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Bioequivalence: general concepts and overview

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Title: Bioequivalence: general concepts and overview


1
Bioequivalencegeneral concepts and overview
  • Dr P Shyam
  • Post graduate
  • Dept. of pharmacology

2
WHAT IS IT???
WHY IS IT???
HOW IS IT???
REGULATION VERSUS


PHARMACEUTICAL COMP.
3
Sulfanilamide disaster(1937)
  • Sulfanilamide was widely hailed as a miracle
    drug
  • Was obtained in tablet or powder form
  • Some pharma company decided to market it as a
    liquid for sore throats
  • But the problem is it does not dissolve in either
    water or alcohol
  • The chemist discovers that it dissolves in sweet
    tasting solvent- diethylene glycol (antifreeze in
    car radiators)
  • No clinical tests were made prior to marketing
  • There were many casualities and led to new
    legislation food, drug and cosmetic act of 1938

4
price of new medicine
  • On average 5 out of 5000 new drug candidates are
    tested in human and only one is approved.
  • Average cost of bringing one medicine on the
    market is 800 millions(4000 crore rupees)
  • It takes 12-15 years to discover and develop a
    new medicine.
  • Patent is usually for 10 years

5
Two kinds of drugs
  • Brand name drug(reference drug)
  • -- innovator drug
  • -- price of new
    medicine
  • Generic drug
  • -- identical or bioequivalent
    to a brand name drug in
  • -- dosage form
  • -- safety
  • -- strength
  • -- route of
    administration
  • -- quality
    -- intended use

6
Facts
  • Generic drugs are safe and effective alternatives
    to brand name prescriptions
  • Generic drugs can help both consumers and the
    government reduce the cost of prescription drugs

7
NDA vs. ANDA Review Process
  • Generic Drug
  • ANDA Requirements
  • Chemistry
  • Manufacturing
  • Controls
  • Labeling
  • Testing
  • Bioequivalence Study (In Vivo, In vitro)
  • Original Drug
  • NDA Requirements
  • Chemistry
  • Manufacturing
  • Controls
  • Labeling
  • Testing
  • Animal Studies
  • Clinical Studies
  • (phases I, II, III)

Note Generic drug applications are termed
"abbreviated" because they are generally not
required to include preclinical (animal) and
clinical (human) data to establish safety and
effectiveness.  Instead, generic applicants must
scientifically demonstrate that their product is
bioequivalent (i.e., performs in the same manner
as the original drug).
8
PK Terms
  • Cmax the max drug conc achieved in sys
    circulation foll drug administration.
  • Tmax the time required to achieve
    maximum concentration in sys circulation.

9
Plasma concentration-time curve
10
Definitions
  • Bioavailability- defined as the fraction of a
    dose reaching the systemic circulation as
    unchanged drug following administration by any
    route other then iv.
  • Pharmaceutical Equivalent- drug products that
    contain identical amounts of the active drug
    ingredient in identical dosage forms but not the
    excipients.
  • Pharmaceutical Alternatives- drug products that
    contain the identical therapeutic moiety not
    necessarily in the same amount or dosage form.

11
Bioequivalence
  • Bioequivalent drug products means Pharmaceutical
    Equivalents or Alternatives whose rate and extent
    of absorption do not show a significant
    difference when administered at the same molar
    dose of the therapeutic moiety under similar
    experimental conditions.

12
Definition
  • Simply , we can define bioequivalence as
  • Absence of difference in bioavailability
    of two or more drug products

13
Bioequivalence
14
Bioavailability
(quantifies ABSORPTION ?, Reasons for poor F)
  • The extent and rate at which its active moiety is
    delivered from pharmaceutical form and becomes
    available in the systemic circulation

15
Why do we care about BIOAVAILABILITY?
  • The true dose is not the drug swallowed
  • BUT is the drug available to exert its effect.
  • Bioavailability may vary due to variablity in
  • -- Dissolution
  • -- Absorption
  • -- Survival of metabolism
  • drug with very low bioavailability
  • - Dosage form or drug may not
    dissolve readily
  • - Drug may not be readily pass
    across biological
  • membranes (i.e. be absorbed)
  • - Drug may be extensively
    metabolized during
  • absorption process (first-pass, gut
    wall, liver)

16
Scheme of Oral Dosage Form
Human Intestinal Absorption (HIA)
1,2 Stability Solubility 3 Passive Active
Tr. 4 Pgp efflux 5 - CYP 3A4
Oral Bioavailability (F)
17
Why do we need Bioequivalence studies?
  • No clinical studies are being performed in
    patients with the Generic Product to support its
    Efficacy and Safety.
  • Therefore , trials must be conducted to ensure
    the two products do not differ in safety,
    efficacy and bioavailabilities when administered
    at the same dosage forms

18
Test methods for assessing bioequivalence
  • 1.Comparative bioavailablity(bioequivalence)
    studies -- In vivo measurement of active moiety
    in biologic fluid
  • 2. Comparative pharmacodynamic studies in
    humans(invivo)
  • 3. Comparative clinical trials(invivo)
  • 4. In vitro dissolution tests

19
Conditions where bioequivalence studies are
necessary
  • Oral immediate release drug formulations with
    systemic action when one or more of the following
    criteria apply
  • a) indicated for serious conditions
    requiring assured therapeutic response
  • b) narrow therapeutic window/safety margin
  • c) high first metabolism ( gt 70),
    non-linear pharmacokinetics
  • d) unfavourable physicochemical properties
    eg- low solubility, instability, poor permeability

20
  • 2) Non-oral and Non-parenteral drug formulations
    designed to act by systemic absorption (
    transdermal patches, suppositories, etc.)
  • 3) Sustained release formulations for systemic
    absorption
  • 4) Fixed dose combinations for systemic
    absorption
  • 5) Products for local use (oral, nasal, ocular,
    dermal, rectal, etc) and are intended to act
    without systemic absorption
  • ( comparative clinical or pharmacodynamic
    studies )

21
6) To establish link between
  • a) Early and late clinical trial
    formulations
  • b) Formulations used in
    clinical trials and stabilty
    studies,if different
  • c) Clinical trial formulations
    and to be marketed drugs

22
Conditions where bioequivalence studies are not
necessary
  • 1) When new drugs are to be administered
    parenterally (eg IV, IM, SC,intrathecal
    administration etc) as aqueous solutions(excipient
    s also should be same)
  • 2) When the new drug is a solution for oral use,
    and contains the active substance in the same
    concentration and does not contain an excipient
    that is known or suspected to affect
    gastro-intestinal transit or absorption of the
    active substance.

23
  1. When the new drug is a gas.
  2. When the new drug is a powder for reconstitution
    as a solution.
  3. Drug for local use( otic or opthalmic or topical
    product) prepared as aqueous solution(same
    excipients)
  4. When the new drug is an inhalational product or a
    nasal spray prepared as aqueous solutions

24
BA studies protocol
  • Study objective Scientific question to be
    answered
  • Study design
  • parallel , cross-over.
  • Study circumstances
  • -Subjects informed consent
  • -Subject selection
  • -Study environment, diet, exercise etc
  • Bioanalytical methods

25
Design and conduct of studies
  • Study Design
  • Cross-over design
  • Parallel design
  • Replicate design
  • Steady state design

26
Study Designs
  • Single-dose, two phase, two-way crossover design,
    fasted or fed is the design of choice
  • Alternative
  • Single-dose, parallel, fasted (Long half-life)
  • Single-dose, replicate design (Highly Variable
    Drugs)
  • Multiple-dose, two-way crossover, fasted (Less
    Sensitive, non-linear kinetic)

Parallel or crossover?, Fasted or Fed?, Single or
Multiple?, Replicate or nonreplicate?
27
Study Designs
  • Duration of washout period for cross-over design
    should be approximately gt 5 times the plasma
    half-life
  • However, should be adjusted accordingly for drugs
    with complex kinetic model

28
Study population
  • Number of subjects - minimum 16 , should be
    statistically significant.
  • Informed verbal and written consent of subjects
  • Inclusion criteria
  • - healthy adult volunteers
  • -gender male or female, women should
    not be pregnant and should assure not to become
    pregnant until after the study.

29
Requirements for conducting BA/BE
  • The organization should have a legal identity
  • It must be independent
  • A Good infrastructure is a must.
  • must have a medically qualified investigator
    with relevant experience in PK studies.

30
Site must have trained personnel to perform the
following
  • CPU management- Physician, staff nurses,
    coordinators
  • Analytical lab management
  • Data handling and interpretation
  • Documentation and report preparation
  • Quality control assurance of all operations in
    the center.

31
Samples and records maintenance
  • All samples used in the BA/BE studies should be
    retained by the conducting organization for a
    period of 3years after the study or 1 yr after
    the expiry of the drug , whichever is earlier.
  • All records of the tests conducted should be
    maintained by the sponsor for at least 2 yrs
    after the expiry date of the drug.

32
Bioanalytical methodology
  • Spectro photometry(LC-MS)
  • HPLC

33
Bioanalytical Method Validation
  • Method Validation should include
  • Accuracy
  • Precision
  • Sensitivity
  • Specificity
  • Recovery
  • Stability

34
Criteria for bioequivalence
  • To establish bioequivalence, the calculated 90
    confidence interval for AUC and Cmax should fall
    within the bioequivalence range, usually 80-125.

35
BE Results (90 CI)
36
Documentation
  • Clinical data
  • Details of analytical method validation
  • Analytical data of volunteer plasma samples
  • All comments of the chief investigator regarding
    the data of the study submitted for review.
  • A copy of the final report.

37
Special cases
  • Food effect
  • A single dose cross-over study is recommended
  • Long half life drugs
  • Cross-over design with adequate wash out period
    and single dose studies are used
  • Sustained release formulations
  • multiple dose studies are used

38
Study Design Case 1
  • Crossover Design
  • 2x2 Crossover design
  • A single-dose bioequivalence study is performed
    in normal, healthy, adult volunteers.
  • 18 subjects are hired (Male or Female?).
  • The subjects are randomly selected for each group
    and the sequence of drug administration is
    randomly assigned.
  • One-week washout periods
  • Fasted or Fed?

39
Conclusion
  • Bioequivalence study is a clinical research study
    which facilitates to get drugs at low costs
    without compromising its safety and efficacy
  • Currently saves consumers 60 billion/year (
    30,000 crore rs)
  • In developing countries, like india it assumes a
    high significance because it reduces approx. 50
    rs per prescription

40
References
  • Goodman Gillman, 10th edition
  • Sharma Sharma 1st ed 2007
  • Guidelines for BA/BE studies, CDSCO, DGHS, march
    2005
  • Rani S. Bio-equivalence Issues and Perspectives.
    Indian J Pharmacol 2007 39218-225
  • FDA guidance documents. http//www.fda.gov/cder/gu
    idance

41
  • THANK YOU
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