How to Prove Interchangeability of Generic drugs with Originators

Korean Experience

Sang-Aeh Park

Korea Food and Drug Administration

Outline

KFDA Organization

Milestones in BE on Generics : Korea

Guideline for BE on Generics : Korea

Current Issues

KFDA Organization

Milestones in BE on Generics : Korea

1988, Introduction of BE provision 1994, Mandatory submission of BE data or clinical

trial data on generic drugs for new drugs that had been approved since Jan. 1, 1989

2001, Generic Substitution is limited to approved drugs with BE

2005, Expansion to mandatory objects for BE submission

2010, Expansion to combination drugs for BE submission

Guideline for BE on Generics : Korea

BE submission for Generics

Generic products with New drug substance since ’89.1.1

Generic products with one more out of 507 drug substances including other salts and enantiomers designated by KFDA

Criteria for Biowaiver of BE (1)

1. Oral solutionsQuantitatively & Qualitatively Same Drug substances

Excipients don’t affect the absorbance of DS

2. Injections Excipients are Qualitatively Same

Exception ; Differ from following Excipients

Preservatives

Buffering agents

Antioxidents

Criteria for Biowaiver of BE (2)3. Opthalmic and Otic solutions

Excipients are Qualitatively Same

Exception ; Differ from following Excipients

Preservatives

Buffering agents

Substance to adjust tonicity

Thickening agents

4. Locally acting solutions (Topical)

Criteria for Biowaiver of BE (3)

5. The Additional Strengthsby the Same Manufacturing Process

Compositions of the strengths are Quantitatively proportional

Appropriate in vitro Dissolution data

Linear elimination kinetics over the therapeutic dose

(if only higher strength based on BE of Lower strength)

Criteria for Biowaiver of BE (4)

6. Biopharmaceutical Classification Systems (BCS)

High Solubility on Drug substance

High Permeability on Drug substance

Rapid Dissolution Data on Drug products

ExceptionsNarrow Therapeutic Range Drugs

Extended Release Drugs

Sublingual and Buccal Drugs

Test products

Biobatch for pK evaluationAt least 100,000 units

or

Commercial batch

The difference in the content between RLD & Test

product is not more than 5%

or

The difference from Label Content is not more than

5%

Guideline for BE (1)Study Design

Single dose comparison

Non-replicate crossover study

Fasting condition

☞ Extended Release : Fasting & Fed conditionsHigh Fat Diet (900kcal, Fat 35%)

Number of Subjects

More than 24 subjects (12 for each group)

Add on subjects study if insufficient number

Guideline for BE (2)Selection of Subjects

Healthy adult volunteers (19~55 years)

Non-pregnant females

Exclusion of SubjectsWithin 1 month, Subject with a history of metabolism induction like Barbiturates, Heavy alcohol

Within 3 months, Subject with a history of other BE or Clinical study

For 10 days before BE study, Subject having drugs which affect BE

Guideline for BE (3)

Subject Management

Fasting for at least 10 hours prior to medication

Medication with 240mL water

No water is allowed for 1 hour before and after dose

No food is allowed for at least 4 hours post-dose

Similar position and behavior among subjects for 2 hrs after dose

Guideline for BE (4)Sampling times

More than 12 samples, principally

More than 2 samples prior to Cmax

Sampling schedule is enough to provide a reliable estimate of peak exposure

which is achieved if AUC (0→t) covers at least 80% of AUC (0→∞)

which is more than 3 times of Elimination Half life

which is 72hr • If sampling period is longer than 72hr (Half life is long)

• If Intra-subject variability of Distribution and Elimination is low

Guideline for BE (5)

Analytes to measure (in descending order of priority)

Parent drug, principally

Active Metabolite when appropriate

In whole blood, plasma or serum

Guideline for BE (6)

Measures of Rate and Extent of AbsorptionRate of Absorption : Cmax

Extent of Absorption : AUC

Bioequivalence Criteria

90% confidence interval of difference in the average values of logarithmic AUC and Cmax

: log 0.8 ~ log 1.25

Current Issues

Highly Variable Drugs (HVDs)

KFDA

Ohsong

Seoul

Ohsong Life Science Park

KFDA

KFDA

Thank You for your Attention!

sangaeh@korea.kr