Linee Guida EU e US FDA su Biodisponibilità e Bioequivalenza

Docente:

Prof. Antonio MARZO e-mail: antoniop.marzo@libero.it

Master Universitario di II Livello Ricerca e Sviluppo Pre-Clinico e Clinico del Farmaco

Modulo 4 – Sviluppo Clinico dei Farmaci

Chieti, 14-15 novembre 2013

Linee Guida Europee (1)

٭ III/54/89-EN

„Investigation of Bioavailability and Bioequivalence“

٭ III/3601/91-EN

„Investigation of Chiral Active Substances“

٭ CPMP/EWP/239/95 (Forme Topiche)

„Note for Guidance on the Clinical Requirements for Locally Applied, Locally Acting Products Containing Known Constituents“

٭ CPMP/EWP/280/96 (Forme a Rilascio Modificato)

„Note for Guidance on Modified Release Oral and Transdermal Dosage Forms: Section II (Pharmacokinetic and Clinical Evaluation)“

Linee Guida Europee (2)

٭ CPMP/EWP/QWP/1401/98

„Note for Guidance on the Investigation of

Bioavailability and Bioequivalence“

٭ EMEA/CHMP/EWP/40326/2006

„Questions & Answers on the Bioavailability and

Bioequivalence Guideline“

٭ CPMP/EWP/QWP/1401/98 Rev. 1

„Guideline for the Investigation of Bioequivalence“

(20 January 2010)

٭ EMA/CPMP/EWP/280/96 Corr. 1, Draft XXIII

„Guideline on the Pharmacokinetic and clinical

evaluation of modified release dosage forms“

Linee Guida US FDA (1)

٭ September 1997

„Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations“

٭ October 1997 „In Vivo Bioequivalence Studies Based on Population and

Individual Bioequivalence Approaches“

٭ January 1999 (Esenzione) „Waiver of In Vivo Bioavailability and Bioequivalence Studies

for Immediate Release Solid Oral Dosage Forms Containing Certain Active Moieties/Active Ingredients Based on a Biopharmaceutics Classification System“

Linee Guida US FDA (2)

٭ December 1999 „Skin Irritation and Sensitization Testing of Generic Transdermal

Drug Products“

٭ January 2001 „ Statistical Approaches to Establishing Bioequivalence“

٭ May 2001 „ Bioanalytical Method Validation“

٭ December 2002 „Food-Effect Bioavailability and Fed Bioequivalence Studies“

٭ March 2003 „Bioavailability and Bioequivalence Studies for Orally

Administered Drug Products – General Considerations“

Definizioni (1)

Pharmaceutical Equivalence ٭

Medicinal products are pharmaceutically equivalent if they contain the same amount of the same active substance(s) in the same dosage forms that meet the same or comparable standards.

Pharmaceutical equivalence does not necessarily imply bioequivalence as differences in the excipients and/or the manufacturing process can lead to faster or slower dissolution and/or absorption.

Pharmaceutical Alternatives ٭

Medicinal products are pharmaceutical alternatives if they contain the same active moiety but differ in chemical form (salt, ester, etc.) of that moiety or in the dosage form or strength.

Definizioni (2)

Bioavailability ٭

Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action.

Bioequivalence ٭

Two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same.

Farmaci per via orale

Studi clinici di BE nel volontario sano

Immediate-release e filmati (film-coated) BE a digiuno in dose singola Nota: per farmaci con lunga emivita anche steady-state

Gastroprotetti (enteric-coated) BE a digiuno in dose singola

BE dopo cibo in dose singola

Cessione temporizzata (extended-release) BE a digiuno in dose singola BE dopo cibo in dose singola

BE in Steady State

Attivi per via sistemica (es. Cerotti di nitroglicerina)

BE in dose singola

BE in dose ripetuta nel volontario sano

Tollerabilità e adesività

Attivi topicamente

BE sull‘efficacia e sulla tollerabilità nella target population

con il criterio della „non inferiorità“

Farmaci topici

a) Farmaci solubili a tre pH: 1.2, 4.5, 6.8

b) Farmaci somministrati in soluzione sia il Test che il

Reference

c) In presenza di linearità tra le dosi e farmacocinetica

e in diverse altre situazioni, in caso di più posologie é

ammesso lo studio di bioequivalenza su una sola

posologia (strength).

Esenzioni da studi di BE

Open questions on bioequivalence: some problems and some solutions. A. Marzo – Pharmacol. Res., 40:357-368 (1999)

Bioequivalence of endogenous substances facing homeostatic equilibria: an example with potassium.

A. Marzo, D. Vuksic, F. Crivelli - Pharmacol. Res., 42:523-525 (2000)

Bioequivalenza di farmaci generici: aspetti regolatori, ispezioni e frodi. A. Marzo, M. Fibbioli – Cronache Farmaceutiche, 44:76-78 (2001)

The degree of predictivity in pilot studies on six subjects in bioequivalence trials. A. Marzo, M. Fibbioli, C. Marone, et al. – Pharmacol. Res., 49:283-286 (2003)

Open Questions on BE (1)

Open Questions on BE (2)

Bioequivalence behind the scenes. A. Marzo – Pharm. Dev. Reg., 1:179-189 (2003)

Open questions on bioequivalence: the case of multiple peak phenomenon. A. Marzo, V. Reiner – J. Pharm. Pharmacol., 56: 281-282 (2004)

Open questions on bioequivalence: an updated reappraisal A. Marzo – Curr. Clin. Pharmacol., 2: 179-189 (2007)

Open questions on bioequivalence: what about the time interval between two consecutive trials? A. Marzo – Arzneim.Forsch., 57: 505-506 (2007)

How improved sensitivity of bioassays and terminal half-life of drugs impact on bioequivalence trials. A. Marzo, E. Fontana – Arzneim.Forsch., 59: 55-58 (2009)