drs. jan welink who workshop on prequalification of medicines programme, abu dhabi, 11-13 october,...

Drs. Jan Welink

WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

Bioequivalence-regulatory requirements


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)



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

………………………………


BioequivalenceBioequivalence

Reference Test

Pharmaceutical EquivalentProducts

Possible Differences

Drug particle size, ..

Excipients

Manufacturing process

Equipment

Site of manufacture

Batch size ….

Documented Bioequivalence= Therapeutic Equivalence



Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:

-difference excipients

-difference manufacturing process

-other variables

drug performance?



Therapeutic equivalent does not necessarily imply bioequivalence:

-sensitivity

-different formulations (IR/CR)

-different active substance

equivalence?



acceptance criteria: comparative rate and extent of absorption

pharmaceutical equivalence

method: in principle comparative pharmacokinetics (AUC, Cmax)


EXPERIMENTAL DESIGNEXPERIMENTAL DESIGN



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


Plasma concentration time profilePlasma concentration time profile

Cmax

Tmax

AUC

time


Bioequivalence IR formulations– single doseBioequivalence IR formulations– single dose

minimize variability not attributable to formulations

Basic design considerations:

goal: compare performance2 formulations

minimize bias


Bioequivalence IR formulations– single doseBioequivalence IR formulations– single dose

single dose, two-period, crossover

Golden standard study design:

Reference (comparator)/Test (generic)

healthy volunteers


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


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


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


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


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


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



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



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


SamplingSampling

Number of samples.

Blood sampling:

Time of sampling (extrapolated AUC max. 20%).

Washout phase long enough.

Sampling times (Cmax!). knowledge drug

substance


SamplingSampling

Time of sampling (extrapolated AUC max. 20%).


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


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


Choice of the comparator:


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


Decision tree

Choosing national comparator complex

WHO provides criteria decision tree

YESNO

YES

NO

NO

?

?

?


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?!


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.


Prequalification program


EOI


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



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



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


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]


Statistical considerationsStatistical considerations



Bioequivalence:

= bioavailability with pre-defined criteria for the rate

and extent of absorption!!



Reference Test

2 pharmaceutical products

Bioequivalent??



How similar is similar?



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)


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



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(



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”



Sponsors have to use a validated software– E.g. SAS, SPSS, Winnonlin, etc.



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%



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)



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



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



80 100 125



why log-transformation:



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


OutliersOutliers

‘Outliers’

Definition:

♦ aberant/irregular values (e.g. no plasma concentration, ‘late’ high concentrations….)


OutliersOutliers

‘Outliers’

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


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.


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


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



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


pH!



single dose, two-period, crossover, fasting

Modified release (MR) oral dosage forms:Requested BE studies for controlled release formulations:


single dose, two-period, crossover, fed


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)



In case of more strengths :

type of formulation should be taken into account.

multiple unit formulations

single unit formulations



Single dose studies.

Most submitted bioequivalence studies are:

Crossover design.

Non replicate.

Fasted conditions. depends on drug

substance!


End

Thank you for your attention

drs. jan welink who workshop on prequalification of medicines programme, abu dhabi, 11-13 october,...

Documents

abu dhabi

prequalification project

therapeutic equivalence

bias slide

rate of absorption slide

c max slide

documented bioequivalence

experimental design