bioavailability & bioequivalence studies for drug products

Bioavailability & Bioequivalence Studies Bioavailability & Bioequivalence Studies for Drug Products for Drug Products

ASEANASEAN--EU Programme for Regional EU Programme for Regional Integration Support Integration Support –– Phase II (APRIS II)Phase II (APRIS II)

[Assistance to ASEC and Pharmaceutical [Assistance to ASEC and Pharmaceutical Product Working Group]Product Working Group]

Kuala Lumpur, MalaysiaKuala Lumpur, Malaysia

7 7 –– 8 December 2009 8 December 2009 22

Key Elements of BA / BE Study Designs & Case StudiesKey Elements of BA / BE Study Designs & Case Studies15.30 15.30 –– 17.3017.30

Session IVSession IV

Key Elements of BA / BE Study DesignsKey Elements of BA / BE Study Designs14.00 14.00 –– 15.0015.00

Session IIISession III

Bioavailability (BA) / Bioequivalence (BE) DefinitionsBioavailability (BA) / Bioequivalence (BE) Definitions10.30 10.30 –– 12.0012.00

Session IISession II

Global Generic Market OverviewGlobal Generic Market Overview09.00 09.00 –– 10.0010.00

Session ISession I

Day 1 AgendaDay 1 Agenda

3

Session 1Session 1

Global Generic Market OverviewGlobal Generic Market Overview

3

4

Global Top 10 Best Sellers Global Top 10 Best Sellers

19931993SchizophreniaSchizophreniaJ&JJ&JRisperdalRisperdal

19961996HypertensionHypertensionNovartisNovartisDiovanDiovan

19961996SchizophreniaSchizophreniaEli LillyEli LillyZyprexaZyprexa

19981998RheumatroidRheumatroid arthritisarthritisAmgenAmgenEnbrelEnbrel

19981998Rheumatoid arthritisRheumatoid arthritisJ&JJ&JRemicadeRemicade

HypertensionHypertension

GI disorderGI disorder

ThrombosisThrombosis

AsthmaAsthma

CholesterolCholesterol

Medical UseMedical Use

19921992PfizerPfizerNorvascNorvasc

20002000AstraZenecaAstraZenecaNexiumNexium

19971997BristolBristol--Myers SquibbMyers SquibbPlavixPlavix

20002000GlaxoSmithKlineGlaxoSmithKlineAdvairAdvair

19961996PfizerPfizerLipitorLipitor

ApprovedApprovedCompanyCompanyBrand Brand

5

Global Pharmaceutical ManufacturingGlobal Pharmaceutical Manufacturing

6

Global Pharmaceutical Growth TrendGlobal Pharmaceutical Growth Trend

7%

9.7%

17%

0%2%4%6%8%

10%12%14%16%18%

OverallMarketGrowth

Generic DrugGrowth

BiotechDrugs

Growth

Source: IMS Health MIDAS - 2005

7

Expiring Generic Prescription Drugs Expiring Generic Prescription Drugs

•• 20102010•• FlomaxFlomaxEnlarged ProstateEnlarged Prostate

•• 20112011•• 20122012

•• ActosActos•• AvandiaAvandia

DiabetesDiabetes

•• 20112011•• 20122012

•• EffexorEffexor XRXR•• LexaproLexapro

DepressionDepression

•• 20082008•• 20092009•• 20112011•• 20122012

•• DepakoteDepakote•• LamictalLamictal•• ZyprexaZyprexa•• SeroquelSeroquel

Bipolar DisorderBipolar Disorder

•• 20122012•• SingulairSingulairAllergyAllergyAsthmaAsthma

YearYearDrug NameDrug NameCategoryCategory

8


•• 20072007•• 20072007•• 20072007•• 20072007

•• LotrelLotrel•• NorvascNorvasc•• CoregCoreg•• ToprolToprol XLXL

High Blood PressureHigh Blood Pressure

•• 20092009•• 20092009•• 20112011

•• PrevacidPrevacid•• AciphexAciphex•• ProtonixProtonix

HeartburnHeartburn

•• 20122012•• PlavixPlavixHeart AttackHeart Attack

•• 20092009•• ValtrexValtrexGenital HerpesGenital Herpes

•• 20082008•• DepakoteDepakoteEpilepsyEpilepsy


9


•• 20082008•• 20112011

•• RisperdalRisperdal•• ZyprexaZyprexa

SchizophreniaSchizophrenia

•• 20082008•• FosamaxFosamaxOsteoporosisOsteoporosis

•• 20082008•• 20092009•• 20092009

•• DepakoteDepakote•• TopamaxTopamax•• ImitrexImitrex

MigraineMigraine

•• 20072007•• AmbienAmbienInsomniaInsomnia

•• 20112011•• LipitorLipitorHigh CholesterolHigh Cholesterol


10

Global Generics MarketGlobal Generics Market

•• Leading Companies & Global Generics Leading Companies & Global Generics Market ShareMarket Share

Teva 18%Sandoz 10%

Mylan6%

Watson 6%

Stada = ratiopharm3%

Actavis = Ranbaxy2%

Others 50%

Source: BCC Report PHM009E Generic Drugs: The Global Market

11

Source: The US Generic Drugs Industry Overview, Themedica 2009

12

Top 8 Global Generic Markets, 2009Top 8 Global Generic Markets, 2009

Account for 84% total global generics salesAccount for 84% total global generics sales•• USUS

–– US$ 33 US$ 33 bnbn–– 42% global sales42% global sales–– 79% of all approved drugs have generics79% of all approved drugs have generics–– Generic growth forecastGeneric growth forecast

•• 9.2%, 20109.2%, 2010--20122012•• GermanyGermany•• FranceFrance•• UKUK•• CanadaCanada•• ItalyItaly•• SpainSpain•• JapanJapan

Major Growth in:

• Respiratory

• CNS

• GI

• Anticancer

• Cardiovascular

• Anti-infective

• Antiarthritics

13 14

Global Generics Market Global Generics Market

99129.3129.320142014

848420092009

808020082008

CAGR, %CAGR, %Market Size, US$ Market Size, US$ bnbnYearYear

Highest growth rate in major markets:• Japan• 12.2% share• US$ 5.4 � 9.6 bn (2009 – 2014)

15

Global Generic TrendGlobal Generic Trend

�� Generic production is growing at a faster rate than Generic production is growing at a faster rate than innovative new drug productioninnovative new drug production

�� Shift in generic productionShift in generic production�� Away from the developed markets (U.S., Europe and Japan)Away from the developed markets (U.S., Europe and Japan)

�� Significant growth regions:Significant growth regions:

�� IndiaIndia

�� ChinaChina

�� Southeast AsiaSoutheast Asia

�� BrazilBrazil

�� Middle EastMiddle East

�� RussiaRussia

�� MexicoMexico16

Emerging Market LeadersEmerging Market Leaders

IndiaIndia•• Low costLow cost

•• High qualityHigh quality

•• Finished Finished productsproducts

ChinaChina•• Low costLow cost

•• High qualityHigh quality

•• API + API + intermediatesintermediates

17

Global Generics Market SummaryGlobal Generics Market Summary

•• Volatile timeVolatile time•• Demand is increasing steadily due to healthcare cost controlDemand is increasing steadily due to healthcare cost control•• Fierce price competition Fierce price competition �� slashed profit marginsslashed profit margins•• Major growth driver: blockbuster brands coming off patentMajor growth driver: blockbuster brands coming off patent•• Rising stars:Rising stars:

–– China, India, Eastern European countries, and Brazil China, India, Eastern European countries, and Brazil

•• Global generic marketGlobal generic market–– 2009 2009 US$ 84 billionUS$ 84 billion–– 20142014 US$129.3 billionUS$129.3 billion–– 9% Compound Annual Growth Rate (CAGR)9% Compound Annual Growth Rate (CAGR)

•• Generics penetration intensified:Generics penetration intensified:–– Japan = 6%Japan = 6%–– US = 10%US = 10%–– Germany = 18% Germany = 18%

BCC Report, Generic Drugs: the Global Market, July 2009 18

AsiaAsia--Pacific Pacific PharmaPharma HighlightHighlight

Key Market Trends & Outlook:Key Market Trends & Outlook:•• 33rdrd largest largest pharmapharma market globally:market globally:

–– North America > Europe > AsiaNorth America > Europe > Asia--Pacific Pacific

•• Robust growthRobust growth–– AsiaAsia--Pacific Growth: 9% ~ 12% over 2006Pacific Growth: 9% ~ 12% over 2006--20102010

–– NA & Europe: 5 NA & Europe: 5 –– 8%8%

•• Generic drug markets set to take offGeneric drug markets set to take off–– Patents US$20+ billion in sales expiring in 2008Patents US$20+ billion in sales expiring in 2008

•• Major emerging market for orphan drugs developmentMajor emerging market for orphan drugs development

•• 2009 is likely to be extremely difficult, but Asia2009 is likely to be extremely difficult, but Asia--Pacific Pacific pharmapharma industry expected to hold up reasonably wellindustry expected to hold up reasonably well

19


Key Market Trends & Outlook:Key Market Trends & Outlook:•• Key pharmaceutical markets: Key pharmaceutical markets:

–– Australia, Japan, China, India, South Korea and Taiwan Australia, Japan, China, India, South Korea and Taiwan

–– 6 Asia6 Asia--Pacific pharmaceutical leaders that have FDAPacific pharmaceutical leaders that have FDA

•• Smaller, emerging markets: Smaller, emerging markets: –– Singapore, Malaysia and VietnamSingapore, Malaysia and Vietnam

•• Outsourcing leading the wayOutsourcing leading the way

•• Many regulatory changes in the past yearsMany regulatory changes in the past years

•• ↑↑ reliance on IT reliance on IT technologies to streamline operations and technologies to streamline operations and researchresearch

20


•• Example “Philippines” Example “Philippines” –– Estimated domestic Estimated domestic pharmapharma market:market:

•• US$2.61 US$2.61 bnbn, 2007 , 2007 �� US$4 US$4 bnbn, 2012, 2012–– International : local = 65 : 35, with about equal production volInternational : local = 65 : 35, with about equal production volumeume

•• DoubleDouble--digit yearly growth over the next 5 yearsdigit yearly growth over the next 5 years•• 85% via drug stores85% via drug stores•• 15% via hospitals & clinics15% via hospitals & clinics

–– Top importersTop importers•• Switzerland: US$65 million, 12.4%Switzerland: US$65 million, 12.4%•• Germany: US$51 million, 9.8%Germany: US$51 million, 9.8%•• France: US$48 million, 9.3%France: US$48 million, 9.3%•• Australia: Us$46 million, 8.9%Australia: Us$46 million, 8.9%•• Ireland: US$37 million, 7.07%Ireland: US$37 million, 7.07%•• US: US$31 million, 5.1%US: US$31 million, 5.1%

21


•• Example “Philippines” Example “Philippines” –– Top drug categories, 2007, Top drug categories, 2007, Pharmaceutical & Healthcare Association of the PhilippinesPharmaceutical & Healthcare Association of the Philippines

•• Calcium antagonists Calcium antagonists �� hypertensionhypertension•• NonNon--narcotic analgesics narcotic analgesics �� pain reliefpain relief•• Infant formulas Infant formulas �� nutritionnutrition•• CephalosporinsCephalosporins & combination & combination �� infectioninfection•• Broad spectrum penicillin Broad spectrum penicillin �� infectioninfection

–– Cost of medicines in the Philippines high: Cost of medicines in the Philippines high: •• 22ndnd highest in Asia next to Japanhighest in Asia next to Japan•• WHO report: medicines sold in the Philippines at 4 WHO report: medicines sold in the Philippines at 4 -- 18 times 18 times

higher than international counterpartshigher than international counterparts•• More Filipinos go for Generics (2009 DOH report: 6/10)More Filipinos go for Generics (2009 DOH report: 6/10)•• Government actively promoting genericsGovernment actively promoting generics

–– Cheaper & Quality Medicines Act, 2008Cheaper & Quality Medicines Act, 200822


•• Significant risks still remainSignificant risks still remain–– Will Asian companies (with a few exceptions, e.g. Japan Will Asian companies (with a few exceptions, e.g. Japan

and Singapore) continue to be technological followers or and Singapore) continue to be technological followers or freefree--riders?riders?

•• Most promising when combining these:Most promising when combining these:–– Education + Quality of scientistsEducation + Quality of scientists

–– IP law reform IP law reform

–– Market growth + competitivenessMarket growth + competitiveness

–– Pricing control strategy & mechanismsPricing control strategy & mechanisms

–– Growing convergence with international regulatory Growing convergence with international regulatory standardsstandards

23

ASEAN ASEAN PharmaPharma SituationSituation

•• Net importers of pharmaceuticalsNet importers of pharmaceuticals•• Most with no capability for new drug developmentMost with no capability for new drug development•• Major pharmacy: Major pharmacy: genericgeneric industryindustry•• Regulatory situation:Regulatory situation:

–– Most have drug regulatory system: laws, rules, agenciesMost have drug regulatory system: laws, rules, agencies–– Limited human & financial resources for regulatory Limited human & financial resources for regulatory

framework & capacitiesframework & capacities–– Gaps between regulation & actual enforcementGaps between regulation & actual enforcement–– Problems:Problems:

•• Substandard drugsSubstandard drugs•• CounterfeitsCounterfeits•• Illegal drug outletsIllegal drug outlets 24

AsiaAsia--Pacific Generic MarketPacific Generic Market

Generic Generic PharmaPharma Market ComparisonMarket Comparison, , by Frost & Sullivanby Frost & Sullivan

4.04.0MatureMatureTaiwanTaiwan

10.610.6GrowthGrowthSingaporeSingapore

19.719.7GrowthGrowthPhilippinesPhilippines

12.512.5GrowthGrowthMalaysiaMalaysia

CAGR%, 2001 CAGR%, 2001 -- 77Market TypeMarket TypeCountryCountry

25

Session 2Session 2

•• General BA/BE OverviewGeneral BA/BE Overview–– ScopeScope

–– Glossary & DefinitionsGlossary & Definitions

–– Pertinent ReferencesPertinent References

•• ASEAN BA/BE GuidelinesASEAN BA/BE Guidelines

26

Why is Equivalence Important?Why is Equivalence Important?

The most expensive The most expensive drug is the one that drug is the one that

does not work !!does not work !!

27

PharmacokineticsPharmacokinetics

• The application of kinetics to a Pharmakon (Greek word to specify drugs and poisons)

• Integral in drug development, esp. biological properties of a drug

• The time course and fate of drugs in the body• Absorption, Distribution, Metabolism (biotransformation)

and Excretion (ADME)

• Pharmacodynamics (response) + pharmacokinetics �– how the drug affects the body and how the body affects the drug

28


• Intravenous (IV) dosing study– Most comprehensive insight about a drug's inherent

pharmacokinetic properties– Route of administration (ROA): greatest quantitative

potential• Permits a mass balance approach in

– Distribution– Clearance– Body processes associated with excretion and metabolic

elimination» e.g. renal, hepatic

29


• Non-IV ROA’s– Oral, inhalation, topical (e.g. patch, cream, gel..), rectal– Oral, especially, introduces an uncertainty in absorption

• Most important property for systemic conditions– Ability to deliver the active ingredient to the bloodstream– Sufficient amount– Cause the desired response

30

GI Factors Contributing to Oral BA GI Factors Contributing to Oral BA

31

Pharmacokinetic TerminologyPharmacokinetic Terminology

•• AUC: AUC: –– area under the concentrationarea under the concentration--time curve time curve ⇒ ⇒ measure of measure of

the extent of bioavailabilitythe extent of bioavailability

•• CCmaxmax: : –– the observed maximum concentration of drug the observed maximum concentration of drug ⇒⇒

measure of both the rate of absorption and the extent of measure of both the rate of absorption and the extent of bioavailabilitybioavailability

•• ttmaxmax: : –– the time after administration of drug at which Cthe time after administration of drug at which Cmaxmax is is

observed observed ⇒⇒ measure of the rate of absorptionmeasure of the rate of absorption32

Plasma concentration time profilePlasma concentration time profile

Cmax

Tmax

AUC

time

concentration

33

BioavailabilityBioavailability

•• The The extentextent and and raterate at which its at which its activeactive moiety is moiety is delivered from pharmaceutical form and delivered from pharmaceutical form and becomes availablebecomes available in the in the systemicsystemic circulationcirculation

•• Theory basis:Theory basis:–– Intravenous administration = 100% bioavailability Intravenous administration = 100% bioavailability

34

BioavailabilityBioavailability

• The property of a dosage form• Also called:

– Physiologic availability– Biologic availability– Bioavailability

• Two essential features– How fast the drug enters the systemic circulation: rate of absorption

• Cmax

– How much of the nominal strength enters the body: extent of absorption • AUC

• Therapeutic effect = Function of the drug concentration in a patient's blood

• Onset of Response• Time-dependent Extent of Response

• Rate of Drug Absorption• Extent of Drug Absorption

Pharmacokineticsconc. vs time

Co

nc.

(mg

/L)

Time (h)0 25

0.0

35

Factors Affecting Oral BioavailabilityFactors Affecting Oral Bioavailability

• Patient idiocyncracy– Meals & timing– Age– Gender– Disease– Genetic traits– GI physiology– …

• Dosage-form-related– Chemical nature of the drug

• Salts• Acids

– Physical property of the drug

• crystal structure• Particle size

– Formulation factors• non-active ingredients• manufacturing (e.g. tablet

hardness) variables

36

Comparative BAComparative BA

• Why do we do BA comparison?– Comparison

• Route of administration• New vs. old formulation• Generics vs. reference product

– Obtain drug concentration profiles– Apply statistical analysis

37

Typical Reformulation BA StudyTypical Reformulation BA Study

• Objectives– Comparing BA: Reformulation vs. Original product– Determine their equivalence

• Primary endpoints– Administer both the reformulated and the original products– Determine the time-dependent concentrations of the

administered drug in the collected blood (or plasma/serum) of each subject

• Secondary endpoints– Administer both the reformulated and the original products – Determine the time-dependent concentrations of potentially

important metabolites (active and contributing to the product's therapeutic response) in the collected blood (or plasma/serum) of each subject

• Other exploratory endpoints 38


• Study design– Effects of formulation can be distinguished– When comparing 2 formulations

• Randomized two-period, two-sequence crossover study

– Apply an adequate washout period between periods to avoid drug carryover effects

– Tight control over all facets of the study– Pay attention to subject’s fasting details:

• Time, fluid intake & frequency, meals, sequential blood sampling…

– Analytical method validation

39


• Study population– Usually healthy volunteers– Preferably non-smokers– Some may be conducted in patients

• Specific exclusion criteria– Commonly excluded: women of childbearing potential if there is

a potential risk • Tools for assessing primary endpoints

– Validated analytical method• Specific criteria for early withdrawal and discontinuation

– Include sufficient number of subjects to allow all phases of thestudy to be completed successfully

– Subjects shall retain the right to discontinue the trial– Reasons to discontinue:

• Adverse drug reactions, personal preferences…– Report all withdrawals 40

New Formulation Development BANew Formulation Development BAModified ReleaseModified Release

• What is a Delayed-release product?– Does not release the actives immediately– Usually release the actives later– Could exhibit an absorption lag time

41


• Purpose of the required studies – to determine if the following conditions are met:– The drug product meets the controlled release claims made– The BA profile rules out the occurrence of what is called "dose

dumping“• Premature release of the drug from the dosage form

– The formulation provides consistent performance between individual dosage units

– The steady state performance, in comparison to an available conventional product, is equivalent

– Clinical studies are usually required if BA comparisons indicate“difference”

42


• Study designs for modified-release products:– A single dose crossover comparison of

• A conventional, immediate release product, and• The modified release product• Ideally, also includes a solution or suspension of

the same drug in the same strength– A single dose food-effect study– A steady-state study

43

What About Equivalence?What About Equivalence?

•• Innovation product vs. Subsequent followersInnovation product vs. Subsequent followers

•• First to Market = “Innovation” ProductFirst to Market = “Innovation” Product

•• Need to prove:Need to prove:–– QualityQuality

–– Safety and efficacySafety and efficacy

•• Based on extensive clinical trialsBased on extensive clinical trials

•• ExpensiveExpensive

•• Time consumingTime consuming

44

EquivalenceEquivalenceOther Products with Same APIsOther Products with Same APIs

•• Also called:Also called:–– SubsequentSubsequent--entry productsentry products

–– Generic productsGeneric products

–– Multisource productsMultisource products

45

EquivalenceEquivalenceWhich one is it? BE or TE or PE?Which one is it? BE or TE or PE?

•• Bioequivalence (BE):Bioequivalence (BE):–– Products are pharmaceutically equivalentProducts are pharmaceutically equivalent

–– BioavailabilitiesBioavailabilities (both rate and extent) after (both rate and extent) after administration in the same molar dose are so similar administration in the same molar dose are so similar that their effects can be that their effects can be expected to be essentially expected to be essentially the samethe same

•• Therapeutic Equivalence (TE):Therapeutic Equivalence (TE):–– Pharmaceutically equivalentPharmaceutically equivalent

–– Same safety and efficacySame safety and efficacy profiles profiles after after administration of same doseadministration of same dose

46

Pharmaceutical Equivalence vs. BEPharmaceutical Equivalence vs. BE

•• Pharmaceutical Equivalence (PE) CriteriaPharmaceutical Equivalence (PE) Criteria–– Same amount of the same APISame amount of the same API

•• May use different May use different excipientsexcipients

–– Same or comparable dosage formSame or comparable dosage form

–– Same route of administrationSame route of administration

–– Same mfg process not necessarySame mfg process not necessary

•• Is pharmaceutical equivalence enough for Is pharmaceutical equivalence enough for Generics?Generics?

47

Sometimes PE is NOT EnoughSometimes PE is NOT Enough

•• Therapeutic Equivalence (TE):Therapeutic Equivalence (TE):–– Must be pharmaceutically equivalent, andMust be pharmaceutically equivalent, and

–– Same safety and efficacy profiles after administration Same safety and efficacy profiles after administration of same doseof same dose

•• PE PE ≠≠ TETE–– Pharmaceutical equivalence does not necessarily Pharmaceutical equivalence does not necessarily

imply therapeutic equivalenceimply therapeutic equivalence

–– Why? Why?

–– Differences in the Differences in the excipientsexcipients and/or the manufacturing and/or the manufacturing process process ��differences in product performancedifferences in product performance

48

Sometimes PE is EnoughSometimes PE is Enough

•• Aqueous solutionsAqueous solutions–– Intravenous solutionsIntravenous solutions

–– Intramuscular, subcutaneousIntramuscular, subcutaneous

–– Oral solutionsOral solutions

–– OticOtic or ophthalmic solutionsor ophthalmic solutions

–– Topical preparationsTopical preparations

–– Solutions for nasal administrationSolutions for nasal administration

•• Powders for reconstitution as solutionPowders for reconstitution as solution

•• GasesGases

49

How to Assess Equivalence?How to Assess Equivalence?

•• Suitable methods:Suitable methods:–– Comparative pharmacokinetic studiesComparative pharmacokinetic studies

–– Comparative Comparative pharmacodynamicpharmacodynamic studiesstudies

–– Comparative clinical trialsComparative clinical trials

–– Comparative Comparative in vitroin vitro teststests

50

Comparative BA for Generics Comparative BA for Generics –– BE StudiesBE Studies

• The deductive inference concept - Central to BE testing1.The reference drug product has established

acceptable safety and efficacy 2.Time-dependent drug concentrations in blood from

the reference product are intimately linked to its therapeutic effects

3.Chemically equivalent and pharmaceutically equivalent products are bioequivalent

4.Bioequivalent products by inference are considered therapeutically equivalent

51

Comparative BA for Generics Comparative BA for Generics –– BE StudiesBE Studies

• A full array of trials usually not needed for the reference product

• The generic product by inference is regarded as therapeutically equivalent to the reference product

• Usually proven through single dose administrations– Designed to test inherent product absorption properties– Focus:

• Rate and extent of absorption of the active ingredient and/or primary active metabolite(s)

– Generally specify healthy normal controls

52

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trati

on

(n

g/m

L)

Test/Generic

Reference/Brand

53

BioequivalenceBioequivalence

ASEAN BA BE GuidelinesASEAN BA BE Guidelines

Glossary & DefinitionsGlossary & Definitions

55

ASEAN Generic SituationASEAN Generic Situation

•• Generic RegistrationGeneric Registration–– Data usually not requiredData usually not required

•• NonNon--clinicalclinical•• ClinicalClinical

–– Usually requiredUsually required•• Bioequivalent to Reference ProductBioequivalent to Reference Product

–– Similar bioavailability in systemic circulationSimilar bioavailability in systemic circulation–– Similar rate/extent of availability of active ingredientsSimilar rate/extent of availability of active ingredients

•• Same as RFSame as RF–– Route of administrationRoute of administration–– Safety/efficacy profilesSafety/efficacy profiles–– Dosage formDosage form–– Indications, Dosing regimen, Patient populationIndications, Dosing regimen, Patient population

56

BA BE DefinitionsBA BE Definitions

•• Pharmaceutical equivalencePharmaceutical equivalence–– Medicinal products containingMedicinal products containing–– The same amount of the same active substancesThe same amount of the same active substances–– In the same dosage formsIn the same dosage forms

•• Meet the same or comparable standardsMeet the same or comparable standards

•• Pharmaceutical alternativesPharmaceutical alternatives–– Medicinal products containingMedicinal products containing–– The same active moiety butThe same active moiety but–– Differ in chemical form (e.g., salt, ester, etc) of the Differ in chemical form (e.g., salt, ester, etc) of the

moiety, ormoiety, or–– Differ in the dosage form, orDiffer in the dosage form, or–– Differ in strengthDiffer in strength

57


•• BioavailabilityBioavailability–– The rate & extent to which the active substance or The rate & extent to which the active substance or

active moiety is absorbed from a pharmaceutical form active moiety is absorbed from a pharmaceutical form and becomes available at the site of actionand becomes available at the site of action

•• BioequivalenceBioequivalence–– Two medicinal products are BE if they are Two medicinal products are BE if they are

pharmaceutically equivalent or pharmaceutical pharmaceutically equivalent or pharmaceutical alternatives and if their BA after administration in the alternatives and if their BA after administration in the same molar dose are similar to such degree that their same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will effects, with respect to both efficacy and safety, will be essentially the samebe essentially the same

58


•• What’s “essentially similar”?What’s “essentially similar”?–– European Court of Justice 1998 RulingEuropean Court of Justice 1998 Ruling–– A medicinal product is essentially similar to an original A medicinal product is essentially similar to an original

where it satisfies the criteria of having the same where it satisfies the criteria of having the same qualitative and quantitative composition in terms of qualitative and quantitative composition in terms of active substances, of having the same active substances, of having the same pharamaceuticalpharamaceutical form, and of being BE unless it is form, and of being BE unless it is apparent in the light of scientific knowledge that it apparent in the light of scientific knowledge that it differs from the original as regards to safety and differs from the original as regards to safety and efficacyefficacy

–– Different salts, esters, ethers, isomers, complexes or Different salts, esters, ethers, isomers, complexes or derivatives are now considered to be the same substance derivatives are now considered to be the same substance unless they differ unless they differ signioficantlysignioficantly in regard to safety or in regard to safety or efficacy in accordance with the “Generics” rulingefficacy in accordance with the “Generics” ruling

59


•• Therapeutic equivalenceTherapeutic equivalence–– A medicinal product is therapeutically equivalent with A medicinal product is therapeutically equivalent with

another product if it contains the same active another product if it contains the same active substance or therapeutic moiety and, clinically, shows substance or therapeutic moiety and, clinically, shows the same efficacy and safety as that product, whose the same efficacy and safety as that product, whose efficacy and safety has been establishedefficacy and safety has been established


Design & Conduct of StudiesDesign & Conduct of Studies

61

BA BE Study Design & ConductBA BE Study Design & Conduct

•• Follow ICH/EU regulations on Good Clinical Follow ICH/EU regulations on Good Clinical PracticePractice

•• The rights, safety, and wellThe rights, safety, and well--being of all trial being of all trial subjects must always be respected and should subjects must always be respected and should be given special attentionbe given special attention

62

Study DesignStudy Design

•• Comparative BA study designed to establish equivalence Comparative BA study designed to establish equivalence between test and reference productsbetween test and reference products

•• Usually singleUsually single--dose studies would sufficedose studies would suffice

•• However, make sure thatHowever, make sure that–– The formulation effect can be distinguished from other effectsThe formulation effect can be distinguished from other effects

–– If the # of formulations = 2If the # of formulations = 2

•• Design of choice should include a twoDesign of choice should include a two--period, twoperiod, two--sequence sequence crossover designcrossover design

•• Sampling plan should allow for adequate estimation of Sampling plan should allow for adequate estimation of the extent of absorptionthe extent of absorption–– Best to carry out over a full 24Best to carry out over a full 24--hr cycle if the circadian rhythm hr cycle if the circadian rhythm

has a known effect on BAhas a known effect on BA

63

Study SubjectsStudy Subjects

•• Selection objectiveSelection objective–– Minimize variabilityMinimize variability–– Permit detection of differences between productsPermit detection of differences between products

•• Usually healthy volunteers, both gendersUsually healthy volunteers, both genders–– Taking into consideration risk to women of childbearing Taking into consideration risk to women of childbearing

potentialpotential–– 18 18 –– 55 years55 years–– Informed consentInformed consent–– Normal weight range, BMI 18Normal weight range, BMI 18--3030

•• Asians: 18 Asians: 18 –– 2525–– Use clinical lab tests to screen for suitabilityUse clinical lab tests to screen for suitability–– NonNon--smokers, no history of alcohol/drug abuse preferredsmokers, no history of alcohol/drug abuse preferred 64

Study SubjectsStudy Subjects

•• When to consider including patientsWhen to consider including patients–– The active has known adverse effects, andThe active has known adverse effects, and

–– Effects / risks unacceptable for healthy volunteersEffects / risks unacceptable for healthy volunteers

–– Under suitable precautions & supervisionUnder suitable precautions & supervision

–– Must justifyMust justify

•• Consider genetic Consider genetic phenotypingphenotyping–– Exploratory BA studiesExploratory BA studies

–– All studies using parallel group design, orAll studies using parallel group design, or

–– Crossover studies for safety or pharmacokineticsCrossover studies for safety or pharmacokinetics

65

Study ConditionsStudy Conditions

•• StandardizationStandardization–– Diet & Fluid intakeDiet & Fluid intake

•• Avoid food & drinks that may interact with physiological functioAvoid food & drinks that may interact with physiological functionsns

•• Specify time of day for ingestion for oral drugsSpecify time of day for ingestion for oral drugs

•• Constant volume of fluid, e.g., 150 ml min.Constant volume of fluid, e.g., 150 ml min.

•• Prior to & during each study phasePrior to & during each study phase–– Allow water as desired except for 1 hr before & after drug Allow water as desired except for 1 hr before & after drug

administrationadministration

–– Hot drink / juice OK after 3 hrs of drug administrationHot drink / juice OK after 3 hrs of drug administration

–– Standard meals no less than 4 hrs after drug administrationStandard meals no less than 4 hrs after drug administration

–– ExerciseExercise

–– Preferably:Preferably:

•• Fasting during the night prior to administration of the productsFasting during the night prior to administration of the products66

Study ConditionsStudy Conditions

•• StandardizationStandardization–– DosingDosing

•• Generally one unit of the highest marketed strength Generally one unit of the highest marketed strength

•• Smaller dose if adverse events too greatSmaller dose if adverse events too great

–– Other medicinesOther medicines

•• Should not be allowed during a suitable period before Should not be allowed during a suitable period before & during the & during the stidustidu

67

Chemical AnalysisChemical Analysis

•• GLP standardsGLP standards–– EMEA/OECD GLPEMEA/OECD GLP

–– WHO GLPWHO GLP

–– ISO/IEC 17025/1999ISO/IEC 17025/1999

•• Method criteriaMethod criteria–– WellWell--characterizedcharacterized

–– Fully validated & documentedFully validated & documented

–– Reliable resultsReliable results

–– Satisfactory interpretationSatisfactory interpretation

SIX CHARACTERISTICS:

1. Stability• stock solution• analytes

2. Specificity3. Accuracy4. Precision5. Quantification limit6. Response function

68

Chemical Analysis Method ValidationChemical Analysis Method Validation

•• Two phasesTwo phases–– PrestudyPrestudy phasephase

•• Verify the compliance of the 6 characteristicsVerify the compliance of the 6 characteristics–– Study phaseStudy phase

•• Apply validated methods to the actual analysis of Apply validated methods to the actual analysis of samples from the samples from the biostudybiostudy

•• Confirmation ofConfirmation of–– StabilityStability–– AccuracyAccuracy–– PrecisionPrecision

•• Biological sample reparation method should be Biological sample reparation method should be validatedvalidated

69

More on Chemical AnalysisMore on Chemical Analysis

•• Calibration requiredCalibration required

•• QC samples should be runQC samples should be run

•• SOPs for all proceduresSOPs for all procedures–– PrePre--establishedestablished

–– Report & justify all modificationsReport & justify all modifications

–– Modification requires revalidationModification requires revalidation

70

Reference vs. Test ProductsReference vs. Test Products

•• Reference product selection must be justifiedReference product selection must be justified

•• Reference product selection must be approved by Reference product selection must be approved by the regulatory authoritythe regulatory authority

•• Test product preparation based on GMPTest product preparation based on GMP–– Report batch control resultsReport batch control results

–– Oral solid formsOral solid forms

•• Batch size, greater of the two: Batch size, greater of the two: –– min 1/10 production scale, ormin 1/10 production scale, or

–– 10,000 units10,000 units

•• Use the full production batch if < 100,000 unitsUse the full production batch if < 100,000 units

71

Statistical AnalysisStatistical Analysis

•• 90% Confidence Interval90% Confidence Interval

•• Use ANOVA for pharmacokinetic dataUse ANOVA for pharmacokinetic data

•• Normally evaluate average BE, not individual BENormally evaluate average BE, not individual BE

•• Acceptance range for pharmacokinetic parametersAcceptance range for pharmacokinetic parameters

0.80 0.80 –– 1.251.25CmaxCmax ratioratio

0.80 0.80 –– 1.251.25AUC ratioAUC ratio


ReportingReporting

73

ReportingReporting

•• ProtocolProtocol•• Conduct & evaluationConduct & evaluation

–– GCP regulationsGCP regulations–– EU guidelinesEU guidelines–– ICH E3 guidelinesICH E3 guidelines

•• Responsible investigatorsResponsible investigators•• Study siteStudy site•• Study periodStudy period•• Name & batch # of Name & batch # of

products usedproducts used•• Product compositionsProduct compositions•• Finished product specFinished product spec

•• Comparative dissolution Comparative dissolution profilesprofiles

•• Signed statement Signed statement confirming test product = confirming test product = the one submitted for the one submitted for authorizationauthorization

•• DropDrop--out & out & withdrawlwithdrawl of of subjectssubjects

•• Justification of data Justification of data deletiondeletion

•• Analytical validation reportAnalytical validation report•• ….….

74

ASEAN BE Study Reporting FormatASEAN BE Study Reporting Format

•• Study titleStudy title

•• Name of sponsorName of sponsor

•• Name & address of clinical laboratoryName & address of clinical laboratory

•• Name & address of analytical laboratoryName & address of analytical laboratory

•• Dates of clinical study (start, completion)Dates of clinical study (start, completion)

•• Signature PageSignature Page–– Name of Principal & Clinical investigatorsName of Principal & Clinical investigators

–– SignatureSignature

–– DateDate

•• List of other study personnelList of other study personnel

75


•• Study ProtocolStudy Protocol–– IntroductionIntroduction

–– Study objectiveStudy objective

–– Study treatmentsStudy treatments

–– Study methodsStudy methods

–– Reference & Test product informationReference & Test product information

–– Name, Batch number, Batch size of test product, Formulation, Name, Batch number, Batch size of test product, Formulation, Actives, Amount of actives, Expiry date, Finished product spec, Actives, Amount of actives, Expiry date, Finished product spec, Comparative dissolution profilesComparative dissolution profiles

•• Clinical & Safety RecordsClinical & Safety Records

•• Assay Methodology & ValidationAssay Methodology & Validation–– Assay method descriptionAssay method description

–– Validation procedure & resultsValidation procedure & results76


•• Pharmacokinetic Parameters & TestsPharmacokinetic Parameters & Tests–– Definition & calculationsDefinition & calculations

–– Figures & tablesFigures & tables

•• Statistical AnalysesStatistical Analyses

•• Results & DiscussionResults & Discussion

•• ConclusionsConclusions

•• AppendicesAppendices–– Study protocolStudy protocol

–– Letter of approval of institutional review board / Letter of approval of institutional review board / independent ethical committeeindependent ethical committee

77

ACTR BE/BA PreparationACTR BE/BA Preparation

77

•• Fundamentals to ensure equivalent productsFundamentals to ensure equivalent products–– ↓↓ variability & biasvariability & bias

•• Clinical studyClinical study–– GxPsGxPs

•• Study designStudy design–– Healthy volunteersHealthy volunteers–– Study subjects receive each formulation only onceStudy subjects receive each formulation only once–– Single dose, 2Single dose, 2--period, crossover, adequate washoutperiod, crossover, adequate washout

•• PrePre--submission strongly encouraged, work with submission strongly encouraged, work with regulatory authority in advanceregulatory authority in advance–– Verify RP choice prior to BE studyVerify RP choice prior to BE study

Singapore Example

78

ACTR BE/BA PreparationACTR BE/BA Preparation

78

•• Justification requiredJustification required•• Comparative BA studies Comparative BA studies

requiredrequired–– Dosage formDosage form–– Solubility dataSolubility data–– Dissolution profiles, across Dissolution profiles, across

3 pH media3 pH media–– PK profilePK profile–– Clinical consequencesClinical consequences–– Formulation considerationFormulation consideration

•• BE studies usually not BE studies usually not requiredrequired–– SolutionsSolutions–– Solutions for injectionSolutions for injection–– Powder for reconstitutionPowder for reconstitution–– Oral suspensionOral suspension–– Topical products without Topical products without

systemic effectssystemic effects–– OticOtic/ ophthalmic products/ ophthalmic products

Singapore Example - Biowaiver

79

Sessions 3 Sessions 3 -- 44

Key Elements of BA / BE Study DesignsKey Elements of BA / BE Study Designs

-- USFDA Examples USFDA Examples --

BiowaiversBiowaivers

Case StudiesCase Studies80

OutlineOutline

•• US FDA ExampleUS FDA Example–– Key Elements of BA / BE Study DesignsKey Elements of BA / BE Study Designs

•• DesignDesign•• SubjectsSubjects•• Investigation ConsiderationsInvestigation Considerations•• Chemical Analysis & ReferencesChemical Analysis & References•• Statistical AnalysisStatistical Analysis•• ReportingReporting

•• Special Considerations & Case StudiesSpecial Considerations & Case Studies–– BiowaiversBiowaivers–– Food EffectsFood Effects

81

US FDA Generics DefinitionUS FDA Generics Definition

•• A generic drug is the same as a brand name drug in A generic drug is the same as a brand name drug in dosage, safety, strength, how it is taken, quality, dosage, safety, strength, how it is taken, quality, performance, and intended use. Before approving a performance, and intended use. Before approving a generic drug product, FDA requires many rigorous tests generic drug product, FDA requires many rigorous tests and procedures to assure that the generic drug can be and procedures to assure that the generic drug can be substituted for the brand name drug. The FDA bases substituted for the brand name drug. The FDA bases evaluations of substitutability, or "therapeutic evaluations of substitutability, or "therapeutic equivalence," of generic drugs on scientific evaluations. equivalence," of generic drugs on scientific evaluations. By law, a generic drug product must contain the identical By law, a generic drug product must contain the identical amounts of the same active amounts of the same active ingredient(singredient(s) as the brand ) as the brand name product. Drug products evaluated as name product. Drug products evaluated as "therapeutically equivalent" can be expected to have "therapeutically equivalent" can be expected to have equal effect and no difference when substituted for the equal effect and no difference when substituted for the brand name product.brand name product.

Source: US FDA, http://www.fda.gov/cder/drugsatfda/glossary.htm

82

•• Therefore, a generic drug product must be Therefore, a generic drug product must be the same as brand drug in:the same as brand drug in:�� Active ingredientActive ingredient

�� StrengthStrength

�� Dosage formDosage form

�� Route of administrationRoute of administration

�� QualityQuality

�� Therapeutic effectTherapeutic effect


83

Determination based on AssumptionDetermination based on Assumption

•• Therapeutic Therapeutic EquivalnceEquivalnce = =

–– Pharmaceutical equivalence + BioequivalencePharmaceutical equivalence + Bioequivalence

•• When administered under conditions specified When administered under conditions specified

in the labeling, expected to have the same:in the labeling, expected to have the same:

−− Clinical effectClinical effect

−− Safety profileSafety profile

84

Brand Name Drug Brand Name Drug --NDA Submission:NDA Submission:•• ChemistryChemistry•• ManufacturingManufacturing•• ControlsControls•• LabelingLabeling•• TestingTesting•• Preclinical/ClinicalPreclinical/Clinical•• BioavailabilityBioavailability

Generic Drug Generic Drug ––ANDA Submission:ANDA Submission:•• ChemistryChemistry•• ManufacturingManufacturing•• ControlsControls•• LabelingLabeling•• TestingTesting

•• BioequivalenceBioequivalence

Generics Approval ConsiderationsGenerics Approval Considerationsby the US FDAby the US FDA

Source: CDER, US FDA

85

FDA Requirements for DrugsFDA Requirements for Drugs

FDA monitors drug quality after approval.

FDA periodically inspects manufacturing plants.

Manufacturer must report adverse reactions and serious adverse health effects to the FDA.

Manufacturer must seek FDA approval before making major manufacturing changes or reformulating the drug.

FDA reviews the drug's labeling.

FDA reviews the actual drug product.

FDA reviews the active and inactive ingredients used in the formulation before the drug is marketed.

FDA evaluates the manufacturer's adherence to good manufacturingpractices before the drug is marketed.

For reformulations of a brand-name drug or generic versions of a drug, FDA reviews data showing the drug is bioequivalent to the one used in the original safety and efficacy testing.

GenericGenericBrandBrandSource: US FDA

86

US FDA Generics US FDA Generics

ReviewReview

Bioequivalence Review

Labeling Review

Chemistry & Micro Review

Request for Plant Inspection

APPLICANT

ANDA

Acceptable & Complete

Application Review

N Chem/Micro

OK?

Labeling

OK?

BE

OK?

PreApproval

Inspection Results

OK?

Not Approvable

Letter

Approval Withheld until

Results Satisfactory

Bio Deficiency LetterAPPROVED

ANDA

NN N

N

Y Y Y

Y

Y

Refuse to Receive LetterSource: CDER, US FDA

87

APPROVED DRUG PRODUCTS - US

Electronic Orange Book -http://www.fda.gov/cder/ob/

88

•• All FDA approved drug products listed All FDA approved drug products listed (NDA’s, OTC’s & ANDA’s)(NDA’s, OTC’s & ANDA’s)–– Codes for therapeutic equivalenceCodes for therapeutic equivalence

�� “A” = Substitutable“A” = Substitutable�� “B” = Inequivalent, NOT Substitutable“B” = Inequivalent, NOT Substitutable

–– Expiration dates: patent and exclusivityExpiration dates: patent and exclusivity

–– Reference Listed Drugs (brand drugs) identified by Reference Listed Drugs (brand drugs) identified by FDA for generic companies to compare with their FDA for generic companies to compare with their proposed productsproposed products

Orange BookOrange Book

89

BE for Generics BE for Generics -- USUS

• Why do we need BE?– Therapeutic equivalence (TE)– Bioequivalent products can be substituted for each

other without any adjustment in dose or other additional therapeutic monitoring

– The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner

90


• When is BE needed?– Determine rate & extent of absorption of each

therapeutic moiety• Potential generic products for which there is an

existing, approved reference• Potential new drug products where adequate

clinical studies have been conducted– New salts– New dosage forms

• Reformulated drug products

91


•• Chemistry Chemistry •• Components and compositionComponents and composition

•• Manufacturing and controlsManufacturing and controls

•• Batch formulation and recordsBatch formulation and records

•• Description of facilitiesDescription of facilities

•• Specs and testsSpecs and tests

•• PackagingPackaging

•• StabilityStability

92


•• Manufacturing Compliance ProgramsManufacturing Compliance Programs–– Purpose Purpose -- To assure quality of marketed drug To assure quality of marketed drug

productsproducts

–– Mechanisms Mechanisms -- Product TestingProduct Testing

•• SurveillanceSurveillance

•• Manufacturing/Testing plant inspectionsManufacturing/Testing plant inspections

•• Assess firm’s compliance with good Assess firm’s compliance with good manufacturing processesmanufacturing processes

93


General Considerations

• Subject– Usually healthy normal subjects– Usually both genders– Must use patients

• If safety risk to healthy normal subjects– Pharmacokinetic (PK) variability determines # of

subjects• Highly variable drug, #

94



• Examples of subject using patients– Clozapine

• BE, steady state study• Schizophrenic patients• Established regimens

– Etoposide• BE, first dose of treatment cycle• Cancer patients

95



• Dosing– Single-dose studies

• Usually for immediate release drugs• Considered most sensitive

– Multiple-dose / steady-state studies• Usually for modified released drugs, in addition to

single-dose studies• Potential analytical issues• Usually have to deal with variability issues

96



• Method validation– Bioanalytical methods must be validated

• Assay selectivity• Assay precision & accuracy• Stability of stored analytes in matrices• Recovery of analytes & internal standard• Assay limit of quantitation (LOQ)

97



• Statistics– Use ANOVA with 2 one-sided tests to analyze data– BE criteria

• 90% confidence intervals of means• Test/Reference ratio: 0.800 – 1.250

– Questions• What does this mean?• Can there be a 45% spread?

– Rounding not permitted (either up or down)

98



• Statistics–– Bioequivalence criteriaBioequivalence criteria

•• ANOVA two oneANOVA two one--sided tests proceduresided tests procedure–– Test (T) not significantly less than Reference (R)Test (T) not significantly less than Reference (R)

–– R not significantly less than TR not significantly less than T

–– Significant difference is 20% (Significant difference is 20% (αα = 0.05 significance = 0.05 significance level)level)

»» T/R = 80/100 = 80%T/R = 80/100 = 80%

»» R/T = 80% (all data expressed as T/R so this R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)becomes 100/80 = 125%)

99


Source: US FDA, http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_06_BioINequivalence.pdf

100

Possible BE Results (90% CI)Possible BE Results (90% CI)

T/R (%)80% 125%

US FDA’s BE ApproachesUS FDA’s BE Approaches

BE Study Design Elements102


• Pharmacokinetic PK study – drug concentrations measured in plasma

– INIVC (In vitro-in vivo correlation)

• PK study – drug concentrations measured in urine• Acute pharmacological effect measured as a function of

time– BE study with pharmacodynamic endpoints

• Well-controlled clinical trial in humans– BE study with clinical endpoints

• Currently available in vitro test– Must be acceptable to FDA– Must ensure BA

• Any other approach deemed adequate by FDA to establish BA or BE

103


• INIVC (In vitro-in vivo correlation)– Develop formulations with varying release rates– Correlate in vitro dissolution with in vivo absorption

– In vivo studies may be waived if an IVIVC is established• IV solutions• Oral solutions• Non-BE strengths of solid oral dosage forms• BCS Class I drugs• DESI drugs with no BE issues

– Evaluate both internal & external predictability

Drugs entering US market, 1938 – 1962, approved for safety but not effectiveness

104

BE Study Design BE Study Design –– USFDAUSFDA

• PK study – drug concentrations measured in urine– Appropriate when drug can not be reliably measured

in plasma– Example: Alendronate Sodium tablets at 5, 10, 35,

40, 70 mg• Plasma concentrations & redistribution from bone

too low to be detected properly• Food intake also significantly reduces BA• So, FDA asks for:

– Single-dose fasting BE on the 70 mg strength– Measure Alendronate in urine– Biowaivers will be considered for the lower strengths

105


• Acute pharmacological effect measured as a function of time - BE study with pharmacodynamic endpoints

– Basis for decision• Ability of corticosteroids to produce vasoconstriction or blanching

in skin– Example: Topical Corticosteroid

• Mometasone fluroate cream, 0.1%• Pilot study

– Apply reference drug to arm– Obtain ED50 value of X minutes

• Pivotal study– Apply test and reference drugs to both arms, multiple sites for X

minutes– Apply reference drug for 0.5X and 2X minutes– Monitor blanching response of skin for 24 hours after removing drug– Perform BE statistics

106


• BE study with clinical endpoints– Drug products not systemically absorbed

• Topical drug products• Locally acting GI drug products

– Design characteristics• Randomized• Blinded• Balanced• Parallel

– Patients receive:• Test drug• Reference drug• Placebo

– To ensure that patients respond to test and reference products

107


• BE study with clinical endpoints– Example: Topical Acne Gel, Tretinoin, at 0.025, 0.05

& 0.1%• FDA asks for:

– BE studies with clinical endpoints on the 0.025% & 0.1% strengths

– So that the endpoints relevant to the healing of lesions

• Biowaiver granted on the 0.05% strength– Why? All strengths were proportionally similar

108


• Currently available in vitro test– Applicable: locally acting drug products

• Nasal sprays, suspensions• Oral cholestyramine suspensions, tablets,

capsules

109

BE Study Designs Summary BE Study Designs Summary -- USFDAUSFDA(21 CFR 320.24)(21 CFR 320.24)

•• In vivo measurement of active moiety In vivo measurement of active moiety or moieties in biologic fluidor moieties in biologic fluid

•• In vivo pharmacodynamic comparisonIn vivo pharmacodynamic comparison

•• In vivo limited clinical comparisonIn vivo limited clinical comparison

•• In vitro comparisonIn vitro comparison

•• Any other approach deemed Any other approach deemed appropriate by FDAappropriate by FDA

FeV1 AlbuterolBlanching StudyTopical Corticosteroid

Questran - Binding StudiesNasal Solutions-Sprayer EvaluationPropofol - Droplet Size

TopicalsNasal Suspensions

110

•• SingleSingle--dose, twodose, two--way crossover, fastedway crossover, fasted

•• SingleSingle--dose, twodose, two--way crossover, fedway crossover, fed

•• AlternativesAlternatives

–– SingleSingle--dose, parallel, fasteddose, parallel, fasted

–– SingleSingle--dose, replicate designdose, replicate design

–– MultipleMultiple--dose, twodose, two--way crossover, fastedway crossover, fasted

–– Clinical endpoint studyClinical endpoint study

BE Study Designs Summary BE Study Designs Summary -- USFDAUSFDA(21 CFR 320.24)(21 CFR 320.24)

Long Half-Life (wash-out)Amiodarone, Etidronate

Highly Variable Drugs

Less SensitiveClozapine (Patient Trials)Chemotherapy Trials

TopicalsNasal Suspensions

111

Summary Summary -- US FDA BEUS FDA BESimple Solid Oral Dosage FormSimple Solid Oral Dosage Form

•• BE study to compare test vs. reference productBE study to compare test vs. reference product–– Rate & extent of BARate & extent of BA–– At site of actionAt site of action

•• Compare plasma concentration for systemically Compare plasma concentration for systemically available drugsavailable drugs

•• BE study uses metrics BE study uses metrics CmaxCmax & AUC& AUC–– 90% CI of test/reference ratios must be within 80 90% CI of test/reference ratios must be within 80 ––

125%125%

•• Compare Test and Reference Compare Test and Reference TmaxTmax valuesvalues–– Evaluate differences clinicallyEvaluate differences clinically

112

Types of Solid Oral Dosage FormTypes of Solid Oral Dosage FormUS FDA Orange BookUS FDA Orange Book

•• CapsuleCapsule•• Capsule, DelayedCapsule, Delayed--

Release pellets (DR)Release pellets (DR)•• Capsule, DRCapsule, DR•• Capsule, ExtendedCapsule, Extended--

Release (ER)Release (ER)•• GranuleGranule•• Granule, DRGranule, DR•• Powder, EFPowder, EF•• SuspensionSuspension•• Suspension, ERSuspension, ER•• TabletTablet

•• Tablet, chewableTablet, chewable•• Tablet, coated particlesTablet, coated particles•• Tablet, DRTablet, DR•• Tablet, DR, orally Tablet, DR, orally

disintegratingdisintegrating•• Tablet, effervescentTablet, effervescent•• Tablet, ERTablet, ER•• Tablet, for suspensionTablet, for suspension•• Tablet, orally Tablet, orally

disintegratingdisintegrating•• Troche/lozengeTroche/lozenge

BiowaiverBiowaiver

The regulatory acceptance of in vitro testing as a reliable surrogate for an in vivo BE study

114

BiowaiversBiowaivers GuidelinesGuidelines

• EU Guidelines– EMEA BA/BE 2001. Note for guidance on the investigation of

bioavailability & bioequivalence

• US Guidelines– FDA SUPAC-IR 1995. Immediate release solid oral dosage forms. Scale-

up & post-approval changes– FDA IVIVC 1997. Extended release oral dosage forms: development,

evaluation & application of in vitro/in vivo correlations– FDA BCS 2000. Waiver of in vivo bioavailability (BA) & bioequivalence

studies for immediate release solid oral dosage forms based on aBiopharmaceutics Classification System

– FDA BA/BE 2003. Bioavailability & bioequivalence studies for orally administered drug products – general considerations

• WHO Guidelines– The WHO Guidance: Multisource (generic) pharmaceutical products:

guidelines on reegistration requirements to establish interchangeability. Latest revision 2005a

115

BE BE BiowaiversBiowaivers for Generics for Generics -- USUS

Biowaivers – IV Solutions

• Parenteral solution intended for injection, or an otic or ophthalmic solution

• Both Actives & Inactives must be of the same amounts as the reference drug

• Data requested by the FDA:– Same composition as the reference drug– Data needed for a biowaiver request:

• CMC• Labeling• Formulation 116


Biowaivers – Oral Solutions

• Oral generics can contain different excipients, but• Must not contain an excipient that will significantly

affect absorption of the active• Inactives should not present safety issues

117


Biowaivers – Solid Oral Dosage Forms

• Acceptable in vivo BE must be established for one strength– Usually the highest strength

• Must have acceptable dissolution for all strengths

• Strengths must be proportionally similar to the bio-strength

118

Biowaiver Based on BCSBiowaiver Based on BCS

A biowaiver based solubility and permeability consideration of active pharmaceutical ingredient, as well as dissolution profile similarity of the multisource (e.g., test, generic) and the comparator (e.g., name brand, reference) product in pH 1.2, 4.5 and 6.8media.

Source: WHO Technical Report Series, No. 937, 2006, Page: 347-390.

119

Absorption PathwayAbsorption Pathway

SolidDose

Drug in

Solution

AbsorbedDrug at

the Metabolic

Sites

Dissolution

Membrane

Transfer

Solubility Permeability

Systemic Circulation

Metabolism

Liver

Extraction

PortalVein

PlasmaConc.

120

BiophamaceuticsBiophamaceutics Classification System of Classification System of Drug SubstanceDrug Substance

• BCS– Scientific framework for classifying drug substances based on their

aqueous solubility and intestinal permeability– When combined with the dissolution of the drug product, the BCS takes

into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinal permeability

• BCS Classification of Drug Substances: – Class 1: High Solubility – High Permeability

• Pre-requisite for requesting FDA biowaivers

– Class 2: Low Solubility – High Permeability – Class 3: High Solubility – Low Permeability

–– Class 4: Low Solubility Class 4: Low Solubility –– Low Permeability Low Permeability

EMEA Position:Class I & III might be

eligible for biowaiversVet Products

121


•• If two drug products, containing the same drug, have If two drug products, containing the same drug, have the same concentration time profile at the intestinal the same concentration time profile at the intestinal membrane surfacemembrane surface�� they will have the same rate and extent of availability at the they will have the same rate and extent of availability at the

site of actionsite of action

•• If two drug products have the same in vivo If two drug products have the same in vivo dissolution profile under all luminal conditionsdissolution profile under all luminal conditions�� they will have the same rate and extent of availability at the they will have the same rate and extent of availability at the

site of actionsite of action

122


Drug Substance

Solubility

Permeability

High

High

Drug Product DissolutionVery Rapid

Low

Low

RapidSlow

VPShah-Ukraine-07

123 124

Dissolution CharacteristicsDissolution Characteristics

•• To quality for To quality for biowaiversbiowaivers, both the generic and , both the generic and reference products must have similar dissolution reference products must have similar dissolution profile in all 3 media profile in all 3 media –– pH 1.2, 4.5 & 6.8pH 1.2, 4.5 & 6.8

85% in 30 min85% in 30 minRapidly dissolvingRapidly dissolving

85% in 30+ min85% in 30+ minSlowly dissolvingSlowly dissolving

85% in 15 min85% in 15 minVery rapidly dissolvingVery rapidly dissolving

125


• BCS Class 1 Drugs – FDA Biowaiver Requirements:

•• Can be established via in vivo or in vitro methodsCan be established via in vivo or in vitro methodsHighly Highly permeablepermeable

•• At 0.1N At 0.1N HClHCl pH 1.2, pH 4.5, and pH 6.8 bufferspH 1.2, pH 4.5, and pH 6.8 buffers

•• 900 ml900 ml

•• Use paddles at 50 rpm, or basket at 100 rpmUse paddles at 50 rpm, or basket at 100 rpm

Rapidly Rapidly dissolvingdissolvingconditionsconditions

•• An amount of drug comparable to the highest strengthAn amount of drug comparable to the highest strength

•• Must be soluble in 250 ml of solutionMust be soluble in 250 ml of solution

•• Over a wide pH rangeOver a wide pH range

Highly Highly solublesoluble

126


• BCS Class 1 Drugs – FDA Biowaiver Example:– Ofloxacin tablets at 200, 300, 400 mg

• Solubility > 400 mg/250 ml• Oral bioavailability > 95%• Dissolution rapid at pH 1.2, 4.5, & 6.8

127


Biowaivers – DESI Drugs

• In vivo BE studies for solid oral dosage forms must meet the following:– Approved in the US before 1962– DESI expert panel has determined it to be efficacious– No BE issues– Have acceptable dissolution data

128

BE BE BiowaiversBiowaivers for Generics for Generics -- EUEU

Biowaivers – Immediate Release Vet Products

• Class I BCS Active Substance– Very rapid in-vitro dissolution for both the test &

reference products– Excipients do not have relevant impact on BE

• Class III BCS Active Substance– Very rapid in-vitro dissolution for both the test &

reference products– Excipients qualitatively the same + quantitatively very

similar

> 85% within 15 min.

Case StudiesCase Studies

Food Effects130


Food Effects on BA – Potential Mechanisms:• Delay gastric emptying• Stimulate bile flow• Change GI pH• Increase splanchnic blood flow• Change luminal metabolism of a drug substance• Physically or chemically interact with a dosag form or a

drug substance

Meals high in total calories & fat �� more likely to affect the GI physiology �� higher impact on BA

2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies

131


Drug Products where FDA requests Fed BE Studies

• Immediate-release drug products• Modified-release drug products

2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies132



• Immediate-release drug products (IR)– Safety concern

• When a drug should not be given on an empty stomach– Labeling requirement

• When the FDA-approved label contains statements about effect of food on absorption or administration


133



• Modified-release drug products (MR)– Delayed-release– Extended-release– Compare potential for dose-dumping– Not necessary to conduct fed BE for all strengths of MR

products

2002 FDA Guidance for Industry, Food-effect BA & Fed BE Studies134


For Single-dose Fed BE Studies

• Most solid oral drugs– Both fasting & fed BE should be included

• High fat, high calorie meal recommended– Calories from fat: at least 50% – Total calories: 800 – 1000 Kcal

• Drug given timing: ≤ 30 min of consuming a high-fat meal


135


Fasting Considerations• Most sensitive & discriminating form of BE test designs• Required for ALL systemically available drug unless

safety concerns• Example: Mefloquine HCL Tablets 250mg

– ROA: Oral– Type of study: Fed– Design: Single-dose, parallel design in-vivo– Subjects: General population, normal healthy males & females– FDA comment:

• Fasting BE not recommended– Mefloquine known to cause GI problems under fasting

– Analyte to measure: Mefloquine in plasma– BE based on: 90% CI, Mefloquine– Dissolution methods database available from FDA

136


• FDA’s recommendation for test meals for Food-effect BA and Fed BE studies– Use meal conditions expected to provide the greatest effects on GI

physiology so that systemic drug availability is maximally affected– A high-fat & high-calorie meal is recommended – Meal calorie breakdown should be included in the study report:

• Protein: 150• Carbohydrate: 250• Fat: 500-600

– If the test meal’s caloric breakdown is significantly different, the sponsor should provide a scientific rationale for this difference

– In NDAs, the sponsor can choose to conduct food-effect BA studies using meals with different combinations of fats, carbohydrates, and proteins for exploratory or label purposes. However, one of the meals for the food-effect BA studies should be the high-fat, high-calorie test meal described above

137

Case Study Case Study –– Food EffectsFood Effects

•• Food Prolongs Absorption RateFood Prolongs Absorption Rate–– Typically seen in:Typically seen in:

•• Highly soluble, highly permeable, rapidly absorbed Highly soluble, highly permeable, rapidly absorbed drug substancesdrug substances

•• Major mechanismMajor mechanism–– Delayed gastric emptyingDelayed gastric emptying

–– Example: Example: LamivudineLamivudine

138


•• Food Prolongs Absorption Rate Food Prolongs Absorption Rate –– Example: Example: LamivudineLamivudine

May give with or without foodMay give with or without foodLabeling on Labeling on Dosage & Dosage & AdministrationAdministration

•• Fed state absorption, Fed state absorption, TmaxTmax: 3.2 hr: 3.2 hr

•• Fasted state absorption, Fasted state absorption, TmaxTmax: 0.9 hr: 0.9 hr

•• Fed state Fed state CmaxCmax: 40% lower than in fasted: 40% lower than in fasted

statestate

•• No significant AUC differenceNo significant AUC difference

Clinical Clinical pharmacology pharmacology findingfinding

139


•• Food Decreases AbsorptionFood Decreases Absorption–– Major mechanismsMajor mechanisms

•• Instability in gastric acidsInstability in gastric acids

•• Physical/chemical binding with food componentsPhysical/chemical binding with food components

•• Increased firstIncreased first--pass metabolism & pass metabolism & cleanracecleanrace

–– May lead to decreased efficacyMay lead to decreased efficacy

–– Example: Example: DidanosineDidanosine

140


•• Food Decreases Absorption Food Decreases Absorption –– Example: Example: DidanosineDidanosine

•• Administer once daily on an empty stomachAdminister once daily on an empty stomachLabeling on Labeling on PrecautionsPrecautions

•• Unstable in acid solutionUnstable in acid solution

•• Protected by enteric coatingProtected by enteric coatingLabeling on Labeling on DescriptionDescription

•• Should be taken on an empty stomachShould be taken on an empty stomachLabeling on Dosage Labeling on Dosage & Administration& Administration

•• CmaxCmax reduced by 46%reduced by 46%

•• AUC reduced by 19%AUC reduced by 19%Clinical Clinical pharmacology pharmacology findingfinding

141


•• Food Increases AbsorptionFood Increases Absorption–– Major mechanismsMajor mechanisms

•• Inhibition of firstInhibition of first--pass effectpass effect

•• Physicochemical / physiological effectsPhysicochemical / physiological effects

•• Increased bile releaseIncreased bile release

•• Longer gastric residence timeLonger gastric residence time

–– Food may affect efficacy and/or safetyFood may affect efficacy and/or safety

–– Example: Example: IsotretinoinIsotretinoin, , EfavirenzEfavirenz

142


•• Food Increases Absorption Food Increases Absorption –– Example: Example: IsotretinoinIsotretinoin

•• Should always take with foodShould always take with food

•• Failure to take with food will significantly decrease Failure to take with food will significantly decrease absorptionabsorption

•• Practitioners should question patients about compliance Practitioners should question patients about compliance with food instructions before adjusting doses upwardwith food instructions before adjusting doses upward

Labeling on Dosage Labeling on Dosage & Administration& Administration

•• CmaxCmax more than doubledmore than doubled

•• AUC more than doubledAUC more than doubled

•• TmaxTmax also prolongedalso prolonged


143


•• Food Increases Absorption Food Increases Absorption –– Example: Example: EfavirenzEfavirenz

•• It is recommended that XXXX be taken on an empty It is recommended that XXXX be taken on an empty stomach, preferably at bedtimestomach, preferably at bedtime

•• Taking XXXX with food may lead to increased adverse Taking XXXX with food may lead to increased adverse eventsevents

Labeling on Dosage Labeling on Dosage & Administration& Administration

•• AUC increased by 22%, AUC increased by 22%, CmaxCmax increased by 39% with a increased by 39% with a high fat, high calorie mealhigh fat, high calorie meal

•• AUC increased by 17%, AUC increased by 17%, CmaxCmax increased by 51% with a increased by 51% with a low fat, normal calorie meallow fat, normal calorie meal


144


•• No effectsNo effects–– Major mechanismsMajor mechanisms

•• Relatively insensitive to changes in the GI tractRelatively insensitive to changes in the GI tract

•• Rapidly, completely absorbedRapidly, completely absorbed

•• WellWell--absorbed from both large & small intestineabsorbed from both large & small intestine

–– Example: Example: FinasterideFinasteride

145


•• No Food Effect No Food Effect –– Example: Example: FinasterideFinasteride

•• Can be administered with or without mealsCan be administered with or without mealsLabeling on Dosage Labeling on Dosage & Administration& Administration

•• BA not affected by foodBA not affected by foodClinical Clinical pharmacology pharmacology findingfinding

Case StudyCase Study

Albuterol Metered-dose Inhaler

147

Case Study Case Study –– AlbuterolAlbuterol InhalerInhaler

•• ObjectiveObjective–– Determine the potency of each generic Determine the potency of each generic albuterolalbuterol MDI MDI

actuation relative to actuation relative to VentolinVentolin administration administration

•• Drugs:Drugs:–– Generic drugs: Generic drugs: albuterolalbuterol meteredmetered--dose inhalersdose inhalers

–– Reference drug: Reference drug: VentolinVentolin ((GlaxoGlaxo WellcomeWellcome))

148


•• DesignDesign–– Randomized, doubleRandomized, double--blind, balanced, crossoverblind, balanced, crossover–– Placebo inhalers used to maintain blinding of inhaler & dosesPlacebo inhalers used to maintain blinding of inhaler & doses–– Reference Reference VentolinVentolin MDI: 90 MDI: 90 µgµg/actuation/actuation–– 1 treatment on each of 4 study days1 treatment on each of 4 study days–– A histamine A histamine bronchoprovocationbronchoprovocation procedure was initiated 1.25 hr procedure was initiated 1.25 hr

prior to and 15 min after treatmentprior to and 15 min after treatment

•• SubjectsSubjects–– Adult patients, 18 Adult patients, 18 –– 65 yrs, n = 2465 yrs, n = 24–– NonsmokingNonsmoking–– Clinically screened for mildClinically screened for mild--toto--moderate asthmamoderate asthma

•• FEV1, > 60% of predicted; and provocative concentration of FEV1, > 60% of predicted; and provocative concentration of histamine causing a 20% fall in FEV1 [PC20], ≤ 8 mg/histamine causing a 20% fall in FEV1 [PC20], ≤ 8 mg/mLmL at at screeningscreening

149


•• MeasurementsMeasurements–– Primary outcome: histamine PC20, measured after treatmentPrimary outcome: histamine PC20, measured after treatment

•• ResultsResults–– Significant doseSignificant dose--effect relationship (p < 0.0001)effect relationship (p < 0.0001)–– Not significant:Not significant:

•• Deviation from parallelism of the Generic & Reference doseDeviation from parallelism of the Generic & Reference dose--response curves (p = 0.95)response curves (p = 0.95)

•• Differences in overall mean response between the Generic & Differences in overall mean response between the Generic & Reference (p = 0.68)Reference (p = 0.68)

–– EstimationEstimation•• 1 actuation of Generic equivalent to 1.01 puffs of Reference1 actuation of Generic equivalent to 1.01 puffs of Reference•• CI 90% R/T = 0.69 CI 90% R/T = 0.69 –– 1.501.50

•• ConclusionConclusion–– Generic is bioequivalent to ReferenceGeneric is bioequivalent to Reference

150

Case Study Case Study ––AlbuterolAlbuterol InhalerInhaler

Mean effects of the generic (Norton) and Ventolin MDIs on

PC20

Source:Stewart B A et al. Demonstration of In Vivo Bioequivalence of a Generic AlbuterolMetered-Dose Inhaler to Ventolin. Chest 2000;117:714-721

Geometric mean PC20 (±SEM) measured 30 to 45 min after test MDI dosing

The same results express as activity ratio (± SEM)

• Significant dose-response Relationship (p < 0.0001)

• 1 puff Generic = 1.01 puffs Reference

151

Case Study Case Study ––AlbuterolAlbuterol InhalerInhaler

Top: Relationship between s/b and difference between response to

test and Ventolin MDIs

Source:Stewart B A et al. Demonstration of In Vivo Bioequivalence of a Generic AlbuterolMetered-Dose Inhaler to Ventolin. Chest 2000;117:714-721

Estimated potency of test inhaler relative to the Ventolin MDI and its 90% CI


Generic IR Tablets

153

Generic IR TabletsGeneric IR Tablets

•• Reference drug productReference drug product–– SotalexSotalex®® tablets C & Dtablets C & D

–– API API -- antiarrhythmicantiarrhythmic: : sotalolsotalol HClHCl

•• Generic drug productsGeneric drug products–– 80 & 160 mg IR tablets80 & 160 mg IR tablets

–– API API -- antiarrhythmicantiarrhythmic: : sotalolsotalol HClHCl

Source: Alt et al 2004, Rote Liste 2004

154


•• DataData–– API = BCS Class 1API = BCS Class 1

•• BA 90%, rapidly absorbedBA 90%, rapidly absorbed

•• In vitro/in vivo: high permeabilityIn vitro/in vivo: high permeability

–– In vitro dissolution profiles conducted in 0.1N In vitro dissolution profiles conducted in 0.1N HClHCl and pH 4.5 & and pH 4.5 & 6.8 phosphate buffers, paddle, 75 rpm6.8 phosphate buffers, paddle, 75 rpm

•• Dissolved >85% in 15 min in all mediaDissolved >85% in 15 min in all media

–– ExcipientsExcipients in the generic: well established and in amounts in the generic: well established and in amounts common in IR tablets, and unlikely to affect the absorptioncommon in IR tablets, and unlikely to affect the absorption

•• High conc. (0.755g/200 ml) High conc. (0.755g/200 ml) mannitolmannitol may lead to lower may lead to lower absorptionabsorption

•• But the amount of But the amount of mannitolmannitol present is below 1/3 of the present is below 1/3 of the concentration that would accelerate small intestine transit concentration that would accelerate small intestine transit timetime


155


•• Regulatory decision on Regulatory decision on biowaiverbiowaiver–– Germany: acceptedGermany: accepted

•• In compliance with the EMEA, BA/BE 2001In compliance with the EMEA, BA/BE 2001

•• USA: acceptance expected USA: acceptance expected


156

ReferencesReferences

•• US FDA Individual Product BE US FDA Individual Product BE Recommendations Dissolutions Methods Recommendations Dissolutions Methods DatabaseDatabase–– http://www.fda.gov/Drugs/GuidanceComplianceRegulhttp://www.fda.gov/Drugs/GuidanceComplianceRegul

atoryInformation/Guidances/ucm075207.htmatoryInformation/Guidances/ucm075207.htm

157

BA / BE Study Design WorkshopBA / BE Study Design Workshop14.00 14.00 –– 16.3016.30

Session IIISession III

Special Considerations for BA / BE Study Designs, part 2Special Considerations for BA / BE Study Designs, part 2

Special ConsiderationsSpecial Considerations

10.30 10.30 –– 12.0012.00

Session IISession II

Special Considerations for BA / BE Study Designs, part 1Special Considerations for BA / BE Study Designs, part 1


09.00 09.00 –– 10.0010.00

Session ISession I

Day 2 AgendaDay 2 Agenda

158

Session 1Session 1

Special Considerations for BA / BE Study Special Considerations for BA / BE Study Designs, Part 1Designs, Part 1


159

Model of Oral Dosage Form PerformanceModel of Oral Dosage Form Performance

TherapeuticEffect

Dosage Form

Gut WallDrug in Solution Blood

Site of Activity

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurement

ln DoseDoseSource: US FDA160

Endogenous Drug BEEndogenous Drug BE

•• Endogenous products are not covered by the general Endogenous products are not covered by the general BA/BE Guidance documentsBA/BE Guidance documents–– FDA FDA GuidancesGuidances on on KClKCl and and levothyroxinelevothyroxine

•• Require special considerationsRequire special considerations–– Case by caseCase by case

•• Examples of endogenous drug products:Examples of endogenous drug products:–– UrsodiolUrsodiol–– Iron productsIron products–– CalcitriolCalcitriol–– KClKCl–– EstradiolEstradiol–– ProgesteroneProgesterone–– TestosteroneTestosterone–– FSHFSH–– LevothyroxineLevothyroxine

161

Endogenous Drug BEEndogenous Drug BE

•• Potential issuesPotential issues–– Differentiation between endogenous & exogenous Differentiation between endogenous & exogenous

sourcessources

–– Assay sensitivityAssay sensitivity

–– Feedback impactFeedback impact

–– Circadian rhythmCircadian rhythm

–– Baseline correction & methods of correctionBaseline correction & methods of correction

–– Moving baselinesMoving baselines

–– Need for special populationNeed for special population

162

Model of Oral Dosage Form Endogenous Model of Oral Dosage Form Endogenous Drug PerformanceDrug Performance

TherapeuticEffect

Dosage Form

Gut WallDrug in Solution

BloodSite of Activity

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurement

ln DoseDose

Body Production Feedback

Source: US FDA

163

BE of BE of LevothyroxineLevothyroxine (LT(LT44 ))The Blakesley StudyThe Blakesley Study

Blakesley V, et al. Thyroid. 2004;14:191-200

FDA Citizen Petition No. 2003P-0387


164

BlakesleyBlakesley Study DesignStudy Design

•• LTLT44 Drug products:Drug products:––LevoLevo--tt ((SandozSandoz, generic) vs. , generic) vs. SynthroidSynthroid (Abbott, brand)(Abbott, brand)

•• 36 healthy volunteers (18M, 18F) 36 healthy volunteers (18M, 18F)

•• FFasting, openasting, open--label, randomized, threelabel, randomized, three--period, period, crossovercrossover; 42 to 54 days between periods; 42 to 54 days between periods

•• LTLT44 doses administereddoses administered––Regimen A: 600 Regimen A: 600 µµg (12 x 50 g (12 x 50 µµg Synthroid)g Synthroid)

––Regimen B: 450 Regimen B: 450 µµg (9 x 50 g (9 x 50 µµg Synthroid)g Synthroid)

––Regimen C: 400 Regimen C: 400 µµg (8 x 50 g (8 x 50 µµg g SynthroidSynthroid))

165

Time (hours)0 12 24 36 48 60 72 84 96

0

2

4

6

8

Regimen A: 600 µg Dose

Regimen B: 450 µg Dose

Regimen C: 400 µg Dose

Time (hours)

0 8 16 24 32 40 48

T4

Co

nce

ntr

atio

n (

mg

/dL

)

Blakesley V, et al. Thyroid. 2004;14:191-200.

BlakesleyBlakesley Study ResultsStudy Results

Endogenous hormone correction

166

BE Studies ComparisonBE Studies Comparison

AUC0-48 .6 .8 1.0 1.25 1.4

Sandoz L-T4vs. Synthroid

Sandoz L-T4vs. Levoxyl

.8 1.25Range of Bioequivalence

Petition to the FDA Docket No. 2003P-0387

167

Approved LTApproved LT44 ProductsProducts

BXNot interchangeable

JonesLevoxylAB3

AbbottSynthroidAB2

StevensUnithroidAB1

Mfg NameReference DrugBE Class

168

What’s This Petition All About?What’s This Petition All About?

Complaint:Complaint:• The mean bioavailability of the generic

Sandoz product is, on average, 12.5% greater than that of Synthroid after baseline correction

•• But based on FDA’s criteria for BE, Sandoz But based on FDA’s criteria for BE, Sandoz levothyroxine was allowed to be labeled as levothyroxine was allowed to be labeled as bioequivalent to both Synthroid and Levoxylbioequivalent to both Synthroid and Levoxyl

Petition to the FDA Docket No. 2003P-0387

169



• Statistics– Use ANOVA with 2 one-sided tests to analyze data– BE criteria

• 90% confidence intervals of means• Test/Reference ratio: 0.800 – 1.250

– Questions• What does this mean?• Can there be a 45% spread?

– Rounding not permitted (either up or down)

170



• Statistics–– Bioequivalence criteriaBioequivalence criteria

•• ANOVA two oneANOVA two one--sided tests proceduresided tests procedure–– Test (T) not significantly less than Reference (R)Test (T) not significantly less than Reference (R)

–– R not significantly less than TR not significantly less than T

–– Significant difference is 20% (Significant difference is 20% (αα = 0.05 significance = 0.05 significance level)level)

»» T/R = 80/100 = 80%T/R = 80/100 = 80%

»» R/T = 80% (all data expressed as T/R so this R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)becomes 100/80 = 125%)

171


Source: US FDA, http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_06_BioINequivalence.pdf

172

Possible BE Results (90% CI)Possible BE Results (90% CI)

T/R (%)80% 125%

173

Why is the Question Important?Why is the Question Important?

• Are patients getting therapeutically equivalent prescriptions when substitution occurs at the dispensing pharmacy?– Rx: no substitution– Rx: brand name only– Rx: dispense as written– Too complex for clinicians & pharmacists

174

•• Therefore, a generic drug product must be Therefore, a generic drug product must be the same as brand drug in:the same as brand drug in:�� Active ingredientActive ingredient

�� StrengthStrength

�� Dosage formDosage form

�� Route of administrationRoute of administration

�� QualityQuality

�� Therapeutic effectTherapeutic effect


175

Brand Name Drug Brand Name Drug --NDA Submission:NDA Submission:•• ChemistryChemistry•• ManufacturingManufacturing•• ControlsControls•• LabelingLabeling•• TestingTesting•• Preclinical/ClinicalPreclinical/Clinical•• BioavailabilityBioavailability

Generic Drug Generic Drug ––ANDA Submission:ANDA Submission:•• ChemistryChemistry•• ManufacturingManufacturing•• ControlsControls•• LabelingLabeling•• TestingTesting

•• BioequivalenceBioequivalence

Generics Approval ConsiderationsGenerics Approval Considerationsby the US FDAby the US FDA

Source: CDER, US FDA

176

Study Design: Basic design considerationStudy Design: Basic design consideration

•• When comparing performance of two productsWhen comparing performance of two products

–– Minimize variability not attributable to formulationsMinimize variability not attributable to formulations

–– Minimize biasMinimize bias

177

Study Design: Basic design considerationStudy Design: Basic design consideration

•• BE of a generic equivalent, G, of name brand BE of a generic equivalent, G, of name brand drug Ndrug N

•• Study DesignStudy Design–– Healthy subjectsHealthy subjects

–– Two treatmentsTwo treatments

•• One for GOne for G

•• One for NOne for N

–– Two sequencesTwo sequences

•• GG--NN

•• NN--GG

178

Overview of BE Study DesignsOverview of BE Study Designs

TEST drug & REFERENCE drug

Immediate Release

Modified Release

Single Dose Fasting

Single Dose Fed

AUCCmaxTmax

λz (Kel)T1/2

Extended Release(Controlled Release)

Delayed Release(Enteric Coated)

Single Dose Fasting

Single Dose Fed

AUCCmaxTmax

λz (Kel)T1/2

Terminal elimination rate constantTime to half peak concentration

179

EFFUDEXEFFUDEX55--FUFU

FDA Citizen Petition 2004P-0557


180

EFFUDEXEFFUDEX

http://www.efudex.com/index.jspf

181

EFFUDEXEFFUDEX

•• EffudexEffudex–– Fluorouracil Topical Treatment of Solar or Actinic Fluorouracil Topical Treatment of Solar or Actinic KeratosesKeratoses & &

Superficial Basal Cell Carcinoma (5% strength)Superficial Basal Cell Carcinoma (5% strength)

•• IndicationsIndications–– Multiple actinic / solar Multiple actinic / solar keratosiskeratosis

–– Superficial basal cell carcinomasSuperficial basal cell carcinomas

•• Citizen Petition 2004PCitizen Petition 2004P--0557 filed by 0557 filed by ValeantValeant, December , December 2004, asking the FDA not to approve of ANDA for 2004, asking the FDA not to approve of ANDA for generic versions unlessgeneric versions unless–– BE is established for each different site of action for each BE is established for each different site of action for each

indication indication

–– BE is established in the most difficult condition to treatBE is established in the most difficult condition to treat

182

EFFUDEXEFFUDEX

•• FDA denied FDA denied Valeant’sValeant’s CP & approved of Spear’s CP & approved of Spear’s ANDA for a generic ANDA for a generic flurouracilflurouracil cream 5% cream 5% product, April 11, 2008product, April 11, 2008–– “…it has not been the Agency’s policy to require that “…it has not been the Agency’s policy to require that

BE BE bebe shown in every indication if drug release from shown in every indication if drug release from the dosage form and appearance at the site or sites the dosage form and appearance at the site or sites of activity has been demonstrated…”of activity has been demonstrated…”

–– “If a study demonstrated efficacy for a 5“If a study demonstrated efficacy for a 5--FU FU formulation to treat Actinic formulation to treat Actinic KeratosesKeratoses, this would , this would provide assurance that the formulation would provide assurance that the formulation would penetrate the skin sufficiently to treat penetrate the skin sufficiently to treat sBCCsBCC.”.”

•• ValeantValeant sued FDA on April 25, 2008sued FDA on April 25, 2008–– Requested to suspend approval of Spear’s ANDARequested to suspend approval of Spear’s ANDA

183

EFFUDEXEFFUDEX

•• FDA, Assoc. Commissioner for Policy and FDA, Assoc. Commissioner for Policy and Planning issued an administrative order staying Planning issued an administrative order staying the approval of generic fluorouracil cream 5% the approval of generic fluorouracil cream 5% until May 30, 2008until May 30, 2008–– Due to “outstanding questions regarding this approval Due to “outstanding questions regarding this approval

that the Agency must consider"that the Agency must consider"

•• Spear suspended all further sales and shipmentSpear suspended all further sales and shipment

•• October 2009, the U.S. District Court for the October 2009, the U.S. District Court for the Central District of California upheld FDACentral District of California upheld FDA’’s s positionposition

184

ColazalColazalBalsalazide Disodium

FDA Citizen Petition No. CP 2005P-1461


185

Local Acting Oral DrugsLocal Acting Oral DrugsColazalColazal –– CP 2005PCP 2005P--1461 by Salix1461 by Salix

• API = Balsalazide disodium:– Orally administered – locally acting GI product– Enzymatically cleaved in the colon � Mesalamine (anti-

inflammatory)– Indications – reduce inflammation associated with

ulcerative colitis• Site of action: colon

186


• API = Balsalazide disodium• Salix’ citizen petition to the FDA to require all generic

ANDAs to include efficacy & safety data from comparative clinical trials:– FDA to establish guidance on BE standards for oral, locally acting

GI drugs prior to approval of any generic ANDAs– In vivo BE to use ulcerative colitis patients in remission instead of

normal health subjects– In vivo BE to include specific analyte (N-Acetyl-5-Aminosalicylic acid

in plasma) measurement in adults and pediatrics– In vivo BE to use a fed, a sprinkling and a fasting study– In vivo BE to include pharmacokinetic studies in the pediatric

population and measure plasma levels of balsalazide, mesalamine, & N-acetyl -5-ASA

187


• API = Balsalazide disodium• FDA’s conclusion the CP on December 28, 2007

– Both fasting & fed studies should be conducted for BE, as a result of labeling changes

– Other requests denied• Solubility• Mechanism of release• Ability to measure plasma concentrations and relation of plasma

concentrations to release at the site of action• Sensitivity of clinical studies to detect differences in product

performance

• ANDAs for generics approved on Dec 28, 2007

188

Interchangeable or Not?Interchangeable or Not?

• Let’s walk down the history lane…– 1938: Food, Drug & Cosmetic Act– Prior to 1962, proven safe but not necessarily effective– 1950s: generics started to appear– 1960s: Thalidominde disaster– 1962: Kefauver Harris Drug Amendments Act, S&E

•• Cost of medicine went upCost of medicine went up–– 19702: Generics found to have BA problems19702: Generics found to have BA problems–– 1984: Hatch1984: Hatch––Waxman AWaxman Actct

•• ANDA for genericsANDA for generics•• BE requiredBE required

–– 80 80 –– 125%125%

189

Price of Medicine vs. Generic AvailabilityPrice of Medicine vs. Generic Availability

Source: FDA, retail sales data from IMS Health

190


• Let’s walk down the history lane…– 1986 FDA public hearing on BE determination method

• Conclusion: 80 – 125% rule satisfactory and clinically acceptable, but• Both pro- & anti- camps agreed acceptable bioavailability variation for

generic– Most meds: 11%– Critical dose meds: 5%

– 1989 generics submissions scandal: S&E of generics rejuvenated• FDA employees bribed to expedite approval• Fraudulent submissions to the FDA for approval of generic drugs &

GMP violations• � extensive FDA inspections• Hundreds of generic drug applications reexamined

– including narrow therapeutic index drugs: aminophylline tablets– Only 27 samples (1%) failed to comply – Only 5 of those (all aminophylline tablets) failed to meet USP standards– None of the defects deemed to pose a public health hazard

191


• Let’s walk down the history lane…– Joint guidelines by the FDA & EMEA on BA/BE

• Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations

• Other data may be needed beyond BE assurance– Analytical methods validation

– In vitro/in vivo correlation

•• FDA letter to health practitionersFDA letter to health practitioners–– ““Products evaluated as therapeutically equivalent are expected toProducts evaluated as therapeutically equivalent are expected to

have equivalent clinical effect whether the product is a brand nhave equivalent clinical effect whether the product is a brand name ame or a generic drug productor a generic drug product

–– It is not necessary for the health care provider to approach anyIt is not necessary for the health care provider to approach any one one therapeutic class of drug product differently from any other clatherapeutic class of drug product differently from any other class, ss, when there has been a determination of therapeutic equivalence bwhen there has been a determination of therapeutic equivalence by y FDA for the drug products under consideration.FDA for the drug products under consideration.”” 192


• Let’s walk down the history lane…– What did the end users say about generic substitution?

•• Physicians, pharmacists and patientsPhysicians, pharmacists and patients•• PharmacistsPharmacists

–– Supported the use of generic drugsSupported the use of generic drugs

–– Quality, price and supplier consistencyQuality, price and supplier consistency

•• PatientsPatients–– 72% accepted generics on pharmacist72% accepted generics on pharmacist’’s recommendations recommendation

–– 76% agreed on generics on doctor76% agreed on generics on doctor’’s suggestions suggestion

•• PhysiciansPhysicians–– Only 17% could correctly identified FDAOnly 17% could correctly identified FDA’’s BE standardss BE standards

193


• Let’s walk down the history lane…– Conflicting findings on differences in brand – generics substitution

• 1997 US Case – FDA looked at all approved generics:– AUC: 3.25% (SD, 2.97) to 3.47% (SD, 2.84)– Cmax: 4.29% (SD, 3.72)

• 1984 - 1986 US Case:– AUC: 3.5%

• 1995 - 1996, UK Case:– UK Medicines Control Agency (MCA) examined 2427 generics– 228 deficiencies

– MCA requested 84 product quality improvements in labelling, packaging, methods of analysis, and products specifications

194


• Let’s walk down the history lane…– FDA’s philosophy

•• PMS PMS -- one of the best mechanisms to protect patients from one of the best mechanisms to protect patients from problems problems

•• FDA adverse event alert & maintenance system to update drug FDA adverse event alert & maintenance system to update drug labeling, reevaluate approval or marketinglabeling, reevaluate approval or marketing

–– The Spontaneous Reporting SystemThe Spontaneous Reporting System

»» Computerized database Computerized database –– early warning system for adverse early warning system for adverse eventsevents

»» Adverse drug reactions primarily reported by health Adverse drug reactions primarily reported by health professionalsprofessionals

»» 1960s 1960s -- January 1997, serve as an early warning system for January 1997, serve as an early warning system for adverse drug reactions not detected during adverse drug reactions not detected during prermarketingprermarketingtesting. This system has been replaced by the Adverse Events testing. This system has been replaced by the Adverse Events Reporting SystemReporting System

195



• FDA adverse event alert & maintenance system to update drug labeling, reevaluate approval or marketing

– The Adverse Events Reporting System» Replacing the above» Electronic submission» International compatibility

– MedWatch» For both health professionals & the public» Voluntary reporting of serious AE

– FDA Therapeutic Inequivalence Action Coordinating Committee (TIACC)

» To identify and evaluate reports of therapeutic failures and toxicity that could indicate that one product is not equivalent to another similar product

» A mechanism for timely follow up on reports of therapeutic inequivalence and full-scale investigation 196



• FDA adverse event alert & maintenance system to update drug labeling, reevaluate approval or marketing

– FDA Therapeutic Inequivalence Action Coordinating Committee (TIACC)

» What can the TIACC do?» Remove inequivalent products from the market» Evaluate and change the TE rating of products» Recommend a grandfathered product to submit a new drug

application» Test and evaluate BE/dissolution relationship» Recommend appropriate dissolution specifications for narrow

therapeutic drugs» Evaluate toxicity profile of injectables and mandate appropriate

controls…

197


• Let’s walk down the history lane…– The Orange Book Designation

• A = substitutable– No known/suspected BE problems– The second letter = the dosage form

» AT = BE, topical dosage as compared to the topical dosage form of the reference drug

» AB = Actual or potential BE problems have been resolved with adequate in vivo and/or in vitro evidence

• B = non-interchangeable– NOT being therapeutically equivalent– BC, BD, BE, BN, BP, BR, BS, BT, BX, where the second

letter indicate the dosage form 198

Interchangeable or Not?Interchangeable or Not?From Brand to GenericsFrom Brand to Generics

• Anti-arrhythmics (e.g., Amiodarone)– Uncertain combination impact exists:

• Advanced age• Current diseases• Concomitant drug therapy on bioequivalence

– Best to start on the Brand name medicines first– Avoid presumed BE dosage forms– Switch and continue with generics used in the titration to

an effective antiarrythmic response

199


• Anticoagulants (e.g., Warfarin)– Conflicting views from the guidelines issued by the FDA

and the health practitioners (the Institute for Clinical Systems Improvement)

– BE results suggest both S & E to initiate therapy with the generics

• Patients take a single warfarin product whenever possible

• Followed by additional monitoring after substitution of one warfarin product for another

–– Timely detection of patient’s antiTimely detection of patient’s anti--coagulation responsecoagulation response

200


• Antiepileptics (Phenytion, Carbamezapine)– Generic substitution can be approved only if safety and

efficacy are not compromised– Avoid switching between formulations except when

medically necessary– Monitor blood levels closely at the time of any known or

suspected switch to a different formulation– Adjust & readjust medication doses accordingly– Avoid unilateral switch by pharmacists to different

products

201


• Thyroxine– First approved product: Synthroid (Levothyroxine), 1955– Recommended:

• Obtain a thyroid stimulating hormone (TSH) level within eight to twelve weeks of changing a levothyroxine dose or brand and every six to twelve months thereafter

202


• Highly variable drugs – Medicines demonstrating a high variability in

pharmacokinetic parameters � a challenge in BE testing• Could be due to high intra-subject variability• Examples:

– Propafenone IR– Verapamil– Nadolol

• Current 80 – 125% standard suitable?– A new specific FDA guidelines for this category

203


• Brand-generic substitution concerns and questions– One single regulatory acceptance range (80 – 125%) for

all drug products?– The use of single dose studies in BE studies, while all

drugs are usually used in multiple doses– Extrapolation of BE in normal healthy volunteers

applicable to all patients populations? – BE studies performed on a small number of subjects

only…– Different generic BE versions of a branded reference

product• Assumption is the generics are freely interchangeable• Where’s the data to suggest this? 204

Session 2Session 2

•• ASEAN Status SummaryASEAN Status Summary

•• Special Considerations for BA / BE StudiesSpecial Considerations for BA / BE Studies–– Good Laboratory Practice (GLP) in a NutshellGood Laboratory Practice (GLP) in a Nutshell

–– Good Clinical Practice (GCP) in a NutshellGood Clinical Practice (GCP) in a Nutshell

–– InterInter--relationship & Conductrelationship & Conduct

205

ASEAN Survey ResultASEAN Survey Result

•• Survey on Requirement of GCP, GLP & BE Study Survey on Requirement of GCP, GLP & BE Study Report in AMS, 2008Report in AMS, 2008, reported at the 4th Meeting of , reported at the 4th Meeting of ASEAN BA/BE Taskforce Vientiane, 18 February 2008ASEAN BA/BE Taskforce Vientiane, 18 February 2008

•• 9 AMS participated9 AMS participated–– BruneiBrunei

–– CambodiaCambodia

–– IndonesiaIndonesia

–– Lao PDRLao PDR

–– MalaysiaMalaysia

–– PhilippinesPhilippines

–– SingaporeSingapore

–– Thailand Thailand

–– VietnamVietnam

GCP Requirements for BE CenterGCP Requirements for BE CenterGLP Requirements for BE CenterGLP Requirements for BE CenterBE Study ReportBE Study Report

206

ASEAN GCP StatusASEAN GCP Status

•• 5 out of 9 countries have GCP regulation: 5 out of 9 countries have GCP regulation:

−− 4 of the 5 countries have National GCP guideline & 4 of the 5 countries have National GCP guideline &

mechanism for authorization of clinical trials, including mechanism for authorization of clinical trials, including

BE studies and related Guidance or SOPsBE studies and related Guidance or SOPs

−− 5 countries are in line with ICH GCP (E6)5 countries are in line with ICH GCP (E6)

−− 1 of the 5 countries is also in line with FDA Guidance1 of the 5 countries is also in line with FDA Guidance

−− 2 of the 5 countries are also in line with EMEA Note 2 of the 5 countries are also in line with EMEA Note

for Guidance on Clinical Practice as well as WHO for Guidance on Clinical Practice as well as WHO

Handbook for Good Clinical Research PracticeHandbook for Good Clinical Research Practice

•• 4 countries do not have GCP regulation 4 countries do not have GCP regulation

207

ASEAN GLP StatusASEAN GLP Status

•• GLP guidance in line withGLP guidance in line with–– ISO 17025 ISO 17025 –– OECDOECD–– WHO GLPWHO GLP

•• 4 of the 5 conduct GLP inspection4 of the 5 conduct GLP inspection

208

BE study reports received in the past 6 monthsBE study reports received in the past 6 months

0

10

20

30

40

50

60

70

Indonesia Malaysia Philippines Singapore Thailand Vietnam

25

66

30

13

25

2

209

ASEAN BE Study Report FormatASEAN BE Study Report Format

•• In line with international standardsIn line with international standards

•• FDAFDA

•• WHO TRS 937 WHO TRS 937

•• ICH E3 ICH E3

210

ASEAN GLP ASEAN GLP

•• DefinitionDefinition–– A A quality system concerned with the quality system concerned with the organisationalorganisational

process and the conditions under which nonprocess and the conditions under which non--clinical clinical health and environmental safety studies are planned, health and environmental safety studies are planned, performed, monitored, recorded, archived and performed, monitored, recorded, archived and reportedreported

•• GLP standardsGLP standards–– EMEA/OECD GLPEMEA/OECD GLP

–– WHO GLPWHO GLP

–– ISO/IEC 17025/1999ISO/IEC 17025/1999

211

GLP in a Nutshell GLP in a Nutshell

Adequate FacilityProtocols

Qualified Personnel

Proper Documentation & Archiving

Accurate Data Specifications

Suitable Test Systems

Effective SOPs

212

GLP ComparisonGLP Comparison

For For nonclinicalnonclinical safety testing & safety testing & NonclinicalNonclinical health & environmental health & environmental safety studiessafety studies

••Pharmaceutical productsPharmaceutical products

••Pesticide productsPesticide products

••Cosmetic ProductsCosmetic Products

••VetirinaryVetirinary drugsdrugs

••Food additives, feed additivesFood additives, feed additives

••Industrial chemicalsIndustrial chemicals

For For nonclinicalnonclinical lab studieslab studies

••Food & color additivesFood & color additives

••Animal food additivesAnimal food additives

••Human/animal drugsHuman/animal drugs

••Medical devices for human Medical devices for human useuse

••Biological productsBiological products

••Electronic productsElectronic products

ScopeScope

OECDOECDFDAFDATopicTopic

213


The persons, premises and The persons, premises and operational operational unit(sunit(s) that are ) that are necessary for conducting the nonnecessary for conducting the non--clinical health and environmental clinical health and environmental safety study. For multisafety study. For multi--site studies, site studies, those which are conducted at more those which are conducted at more than one site, the test facility than one site, the test facility comprises the site at which the comprises the site at which the Study Director is located and all Study Director is located and all individual test sites, which individual test sites, which individually or collectively can be individually or collectively can be considered to be test facilities.considered to be test facilities.

A person who actually conducts A person who actually conducts a a nonclinicalnonclinical laboratory study, laboratory study, i.e., actually uses the test article i.e., actually uses the test article in a test system. Testing facility in a test system. Testing facility includes any establishment includes any establishment required to register under required to register under section 510 of the act that section 510 of the act that conducts conducts nonclinicalnonclinical laboratory laboratory studies and any consulting studies and any consulting laboratory described in section laboratory described in section 704 of the act that conducts 704 of the act that conducts such studies. Testing facility such studies. Testing facility encompasses only those encompasses only those operational units that are being operational units that are being or have been used to conduct or have been used to conduct nonclinicalnonclinical laboratory studies.laboratory studies.

Testing Testing FacilityFacility


214


A defined system, including A defined system, including personnel, which is personnel, which is independent of study independent of study conduct and is designed to conduct and is designed to assure test facility assure test facility management of compliance management of compliance with these Principles of with these Principles of Good Laboratory PracticeGood Laboratory Practice

Any person or Any person or organizational element, organizational element, except the study director, except the study director, designated by testing designated by testing facility management to facility management to perform the duties perform the duties relating to quality relating to quality assurance of assurance of nonclinicalnonclinicallaboratory studieslaboratory studies

Quality Quality Assurance Assurance UnitUnit


215


The individual responsible The individual responsible for the overall conduct of for the overall conduct of the the nonclinicalnonclinical health and health and environmental safety study environmental safety study

The individual The individual responsible for the responsible for the overall conduct of a overall conduct of a nonclinicalnonclinical laboratory laboratory studystudy

Study Study DirectorDirector


216


Principal Investigator means an individual Principal Investigator means an individual who, for a multiwho, for a multi--site study, acts on behalf site study, acts on behalf of the Study Director and has defined of the Study Director and has defined responsibility for delegated phases of the responsibility for delegated phases of the study. The Study Director's responsibility study. The Study Director's responsibility for the overall conduct of the study cannot for the overall conduct of the study cannot be delegated to the Principal be delegated to the Principal Investigator(sInvestigator(s); this includes approval of ); this includes approval of the study plan and its amendments, the study plan and its amendments, approval of the final report, and ensuring approval of the final report, and ensuring that all applicable Principles of Good that all applicable Principles of Good Laboratory Practice are followed.Laboratory Practice are followed.

Principal Principal InvestigatorInvestigator


217


Any material derived from a test Any material derived from a test system for examination, analysis, system for examination, analysis, or retentionor retention

Any material derived from a Any material derived from a test system for examination test system for examination or analysisor analysis

SpecimenSpecimen

Any biological, chemical or Any biological, chemical or physical system or a combination physical system or a combination thereof used in a studythereof used in a study

Any animal, plant, Any animal, plant, microorganism, or subparts microorganism, or subparts thereof to which the test or thereof to which the test or control article is administered control article is administered or added for study. Test or added for study. Test system also includes system also includes appropriate groups or appropriate groups or components of the system components of the system not treated with the test or not treated with the test or control articles control articles

Test Test SystemSystem


218


An article that is the subject of a An article that is the subject of a studystudy

Any food additive, color Any food additive, color additive, drug, biological additive, drug, biological product, electronic product, product, electronic product, medical device for human medical device for human use, or any other article use, or any other article subject to regulationsubject to regulation

Test Test ArticleArticle

Batch means a specific quantity Batch means a specific quantity or lot of a test item or reference or lot of a test item or reference item produced during a defined item produced during a defined cycle of manufacture in such a cycle of manufacture in such a way that it could be expected to way that it could be expected to be of a uniform character and be of a uniform character and should be designated as such.should be designated as such.

Batch means a specific Batch means a specific quantity or lot of a test or quantity or lot of a test or control article that has been control article that has been characterized according to characterized according to Sec. 58.105(a).Sec. 58.105(a).

BatchBatch


219


Any article used to provide Any article used to provide a basis for comparison with a basis for comparison with the test itemthe test item

Any food additive, color Any food additive, color additive, drug, biological additive, drug, biological product, electronic product, product, electronic product, medical device for human medical device for human use, or any article other than use, or any article other than a test article, feed, or water a test article, feed, or water that is administered to the that is administered to the test system in the course of a test system in the course of a nonclinicalnonclinical laboratory study laboratory study for the purpose of for the purpose of establishing a basis for establishing a basis for comparison with the test comparison with the test articlearticle

Control Control ArticleArticle


220


The date the Study Director signs The date the Study Director signs the final reportthe final report

The date the final report is The date the final report is signed by the study directorsigned by the study director

Study Study Completion Completion DateDate

The date the Study Director signs The date the Study Director signs the study planthe study plan

The date the protocol is The date the protocol is signed by the study directorsigned by the study director

Study Study Initiation Initiation DateDate


Source: Comparison Chart of FDA and EPA GLP Regulations and OECDPrinciples of GLP. US FDA June 2004

221

GCP OverviewGCP Overview

• GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials or studies

• GCP compliance provides public assurance that the rights, safety and well-being of human subjects involved in research are protected

222

Goals of GCPGoals of GCP

• Protect the rights, safety and welfare of humans participating in research

• Aassure the quality, reliability and integrity of data collected

• Provide standards and guidelines for the conduct of clinical research

• GCP = Ethics + Quality Data

223

Basis for Ethical Conduct of Clinical ResearchBasis for Ethical Conduct of Clinical Research

• The Nuremberg Code (1947)

• The Declaration of Helsinki (1964)• The Belmont Report (1979)

• ICH GCP E6• ISO 14155

• Other International GCP Guidelines

224


• The Nuremberg Code (1947)– Voluntary participation– Informed Consent– Minimization of risk

225



• The Declaration of Helsinki (1964)– Well-being of subject takes precedence– Respect for persons– Protection of subjects health and rights– Special protection for vulnerable populations

226




– Respect for Persons• Informed consent• Protection of vulnerable populations

– Beneficence• Non-malfeasance

– Justice• Fairness

227




• ICH GCP E6– GCP is an international quality standard that is provided

by the International Conference on Harmonisation (ICH)– Goals: Harmonize technical procedures and standards;

improve quality; speed time to market

228




• ICH GCP E6• ISO 14155

– ISO 14155: Clinical Investigation of Medical Devices for Human Subjects

• Assists sponsors, monitors, and clinical investigators in the design and conduct of device clinical investigations

• Assists regulatory bodies and ethics committees in their roles of reviewing clinical investigational plans

229

13 Principles of ICH GCP13 Principles of ICH GCP

• Ethics:– Ethical conduct of clinical trials– Benefits justify risks– Rights, safety, and well-being of subjects prevail

• Protocol and science:– Nonclinical and clinical information supports the trial – Compliance with a scientifically sound, detailed protocol

• Responsibilities: – IRB/IEC approval prior to initiation– Medical care/decisions by qualified physician – Each individual is qualified (education, training, experience) to

perform his/her tasks

• Informed Consent: – Freely given from 230

13 Principles of ICH GCP13 Principles of ICH GCP

• Data quality and integrity: – Accurate reporting, interpretation, and verification – Protects confidentiality of records

• Investigational Products – Conform to GMP’s and used per protocol

• Quality Control/Quality Assurance – Systems with procedures to ensure quality of every

aspect of the trial

231

GCP Responsibility ChainGCP Responsibility Chain

• Sponsors • Clinical Investigators (CIs)• Independent Ethics Committees (IECs)

– Institutional Review Boards (IRBs)

• Contract Research Organizations (CROs)• Research nurses• Clinical Research Coordinators (CRCs)• Clinical Research Associates (CRAs) • Medical monitors• Data entry personnel• Others

232

GCP In a NutshellGCP In a Nutshell

•• Protection of the rights of subjectsProtection of the rights of subjects•• Good documentationGood documentation•• MonitoringMonitoring

233

•• Chapter 1 Chapter 1 -- GlossaryGlossary

•• Chapter 2 Chapter 2 -- Principles of ICH GCPPrinciples of ICH GCP

•• Chapter 3 Chapter 3 -- Institutional Review BoardInstitutional Review Board

•• Chapter 4 Chapter 4 -- Investigator Investigator

•• Chapter 5 Chapter 5 -- SponsorSponsor

•• Chapter 6 Chapter 6 -- Protocol and AmendmentsProtocol and Amendments

•• Chapter 7 Chapter 7 -- Investigator’s BrochureInvestigator’s Brochure

•• Chapter 8 Chapter 8 -- Essential DocumentsEssential Documents

ICH GCPICH GCP

234

•• IRB is required toIRB is required to–– Review informed consent, protocol, advertisements, Review informed consent, protocol, advertisements,

and the Investigator's Brochure.and the Investigator's Brochure.

–– Submit documents:Submit documents:

•• Subject recruitment proceduresSubject recruitment procedures

•• Written information provided to subjectsWritten information provided to subjects

•• Information about subject compensationInformation about subject compensation

•• Investigator's current CV and/or other documents Investigator's current CV and/or other documents evidencing qualificationsevidencing qualifications

IRB Responsibilities (ICH 3.1)IRB Responsibilities (ICH 3.1)

235

•• IRBsIRBs required composition:required composition:

–– At least five membersAt least five members

–– One nonOne non--scientific memberscientific member

–– One member not affiliated with the institutionOne member not affiliated with the institution

–– Members involved in the protocol not have a Members involved in the protocol not have a voting rolevoting role

IRB Composition (ICH 3.2)IRB Composition (ICH 3.2)

236

•• Additional FDA requirements on IRB (Additional FDA requirements on IRB (56.107a56.107a--ff):):–– One scientific memberOne scientific member

–– Diversity in race, gender, cultural backgroundsDiversity in race, gender, cultural backgrounds

–– Varying backgrounds Varying backgrounds -- not composed of only one not composed of only one professionprofession

–– Members qualified to assess the acceptability of the Members qualified to assess the acceptability of the protocol with institutional SOPs & professional protocol with institutional SOPs & professional practice standardspractice standards

–– Members with a conflicting interest cannot vote for Members with a conflicting interest cannot vote for protocol approvalprotocol approval

IRB Composition IRB Composition -- USUS

237

•• Investigators required to maintain a list of Investigators required to maintain a list of appropriately qualified persons to whom appropriately qualified persons to whom significant trialsignificant trial--related duties have been related duties have been delegated.delegated.

Investigator Agreements (ICH 4.1)Investigator Agreements (ICH 4.1)

238

•• Investigators to demonstrate potential for recruiting Investigators to demonstrate potential for recruiting the required number of patients within the agreed the required number of patients within the agreed recruitment periodrecruitment period

–– Retrospective data Retrospective data

–– Patient database analysisPatient database analysis

Investigator Resources (ICH 4.2)Investigator Resources (ICH 4.2)

239

•• Investigators required toInvestigators required to–– Inform subjects when medical care is needed for an Inform subjects when medical care is needed for an

intercurrentintercurrent illnessillness

–– Make every reasonable effort to ascertain the Make every reasonable effort to ascertain the reason(sreason(s) for subject early withdrawal (although the ) for subject early withdrawal (although the subject is not obliged to give a reason)subject is not obliged to give a reason)

•• ICH recommendationICH recommendation–– Investigators inform the subject’s primary physician Investigators inform the subject’s primary physician

of trial participation (with the subject’s permission)of trial participation (with the subject’s permission)

Subject Medical Care (ICH 4.3)Subject Medical Care (ICH 4.3)

240

•• Investigators (or their designees) to document Investigators (or their designees) to document and explain any deviation from the approved and explain any deviation from the approved protocolprotocol

Protocol Compliance (ICH 4.5)Protocol Compliance (ICH 4.5)

241

•• ICH allows the delegation of study drug ICH allows the delegation of study drug dispensing, patient counselling, and drug dispensing, patient counselling, and drug accountability to a designeeaccountability to a designee

Investigational Product (ICH 4.6)Investigational Product (ICH 4.6)

242

•• ICH allows the delegation of the informed ICH allows the delegation of the informed consent process to a designeeconsent process to a designee

•• ICH requires the person conducting the ICH requires the person conducting the informed consent process to sign and informed consent process to sign and date the consent formdate the consent form

•• ICH requires that the subject receive a ICH requires that the subject receive a signed and dated copy of the consent signed and dated copy of the consent form. FDA only requires that a copy be form. FDA only requires that a copy be providedprovided

Informed Consent (ICH 4.8)Informed Consent (ICH 4.8)

243

•• ICH requirements but not required by the US ICH requirements but not required by the US FDA:FDA:–– Discussion of trial treatments and probability of Discussion of trial treatments and probability of

random assignmentrandom assignment

–– Subject responsibilitiesSubject responsibilities

–– Anticipated payment, if any, to the subjectAnticipated payment, if any, to the subject

–– Important potential risks and benefits of alternative Important potential risks and benefits of alternative treatmenttreatment

–– Authorization to access medical records by regulatory Authorization to access medical records by regulatory authorities (FDA and foreign)authorities (FDA and foreign)

Informed ConsentInformed Consent

244

•• Investigators (or designees) required to:Investigators (or designees) required to:–– Document explanations for discrepancies between Document explanations for discrepancies between

data in the data in the CRFsCRFs and the source documentsand the source documents

–– Initial, date and explain (if necessary) all CRF Initial, date and explain (if necessary) all CRF changes/corrections. CRF designees must be changes/corrections. CRF designees must be documenteddocumented

–– Endorse & retain records of all CRF changes Endorse & retain records of all CRF changes made by the Sponsormade by the Sponsor

Records and Reports (ICH 4.9)Records and Reports (ICH 4.9)

245

•• Retention of “essential documents” for at least Retention of “essential documents” for at least two years after the approval of a marketing two years after the approval of a marketing application in anapplication in an ICH regionICH region or until there is no or until there is no pending or contemplated applications in an pending or contemplated applications in an ICH ICH regionregion or development is formally discontinued or development is formally discontinued

Records and Reports (ICH 4.9)Records and Reports (ICH 4.9)

246

•• Sponsors to secure agreement from all Sponsors to secure agreement from all involved parties to ensure direct access of involved parties to ensure direct access of study records to foreign regulatory authoritiesstudy records to foreign regulatory authorities

Sponsor QA/QC (ICH 5.1)Sponsor QA/QC (ICH 5.1)

247

•• Sponsors to inform Investigators in writing of:Sponsors to inform Investigators in writing of:

–– Study record retention requirementsStudy record retention requirements

–– Notification of when records are no longer Notification of when records are no longer neededneeded

Record Keeping (ICH 5.5)Record Keeping (ICH 5.5)

248

•• Sponsors to provide insurance or indemnify Sponsors to provide insurance or indemnify the investigator against claims arising from the investigator against claims arising from the trialthe trial

Compensation (ICH 5.8)Compensation (ICH 5.8)

249

•• Financial aspects of the trial to be documented Financial aspects of the trial to be documented in an agreement between the Sponsor and in an agreement between the Sponsor and InvestigatorInvestigator

•• No specific requirements on the investigator’s No specific requirements on the investigator’s financial disclosurefinancial disclosure

Financing (ICH 5.9)Financing (ICH 5.9)

250

•• Sponsors to obtain a statement from Sponsors to obtain a statement from Investigators that their local IRB is organized and Investigators that their local IRB is organized and operates according to GCP and applicable laws operates according to GCP and applicable laws and regulationsand regulations

IRB Review (ICH 5.11)IRB Review (ICH 5.11)

251

•• Sponsors to obtain documentation of IRB Sponsors to obtain documentation of IRB approval prior to shipping investigational product approval prior to shipping investigational product to an Investigatorto an Investigator

Supplying IP (ICH 5.14)Supplying IP (ICH 5.14)

252

FDA Inspections on GCP & GLPFDA Inspections on GCP & GLP

•• What Piques FDA’s Interest?What Piques FDA’s Interest?–– Proper protocol approval?Proper protocol approval?

–– Was the approved protocol followed by the Was the approved protocol followed by the investigator? By whom, in which steps?investigator? By whom, in which steps?

–– Accountability for the test productAccountability for the test product

–– Informed consent obtained properly?Informed consent obtained properly?

–– Source document match the data submitted?Source document match the data submitted?

–– Monitor’s accountability & communicationMonitor’s accountability & communication

253

FDA Inspections on GCP & GLPFDA Inspections on GCP & GLP

•• Common Reasons for Warning Letters Common Reasons for Warning Letters –– Failure Failure in the following areas:in the following areas:–– Informed consent issuesInformed consent issues

–– IRB/EC approval & issuesIRB/EC approval & issues

–– Protocol deviationsProtocol deviations

–– Reporting of AEReporting of AE

–– Study recordsStudy records

–– Investigator responsibilities (e.g., lack of control)Investigator responsibilities (e.g., lack of control)

–– Regulatory documentationRegulatory documentation

254

Session 3Session 3

BA / BE Study Design WorkshopBA / BE Study Design Workshop

255

Session 3 OutlineSession 3 Outline

BA / BE Study Design WorkshopBA / BE Study Design Workshop•• Delegations will be grouped into various working Delegations will be grouped into various working

teamsteams

•• Each team will be asked to design a BA / BE study Each team will be asked to design a BA / BE study scheme for a specific drug productscheme for a specific drug product

•• Team presentation & discussionTeam presentation & discussion

256

BE Basic ConsiderationsBE Basic Considerations

•• Key Objective:Key Objective:–– Compare product performanceCompare product performance

•• Minimize variability Minimize variability

•• Minimize biasMinimize bias

257

BE General Study DesignBE General Study Design

•• SingleSingle--dose, twodose, two--period, crossoverperiod, crossover

•• Healthy volunteersHealthy volunteers

•• Subjects receive each formulation onceSubjects receive each formulation once

•• Adequate washoutAdequate washout

258

When to Consider Multiple Dosing?When to Consider Multiple Dosing?

•• Drug is too potent/toxic for administration in Drug is too potent/toxic for administration in healthy volunteershealthy volunteers–– Patients / no interruption of therapyPatients / no interruption of therapy

•• For extended/modified release products For extended/modified release products (ER/MR)(ER/MR)–– Accumulation using recommended dosing intervalAccumulation using recommended dosing interval–– In addition to singleIn addition to single--dose studiesdose studies

•• NonNon--linear pharmacokinetics at steadylinear pharmacokinetics at steady--state state (e.g., (e.g., saturablesaturable metabolism)metabolism)

•• Assay not sufficiently sensitive for singleAssay not sufficiently sensitive for single--dose dose studystudy

259

Crossover vs. Parallel DesignsCrossover vs. Parallel Designs

•• Testing suitable for Crossover Designs:Testing suitable for Crossover Designs:–– IntraIntra--subject comparisonsubject comparison

–– Lower variabilityLower variability

–– Generally fewer subjects requiredGenerally fewer subjects required

•• Parallel design possible in:Parallel design possible in:–– Drug with very long halfDrug with very long half--lifelife

–– Crossover design not practicalCrossover design not practical

–– Watch out:Watch out:

•• Have enough subjectsHave enough subjects

•• Have adequate sample collection Have adequate sample collection

•• Completion of Gastrointestinal transit / absorption processCompletion of Gastrointestinal transit / absorption process

•• 72 hours normally sufficient72 hours normally sufficient

260

Fasted or Fed?Fasted or Fed?

•• Fasted design preferredFasted design preferred–– Minimize variability not attributable to formulationMinimize variability not attributable to formulation

–– Better able to detect formulation differencesBetter able to detect formulation differences

•• Usually use Fed design whenUsually use Fed design when–– Significant gastrointestinal (GI) disturbance caused by Significant gastrointestinal (GI) disturbance caused by

fasted administrationfasted administration

–– Product labeling restricts administration to fed stateProduct labeling restricts administration to fed state

261

Questions?Questions?

Contact your speaker:Contact your speaker:

Wen Schroeder, Wen Schroeder, RACRACPresidentPresident

SEKI Cosmeticals USASEKI Cosmeticals USA

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