Generic Drugs

Dr Wong Tee Wee Regulatory Consultant Pharmaceuticals & Biologics Branch Therapeutics Products Division Health Products Regulation Group Health Sciences Authority

All Rights Reserved 2008 Health Sciences Authority | 2

Singapores definition
Essentially similar to a currently registered product in Singapore (Reference product, RP) Generic drug application dont require nonclinical and clinical data but must fulfill:
Generic drug (Test product, TP) is bioequivalent to RP Route of administration of TP is same as RP Pharmaceutical dosage form of TP is same as RP Condition of use of TP is same as RP Indication, dosing regimen, patient population

All Rights Reserved 2008 Health Sciences Authority | 3

Current requirement
Bioequivalence (BE) data required for
Oral solid dosage form POM

Request for additional information if deemed appropriate

All Rights Reserved 2008 Health Sciences Authority | 4

Current requirement
Reference guidelines
ASEAN guideline on the conduct of bioavailability and bioequivalence studies CPMP/EWP/QWP/1401/98 (to be replace with new version soon) FDA related guidelines on BE WHO guidelines, Technical Report Series

All Rights Reserved 2008 Health Sciences Authority | 5

Bioequivalence
Pharmaceutical equivalent (PE)
Similar bioavailability in systemic circulation Similar rate and extent of availability of active ingredient Similar dosage form Similar route of administration

All Rights Reserved 2008 Health Sciences Authority | 6

Therapeutic equivalence
Pharmaceutically equivalent Same safety and efficacy profiles after administration of the same dose
BE studies Pharmacodynamic study Clinical efficacy study In vitro study

All Rights Reserved 2008 Health Sciences Authority | 7

BE Study
Clinical study
Requirements of GCP, GMP and GLP Minimize variability Minimize bias GOAL is to compare performance of the 2 products Single dose, 2-period, crossover Healthy volunteers Subjects receive each formulation once Adequate washout

Basic consideration

Study design

All Rights Reserved 2008 Health Sciences Authority | 8

Study Design

Cross over
Intra-subject comparison Lower variability Fewer subjects required

Fasted or Fed
Fasted preferred Minimize variability not attributable to formulation Better to detect formulation differences

Fed study design

Known food effects, e.g. grapefruits Significant GI effects Product labeling restriction Conditions, depend on local diet and customs

All Rights Reserved 2008 Health Sciences Authority | 9

Dissolution data
3 media: pH 1.2, 4.5 and 6.8 Individual tablet dissolution data 12 tablets of each TP and RP Mean, range and RSD data of all 12 tablets F2 calculation
>50 to show similarity

All Rights Reserved 2008 Health Sciences Authority | 10

Biowaiver
BE study generally not required for
Solutions Solutions for injection Powder for reconstitution Oral suspension Topical product without systemic effects Otic and ophthalmic products

All Rights Reserved 2008 Health Sciences Authority | 11

Biowaiver
Submit justification for biowaiver Comparative BA studies required Request based on:
Dosage form Solubility of active ingredient Similar dissolution profiles across 3 pH media PK profile: bioavailability, linearity Clinical consequences Width of margin between minimum effective and minimum toxic plasma concentration Similarities/ differences between formulations considered

All Rights Reserved 2008 Health Sciences Authority | 12

Pre-submission
Strongly encourage Discuss acceptability of BE data with HSA Verify the choice of RP before conducting BE study

All Rights Reserved 2008 Health Sciences Authority | 13

Checklist

All Rights Reserved 2008 Health Sciences Authority | 14

DR Revision
No change Minor editorial

All Rights Reserved 2008 Health Sciences Authority | 15

SQOS P9.1 (Chemicals)

All Rights Reserved 2008 Health Sciences Authority | 16

Thank You

All Rights Reserved 2008 Health Sciences Authority | 17