Transcript WHO requirements on conduct and documentation of BE studies

Bioequivalenceregulatory requirements
Drs. Jan Welink
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Guidance documents
http://apps.who.int/prequal/
* Note to applicants on the choice of comparator products for
the prequalification project
* Guideline on generics
- Annex 7 (Multisource (generic) pharm. products: guidelines on
registration requirements to establish interchangeability)
- Annex 11 (Guidance on the selection of comparator pharm. products for
equivalence assessment of interchangeable multisource (generic)
products)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Guidance documents
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Guidance documents
Europe: http://www.emea.europa.eu
- Guideline on the investigation of bioequivalence
- Note for guidance on modified release oral and
transdermal dosage form: section II.
- Question and answer documents
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WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Bioequivalence
Pharmaceutical Equivalent
Products
Reference
Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Bioequivalence
Pharmaceutical equivalent does not necessarily imply
therapeutic equivalence:
- difference excipients
- difference manufacturing process
- other variables
WHO Workshop on Prequalification of Medicines Programme,
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drug
performance?
Bioequivalence
Therapeutic equivalent does not necessarily imply
bioequivalence:
- sensitivity
- different formulations (IR/CR)
- different active substance
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equivalence?
Bioequivalence
pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, Cmax)
acceptance criteria: comparative rate and extent of absorption
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EXPERIMENTAL DESIGN
WHO Workshop on Prequalification of Medicines Programme,
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Bioequivalence
Important PK parameters
Cmax:
the observed maximum concentration of a drug
 measure of the rate of absorption
AUC:
area under the concentration-time curve
 measure of the extent of absorption
tmax:
time at which Cmax is observed
 measure of the rate of absorption
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Plasma concentration time profile
Cmax
AUC
Tmax
time
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Bioequivalence IR formulations– single dose
Basic design considerations:
minimize variability not
attributable to formulations
minimize bias
goal: compare performance
2 formulations
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Bioequivalence IR formulations– single dose
Golden standard study design:
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)
WHO Workshop on Prequalification of Medicines Programme,
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Bioequivalence IR formulations– single dose
Single dose, two-period crossover:
 Subjects receive in Period I and II Test/Reference
Subjects:
 Healthy volunteers
– randomisation
– Inclusion/exclusion criteria
– Number of subjects
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Bioequivalence – variability
Number of subjects: variability!!
Controllable variation:
- carry-over effects (use of other medicines etc.)
- time-factors (sampling time etc.)
- physiological factors (gastric emptying etc.)
Inescapable variation:
- subject difference (inter- and intra variability)
- formulations differences
- random error
WHO Workshop on Prequalification of Medicines Programme,
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Bioequivalence – variability
Number of subjects:
 Number of subjects
 Required sample size depends on intra-individual
variability either known through reasonable literature
or by means of a pilot study
“low” variability: ~ 12 – 26 volunteers
“high” variability: ~ can be up to 250 volunteers
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Bioequivalence – Test/Reference
Test/Reference:
 TEST formulation:
 not smaller than 100 000 units or 10 % of industrial
batch size (whichever is higher)
 Certificate of Analysis
 Manufacturing date/expire date
 Reference formulation:
 Certificate of Analysis
 Expire date
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Bioequivalence – fast/fed
Administration of Test/Reference:
 Procedure of drug intake:
 time of administration (fasted or fed state)
 liquid volume
 traceability of administrations
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Bioequivalence – fast/fed
 Fasted state e.g.
 Confinement of subjects at least 10 h prior to drug
administration
 Last food intake ~10 h prior to drug intake
 No food or fluids ~2 h prior to drug intake
 Drug administration with ~150-240 ml (e.g.) water
 Light standardized meal not before ~4 h post-dose
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Bioequivalence – fast/fed
 Standardized fluid and food intake (time,
composition, amount)
 Prohibition of alcohol
 Restriction of xanthins (coffee*, tea, coke,
chocolate, chewing gum, grapefruit….)
 Standardized posture
 Restriction of physical activities
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Bioequivalence – fast/fed
 Fed state
Define time of drug administration and food intake
(e. g. drug intake within 30 min. before, immediately before or after the
standardised meal)
High fat meal may serve to investigate the „worst
case“ scenario
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Sampling
Blood sampling:
Number of samples.
Sampling times (Cmax!).
Time of sampling (extrapolated AUC max. 20%).
Washout phase long enough.
WHO Workshop on Prequalification of Medicines Programme,
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knowledge
drug
substance
Sampling
Time of sampling (extrapolated AUC max. 20%).
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Sampling
Washout phase long enough!.
At least > 5 times elimination half-life drug.
 Wash-out-phase
 must be long enough to avoid residual
concentrations
 closely related to the limit of quantitation
 metabolites may be considered
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Selection of strength/dose
4.1.6 Strength and dose
important for application consisting more
strengths (extrapolation of BE data)
elaborate section which
strength/dose should be applied
depends on linearity in PK and
solubility active substance
bracketing approach possible
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EMA guidance
Choice of the comparator:
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Comparator
Example of how a national DRA can select a comparator:
 choose national granted innovator for which quality, safety
and efficacy has been established (nationally authorised
innovator)
 choose WHO comparator product from the comparator list
(WHO comparator product)
 choose innovator product from well-regulated country (ICH et
al. innovator)
 if no innovator can be identified, choice must be justified
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Decision tree
Choosing national comparator complex
WHO provides criteria
decision tree
NO
YES
?
?
YES
NO
NO
?
WHO Workshop on Prequalification of Medicines Programme,
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Comparator
Selection of a comparator for a single
national market:
cannot be translated in case other
countries are at stake
national comparator may be the national
market leader
no problem in that market
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but others!?
EMA (Europe)
Differentiate between use for single market or many countries!
EMA:
For an abridged application claiming essential similarity to a reference product, application to
numerous Member States based on bioequivalence with a reference product from one Member
State can be made.
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Prequalification program
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EOI
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Comparator lists
List of acceptable reference products for the
prequalification project for reproductive health
List of acceptable reference products for the
prequalification project for reproductive health
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Guidance documents
Comparator products:
Comparator products should be obtained from a well regulated market
with stringent regulatory authority i.e., from countries participating in
the International Conference on Harmonization (ICH)
Countries officially participating in ICH are the ICH members European
Union, Japan and USA; and the ICH observers Canada and Switzerland.
Note: some are not available in ICH
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Guidance documents
Information Requirements
Within the submitted dossier, the country of origin of the comparator product should be reported
together with lot number and expiry date, as well as results of pharmaceutical analysis to prove
pharmaceutical equivalence. Further, in order to prove the origin of the comparator product the
applicant must present all of the following documents:
1. Copy of the comparator product labelling. The name of the product, name and address of the
manufacturer, batch number, and expiry date should be clearly visible on the labelling.
2. Copy of the invoice from the distributor or company from which the comparator product was
purchased. The address of the distributor must be clearly visible on the invoice.
3. Documentation verifying the method of shipment and storage conditions of the comparator
product from the time of purchase to the time of study initiation.
4. A signed statement certifying the authenticity of the above documents and that the comparator
product was purchased from the specified national market. The certification should be signed by the
company executive or equivalent responsible for the application to the Prequalification Programme
WHO Workshop on Prequalification of Medicines Programme,
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Comparators
For the Prequalification Program:
* the comparator should be selected from the
comparator list
(http://apps.who.int/prequal/info_applicants/info_for_
applicants_BE_comparator.htma)
* guidance on selection and the to be provided
documents should be followed.
* if comparator is not available, information can be
obtained at: [email protected]
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Statistical considerations
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Bioequivalence
Bioequivalence:
= bioavailability with pre-defined criteria for the rate
and extent of absorption!!
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Bioequivalence
2 pharmaceutical products
Test
Reference
Bioequivalent??
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Statistical considerations
How similar is similar?
WHO Workshop on Prequalification of Medicines Programme,
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Statistical considerations
WHO Workshop on Prequalification of Medicines Programme,
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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)
WHO Workshop on Prequalification of Medicines Programme,
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Choice:
- two one-side test procedure
 Superiority studies
– A is better than B (A = active and B = placebo or gold-standard)
– Conventional one-sided hypothesis test
 Equivalence studies
– A is more or less like B (A = active y B = standard)
– Two-sided interval hypothesis
 Non-inferiority studies
– A is not worse than B (A = active y B = standard with adverse
effects)
– One-sided interval hypothesis
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Statistical considerations
Average Bioequivalence:
two drug products are bioequivalent
‘on the average’ when the (1-2α)
confidence interval around the
Geometric Mean Ratio falls
entirely within 80-125%
(regulatory control of specified limit)
WHO Workshop on Prequalification of Medicines Programme,
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Statistical considerations
Some International Criteria
Country/Region
AUC 90% CI
Cmax 90% CI
Criteria
Criteria
Canada (most drugs)
80 – 125%
none
(point estimate
only)
Europe
80 – 125%
80 – 125%
South Africa (most
drugs)
80 – 125%
75 – 133% (or
broader if justified)
Japan (some drugs)
80 – 125%
Some drugs wider
than 80 – 125%
Worldwide
80 – 125%
“acceptance range
for Cmax may be
wider than for AUC”
WHO Workshop on Prequalification of Medicines Programme,
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Statistical considerations
 Sponsors have to use a validated software
– E.g. SAS, SPSS, Winnonlin, etc.
WHO Workshop on Prequalification of Medicines Programme,
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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%
WHO Workshop on Prequalification of Medicines Programme,
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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)
WHO Workshop on Prequalification of Medicines Programme,
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Statistical considerations
 The sources of variance in the model are
–
–
–
–
Product
Period
Sequence
Subject (Sequence)
– Residual variance
These account
for all the inter-subject
variability
This estimates
Intra-subject
variability
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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, 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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Statistical considerations
80
100
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125
Statistical considerations
why log-transformation:
WHO Workshop on Prequalification of Medicines Programme,
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Statistical considerations
Why parametric testing and not non-parametric:
Non-parametric testing can hide outlying values!
 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
WHO Workshop on Prequalification of Medicines Programme,
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Outliers
‘Outliers’
Definition:
♦ aberant/irregular values (e.g. no plasma
concentration, ‘late’ high concentrations….)
WHO Workshop on Prequalification of Medicines Programme,
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Outliers
 ‘Outliers’
Explanation:
♦ vomiting?
♦ non-compliant volunteers?
♦ bioanalytical failure?
♦ individual pharmacokinetics?
♦ protocol violations?
♦ ……
WHO Workshop on Prequalification of Medicines Programme,
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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.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Regulatory requirements for BE studies
Bioequivalence:
Linear pharmacokinetics
Non narrow therapeutic drug
Non highly variable drug
Decision based upon parent drug data
Decision based upon plasma concentrations
Stereochemistry not an issue
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BE studies for modified release formulations
Modified release (MR) oral dosage forms:
Plasma Conc.-Time curve
prolonged release
Plasma Conc.-Time curve
delayed release
120
120
100
100
100
80
60
40
20
0
Plasma Conc. mg/L
120
Plasma Conc. mg/L
Plasma Conc. mg/L
Plasma Conc.-Time curve
immediate/prolonged release
80
60
40
20
0
0
10
20
30
40
Time (h)
50
60
70
80
60
40
20
0
0
10
20
30
40
50
60
Time (h)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
70
0
10
20
30
40
Time (h)
50
60
70
BE studies for modified release formulations
Modified release (MR) oral dosage forms:
Requested BE studies for enteric coated formulations:
single dose, two-period,
crossover, fasting
single dose, two-period,
crossover, fed
90% CI AUC and Cmax:
80 – 125%
90% CI AUC and Cmax:
80 – 125%
or
not statistical
significant different
WHO Workshop on Prequalification of Medicines Programme,
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pH!
BE studies for modified release formulations
Modified release (MR) oral dosage forms:
Requested BE studies for controlled release formulations:
single dose, two-period,
crossover, fasting
multiple dose, two-period,
crossover, fasting
single dose, two-period,
crossover, fed
90% CI AUC and Cmax: 90% CI AUC and Cmax: 90% CI AUC and Cmax:
80 – 125%;
80 – 125%
80 – 125%
Cmin and PTF!
- dose dumping
- steady state conditions
- EU, not FDA
WHO Workshop on Prequalification of Medicines Programme,
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- FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December
2002)
BE studies for modified release formulations
In case of more strengths:
type of formulation should be taken into account.
multiple unit formulations
single unit formulations
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Bioequivalence
Most submitted bioequivalence studies are:
Single dose studies.
Fasted conditions.
Crossover design.
Non replicate.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
depends on
drug
substance!
End
Thank you for your attention
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010