BIOEQUIVALENCE AND DRUG

PRODUCT ASSESSMENT

PRESENTED BY:
RENALDY DONLANG NONGBET
(MPHARM 1ST SEM PHARMACEUTICS)
CONTENTS
• INTRODUCTION • TYPES OF EVIDENCE TO ESTABLISH
BIOEQUIVALENCE
• OBJECTIVE AND DEFINITION
• NEED FOR BIOEQUIVALENCE • EVALUATION OF DATA
• TYPES OF EQUIVALENCE • BIOWAVERS
• STATISTICAL EVALUATION OF • REFERENCES
BIOEQUIVALENCE DATA

• STUDY DESIGN
INTRODUCTION
• BIOEQUIVALENCE AND BIOAVAILABILITY STUDIES PROVIDE INFORMATION IN OVERALL SET OF
DATA THAT ENSURE AVAILABILITY OF SAFE AND EFFECTIVE MEDICINES.

• IT IS VERY IMPORTANT FOR APPROVAL OF BRAND NAME AND GENERIC DRUGS.

• THE SPONSORS HAVE TO INCLUDE BE AND BA INFORMATION FOR DRUG PRODUCTS IN INDS,
NDAS, ANDAS, AND THEIR SUPPLEMENTS.

• BE AND BA REQUIREMENTS IS SET FORTH IN PART 320 (21 CFR PART 320)

ABBREVATION: CODE OF FEDERAL REGULATIONS(CFR)

OBJECTIVE AND DEFINITIONS
• OBJECTIVE:
THE MAIN OBJECTIVE IS TO MEASURE AND COMPARE THE FORMULATION
PERFORMANCE BETWEEN TWO OR MORE PHARMACEUTICALLY EQUIVALENT DRUG PRODUCT.

• DEFINITION
1. BY UNITED STATES FOOD AND DRUG ADMINISTRATION (USFDA):
THE ABSENCE OF SIGNIFICANT DIFFERENCE IN THE RATE AND EXTENT WO WHICH THE ACTIVE
INGREDIENT OR ACTIVE MOIETY IN PHARMACEUTICAL EQUIVALENTS OR PHARMACEUTICAL
ALTERNATIVES BECOMES AVAILABLE AT THE SITE OF DRUG ACTION WHEN ADMINISTERED AT THE
SAME MOLAR DOSE UNDER SIMILAR CONDITIONS IN AN APPROPRIATELY DESIGNED STUDY.
CONTD…
2. BY WORLD HEALTH ORGANIZATION (WHO)

TWO PHARMACEUTICAL PRODUCTS ARE BIOEQUIVALENT IF THEY ARE

PHARMACEUTICALLY EQUIVALENT OR PHARMACEUTICAL ALTERNATIVE, AND THEIR
BIOAVAILABILITY; IN TERMS OF RATE (CMAX AND TMAX) AND EXTENT OF ABSORPTION (AREA
UNDER CURVE), AFTER ADMINISTRATION OF THE SAME MOLAR DOSE UNDER SAME CONDITIONS,
ARE SIMILAR TO SUCH A DEGREE THAT THEIR EFFECTS CAN BE EXPECTED TO BE ESSENTIALLY
THE SAME.
NEED FOR BIOEQUIVALENCE
• THE NEED OF BIOEQUIVALENCE STUDIES IS INCREASING DUE TO THE LARGE GROWTH OF THE
PRODUCTION AND CONSUMPTION OF GENERIC PRODUCT.

• SINCE NO CLINICAL STUDIES HAVE BEEN PERFORMED IN PATIENT WITH THE GENERIC PRODUCT
TO SUPPORT ITS EFFICACY AND SAFETY.

• BE STUDIES ARE PERFORMED IF THERE IS:

a) A RISK OF BIOEQUIVALENCE OR
b) A RISK OF PHARMACOTHERAPEUTIC FAILURE
TYPES OF EQUIVALENCE
1. CHEMICAL EQUIVALENCE:

TWO OR MORE DRUG PRODUCT CONTAIN SAME LABELLED CHEMICAL IN SAME AMOUNT.

2. PHARMACEUTICAL EQUIVALENCE

TWO OR MORE DRUG ARE IDENTICAL IN STRENGTH, QUALITY, PURITY, CONTENT

UMIFORMITY, DISINTEGRATION AND DISSOLUTION.

3. THERAPEUTIC EQUIVALENCE

IT INDICATES THAT TWO OR MORE DRUG PRODUCT THAT CONTAIN THE SAME THERAPEUTICALLY
ACTIVE INGREDIENTS AND IDENTICAL PHARMACOLOGICAL EFFECT AND CONTROL THE DISEASE
TO THE SAME EXTENT.
CONTD…
4. BIOEQUIVALENCE

IT IS A RELATIVE TERM WHICH DENOTES THAT THE DRUG SUBSTANCE IN TWO OR MORE
IDENTICAL DOSAGE FORM, REACHES THE SYSTEMIC CIRCULATION AT THE SAME RELATIVE RATE
AND RELATIVE EXTENT.
STATISTICAL EVALUATION OF
BIOEQUIVALENCE DATA
• STATISTICAL EVALUATION STUDIES IS BASED ON ANALYSIS OF DRUG BLOOD PLASMA
CONCENTRATION.

• AREA UNDER THE PLASMA CONC. V/S TIME CURVE (AUC) IS USED AS AN INDEX OF EXTENT OF
DRUG ABSORPTION.

• IN THE EARLY 1070S, APPROVAL WAS BASED ON MEAN DATA. MEAN AUC AND CMAX VALES FOR
THE GENERIC PRODUCT HAD TO BE WITHIN 20% OF THOSE OF THE BRAND NAME PRODUCT.
 • Cmax (maximum plasma drug concentration)
• Tmax (time required to achieve a maximal
concentration)
• AUC (total area under the plasma drug
concentration-time curve)
• Drug A is the innovator product and Drug B is the
generic product.
• Drug A: Cmax = 8.1 mg/L; Tmax = 2.6 h; AUC
= 124.9 mg.h/L
• Drug B: Cmax = 7.6 mg/L; Tmax = 2.1 h; AUC
= 112.4 mg.h/L

Fig: Showing bioequivalence of two drugs

STUDY DESIGN
SUCCESSFULLY DETERMINING THE BE OF GENERIC DRUGS TO THEIR RESPECTIVE REFERENCE
DUGS DEPENDS MOSTLY ON DESIGN AND MANAGING THE CONDUCTING OF STUDY SUCH THAT
THE HIGHEST QUALITY SAMPLES ARE OBTAINED.

SOME REGULATORY AUTHORITIES PROVIDE INFORMATION ABOUT REFERENCE LISTED DRUG

(RLD) ON THEIR WEBSITES, WHICH MAKE IT EASY TO PROCEED WITH BA/BE STUDY DESIGN.

ATTENTION SHOULD BE PAID TO SELECTING AS WELL AS COLLECTING THE APPROPRIATE

REFERENCE PRODUCT DETAILS.

GENERALLY, THE STUDY DESIGN DEPENDS ON THE RLD INFORMATION, PHYSIO-CHEMICAL

AND PHARMACOKINETIC PROPERTIES OF THE DRUG, AND REGULATORY REQUIREMENTS OF
THE COUNTRY.
TYPES OF DESIGNS
1. COMPLETE RANDOMIZED DESIGN

• ALL TREATMENT ARE RANDOMLY ALLOCATED AMONG ALL EXPERIMENTAL SUBJECTS.

EXAMPLE: IF THERE IS 20 SUBJECTS, NUMBER THEM FROM 1 TO 20 AND RANDOMLY SELECT NON
REPEATING NUMBER.

ADVANTAGES

a) EASY DESIGN
b) CAN ACCOMMODATE ANY NUMBER OF TREATMENT AND SUBJECT
CONTD…
DISADVANTAGES

a) ALL SUBJECT MUST BE HOMOGENOUS

2. RANDOMIZED BLOCK DESIGNS

SUBJECTS ARE SORTED INTO HOMOGENOUS GROUP CALLED BLOCKS.

METHOD: SUBJECTS HAVING SIMILAR BACKGROUND CHARACTERISTICS ARE FORMED AS

BLOCKS.

ADVANTAGES:

b)DIFFERENT TREATMENT DO NOT NEED EQUAL SAMPLE SIZE

c)CAN ACCOMMODATE ANY NUMBER OF TREATMENT
d)STATISTICAL ANALYSIS IS RELATIVELY SIMPLE
CONTD…
DISADVANTAGES

a)DEGREE OF FREEDOM IS LESS

3. REPEATED MEASURE OR CROSS OVER OR CARRY OVER DESIGN

IT IS RANDOMISED BLOCK DESIGN.

ADMINISTRATION OF TWO OR MORE TREATMENT, ONE AFTER THE OTHER, IS SPECIFIED OR

RANDOM ORDER TO THE SAME GROUP OF PATIENT IS CALLED CROSSOVER DESIGN OR CHANGE
OVER DESIGN.

ADVANTAGES

b)GOOD PRECISION FOR COMPARING TREATMENTS

c)ECONOMIC ON SUBJECTS
CONTD…
DISADVANTAGES

a) ORDER EFFECT WHICH IS CONNECTED WITH THE POSITION IN THE TREATMENT

ORDER

b) CARRY OVER EFFECT

4. CROSSOVER PARALLEL DESIGN

• A PARALLEL DESIGN IS COMPLETELY RANDOMIZED DESIGN IN WHICH EACH

SUBJECT RECEIVE ONE AND ONLY ONE FORMULATION OF THE DRUG IN A
RANDOM ORDER.

• THE SIMPLEST PARALLEL DESIGN, WHICH COMPARES TWO FORMULATION OF THE

DRUG. EACH DRUG CONTAINING EQUAL NUMBER OF SUBJECTS.
TYPES OF EVIDENCE TO ESTABLISH
BIOEQUIVALENCE
IN VIVO MEASUREMENT OF ACTIVE MOIETY OR MOIETIES IN BIOLOGIC FLUID.
IN VIVO PHARMACODYNAMIC COMPARISON.
IN VIVO LIMITED CLINICAL COMPARISON.
IN VIVO COMPARISON.
ANY OTHER APPROACH DEEMED APPROPRIATE BY F.DA
EVALUATION OF DATA
ANALYTICAL DATA

• ANALYTICAL METHOD FOR MEASUREMENT OF DRUG MUST BE VALIDATED FOR ACCURACY,

PRECISION, SENSITIVITY AND SPECIFICITY.

• MORE THAN ONE METHOD DURING BIOEQUIVALENCE STUDY MAY NOT BE VALID BECAUSE
DIFFERENT METHODS MAY YIELD DIFFERENT VALUES.
BIOWAIVERS
• THE TERM BIOWAIVER IS APPLIED TO A DRUG REGULATORY APPROVAL PROCESS WHEN A
DOSSIER (APPLICATION) IS APPROVED BASED ON THE EVIDENCE OF BIOEQUIVALENCE.

• THE BIOWAIVER MEANS THAT THE IN VIVO BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES
MAY BE WAIVED (I.E. NOT NECESSARY FOR THE PRODUCT APPROVAL)

• IN 1995, US DEPARTMENT OF HEALTH AND HUMAN SERVICES, AND US-FDA STARTED THE
BIOPHARMACEUTICAL CLASSIFICATION SYSTEM, WITH THE AIM OF GRANTING SO CALLED
BIOWAIVERS FOR SCALE UP, POST APPROVAL CHANGES (SUPAC).

• APPLICANT CAN REQUEST BIOWAIVER FOR IMMEDIATE RELEASE PRODUCT BASED ON AN

APPROACH TERMED THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM BCS (32)
REFERENCES
• SHARGEL. L. KANFER. I. GENERIC DRUG PRODUCT DEVELOPMENT (SOLID DOSAGE FORM) (PG
NO. 234- 249)

• BIOPHARMACEUTICS AND PHARMACOKINETICS BY D.M. BRAHMANKAR (M.SC, PH.D) (PG NO.

328- 365)
THAN K YO U