Bioequivalence 2 Flashcards
(36 cards)
What are BE studies required for?
any new generic product
an innovator manufacturer to show product to be marketed is BE with the formulation used in clinical trials
innovator manufacturer changes formulation of drug on the market or introduces additional dosage strengths
considering new route of administration
What are some cases where a waiver of BE would be allowed?
some drugs, in vivo BA may be self-evident or not important to products intended purpose
-solution intended for IV use
-topical applied for local use
-oral dosage form not intended to be absorbed
-administered by inhalation
-solution, elixir, syrup, tincture, etc. form of an approved product and contains no inactive ingredients known to affect BA
class I BCS drugs
By descending order of preference, which types of bioequivalence studies are preferred by US-FDA and CAN-TPD?
pharmacokinetic study (PK-BE)
pharmacodynamic study (PD-BE)
comparative clinical study
in vitro study (dissolution study, BCS biowaivers)
When are PD-BE studies used?
when PK approach not possible
-i.e., locally acting drug product
What do PD-BE studies assess?
uses a pharmacological or clinical endpoint
-e.g., FEV for inhaled bronchodilators
What are PD parameters?
AUC of the PD effect vs time curve
peak PD effect
time for peak PD effect
Why are many PD tests difficult to quantify?
placebo effects (increase sample size)
PD variability is large (increase sample size)
What is required for PD-BE studies?
must be validated (accurate, sensitive, reproducible)
demonstration of a dose-response curve
doses should produce a range of response values
instrumental measurements should be made under double-blind conditions
When are clinical studies used for BE?
when neither PK nor PD approach possible
How is BE established in clinical studies?
uses a controlled clinical blind or double blind study –> BE established through evaluation of clinical response
What is used to establish BE for topical antifungal drug products?
clinical studies
What are the disadvantages of clinical studies for BE?
least accurate, least sensitive, least reproductive
considered only when analytical and PD not available
What are PK-BE studies?
uses PK measures to determine rate/extent of drug release from product and absorption into systemic circulation
What is used in PK-BE studies to reflect important differences in T vs R?
exposure concept of BE
-total exposure (AUC for single dose, AUC for multiple dose)
-peak exposure (Cmax)
-early exposure (partial AUC to peak time)
What would the ideal subject be for BE studies?
normal, healthy volunteers
-age 18-55, BMI 18.5-30, normal med exam, no alcohol or drug use, ECG if drug impacts, not pregnant/lactating
may be necessary to conduct studies in pts who are already receiving the drug
What should be considered in the study design of BE studies?
the three fundamental statistical concepts of study designs:
-randomization (allot tx to subjects without selection bias)
-replication (tx applied to more than one experimental unit)
-error control (reduce sources of experimental error)
What is involved in a typical single oral dose (SOD) design?
2 product
2 period
2 sequence
crossover
Differentiate crossover and parallel study design.
crossover:
-diminished intrasubject variation and allows examination of intrasubject variation
-replicated cross-over designs: formulations tested more than once in the same subjects
-more periods and sequences: more than two formulations, or different study conditions
parallel:
-does not allow within-subject comparison (need to increase n)
When do we consider using parallel study design for BE?
drug has very long t1/2
some depot formulations
What does the number of subjects with desired power and significance level depend on?
mean difference between T and R (+/- 20%)
intra-subject variance
power (typically 0.8)
type I error rate of 5%
What is the minimum number of subjects needed for BE studies?
12
-or determine intra-subject variance from first stage then expand the study
-accounting for drop-outs
-accounting for outliers
What are the standardized study conditions for BE studies?
posture, exercise, diet, smoking, alcohol, other drugs
dietary items that effect P450 enzymes and PGP efflux pump
blinding
-subjects, person checking for AE, analyzer
control food and fluid administration
-fast 8h, water consumed up to 1h before admin
-dose at same time every day
-dose taken with 150-250ml of water
-water and food 1 and 4h after
Describe proper conduct of a BE study.
subject takes T or R with 150-250ml water
blood samples taken at intervals to define Cp vs t curve
-minimum 12 samples per subject per dose
-sample for at least 3 half lives
plasma collected and frozen
allow sufficient washout (>10h t1/2) then next formulation taken
monitor and record AE
validated assay determines drug concentration
Which design is used for most BE studies?
SOD
