overview of daca bioequivalence report evaluation presented by solomon shiferaw 31augst 2010
TRANSCRIPT
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