Joint Symposium. Bioequivalence of Orally Inhaled Drug Products

Transcription

1 Joint Symposium Bioequivalence of Orally Inhaled Drug Products Feedback from breakout sessions and the way forward Interim outcomes of discussion forum presented on the day 30 March 2015

2 Recap of the aims To assemble key opinion leaders and challenge our scientific interpretation of the step-by-step approach; To categorise the challenges that remain in establishing equivalence in pulmonary bioavailability; To identify the key challenges to acceptability of in vitro surrogate markers of bioavailability; To establish a consensus on research programmes that are required to address these challenges, and a ranking of their relative importance.

3 1. What are our knowledge gaps in linking systemic drug concentrations to pulmonary therapeutic efficacy? Understanding is impaired by issues with dose and product variability (including reference products) There is a need to be clear what tests are for. Systemic drug concentration provides a sensitive relative measure for comparing products/doses/batches Systemic PK is more sensitive than pharmacodynamics Significance of small oral bioavailability is not widely appreciated and validation of charcoal block is important Imaging may help measure deposition, but requires 3D imaging and linking to PK data Efficacy is difficult to link to local lung concentrations (or APSD, which may be better linked to systemic availability) Measurements used for PD are not standardised or consistently applied, and have poor dose response

4 2. How should we set similarity boundaries in healthy volunteer PK studies that are relevant to therapeutic effect studies in diseased lungs? Healthy volunteer studies are suitable for establishing bioequivalence (and may be preferred) PK studies in healthy volunteers provide a quality test and should not be confused with therapeutic efficacy Uncertainty regarding the importance of metrics AUC0-30, Cmax, Tmax. Are these consistently measured and can studies be compared in metaanalyses? There is a need for evidence or investigation into whether/how changes in deposition change PK, and by how much? Disease state is likely to be important, but variable, through different inspiratory effort, deposition profiles and lung permeability

5 3. Is the total absorbed dose a suitable metric for examining bioavailability and bioequivalence, and how secure is the link to fine particle dose? Total dose should not be the sole metric for determining bioequivalence The acceptance criteria for AUC and Cmax have different degrees of latitude why? It should not be assumed that all the drug deposited is absorbed, especially for poorly water soluble drugs Drugs deposited in different formulations (solutions vs solid particles etc) will redistribute in the lung differently Drugs should be considered on a case-by-case basis. Safety/efficacy index is important - narrow index drugs will need a highly discriminatory test (i.e. PK) as PD is not sufficiently sensitive.

6 4. Is similarity of aerodynamic particle size distribution sufficient to predict systemic PK? For APSD, stages can be grouped according to the product/drug (i.e. based on stability or pharmacology, according to guidelines) - industry choice, but must be justifiable to regulators Groupings are currently performed for QC purposes rather than generating understanding. Studies should include an a priori selection of stages to be grouped Different opinion on whether justification may be data-driven or theoretical Flow is important could healthy volunteers generate different flow effects? More work on airway mechanics / dynamics is required Answer to question is no, or it depends. Weight of evidence is a better approach

7 5. What do existing performance/qc/release tests hide in terms of variability, comparability and equivalency of product performance? The oro-pharyngeal regions is important, but must be considered on a case by case basis. The most reproducible, discriminatory test is the driver for QC Statistical powering of in vitro assays is not performed and statistical methods are not standardised QbD approach is advocated, but what end-points should be used? Retrospective data can be useful to look for critical components. Need to use current metrics until better measures are devised Variation in methods is an issue, and is product specific Use-ability is a device design and development issue

8 6. What are the neglected aerosol properties that are required to predict post-deposition biopharmaceutics and how can we study them? Blend microstructure and particle surface properties of aerosol cloud and components Usefulness of dissolution as a QC test is unproven. Any such test should be reliable, simple and economic. It may be useful for de-risking development rather than QC Regional variation makes it difficult to configure a single dissolution test. BCS for the lung will not be straightforward and likely to be multifactorial

9 Consensus Discussion at the meeting Feedback at the end of the day Summary on website for comment by all delegates Research Priorities These will be derived from the discussion at the meeting and will be made available for comment before publication. These proposals will be designed to address: The requirements and interpretation of volunteer and patient studies in inhaled product development How to close the gap between in vitro test models, quality control product attribute tests and inhaled bioavailability studies

10 Overall Research Priority A consortium driven approach for correlating in vitro data to PK was advocated in all sessions, as an extension of Herbert Wachtel s concept for developing a standard dissolution method.

11 Next steps Consensus points will be made available for comment on the Aerosol Society and APSGB Inhalation Focus Group websites Organizers and key opinion leaders will prepare a consensus paper based on the meeting Publication of the consensus as a peerreviewed article

12 Acknowledgements Alfredo Garcia Arieta; Peter Daley-Yates; Philippe Rogueda; Herbert Wachtel; Burak Ozsogut, Nick Childerhouse, John Pritchard Our sponsors: