Bioequivalence: general concepts and overview

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Bioequivalencegeneral concepts and overview

• Dr P Shyam
• Post graduate
• Dept. of pharmacology

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


PHARMACEUTICAL COMP.
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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

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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

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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

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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

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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).
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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.

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Plasma concentration-time curve
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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.

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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.

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Definition

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

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Bioequivalence
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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

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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)

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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)
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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

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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

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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

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• 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 )

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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

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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.

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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

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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

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Design and conduct of studies

• Study Design
• Cross-over design
• Parallel design
• Replicate design
• Steady state design

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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?
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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

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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.

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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.

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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.

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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.

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Bioanalytical methodology

• Spectro photometry(LC-MS)
• HPLC

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Bioanalytical Method Validation

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

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Criteria for bioequivalence

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

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BE Results (90 CI)
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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.

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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

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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?

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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

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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

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• THANK YOU