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Advisory Committee for Pharmaceutical Science May Advisory Committee for Pharmaceutical Science May 4, 20054, 2005

Using Product Development Using Product Development Information to Address the Information to Address the

Bioequivalence Challenges of Bioequivalence Challenges of Highly-variable Drugs Highly-variable Drugs

Lawrence X. Yu, Ph. D.Lawrence X. Yu, Ph. D.Director for ScienceDirector for Science

Office of Generic DrugsOffice of Generic DrugsFood and Drug AdministrationFood and Drug Administration

Lawrence X. Yu, Ph.D.Director for Science

Office of Generic Drugs, OPS, CDER, FDA

ACPS Meeting, April 14, 2004

Bioequivalence of Highly Variable Drugs

Objectives

• Explore and define bioequivalence issues of highly variable drugs

• Discuss potential approaches

Bioequivalence of Highly Variable Drugs

• Introduction (5 min) Lawrence Yu, Ph.D.• Why Bioequivalence of Highly Variable Drugs Is an Issue? (20 min)

Charlie Diliberti, Barr Lab• Highly Variable Drugs: Sources of Variability (20 min)

Gordon L. Amidon, Ph.D.• Clinical Implications of Highly Variable Drugs (20 min) Leslie

Benet, Ph.D.• Bioequivalence Methods for Highly Variable Drugs (20 min) Laszlo

Endrenyi, Ph.D.• Bioequivalence of Highly Variable Drugs (30 min) Barbara Davit,

Ph.D., Sam Haidar, Ph.D.• BE of HV Drugs Q & A Dale Conner, Pharm.D.

Bioequivalence of Highly Variable (HV) Drugs: Clinical Implications

Why HV Drugs are Safer

Leslie Z. Benet, Ph.D.

Professor of Biopharmaceutical Sciences

University of California San FranciscoFDA Advisory Committee for Pharmaceutical Science

Rockville, MD

April 14, 2004

Highly Variable DrugsFor wide-therapeutic index highly variable drugs we should not have to study an excessive number of patients to prove that two equivalent products meet preset (one size fits all ) statistical criteria.

This is because, by definition, highly variable approved drugs must have a wide therapeutic index, otherwise there would have been significant safety issues and lack of efficacy during Phase 3

Highly variable narrow therapeutic index drugs are dropped in Phase 2 since it is not possible to prove either efficacy or safety.

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Bioavailability: Rate and Extent of Bioavailability: Rate and Extent of Drug Absorption Drug Absorption

ln C

once

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tion

AUC

Time

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Time

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cent

ratio

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Tmax - time of maximum concentration

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Possible Outcome of BE StudiesPossible Outcome of BE Studies

T/R (%)80% 125%

Demonstrate BE

Fail to Demonstrate BE

Fail to Demonstrate BIE

Demonstrate BIE Demonstrate BIE

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What is a Highly Variable Drug?What is a Highly Variable Drug? Within subject CV > 30%Within subject CV > 30%

Number of Subjects Required for Crossover BE Study With 80% Power

0

100

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0% 20% 40% 60% 80% 100%

Intrasubject CV

Num

ber o

f Sub

ject

s R

equi

red

AssumedT/R = 105%AssumedT/R = 110%

Charles DiLiberti

ProgesteroneThe Poster Drug for High Variability

• A repeat measures study of Prometrium® 2x200 mg capsules in 12 healthy post-menopausal females yielded:

Intrasubject CV for AUC of 61% Intrasubject CV for Cmax of 98%• A generic company calculated that a 2 period crossover

BE study for Progesterone Capsules, 200 mg would require dosing in 300 postmenopausal women to achieve adequate statistical power

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ACPS Recommendation, April 14, 2004ACPS Recommendation, April 14, 2004 ““The Committee suggested the need to understand The Committee suggested the need to understand

where the variability originated. The members added that where the variability originated. The members added that prior knowledge of all biostudies may help set more prior knowledge of all biostudies may help set more appropriate specifications to make decisions.appropriate specifications to make decisions.””

Mechanistic Understanding of VariabilityMechanistic Understanding of Variability Drug SubstanceDrug Substance

Common between RLD and genericCommon between RLD and generic FormulationFormulation

Generic could be lower or higherGeneric could be lower or higher Using Product Development Information to help Using Product Development Information to help

understand sources of variabilityunderstand sources of variability

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Therapeutic EquivalenceTherapeutic Equivalence Drug products are considered to be Drug products are considered to be

therapeutic equivalents only therapeutic equivalents only they are approved as safe and effective,they are approved as safe and effective, they are they are pharmaceutical equivalentspharmaceutical equivalents,, they are bioequivalent, they are bioequivalent, they are adequately labeled, and they are adequately labeled, and they are manufactured in compliance with they are manufactured in compliance with

CGMP regulations.CGMP regulations.

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Pharmaceutical EquivalencePharmaceutical Equivalence Same active ingredient(s)

Pharmaceutical solid polymorphism Same dosage form

QbD; design to be equivalent Same route of administration Identical in strength or concentration May differ in characteristics such as shape,

excipients, packaging...

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Why Does Pharmaceutical Why Does Pharmaceutical Equivalence Matter?Equivalence Matter?

User experience and expectationUser experience and expectation Bioequivalence testsBioequivalence tests

Healthy subjectsHealthy subjects Assumption: Equivalence in healthy subjects Assumption: Equivalence in healthy subjects

= Equivalence in patients= Equivalence in patients Pharmaceutical EquivalencePharmaceutical Equivalence OGD has approved over 7000 generic productsOGD has approved over 7000 generic products

Novel drug delivery systemsNovel drug delivery systems

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Highly Variable DrugsHighly Variable Drugs Often have wide therapeutic indexOften have wide therapeutic index

Les Benet April 2004 ACPSLes Benet April 2004 ACPS Clinical trials of the RLD have established the Clinical trials of the RLD have established the

acceptable level of variabilityacceptable level of variability Under an ideal system it should be easier to Under an ideal system it should be easier to

determine equivalence (wide target)determine equivalence (wide target) Design + Demonstration = Therapeutic equivalenceDesign + Demonstration = Therapeutic equivalence We must rely on the design sideWe must rely on the design side

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Possible Outcome of BE StudiesPossible Outcome of BE Studies

T/R (%)80% 125%

Demonstrate BE

Fail to Demonstrate BE

Fail to Demonstrate BIE

Demonstrate BIE Demonstrate BIE

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Product Design for an ANDA of a Highly Product Design for an ANDA of a Highly Variable DrugVariable Drug

Understand what the RLD is supposed to do and Understand what the RLD is supposed to do and origin of variabilityorigin of variability

Design for equivalenceDesign for equivalence Directly evaluate equivalent product Directly evaluate equivalent product

performance: verify the designperformance: verify the design Use bioequivalence study design for highly Use bioequivalence study design for highly

variable drugsvariable drugs

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Share with FDAShare with FDA Product Development ReportProduct Development Report

CTD sectionCTD section ICH Q8ICH Q8

OGD Question based ReviewOGD Question based Review What is the formulation intended to do? (MR,CR) What mechanism does it use to accomplish this? Were any other formulation alternatives investigated

and how did these perform? Is the formulation design consistent with the dosage

form classification in the label?

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Why Provide Design Process to FDA?Why Provide Design Process to FDA? Quality by Design paradigmQuality by Design paradigm Product development report is where you Product development report is where you

demonstrate the drug is highly variabledemonstrate the drug is highly variable Source of variabilitySource of variability Justify use of bioequivalence study design other than Justify use of bioequivalence study design other than

80-125% confidence interval80-125% confidence interval Product development report is where you justify Product development report is where you justify

equivalence of designequivalence of design

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Example: Product A Example: Product A

Variability in active ingredientVariability in active ingredient Formulation design: rapid releaseFormulation design: rapid release

Demonstrate by dissolution comparison under Demonstrate by dissolution comparison under physiologically relevant conditionsphysiologically relevant conditions

Waive if BCS class IWaive if BCS class I Confirm with in vivo study Confirm with in vivo study

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Example: Product BExample: Product B

Variability in the formulation of RLDVariability in the formulation of RLD

Design for equivalence begins with Design for equivalence begins with characterization of RLDcharacterization of RLD

Generic product should target the meanGeneric product should target the mean Current system: no reward for generic that is Current system: no reward for generic that is

less variableless variable

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Product B: Within SubjectProduct B: Within Subject

Single Subject replication

050

100150200250300350400450

0 4 6 8 9 10 11 12 13 14 15 16 17 18 20 22 24 36

time (hr)

Dru

g C

once

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tion

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What is this product supposed to do?What is this product supposed to do? Coated to release at the target pHCoated to release at the target pH If physiological pH fluctuates observe significant If physiological pH fluctuates observe significant

variations in pharmacokineticsvariations in pharmacokinetics Addition to pharmacokineticsAddition to pharmacokinetics

directly evaluate designdirectly evaluate design show that test and reference release at pH targetshow that test and reference release at pH target

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Tablet to Tablet Variability Tablet to Tablet Variability PERCENT DISSOLVED PLOT

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Dissolution Time (Hours)

% o

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laim

123456

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Design GoalDesign Goal Given dissolution variability what should a Given dissolution variability what should a

generic sponsor do?generic sponsor do?

Recognize variability is an issueRecognize variability is an issue Target mean performanceTarget mean performance

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Quality by DesignQuality by Design Pharmaceutical Development Report will Pharmaceutical Development Report will

helphelp

““Understanding what the problem is, as well Understanding what the problem is, as well as the real fundamentals i.e. physical and as the real fundamentals i.e. physical and chemical parameters.”chemical parameters.”

““Making coherent, science based decisions.”Making coherent, science based decisions.”