Safeguarding public health
Experience with the OIP Guideline – A Clinical Perspective from the UK on PK and Equivalence Studies
Dr S.Dissanayake Medicines and Healthcare products Regulatory Agency, UK 12th October 2010
Crown copyright
Revised OIP guideline

In effect since August 2009 Stepwise approach to demonstrate equivalence
-
Step 1. In vitro data Step 2. Lung deposition models (PK / scintigraphy) Step 3. Therapeutic effect / pharmacodynamic models
If equivalence confirmed at steps 1 or 2, may be no need for further data
http://www.ema.europa.eu/htms/human/humanguidelines/efficacy.htm
Slide 2 Crown copyright
1
Rationale for lung deposition studies (PK / scintigraphy)
Highly sensitive models
Salbutamol dose response
Linear DR reliably highlights differences between T vs. R
Slide 3
Crown copyright
Rationale for lung deposition studies (PK / scintigraphy)
-
Substantial literature base Have demonstrated significant differences:
Between devices At different flow rates With different respiratory manoeuvres With different respirable dose / fine particle dose With different particle sizes Between patients and healthy volunteers With different excipients
Slide 4
Crown copyright
2
Relevance of PK
OIP PK an indirect, 'after-the-effect' assay However, BE for non-OIPs frequently does not measure target organ drug levels, e.g., opioids PK sensitive to differences of ≤20%. Less useful to determine BE than bioassays typically sensitive to differences of ~400%
Where PD dose response exists, PK detects differences, i.e., deposition relates to clinical effect1,2 No studies have simultaneously demonstrated PD differences but equivalent PK
1. Pauwels,Eur Resp J 1997 2. Selroos, Clin Immunother 1996
Slide 5
Crown copyright
UK experience with OIP PK
-
Confirms highly discriminative nature of PK OIP BE is a high, not low, hurdle Why is it difficult Variability of inhalation manoeuvres Variability of T/R

下一页