高变异药物的生物等效性试验研究方法

4
Possible BE study outcomes
Normal variability
Pass
Low variability
Pass
Highly variable
Fail
80%
T/R (%)
125%
5
Background
ACPS Meeting, April 14, 2004: Discussion on Highly Variable Drugs
• DBE 1 and 2 have reviewed protocols for BE studies which use this approach • Several ANDAs using the mixed-referencescaled ABE approach are under review 17
12
Discussion of HV Drugs Problem and Potential Solution
• FDA’s Pharmaceutical Sciences Advisory Committee (PSAC) in 2004 suggested reference-scaled average BE approach. • The OGD HV Drug Working Group studied approach by simulating outcome of BE studies of HV drugs under various conditions. • OGD presented results to PSAC in 2006. • The PSAC concurred with approach.
16
Drugs with HV BE Measures: Approach Now Recommended by OGD
• This approach is
– Mixed Scaled Average BE • Normal non-scaled average bioequivalence for CV < 30% • Reference-scaled average bioequivalence (ABE) for CV ≥ 30%
11
Survey of BE data – Summary
• BE studies of HV drugs used more subjects than studies of drugs with lower variability. • Within-subject variability was about 30-40% in most BE studies of HV drugs. • HV drug substances were classified as consistently, borderline, or inconsistently HV. • Certain dispositional and physicochemical characteristics were shared by consistently HV and borderline HV drug substances. • Drug product dissolution variability was high for about half of the inconsistently HV drugs.
Different approaches were considered, e.g., expansion of bioequivalence limits, and scaled average bioequivalence Committee favored scaled average bioequivalence over other approaches FDA working group was created; a research project to evaluate scaling was initiated
ACPS = Advisory Committee for Pharmaceutical Science
7
Drugs with Highly Variable BE Measures: A Need for New BE Approaches?
• Highly variable drugs (HVD) are defined as drugs for which within-subject variability in AUC and/or Cmax > 30% • About 20% of all BE studies reviewed by the OGD from 2003-2005 were of HVD
ACPS = Advisory Committee for Pharmaceutical Science
6
Background
ACPS Meeting, October 6, 2006
Preliminary results of simulation study were presented Committee was in favor of using a point estimate constraint with scaled average BE Most members favored a minimum sample size of 24
10
Common characteristics of HV drug substances
• • • • • • Extensive presystemic metabolism Food effects Low oral bioavailability Instability in gastrointestinal tract Poor aqueous solubility Subcutaneous route of administration
2
Model of oral dosage form performance
Dosage Form Performance
Dosage Form
Drug in Solution
Gut Wall
Blood
Site of Activity
Therapeutic or PD Effect
Formulation
13
Proposal previously discussed for BE studies of HV drugs
• Reference-scaled average BE approach • Three-period BE study
– Administer reference product twice – Administer test product once – Sequences = TRR, RRT, RTR
• Concerns
– Borderline drugs – Submission of unscaled and reference-scaled BE statistics for same product – What if T variability > R variability – Unacceptably high or low T/R mean ratios – Number of study subjects
Bioequivalence Methods for Highly Variable Drugs and Drug Products
Dale P. Conner, Pharm.D. Director Division of Bioequivalence 1 OGD, CDER, FDA
ACPS-CP August 5, 2009 1
– Often drugs achieving low plasma levels
• The no. of subjects needed to show BE of a HVD may be >> for a typical BE study
8
Survey of BE studies submitted to FDA’s OGD -- Objective
• BE criteria scaled to reference variability • Both AUC and Cmax should meet BE acceptance criteria
14
Reference-scaled average BE approach
• Adjust BE limits of HV drugs by scaling to the within-subject variability of the reference product in the 3-way BE study • For both AUC and Cmax:
Introduction
• The FDA accepts an in vivo BE study of a generic product when the 90% confidence intervals of the geometric mean test/reference ratios for AUC and Cmax fall within BE limits. • BE limits are 80 to 125%. • FDA applies these criteria to all BE studies with pharmacokinetic (PK) endpoints.
BE limits, upper, lower = EXP ± 0.223 x σWR σW0 Where σW0 = 0.25