Center for Professional Advancement Generic Drug Approvals Course

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Center for Professional AdvancementGeneric Drug
Approvals Course

• Bioequivalence Bioavailability
• Michael A. Swit, Esq.
• Vice President

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(No Transcript)
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Definitions

• Statutory
• Bioavailability Means The Rate And Extent To
  Which The Active Ingredient Or Therapeutic
  Ingredient Is Absorbed And Becomes Available To
  The Site Of Drug Action. 505(j)(7)(A)
• A Generic Drug Will Be Considered To Be
  Bioequivalent To A Listed Drug If
• The Rate And Extent Of Absorption Of The Generic
  Does Not Show A Significant Difference From The
  Rate And Extent Of Absorption Of The Listed Drug.
   505(j)(7)(B)(i).
• The Extent Of Absorption Of Drug Does Not Show
  Significant Difference From The Extent Of
  Absorption Of The Listed Drug If The Difference
  In Rate Is Intentional. 505(j)(7)(B)(ii).

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Definitions

• Regulatory
• Bioavailability means the rate and extent to
  which the active drug ingredient or therapeutic
  moiety is absorbed from a drug product and
  becomes available at the site of drug action. 21
  C.F.R. 320.1(a).
• Bioequivalence means pharmaceutical equivalents
  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. 21 C.F.R.
   320.1(e).

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Definitions

• Regulatory
• Pharmaceutical Equivalents means drug products
  that contain identical amounts of the identical
  active drug ingredient, i.e., the same salt or
  ester of the same therapeutic moiety, in
  identical dosage forms, but not necessarily
  containing the same inactive ingredients, and
  that meet the identical compendial or other
  applicable standard of identity, strength,
  qaulity, and purity, including potency and, where
  applicable, content uniformity, disintegration
  times and/or dissolution rates. 21 C.F.R.
  320.1(c).

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Bioequivalence

• Procedures For Determining Bioavailability Or
  Bioequivalence. 21 C.F.R.  320.21-.63.
• Considerations For Bioequivalence.
• Statutory/Regulatory.
• Proof that drug is not only pharmaceutically
  equivalent (same active ingredient in same
  strength and dosage form), but also
  bioequivalent.
• Systemic bioequivalence testing is based on
  assumption that therapeutic effect of A drug is A
  function of the concentration of the active
  ingredient in the systemic circulation of A
  person and is thus related to its
  bioavailability.
• Clinical bioequivalence is based on clinical data
  from the reference listed drug (RLD) and
  generic that demonstrate the generic has the same
  safety and effectiveness as the RLD. Often, a
  placebo is required to assure that both drugs are
  superior to the placebo.

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Requirements For Submission Of Bioequivalence
Study Data. 21 C.F.R. 320.21.

• Evidence Demonstrating Bioequivalence To Listed
  Drug.
• Or Information Establishing That A Waiver Is
  Appropriate

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Criteria For Waiver Of In Vivo Bioequivalence21
C.F.R. 320.22

• Drug Products Whose Bioequivalence Is Self
  Evident.
• Parenterals, ophthalmics, and otics with the same
  concentration of active and inactive ingredients
  as the listed drug. (Qualitative and
  quantitative QQ)
• Oral or topical solutions with the same
  concentration of active ingredient and dosage
  form as the listed drug, and any difference in
  inactive ingredients will not significantly
  affect the drug's absorption.
• DESI Drugs Without Known Or Potential
  Bioequivalence Problems.
• Drug Products Whose Bioequivalence Can Be
  Established Through In Vitro Evidence.
• For Good Cause, If Waiver Is Compatible With
  Protection Of Public Health.

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Types Of Evidence To Establish Bioequivalence
21 C.F.R. 320.24.

• In Vivo Testing Of Blood Or Related Biological
  Fluid.
• In Vivo Testing Of Urinary Excretion.
• In Vivo Testing To Measure Pharmacological
  Effect.
• Well-Controlled Clinical Trials.
• In Vitro Testing That Ensures In Vivo
  Bioavailability

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Components Of Bioequivalence Study

• Protocol
• Clinical Report
• Analytical Report
• Pharmacokinetic and Statistical Report
• Statistical Tables, Listings and Graphs

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Guidelines For Single Dose In Vivo
Bioavailability Study (Blood Level). 21 C.F.R.
320.26.

• Investigational New Drug (IND) application not
  required.
• Protocol Example
• At least 24 healthy human volunteers (male and
  female).
• Age 18 - 45
• Weight 10 - 15 for frame size
• No concomitant medications allowed
• Single dose comparison.
• Fasting state of volunteers.
• 10 hours
• No water/fluids 1 hour dosing
• Two-way crossover.
• In first leg, half receive the test (generic)
  product and half the listed drug.
• Adequate wash-out period (at least three times
  the half life of elimination of active ingredient
  or metabolite)

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Key Measures During BE Study

• Samples must be collected with sufficient
  frequency to permit estimate of peak
  concentration (CMax), area under the
  concentration time curve (AUC), and time to peak
  (TMax).
• CMax the observed peak drug concentration
  obtained directly for the experimental data
  without interpolation.
• TMax the observed time to reach peak drug
  concentration obtained directly from the
  experimental data without interpolation.
• AUC(0-t) area under the concentration versus
  time curve from time 0 to time of last
  quantifiable concentration, calculated by the
  trapezodial rule.
• CMax is a surrogate to indicate rate of
  absorption.
• AUC defines extent of absorption

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Other Key Aspects of BE Studies

• Treatment of systemic blood sample centrifuge,
  measure volume, ph, color, temperature control
• In Vitro Dissolution testing using water and acid
  solutions (simulated gastric fluid) to determine
  that potency of generic is within 5 of RLD.
• Validation of assay method.
• Pharmacokinetic parameters. (See Exhibits A and
  B.)

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Exhibit A Pharmacokinetics from Generic Drug
Subject 1
Tmax 6 hours Cmax 47 ug/m/
Conc. (ug/ml)
4
8
12
12
0
4
8
0
Time (hr)
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Exhibit B Pharmacokinetic Data from Generic and
RLD


0
Conc. (ug/ml)


Conc. (ug/ml)








10
12
0
0
2
4
6
8
2
6
10
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Multiple Dose In Vivo Biostudy Guidelines For
Multiple Dose In Vivo Bioavailability Study
(Blood Level)21 C.F.R. 320.27.

• Purpose is to determine steady-state levels of
  the active drug ingredient or therapeutic moiety
  in the body.
• Sufficient blood or urine samples necessary to
  establish maximum and minimum blood
  concentrations on 2 or more consecutive days.

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Clinical Bioequivalence Study

• Submission of protocol for review or reliance on
  guidance
• Dosage Forms -- At present time, clinical trials
  in patients is about only methodology available
  to establish bioequivalence where dosage form
  makes systemic blood level studies not possible
  or unreliable.
• Oral drugs that are not systemically absorbed.
  (e.g., Sucralfate)
• Most topically administered drugs
• Intrauterine
• Surgical antibacterial scrubs

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Clinical Bioequivalence Study

• Must show RLD and generic are superior to placebo
• Must show RLD and generic are equivalent as to
  clinical effect.
• Example Draft 1990 Guidance For Performance Of
  A Bioequivalence Study For Topical Antifungal
  Products requires
• Placebo normally generic without active
  ingredient
• RLD usually from single lot of RLD manufacturer
• Generic drug
• Clinical study that is probably identical to or
  very similar to study used by RLD to obtain
  approval
• IND required
• Measurements
• Mycological
• Clinical
• Therapeutic (combination of mycological and
  clinical)

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Statistical Evaluation Required For Any
Bioequivalence Tests

• Average Bioequivalence Method
• Systemic Blood Level Studies
• 90 Confidence Interval Using The Two One-Sided
  T-Test. CMax And AUC 80 - 125.
• July 1992 Guidance Statistical Procedures For
  Bioequivalence Studies Using A Standard
  Two-Treatment Crossover Design
• Clinical Study
• Statistical model will be determined by FDA
  usually in guidance
• Statistical analysis to demonstrate RLD and
  generic are bioequivalent

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Collateral Issues for BE Studies

• Guidance On Food-Effect Bioavailability And Fed
  Bioequivalence Studies (Dec. 2002) (see
  www.fda.gov/cder/guidance/5194fnl.pdf)
• Retention Of Bioequivalence Samples. 21 C.F.R.
  320.63.
• OGD does not distinguish between systemic blood
  level studies and clinical studies so retention
  samples must be held by clinical investigator or
  third party and not sponsor.
• See 21 C.F.R.  320.38 and 320.63,
• www.fda.gov/cder/ogd/retention_samples.htm.
• See also August 2002 Draft Guidance for Industry,
  Handling and Retention of BA and BE Testing
  Samples www.fda.gov/cder/guidance/4843dft.pdf.

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BE Guidances

• FDA has available approximately 70 guidances for
  bioequivalence tests, including
• Design of study.
• Number of subjects to use.
• Identification of reference product.
• Duration of study.
• Collection times.
• Suggested methods for assay.
• Dissolution testing methodology and
  specifications

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Factors That Can Impact BE Study

• Physicochemical Properties of Drug.
• Physiological Factors.
• Biopharmaceutical Factors.
• Formulation Factors.
• Pharmaceutical Factors.
• Analytical Control.
• Statistical Analysis and Acceptance Criteria.

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Settled Bioequivalence Study Parameters Are
Binding On FDA

• Provision added by Food And Drug Administration
  Modernization Act Of 1997 (FDAMA)
• Applicant to provide written request to FDA for
  determination of acceptable biostudy
• Purpose is to reach agreement on the design and
  size of bioavailability and bioequivalence
  studies needed for approval
• Agreements regarding study parameters reached
  between FDA and the applicant are binding
• Cannot be directly or indirectly changed by field
  or compliance personnel
• Cannot be changed after testing begins, with two
  exceptions
• When applicant agrees to changes in writing
• When director of reviewing division determines
  that A substantial scientific issue essential to
  determining the safety or effectiveness of the
  drug has been identified

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Challenging BE Issues

• Racemic Drugs, Metabolites
• Gender and Age (Including Pediatrics).
• Long Shelf-Life Drugs.
• Locally Acting Drug Products.
• Estrogenic Drugs
• Narrow Therapeutic Index Drugs