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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 ……… ……… ……… ……… 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, Abu Dhabi, 11-13 October, 2010 drug performance? Bioequivalence Therapeutic equivalent does not necessarily imply bioequivalence: - sensitivity - different formulations (IR/CR) - different active substance WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 equivalence? Bioequivalence pharmaceutical equivalence method: in principle comparative pharmacokinetics (AUC, Cmax) acceptance criteria: comparative rate and extent of absorption WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 EXPERIMENTAL DESIGN WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 Plasma concentration time profile Cmax AUC Tmax time WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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, Abu Dhabi, 11-13 October, 2010 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 – 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 – 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 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 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/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/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/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 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, Abu Dhabi, 11-13 October, 2010 knowledge drug substance Sampling Time of sampling (extrapolated AUC max. 20%). WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 EMA guidance Choice of the comparator: WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 Decision tree Choosing national comparator complex WHO provides criteria decision tree NO YES ? ? 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 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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. 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 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 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 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 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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, Abu Dhabi, 11-13 October, 2010 Statistical considerations WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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, 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 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 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, Abu Dhabi, 11-13 October, 2010 Statistical 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 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 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 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 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 Statistical considerations 80 100 WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 125 Statistical considerations why log-transformation: WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 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, Abu Dhabi, 11-13 October, 2010 Outliers ‘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 Outliers ‘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 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, Abu Dhabi, 11-13 October, 2010 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, Abu Dhabi, 11-13 October, 2010 - 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