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Abstract/Summary
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The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by
the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised
together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop
US-FDA joined as co-sponsor – to support global harmonisation of regulatory recommendations for bioequivalence
(BE) assessment.
At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main
conclusions were drawn:
(1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly
variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to
support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a
majority of the workshop participants were in favour of a more frequent application of such approaches. The
regulatory conditions relevant in this context need further concretisation and harmonisation between the regions.
Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE
development programmes.
(2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed
only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously,
BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants
or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions.
Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation
of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in
fed state.
(3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential
benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In
addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.
g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and,
despite significant progress already achieved during previous years, more research is needed before they may be
fully accepted for regulatory purposes.
(4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in
necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure
into BE assessment with more restrictive criteria and the importance of comparison of the product-related within subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were
presented and discussed but need further consideration before harmonisation can be achieved.
The highly interactive meeting and extensive exchange between regulators and scientists from industry and
academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation.
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