regulatory requirements Bioequivalence- regulatory 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)

Guidance documents

Europe: http://www.emea.europa.eu 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 ………………………………

Bioequivalence Pharmaceutical Equivalent Products Reference Test Pharmaceutical Equivalent Products Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence

Bioequivalence Pharmaceutical equivalent does not necessarily imply therapeutic equivalence: - difference excipients - difference manufacturing process - other variables drug performance?

Bioequivalence Therapeutic equivalent does not necessarily imply bioequivalence: - sensitivity - different formulations (IR/CR) - different active substance equivalence?

Bioequivalence pharmaceutical equivalence method: in principle comparative pharmacokinetics (AUC, Cmax) acceptance criteria: comparative rate and extent of absorption

EXPERIMENTAL DESIGN

World Health Organization Bioequivalence World Health Organization 21 April, 2017 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 Note that bioequivalence standards are applied to the pharmacokinetic parameters AUC and Cmax but not to Tmax.

Plasma concentration time profile World Health Organization 21 April, 2017 Cmax AUC This is an example of a plasma concentration time profile following extravascular administration of a drug. The parameters often used in bioequivalence assessments are here marked as AUC, Cmax and Tmax. For definitions, see next page. Tmax time

Bioequivalence IR formulations– single dose Basic design considerations: minimize variability not attributable to formulations minimize bias goal: compare performance 2 formulations

Bioequivalence IR formulations– single dose Golden standard study design: single dose, two-period, crossover healthy volunteers Reference (comparator)/ Test (generic)

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 – 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 – 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 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 Administration of Test/Reference: Procedure of drug intake: time of administration (fasted or fed state) liquid volume traceability of administrations

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

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

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

knowledge drug substance Sampling Blood sampling: Number of samples. Sampling times (Cmax!). knowledge drug substance Time of sampling (extrapolated AUC max. 20%). Washout phase long enough.

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

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

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 EMA guidance depends on linearity in PK and solubility active substance bracketing approach possible

Choice of the comparator:

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

Choosing national comparator complex Decision tree Choosing national comparator complex WHO provides criteria decision tree NO ? YES ? YES NO NO ?

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!?

World Health Organization EMA (Europe) World Health Organization 21 April, 2017 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.

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

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

Guidance documents

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: prequalassessment@who.int

Statistical considerations

= bioavailability with pre-defined criteria for the rate Bioequivalence Bioequivalence: = bioavailability with pre-defined criteria for the rate and extent of absorption!!

2 pharmaceutical products Bioequivalence 2 pharmaceutical products Reference Test Bioequivalent??

Statistical considerations How similar is similar?

Statistical considerations

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)

Non-inferiority studies 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

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)

Statistical considerations Some International Criteria Country/Region AUC 90% CI Criteria Cmax 90% CI Canada (most drugs) 80 – 125% none (point estimate only) Europe South Africa (most drugs) 75 – 133% (or broader if justified) Japan (some drugs) Some drugs wider than 80 – 125% Worldwide “acceptance range for Cmax may be wider than for AUC”

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

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%

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)

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

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

Statistical considerations 80 100 125

Statistical considerations why log-transformation:

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

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

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

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.

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

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

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 pH! 90% CI AUC and Cmax: 80 – 125% 90% CI AUC and Cmax: 80 – 125% or not statistical significant different

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: 80 – 125% 90% CI AUC and Cmax: 80 – 125%; Cmin and PTF! 90% CI AUC and Cmax: 80 – 125% - dose dumping - FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002) - steady state conditions - EU, not FDA

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

depends on drug substance! Bioequivalence Most submitted bioequivalence studies are: Single dose studies. Fasted conditions. depends on drug substance! Crossover design. Non replicate.

Thank you for your attention End Thank you for your attention