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Interchangeability and study design Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 2| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 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) 3| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Guidance documents 4| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Regulatory Authority Mission “Assure that SAFE and EFFECTIVE drugs are marketed in the country and are available to the people” 5| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioavailability Bioavailability Bioavailability means the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. plasma 6| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioavailability relative bioavailability absolute bioequivalence different formulations food-effect interactions 7| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence Bioequivalence: Two medicinal products are bioequivalents if they are pharmaceutical equivalents or alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essential the same. 8| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence Bioequivalence Bioavailability Pharmaceutical equivalent Pharmaceutical alternatives 9| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence Pharmaceutical Equivalent Products Reference Test Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution specifications) 10 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence Therapeutic equivalence of a multiscource product can be assured when the multiscource product is both pharmaceutically equivalent/alternative and bioequivalent. Concept of interchangeability includes the equivalence of the dosage form as well as for the indications and instructions for use. 11 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence Pharmaceutical equivalent does not necessarily imply therapeutic equivalence: - difference excipients - difference manufacturing process - other variables 12 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 drug performance? Bioequivalence Therapeutic equivalent does not necessarily imply bioequivalence: - sensitivity - different formulations (IR/CR) - different active substance 13 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 equivalence? Bioequivalence pharmaceutical equivalence method: in principle comparative pharmacokinetics (AUC, Cmax) acceptance criteria: comparative rate and extent of absorption 14 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence BA and BE are generally required for approvals of innovator and generic (multiscource) products. BE based on blood level determination of Cmax and AUC has become the most commonly used and successful biomarker for safety and efficacy of the drug product. BE products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. 15 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence BRIDGING STUDIES variations scale up innovator clinical batch comm.batch ref. test changed batch ref. test acceptance variations approval innovator approval generic generic test ref. acceptance variations test bioequiv.batch ref. comm. batch scale up 16 | test Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 changed batch variations Bioequivalence Studies necessary for : Oral Immediate Release products – – – – In general Critical use medicines/Narrow therapeutic range drug products Documented BA or BE problems related to API Scientific evidence suggesting polymorphs of API, excipients, and/or process affecting BA – Non-oral, non-parenteral products designed to act systemically Oral Modified Release products Fixed-combination products with systemic absorption where at least one of the API requires an in vivo study 17 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence Cases when pharmaceutical equivalence is enough: Aqueous solutions – – – – – – Intravenous solutions Intramuscular, subcutaneous solutions Oral solutions Otic or ophthalmic solutions Topical products prepared as solutions Aqueous solution for nebulizer inhalation or nasal sprays Powders for reconstitution as solution Gases 18 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Studies Different approach for establishing equivalence PD studies clinical studies in vitro methods ONLY IN EXCEPTIONAL CASE !! 19 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 EXPERIMENTAL DESIGN 20 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 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 21 | tmax: time at which Cmax is observed measure of the rate of absorption Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Plasma concentration time profile Cmax AUC Tmax time 22 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – single dose Basic design considerations: minimize variability not attributable to formulations minimize bias goal: compare performance 2 formulations 23 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – single dose Golden standard study design: single dose, two-period, crossover healthy volunteers Reference (comparator)/ Test (generic) 24 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – 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 25 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – single dose Number of subjects!! - Sample size calculation: e.g. Eur J Drug Metab Pharmacokinet 30 (2005) 41 26 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – fast/fed Administration of Test/Reference: Normally fasted state – overnight fast – drug administration ca. 240 ml water If the SPC of the reference product contains specific recommendations in relation with food intake related to food interaction effects the study should be designed accordingly 27 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – fast/fed Food effect: delay in absorption: Plasma Conc. mg/L Plasma Conc. mg/L no change in absorption: Time (h) Time (h) decrease in absorption: Plasma Conc. mg/L Plasma Conc. mg/L increase in absorption: Time (h) 28 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Time (h) Bioequivalence – fast/fed If the recommendation of food intake is based on pharmacokinetic properties such as higher bioavailability, then a bioequivalence study under fed conditions is generally required If the recommendation of food intake is intended to decrease adverse events or to improve tolerability, a bioequivalence study under fasting conditions is considered acceptable although it would be advisable to perform the study under fed conditions. If the SPC leaves a choice between fasting and fed conditions, then bioequivalence should preferably be tested under fasting conditions as this situation will be more sensitive to differences in pharmacokinetics. 29 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – fast/fed In general: follow SPC. 30 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Sampling Blood sampling: Number of samples. Sampling times (Cmax!). Time of sampling (extrapolated AUC max. 20%). Washout phase long enough. 31 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 knowledge drug substance Extrapolated AUC < 20% time 32 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Extrapolated AUC < 20% time 33 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – multiple dose Multiple dose: More relevant clinically? Less sensitive to formulation differences! 34 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – multiple dose Multiple dose studies in case of….. Drug too potent/toxic for healthy volunteers –patients/ no interruption therapy Extended/modified release formulations – accumulation / unexpected behavior Non-linear PK at steady state Analytical assay sensitivity 35 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – parallel design Crossover: Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required Parallel: R 36 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 T Bioequivalence – parallel design Parallel design may be useful: Drug with very long elimination half-life – Crossover design not practical Parallel design considerations: Number of subjects Adequate sample collection – Complete absorption – 72 hours sufficient in general 37 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – replicate vs. non-replicate Standard approach BE study: non-replicate single administration R and T average bioequivalence 38 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – replicate vs. non-replicate Replicate (RRTT or RRT or TTR): T and/or R administered twice Intra-subject variability Subject X formulation interaction average bioequivalence/ individual bioequivalence 39 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – replicate design Scientific advantages: Comparison within-subject variances T and R Indicate whether T exhibits lower or higher within-subject variability More information (performance/S*F interaction) Reduce number of subjects 40 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence – replicate design Disadvantages: Bigger commitment volunteers More administrations per subject More expensive 41 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 Bioequivalence Most submitted bioequivalence studies are: Single dose studies. Fasted conditions. Crossover design. Non replicate. 42 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 depends on drug substance! End 43 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009