% of the observed effect, and 2,282 and 3,055 for 50% of the observed effect.

The antibody outcome is binary and its planning illustrations can be very large, particularly where the observed difference is small. Such figures are especially dependent on the observed event counts and the calculation assumptions, and should not be treated as a recommended design. These calculations are planning illustrations, not observed power.

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 = -1621.460; pooled standard deviation σ = 5561.120.
2. n = 2 × (1.96 + 0.842)² × 5561.120² / -1621.460² = 184.7, rounded up to 185 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 <- -1621.46                      # observed difference in means
sigma <- 5561.1197773837                     # 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(3247673)
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 = 185 (80% power), 248 (90% power)
 75% of observed effect: n per arm = 329 (80% power), 440 (90% power)
 50% of observed effect: n per arm = 739 (80% power), 989 (90% power)
power.t.test: 185.6 
Simulated power at n = 185 per arm: 0.796 (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. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity adjustment, a testing hierarchy, or a strategy for controlling the overall type I error across the primary comparisons and secondary outcomes. The two primary contrasts compare CT-P16 separately with EU-approved Avastin and US-licensed Avastin. The displayed p-values are unadjusted recalculations, so they should not be interpreted as multiplicity-adjusted findings.

The record does not report how missing AUC measurements were handled, whether participants with incomplete concentration sampling remained in the PK population, or how missing secondary outcome data were treated. It also does not report rules for excluding measurements, handling protocol deviations, or addressing participants who discontinued follow-up. These details can affect both the analyzed population and the precision of estimates.

The endpoint identifies the PK population, but its definition and relationship to the enrolled participants are not reported in the registry record. Arm-level counts for the primary outcome are 46 for CT-P16, 47 for EU-approved Avastin, and 48 for US-licensed Avastin. The record does not describe whether these counts reflect all randomized participants, all treated participants, or a subset meeting analysis criteria.

No interim analyses or stopping rules are reported. The original statistical analysis plan, model specification, adjustment variables, and procedures for estimating AUC0-inf are also not reported. Without these details, the recalculated unadjusted comparisons are best viewed as summaries of the posted data rather than a reconstruction of the trial's full prespecified analysis.

General statistical context: multiplicity procedures can change the interpretation of a collection of tests, and missing-data methods can affect estimates when observations are incomplete. Which approach is appropriate depends on the prespecified objectives and data structure. The registry record does not provide enough information to determine what procedures were planned or used.

15. 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 non-serious adverse event terms

The serious adverse event figures show 0 events among 46 participants at risk in the CT-P16 arm, 0 among 47 in the EU-approved Avastin arm, and 0 among 48 in the US-licensed Avastin arm. Deaths were also recorded as 0 in each arm. These are observed counts within the reported groups.

A zero count does not establish that the risk is zero. In general, when no events are observed in a group, the available data still leave uncertainty about how often such events might occur in a larger or different population. The registry record does not provide uncertainty intervals for these safety counts.

The record lists other adverse events affecting 15 participants in the CT-P16 arm, 22 in the EU-approved Avastin arm, and 17 in the US-licensed Avastin arm. The serious-event figures alone do not describe the full safety profile, and the registry record does not provide detailed event terms in the posted serious-event summary. These counts should be read as descriptive observations from a single-dose study in healthy male subjects.

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

The posted data show similar-looking AUC0-inf group means, with recalculated mean differences of -1621.0 for EU-approved Avastin versus CT-P16 and 983.0 for US-licensed Avastin versus CT-P16. The unadjusted p-values are 0.161 and 0.422, and both uncertainty intervals include zero. These summaries do not establish that the formulations are identical or satisfy a formal similarity criterion.

The study was designed to compare pharmacokinetics, safety, and immunogenicity after a single infusion in healthy male subjects. Its primary result concerns a drug-exposure measure in the PK population. It is not a direct measure of clinical outcomes, and the record does not provide evidence about repeated dosing or populations other than the healthy male subjects enrolled.

A formal similarity conclusion requires a prespecified standard and an analysis that evaluates the data against that standard. The registry record does not report the similarity margin, a sponsor-reported primary analysis, or a formal conclusion about whether the products met such a criterion. The recalculated comparisons should therefore be read as descriptive statistical evidence, not as a substitute for the trial's original decision framework.

The safety summary records no serious adverse events in the reported groups, but the study size and follow-up described in the record do not make zero counts proof that serious events cannot occur. The antibody results are based on small participant counts, and numerical results for time to Cmax are not reported in the registry record.

In general, statistical evidence describes uncertainty in the data under a defined analysis; it does not by itself determine clinical meaning. The record is most informative about the observed single-dose PK summaries and less informative about the details of the original analysis, broader safety experience, and applicability beyond the studied population.

17. Why This Trial Matters Statistically

This trial illustrates why a pharmacokinetic comparison needs to be interpreted through both its estimated differences and their precision. The AUC0-inf means are close in scale, but the mean-difference intervals also span values on either side of zero. Neither a point estimate nor a p-value alone answers a formal similarity question.

The three-arm design separates two distinct comparator questions: CT-P16 versus EU-approved Avastin and CT-P16 versus US-licensed Avastin. The comparisons have different estimates and uncertainty ranges. Combining them into a single conclusion would obscure the fact that each is a separate contrast and that the registry record does not report a multiplicity strategy.

The planning illustrations also demonstrate how sample-size requirements depend on the size of the effect selected for detection. The figures rise as the assumed effect becomes smaller, and binary outcomes with very small observed differences can yield particularly large planning counts. These are illustrations based on observed data, not the original enrollment rationale.

Finally, the registry record distinguishes what can be summarized from what cannot be reconstructed. It reports group means, variability, counts, and outcome definitions, but does not report the original analysis plan, missing-data procedures, similarity margin, or sponsor analyses. Clear separation between posted descriptive results and unreported design details is essential to avoid overstating what the study establishes.

18. 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 study population was healthy male subjects, so the record does not establish how the observed PK summaries apply to other populations. The design involved a single infusion at 5mg/kg, and the registry record does not report repeated-dose results. The primary endpoint is a pharmacokinetic measure rather than a clinical outcome.

The primary comparisons are recalculated from posted summary statistics. The registry record does not report a sponsor analysis, the original statistical analysis plan, the method for estimating AUC0-inf, the interval construction method, or the confidence level for the posted intervals. It also does not report the similarity margin needed to interpret the results as a formal similarity assessment.

Participant counts are reported for the PK outcome, but participant flow and the definition of the PK population are not described. The record does not report missing-data handling, exclusions, or whether the outcome counts include all randomized or treated participants. The randomization method and details of masking are also not reported; the description calls the study double-blind while the masking field records quadruple masking.

The secondary outcome evidence is incomplete in the registry record: time-to-Cmax results are not reported, and the antibody counts are small. Multiplicity handling and the original sample-size justification are not reported. The safety summary provides adverse-event counts but does not, by itself, establish the range or frequency of all possible events.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: To Demonstrate Similarity of Pharmacokinetics and Evaluate Safety of CT-P16, EU-Approved Avastin and US-licensed Avastin — NCT03247673.
• Registry record last updated 2020-03-26; status last verified 2020-03.
• Results first posted 2019-07-25.
• 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.

22. Record Summary

NCT03247673 is a completed Phase 1 randomized, parallel-group study of CT-P16, EU-approved Avastin, and US-licensed Avastin. It enrolled healthy male subjects and compared the products after a single IV infusion at 5mg/kg. The primary outcome was mean AUC0-inf in the PK population.

The posted primary means were 42030.0 h*ug/mL for CT-P16, 40410.0 h*ug/mL for EU-approved Avastin, and 43020.0 h*ug/mL for US-licensed Avastin. Unadjusted comparisons were recalculated from the posted summary statistics. The registry record does not report a sponsor analysis or a formal similarity margin.

The record also lists time to Cmax and anti-drug antibody positivity as secondary outcomes. Numerical time-to-Cmax results are not reported. Serious adverse event counts were 0 in each arm. Details of the original statistical plan, missing-data methods, multiplicity procedures, and sample-size justification are not reported in the registry record.