Bioequivalence trials: design, evaluation, regulatory requirements Laszlo Tothfalusi Ph.D.

BIOEQUIVALENCE “Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent of absorption) after administration in the same molar dose lie within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e. similarity in terms of safety and efficacy.” GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE, EMA (LONDON), 2010.

Different approach for establishing equivalence Studies Different approach for establishing equivalence PD studies clinical studies in vitro methods PK studies

Clinical studies- endpoint Comparative clinical studies in case PK or PD studies can not be performed However: - requires large number of subjects - methodology establishing equivalence has not yet evolved extensively as for PK BE trials - insensitive

Clinical study

In case of local action/ no systemic absorption PD studies- marker Comparative PD studies In case of local action/ no systemic absorption Not recommended when: - active ingredient is absorbed into the systemic circulation - pharmacokinetic study can be conducted

PD studies Comparative PD studies PD measures more variable than PK response relevant efficacy/safety placebo effect method: validated

PD based bioequivalence: -skin blanching response to corticosteroids

In vitro BCS based biowaiver Based on in-vitro in-vivo correlation(IVIVC) study

PK Bioequivalence study is needed for Oral Immediate Release products 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

But BIOEQUIVALENCE TESTING--- is not only for Generics ! BE tests are not only required for the registration of generic drugs but are also carried out during the development of new drugs: e.g. during scale-up and for post-approval changes. The same paradigm is also used for: FDC (Fixed-dose combination), Food effect DDI studies !

Guidance documents…

STUDY DESIGN - standard design: randomized, two-period, two-sequence, single dose cross-over design - alternative designs: parallel design (substances with very long half-lives) and replicate designs (in case of highly variable drugs or drug products)

TWO-GROUP PARALLEL DESIGN RANDOMIZATION group 1 TEST subjects group 2 REFERENCE

Two-Group Parallel Design Advantages Clinical part shorter than a crossover. Straigthforward statistical analysis. No washout period - drugs with long half life. Potentially toxic drugs or effect and/or AEs unacceptable in healthy subjects. Studies in patients Disadvantages More volunteers are needed than for crossover design Tight inclusion-/exclusion criteria to reduce between-subject variability. Phenotyping mandatory for drugs showing polymorphism.

2 x 2 CROSS-OVER DESIGN R T T R RANDOMIZATION period 1 period 2 WASHOUT T sequence 1 subjects sequence 2 T R

Standard 2x2 design Advantages Globally applied standard protocol for bioequivalence, drug-drug interaction, food effect studies. Straigthforward statistical analysis. Disadvantages Frequently not suitable for studies in patients Not optimal for drugs with long half life Not optimal for highly variable drugs / drug products replicate designs with reference-scaling

REPLICATE DESIGN 4-period, 2-sequence, 2-formulation design RANDOMIZATION I II III IV sequence 1 T R T R subjects sequence 2 R T R T wash-out

Replicate designs Two-sequence four-period Two-sequence three-period TRTR | RTRT Two-sequence three-period TRT | RTR and many others… (FDA: TRR | RTR | RRT, aka ‘partial replicate’) The statistical model is complicated and depends on the actual design!

Add-On / Two-Stage Designs Sometimes properly designed studies fail due to ‘true’ bioinequivalence, pure chance (producer’s risk), poor study conduct (increasing variability), false (mainly over- optimistic) assumptions about the CV and/or T/R- ratio – leading to a too small sample size (insufficient power).

From H Schütz, BEBAC AT

After repeated administration (fasting) One bioequivalemce study frequently not enough : modified release products Single dose, fasting Single dose, fed After repeated administration (fasting)

Power vs. Treatment Difference for Bioequivalence

Biowaiver request for different strenghts: The following general requirements must be met where a waiver for additional strength(s) is claimed: the pharmaceutical products are manufactured by the same manufacturing process, the qualitative composition of the different strengths is the same, the composition of the strengths are quantitatively proportional, i.e. the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths (for immediate release products, coating components, capsule shell, colour agents and flavours are not required to follow this rule), If there is some deviation from quantitatively proportional composition, condition c is still considered fulfilled if condition i) and ii) or i) and iii) below apply to the strength used in the bioequivalence study and the strength(s) for which a waiver is considered the amount of the active substance(s) is less than 5 % of the tablet core weight, the weight of the capsule content the amounts of the different core excipients or capsule content are the same for the concerned strengths and only the amount of active substance is changed the amount of a filler is changed to account for the change in amount of active substance. The amounts of other core excipients or capsule content should be the same for the concerned strengths appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo bioequivalence testing (see section 4.2).

EMA Guideline on the Investigation of Bioequivalence, 2010 SAMPLING TIMES “The sampling schedule should include frequent sampling around the predicted tmax to provide a reliable estimate of peak exposure. In particular, the sampling schedule should be planned to avoid Cmax being the first point of the concentration- time curve.” o “The sampling schedule should also cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure which is achieved if AUC0-t covers at least 80% of AUC0-. At least 3 to 4 samples are during the terminal log- linear phase in order to reliably estimate the terminal rate constant, which is needed for a reliable estimate of AUC0-.” Sampling times: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours.

EMA Guideline on the Investigation of Bioequivalence, 2010 PRIMARY PARAMETERS: - AUC0-t or AUC0-72h: extent of absorption - Cmax: extent and rate of absorption - Tmax: rate of absorption

Bioequivalence criteria: 90% CONFIDENCE INTERVAL a 90% confidence interval has to be calculated around the ratio of geometric means obtained for AUC (and Cmax) following administration of test and reference preparation this ratio of geometric means is called the point estimate

 90% CONFIDENCE INTERVAL 90% CI  1.04 (0.91 – 1.20) 1.04 point estimate Evaluation The test/reference ratio is calculated. The 90 % confidence interval (CI) around the ratio is calculated. The width of the CI depends on the variability observed in the study. The location of the CI depends on the observed test/reference-ratio.   0.80 1.04 1.25 Bioequivalence is accepted if CI in th 0.8 – 1.25 range or

HVDPs (EMA) EU GL on BE (2010) Average Bioequivalence (AB) with Expanding Limits (EL)  “ABEL” Based on WR (the intra-subject standard deviation of the reference formulation) calculate the scaled acceptance range based on the regulatory constant k (s = 0.760);

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