OVERVIEW OF DACA BIOEQUIVALENCE REPORT EVALUATION Presented by Solomon Shiferaw 31Augst 2010.

OVERVIEW OF DACA BIOEQUIVALENCE REPORT EVALUATION

Presented by

Solomon Shiferaw

31Augst 2010

Objectives

To provide an overview on the bioequivalence requirement for registration.

To highlight the application assessment for inter changeability of multi-source generic product in FMHACA

To show the constraints for assessment of BE in FMHACA

Introduction

Regulatory Authority Mission

“To assure that Safe and Effective drugs are marketed in the country

and are available to the people”

Introduction

Multi-source drug products need to conform to the same standards of quality, efficacy and safety required of the originator's products.

A reasonable assurance must be provided that they are, as intended, clinically interchangeable with nominally equivalent market products.

Introduction cont.

Assessment of equivalence will normally require

an in vivo study, or

a justification that such a study not be required in a particular case.

Documentation of equivalence for MA

Pharmaceutically equivalent multi-source pharmaceutical products must be shown to be therapeutically equivalent to one another in order to be considered interchangeable

Documentation of equivalence for MA

Bioequivalence:

Approach for establishing equivalence

Comparative CTBE study

(In most case)

In-vitro dissolution studyComparative PD study

Documentation of equivalence for MA

• Acceptance of any test procedure depends on factors like characteristics of the active drug substance and drug product

• concentrations in an accessible fluid (eg plasma)

• Evidence on vitro/in vivo correlation

• Solubility & Permeability of API, etc

General organization of the document for BE

Names and affiliations of the responsible investigator (s) and analyst (s)

Site of the study

Accreditation of the BE site by Local DRA

Detailed information on clinical and analytical facilities of the institution (s)

Period of its execution of BE study

General organization of the document for BE cont.

The names and B. No. of the products used in the study as well as the composition of the test product

Analytical validation report

The responsible investigator (s) should sign for their respective section of the report

General organization of the document for BE cont.

The applicant should submit a signed statement confirming the identity of the test product with the pharmaceutical product, which is submitted for registration

The report of In-vivo BE should include

Study Protocol

Summary of the study

Objectives

The report of In-vivo BE should include

Subjects subjects should be as homogeneous (healthy

volunteers in order to reduce variability other than in the pharmaceutical products)

a clear criteria for inclusion/exclusion non smokers & with out a history of alcohol or

drug abuse problems

The report of In-vivo BE should include

Subject cont. volunteers screening

standard laboratory tests, a medical history and physical examination

Age range of 18-55 with a weight with normal range

In most cases 18-24 subjects but NLT 12

The report of In-vivo BE should include

Design considerations

Minimize variability except attribute

to formulation

Minimize bias

Compare performance

of the two formulations

The report of In-vivo BE should include

Study design Cross over design Vs Parallel Design Randomization Standardization (exercise, diet, fluid intake,

restriction of intake) Single dose Vs Multiple dose Number of treatment group Treatment periods

The report of In-vivo BE should include

Study design cont.

wash out period (NLT 5 t1/2)

Doses, rout of administration

Sampling times and method for collection of samples

The report of In-vivo BE should include

Chemical Analysis Method used to determine plasma conc. Of drugs Should be

Accurate & Precise Selective & Sensitive and Reproducible

The results of Bioanalytical Method Validation

The report of In-vivo BE should include

Test Product Identical to the projected commercial

pharmaceutical product Bio-batch (industrial (ideal), pilot scale)

Reference Product (comparators) Innovator product Market leader product( Registered in Ethiopia)

The report of In-vivo BE should include

Results All results (raw data)

Sufficiently detailed statistical and/or any other procedures for calculating the parameters used

Clinical findings

Representative chromatograms

The report of In-vivo BE should include

Results cont.

Pharmacokinetics Parameters

AUCMeasure of the extent of absorption

Criteria: 80 -120C max

Measure of rate of absorptionCriteria: 80 - 120

T max

Measure of rate of absorption

BE is not required for

Aqueous solutions Intravenous solutions Intramuscular, subcutaneous solutions Oral solutions Ophthalmic or otic solutions Nasal spray

Powder for reconstitution as a solution Gases Inhalation & nasal preparation Topical products

BE study required for

Systemic application of such product require BE study Oral immediate release product Non-oral and Non-parenteral products

Eg. transdermal patches, suppositories

Sustained or modified release products Fixed combination products

In-Vitro dissolution study

Under certain conditions Like Highly soluble and permeable

BCS class I

Different strength of the same formulation ( BE done for 1 strength (usually for higher strength)

Same qualitative composition Same ratio of active ingredients and excipients

Basket Or Paddle

In-Vitro dissolution study

Media for comparative dissolution pH 6.8 buffer pH 4.5 buffer pH 1.2 buffer or 0.1NHCl

In-Vitro dissolution study

Difference factor(f1)

f1 = sum IRt-TtI/sum Rt x100

f1 should NMT 15

Similarity factor(f2):

f2 = 50.Log( 1/ (1+1/nx sum(Rt-Tt)2)1/2x100)

f2 should NLT 50

Challenges in BE Evaluation

Lack of adequate experience and training on BE evaluation

Lack of comparators reference products The guideline is not exhaustive Limited access to the reference materials