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21 July 2016 EMA/CHMP/474782/2016 Committee for Medicinal Products for Human Use (CHMP)

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Exenatide powder and solvent for prolonged-release suspension for injection, 2 mg, and powder and solvent for prolonged-release suspension for injection in pre-filled pen, 2 mg product-specific bioequivalence guidance

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Draft

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10 Draft agreed by Pharmacokinetics Working Party Adopted by CHMP for release for consultation Start of public consultation End of consultation (deadline for comments)

June 2016 21 July 2016 1 August 2016 31 October 2016

11 12 Comments should be provided using this template. The completed comments form should be sent to [email protected] 13 Keywords

Bioequivalence, generics, exenatide

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30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

An agency of the European Union

© European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged.

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Exenatide powder and solvent for prolonged-release suspension for injection, 2 mg, and powder and solvent for prolonged-release suspension for injection in pre-filled pen, 2 mg product-specific bioequivalence guidance

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Disclaimer:

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This guidance should not be understood as being legally enforceable and is without prejudice to the need to ensure that the data submitted in support of a

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marketing authorisation application complies with the appropriate scientific, regulatory and legal requirements.

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Requirements for bioequivalence demonstration (PKWP)*

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Bioequivalence study design**

Single dose: 2 mg, healthy volunteers Multiple dose: 2 mg, patients Background: Single dose and multiple dose studies required for prolonged release formulations with accumulation. cross-over or parallel

Analyte

parent plasma/serum

metabolite blood

Enantioselective analytical method:

both urine yes

Exenatide powder and solvent for prolonged-release suspension for injection, 2 mg, and powder and solvent for prolonged-release suspension for injection in pre-filled pen, 2 mg product-specific bioequivalence guidance EMA/CHMP/474782/2016

no

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Bioequivalence assessment

Main pharmacokinetic variables: Single dose: AUC0-t, AUC0-inf, Cmax (initial burst) and Cmax (extended release phase) Multiple dose: AUC0-τ, Cmax,ss and Cτ,ss Background: In the single dose study, Cmax (initial burst) and Cmax (extended release phase) should be analysed. The Cmax (initial burst) is important from a safety perspective. 90% confidence interval: 80.00– 125.00% for all parameters except from Cmax (initial burst). For Cmax (initial burst)

the upper limit should not exceed 125.00%.

Background: for the initial burst it is sufficient to demonstrate that plasma concentrations are not higher for the generic compared to the reference product. 22

* As intra-subject variability of the reference product has not been reviewed to elaborate this product-specific bioequivalence guideline, it is not possible to

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recommend at this stage the use of a replicate design to demonstrate high intra-subject variability and widen the acceptance range of Cmax Cτ,ss, and partial

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AUC. If high intra-individual variability (CVintra > 30 %) is expected, the applicants might follow respective guideline recommendations.

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** For prolonged release formulations: If a single-dose study with the highest strength has shown that there is low risk of accumulation (i.e. AUCτ > 90% of

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AUCinf), the multiple-dose study may be waived. If low degree of accumulation is expected, the applicants might follow respective guideline

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recommendations.

Exenatide powder and solvent for prolonged-release suspension for injection, 2 mg, and powder and solvent for prolonged-release suspension for injection in pre-filled pen, 2 mg product-specific bioequivalence guidance EMA/CHMP/474782/2016

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Exenatide powder and solvent for prolonged-release suspension for ...

Jul 21, 2016 - ... enforceable and is without prejudice to the need to ensure that the data submitted in support of a. 19 ... Enantioselective analytical method:.

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