Presentation on theme: "Design of Bioequivalence Studies Alfredo García – Arieta, PhD"— Presentation transcript:
1Design of Bioequivalence Studies Alfredo García – Arieta, PhD WHO Workshop on Assessment of Bioequivalence Data, 31 August – 3 September, 2010, Addis Ababa
2Design to achieve the objective BE studies are design to compare the in vivo performance of multisource product with that of comparatorTwo purposes:Provide in vivo measure of pharmaceutical qualitySurrogate of clinical proof of equivalenceIt is necessary:Two minimize variability (within and between subjects)Eliminate bias (unequal carry-over effect in 2x2 designs)
3Conventional Design: 2x2 Randomization to sequences of treatmentPeriod 2Washout (passive)Period 1Multisource productComparator productSequence 1 (AB) (n subjects)Sequence 2 (BA) (n subjects)>5 half-livesA two-period, two sequence, single dose, cross-over, randomized design in healthy volunteers
4Wash-out to avoid carry-over Period 1Wash outPeriod 2Blood samples are collected and assayedBefore and several times after drug administration. No need after 72 hPrior to period 2, pre-dose levels must be <5% of Cmax of 2nd periodWash out period must take into account the slow metabolizersMinimum wash out: 7 days (1 week)
5Alternative designs: Multiple dose Very potent or toxic drugs:Patients (stable) if a single dose study cannot be conducted in healthy volunteers due to tolerability reasonsMultiple dose study in patients is acceptable, when a single dose study is not feasible in patientsMultiple dose if patients cannot have passive wash-out. Usual dosing.Appropriate dosing and sampling to document attainment of steady stateSingle dose if a wash-out period is possibleConc.TimeWash-out (>3-5t1/2)P2 build i-up P1Period 2Period 1BA
6Alternative designs: Multiple dose In the rare situation where problems of sensitivity of the analytical method preclude sufficiently precise plasma concentration measurements after single dose administration and where the concentrations at steady state are sufficiently high to be reliably measured, a multiple dose study may be acceptable as an alternative to the single dose studyHowever, given that a multiple dose study is less sensitive in detecting differences in Cmax, this will only be acceptable if the applicant adequately can justify that the sensitivity of the analytical method cannot be improved and that it is not possible to reliably measure the parent compound after single dose administration taking into account also the option of using a supra-therapeutic dose in the BE study (no solubility or tolerability limitations)
7Alternative designs: Multiple dose In the past a multiple dose study was required in EU for drugs that exhibit non-linear kinetics at steady state (e.g. saturable metabolism, active secretion)No longer required in EUIncluded in WHO guidelineExtended release dosage-forms with a tendency to accumulationIn addition to single dose studiesFasted stateFed state
8Drugs with long elimination t1/2: Parallel Normally wash-out period should not exceed 3-4 weeksIf a larger wash-out period is necessary a parallel design may be more appropriateVariability will be larger, needs higher sample sizeParallel design: Total variability (intra+inter)Cross-over: Intra-subject variabilitySampling: Up to 72 hGroup 1: Treatment ARandomization to treatmentsGroup 2: Treatment B
9Replicate design In case of highly variable drugs (CV>30%) Two distinguish intra-subject variability from other sources of variability: random error, analytical method, …More information:Intra-subject variability of Test product / Multisource (generic)Intra-subject variability of Reference / ComparatorSubject by formulation interactionIf scaling / widening limits based on variabilityFewer subjectsMore administrationsSimilar number of profiles
10PK parameters to characterize World Health OrganizationPK parameters to characterize31 March, 2017AUC0-t or AUC0-inf: extent of systemic exposure / absorptionCmax: peak exposureDepends on rate and extent of absorptionTmax: Time of peak exposureDepends on rate of absorption and rate of eliminationRelevant only in drugs with clinically relevant onset of action (e.g. analgesics)CmaxAUCThis 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.Tmaxtime
11Sampling timesBlood samples with frequency sufficient frequency for assessing Cmax, AUC and other parametersSampling points should include:a pre-dose sample,at least 1–2 points before Cmax,2 points around Cmax and3–4 points during the elimination phase.Consequently at least seven sampling points will be necessary for estimation of the required pharmacokinetic parameters.
12Sampling timesFor most medicines the number of samples necessary will be higher to compensate for between-subject differences in absorption and elimination rate and thus enable accurate determination of the maximum concentration of the API in the blood (Cmax) and terminal elimination rate constant in all subjectsGenerally, sampling should continue for long enough to ensure that 80% of the AUC (0→ infinity) can be accrued, but it is not necessary to sample for more than 72 hoursThe exact duration of sample collection depends on the nature of the API and the input function from the administered dosage form
13Immediate release: Fasting or fed conditions Fasted-state studies are generally preferredLabelling only on an empty stomach, orLabelling irrespective of food intakeFed state:When the product is known to cause gastrointestinal disturbances in the fasted state, orIf labelling restricts administration in the fed stateComposition of meal may depend on local diet and customs
14Fasting conditions Overnight fast of at least 10 hours Participants are allowed free access to waterNo water is allowed during the hour prior to drug admin.The dose should be taken with a standard volume of waterUsually 150–250 ml.2 h after drug admin. water is again permitted ad libitum.A standard meal is usually provided 4 hours after drug ad.
15Additional requirements in EU EMA (2010):For products with specific formulation characteristicsmicroemulsions,solid dispersions, …BE studies performed under both fasted and fed conditions are requiredUnless the product must be taken only in the fasted state or only in the fed state
16Additional requirements in US-FDA In addition to a BE study under fasting conditionsBE study under fed conditions for all orally administered immediate-release drug productsExcept:When both test product and comparator are rapidly dissolving, have similar dissolution profiles, and contain a BCS Class I drug substance,When the label states that the product should be taken only on an empty stomach, orWhen the label does not make any statements about the effect of food on absorption or administration.
17Fasting & fed conditions In cases where information is required in both the fed and fasted states, it is acceptable to conducteither two separate two-way cross-over studies ora four-way cross-over study
18Fed conditions: meal composition In studies performed under fed conditions, the composition of the meal is recommended to be according to the SPC of the originator productThe composition of the meal may depend on local diet and customsIf no specific recommendation is given in the originator SPC, the meal should be a high-fat (approximately 50 percent of total caloric content of the meal) and high- calorie (approximately 800 to 1000 Kcal) meal
19Meal composition in Fed conditions This test meal should derive approximately 150, 250, and Kcal from protein, carbohydrate, and fat, respectivelyThe composition of the meal should be described with regard to protein, carbohydrate and fat content (specified in grams, calories and relative caloric content (%)).
20Considerations for Modified Release Products Types:Prolonged release: sustained-, controlled-, extended-releaseDelayed release: gastro-resistantSeveral studies are required:Single-dose fasted-state cross-over with highest strengthSingle-dose fed-state cross-over with highest strengthHigh-fat meal (time according to SPC or 30 min before drug intake)Multiple-dose fasted state for prolonged release product with a tendency to accumulate (not in FDA)In vitro dissolution studies on alcohol effect (10, 20, 40%)
21Modified Release Products Types:Single-unit formulationsMultiple-unit formulationsProportional formulationsMultiple-unit formulations: testing highest strength is enoughThe other proportional strengths are waived based on dissolutionSingle-unit formulations:US-FDA: BE with the highest strength is enough (and some EU for Enteric)Dissolution at least three media (e.g., pH 1.2, 4.5 and 6.8)EU: All strengths have to be tested in the fasted-state single-dose studyHighest strength in fed-state single-dose or fasted-state multiple-dose