drs. jan welink who workshop on prequalification of medicines programme, abu dhabi, 11-13 october,...
TRANSCRIPT
Drs. Jan Welink
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence-regulatory requirements
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Guidance documentsGuidance 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 documentsGuidance documents
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Guidance documentsGuidance 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
………………………………
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BioequivalenceBioequivalence
Reference Test
Pharmaceutical EquivalentProducts
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
BioequivalenceBioequivalence
Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:
-difference excipients
-difference manufacturing process
-other variables
drug performance?
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BioequivalenceBioequivalence
Therapeutic equivalent does not necessarily imply bioequivalence:
-sensitivity
-different formulations (IR/CR)
-different active substance
equivalence?
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BioequivalenceBioequivalence
acceptance criteria: comparative rate and extent of absorption
pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, Cmax)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
EXPERIMENTAL DESIGNEXPERIMENTAL DESIGN
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BioequivalenceBioequivalence
Important PK parameters
AUC :
area under the concentration-time curve measure of the extent of absorption
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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Plasma concentration time profilePlasma concentration time profile
Cmax
Tmax
AUC
time
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence IR formulations– single doseBioequivalence IR formulations– single dose
minimize variability not attributable to formulations
Basic design considerations:
goal: compare performance2 formulations
minimize bias
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence IR formulations– single doseBioequivalence IR formulations– single dose
single dose, two-period, crossover
Golden standard study design:
Reference (comparator)/Test (generic)
healthy volunteers
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence IR formulations– single dose 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence – variabilityBioequivalence – 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, Abu Dhabi, 11-13 October, 2010
Bioequivalence – variabilityBioequivalence – 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence – Test/Reference 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence – fast/fed Bioequivalence – fast/fed
Administration of Test/Reference:
Procedure of drug intake:
time of administration (fasted or fed state)
liquid volume
traceability of administrations
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence – fast/fedBioequivalence – 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence – fast/fedBioequivalence – 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence – fast/fedBioequivalence – 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
SamplingSampling
Number of samples.
Blood sampling:
Time of sampling (extrapolated AUC max. 20%).
Washout phase long enough.
Sampling times (Cmax!). knowledge drug
substance
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
SamplingSampling
Time of sampling (extrapolated AUC max. 20%).
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
SamplingSampling
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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Selection of strength/doseSelection 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
bracketing approach possible
EMA guidancedepends on linearity in PK and solubility active
substance
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Choice of the comparator:
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
ComparatorComparator
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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Decision tree
Choosing national comparator complex
WHO provides criteria decision tree
YESNO
YES
NO
NO
?
?
?
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
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 but others?!
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
EMA (Europe)EMA (Europe)
Differentiate between use for single market or many countries!
Austria
France
Latvia
Poland
Belgium
Germany
Liechtenstein
Portugal
Cyprus
Greece
Lithuania
Slovak Republic
Czech Republic
Hungary
Luxemburg
Slovenia
Denmark
Iceland
Malta
Spain
Estonia
Ireland
The Netherlands
Sweden
Finland
Italy
Norway
United Kingdom
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.
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Prequalification program
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
EOI
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Guidance documentsGuidance 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Guidance documentsGuidance 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, Abu Dhabi, 11-13 October, 2010
ComparatorsComparators
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 considerationsStatistical considerations
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BioequivalenceBioequivalence
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
BioequivalenceBioequivalence
Reference Test
2 pharmaceutical products
Bioequivalent??
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical considerations
How similar is similar?
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical considerations
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical 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, Abu Dhabi, 11-13 October, 2010
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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical 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, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical considerations
Some International Criteria
Country/RegionAUC 90% CI
Criteria
Cmax 90% CI
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, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical considerations
Sponsors have to use a validated software– E.g. SAS, SPSS, Winnonlin, etc.
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical 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, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical 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, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical considerations
The sources of variance in the model are– Product– Period– Sequence– Subject (Sequence)
– Residual variance
These accountfor all the inter-subjectvariability
This estimatesIntra-subject variability
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical 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
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical considerations
80 100 125
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical considerations
why log-transformation:
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Statistical considerationsStatistical 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, Abu Dhabi, 11-13 October, 2010
OutliersOutliers
‘Outliers’
Definition:
♦ aberant/irregular values (e.g. no plasma concentration, ‘late’ high concentrations….)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
OutliersOutliers
‘Outliers’
Explanation: ♦ vomiting?♦ non-compliant volunteers?♦ bioanalytical failure?♦ individual pharmacokinetics?♦ protocol violations?♦ ……
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
OutliersOutliers
‘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 studiesRegulatory requirements for BE studies
Bioequivalence: Linear pharmacokinetics
Non narrow therapeutic drug
Non highly variable drug
Decision based upon parent drug data
Stereochemistry not an issue
Decision based upon plasma concentrations
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BE studies for modified release formulationsBE studies for modified release formulations
Modified release (MR) oral dosage forms:
Plasma Conc.-Time curveimmediate/prolonged release
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70
Time (h)
Pla
sm
a C
on
c. m
g/L
Plasma Conc.-Time curveprolonged release
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70
Time (h)
Pla
sm
a C
on
c. m
g/L
Plasma Conc.-Time curvedelayed release
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70
Time (h)
Pla
sm
a C
on
c. m
g/L
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BE studies for modified release formulationsBE studies for modified release formulations
single dose, two-period, crossover, fasting
Modified release (MR) oral dosage forms:Requested BE studies for enteric coated formulations:
not statistical significant different
90% CI AUC and Cmax:80 – 125%
or
single dose, two-period, crossover, fed
90% CI AUC and Cmax:80 – 125%
pH!
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BE studies for modified release formulationsBE studies for modified release formulations
single dose, two-period, crossover, fasting
Modified release (MR) oral dosage forms:Requested BE studies for controlled release formulations:
90% CI AUC and Cmax:80 – 125%
single dose, two-period, crossover, fed
90% CI AUC and Cmax:80 – 125%
multiple dose, two-period, crossover, fasting
-steady state conditions
-EU, not FDA
90% CI AUC and Cmax:80 – 125%;
Cmin and PTF! -dose dumping
- -FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BE studies for modified release formulationsBE 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
BioequivalenceBioequivalence
Single dose studies.
Most submitted bioequivalence studies are:
Crossover design.
Non replicate.
Fasted conditions. depends on drug
substance!
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
End
Thank you for your attention