Statistical considerations

Drs. Jan Welink

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Bioequivalence

The primary concern in bioequivalence assessment

is to limit the risk of a false declaration of equivalence.
Statistical analysis of the bioequivalence trial should
demonstrate that the clinically significant difference
in bioavailability is unlikely..

WHO working document multisource (generic) pharmaceutical products: ]

Guidelines on registration requirements to establish interchangeability,
[Nov. 2005

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Bioequivalence
2 pharmaceutical products
Test

Reference

Bioequivalent??

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Bioequivalence

Important PK parameters

: AUC
area under the concentration-time curve
measure of the extent of absorption
Cmax

AUC

: Cmax
the observed maximum concentration of a drug
measure of the rate of absorption
:tmax
time at which Cmax is observed
measure of the rate of absorption

Tmax

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

How similar is similar?

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations
Statistical test should take into account
The consumer (patient) risk of erroneously accepting
bioequivalence (primary concern health authorities)
Minimize the producer (pharmaceutical company)
risk of erroneously rejecting bioequivalence

Choice:
- two one-side test procedure
- confidence interval ratio T/R 100 (1-2)
- set at 5% (90% CI)

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

Consumer Risk
The risk of declaring two product BE when theyre
not is called the consumer risk

In statistical terms, this is a Type I error

The risk of rejecting the null hypothesis when its true

The consumer risk is set at 5%

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

Producer Risk
The risk of declaring two products NOT
BE when they truly are BE is called the
producer risk
In statistical terms, this is a Type II error
The risk of accepting the null hypothesis
when its false

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

The risks are related

If the consumer risk is reduced, the producer
risk increases

In statistical terms, if you lower the acceptable

risk of making a Type I error, the risk of making a
Type II error increases

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

:Average Bioequivalence

two drug products are bioequivalent

on the average when the (1-2)
confidence interval around the
Geometric Mean Ratio falls
entirely within 80-125%
)regulatory control of specified limit (

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations
Some International Criteria
Country/Region

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AUC 90% CI

Cmax 90% CI

Criteria

Criteria

Canada (most drugs)

80 125%

none
(point estimate
only)

Europe (some drugs)

80 125%

75 133%

South Africa (most

drugs)

80 125%

75 133% (or
broader if justified)

Japan (some drugs)

80 125%

Some drugs wider

than 80 125%

Worldwide (WHO)

80 125%

acceptance range
for Cmax may be
wider than for AUC

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

Geometric90%CI 100. exp

( LSM A LSM b t df , 0.05 SEab )

Least Square
Means from ANOVA
t-statistic with
0.05 in one
tail

Standard
Error

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

BE Limits
The concept of the 20% difference is the basis of BE
limits (goal posts)
If the concentration dependent data were linear, the BE
limits would be 80-120%
On the log scale, the BE limits are 80-125%
The 90%CI must fit entirely within specified BE limits e.g.
80-125%

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations
..:Variables

Log transformation:
For all concentration dependent pharmacokinetic variables (AUC
and Cmax)

Analysis of log-transformed data by means of ANOVA (analysis of

variance)
includes usually formulation, period, sequence or carry-over, and subject factors
parametric test (normal theory)

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

The sources of variance in the model are

Product
Period
Sequence
Subject (Sequence)

These account
for all the inter-subject
variability

Residual variance

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

This estimates
Intra-subject
variability

Statistical considerations

The width of the 90%CI depends on

The magnitude of the WSV (ANOVA-CV (residual variance))
The number of subjects in the BE study
The bigger the WSV (within- or intra-subject variability), the wider the CI

If the WSV is high, more subjects are needed to give

statistical power compared with when the WSV is low

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

ANOVA CV
intra-subject
variability
unexplained
random
variability
analytica
l
variabilit
y
subject by
formulation
interaction
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations

80

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100

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

125

Statistical considerations
:why log-transformation

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Statistical considerations
:Why parametric testing and not non-parametric
!applicant: after log transformation not normal distributed
based upon test for normality, however these are
insensitive and it concerns a small study
normally after log transformation AUC and Cmax are
normal distributed
reason for non-normality should be explained

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Outliers

Outliers

Definition:

aberant/irregular values (e.g. no plasma

concentration, late high concentrations.)

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Outliers
Outliers
Explanation:
vomiting?
non-compliant volunteers?
bioanalytical failure?
individual pharmacokinetics?
protocol violations?

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Outliers
Outliers
Handling:
pharmacokinetic data can only be excluded based on non-statistical
reasons that have been defined previously in the protocol.
Exclusion of data can never be accepted on the basis of statistical
analysis or for pharmacokinetic reasons alone, because it is impossible
to distinguish between formulation effects and pharmacokinetic effects.
Results of statistical analyses with and without the excluded subjects
should be provided. (excerpt from Q&A Doc Ref: EMEA/CHMP/EWP/40326/2006)

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Power calculation

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

End

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009