Master Universitario di II Livello
Ricerca e Sviluppo Pre-Clinico e Clinico del Farmaco
Modulo 4 – Sviluppo Clinico dei Farmaci
Linee Guida EU e US FDA su
Biodisponibilità e Bioequivalenza
Docente:
Prof. Antonio MARZO
e-mail: [email protected]
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)

Cessione temporizzata (extended-release)
BE a digiuno in dose singola
BE dopo cibo in dose singola
BE a digiuno in dose singola
BE dopo cibo in dose singola
BE in Steady State
Farmaci topici

Attivi per via sistemica (es. Cerotti di nitroglicerina)
BE in dose singola
BE in dose ripetuta
Tollerabilità e adesività

nel volontario sano
Attivi topicamente
BE sull‘efficacia e sulla tollerabilità nella target population
con il criterio della „non inferiorità“
Esenzioni da studi di BE
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).
Open Questions on BE (1)
 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., 42:523525 (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 (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)