The FDA Process for Approving Generic Drugs Gary J. Buehler, R.Ph.Dale Conner, Pharm. D. DirectorDirector, Division of Bioequivalence Office of Generic

The FDA Process for The FDA Process for Approving Generic DrugsApproving Generic Drugs

Gary J. Buehler, R.Ph.Gary J. Buehler, R.Ph. Dale Conner, Pharm. D.Dale Conner, Pharm. D.

DirectorDirector Director, Division of Director, Division of

BioequivalenceBioequivalence

Office of Generic DrugsOffice of Generic Drugs

Center for Drug Evaluation & Research U.S. Food & Drug Administration

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Did you know that generic Did you know that generic drugs...drugs...

• Are safe and effective alternatives to brand Are safe and effective alternatives to brand name prescriptionsname prescriptions

• Can help both consumers and the Can help both consumers and the government reduce the cost of prescription government reduce the cost of prescription drugsdrugs

• Are currently used in 50% of all Are currently used in 50% of all prescriptions dispensedprescriptions dispensed

• Save an average of $50 for every Save an average of $50 for every prescription soldprescription sold


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Hatch-Waxman Amendments Hatch-Waxman Amendments to FFD&C Act - 1984to FFD&C Act - 1984

• Considered one of the most successful Considered one of the most successful pieces of legislation ever passedpieces of legislation ever passed

• Created the generic drug industryCreated the generic drug industry

• Increased availability of genericsIncreased availability of generics• 1984 12% prescriptions were generic1984 12% prescriptions were generic

• 2000 44% prescriptions were generic - yet only 2000 44% prescriptions were generic - yet only 8% of revenue for prescription drugs8% of revenue for prescription drugs

• Compromise legislation to benefit both Compromise legislation to benefit both brand and generic firmsbrand and generic firms

Continued


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Hatch-Waxman Amendments Hatch-Waxman Amendments to FFD&C Act - 1984to FFD&C Act - 1984

• Allowed generic firms to rely on findings Allowed generic firms to rely on findings of safety and efficacy of innovator drug of safety and efficacy of innovator drug after expiration of patents and after expiration of patents and exclusivities (do not have to repeat exclusivities (do not have to repeat expensive clinical and pre-clinical trials)expensive clinical and pre-clinical trials)

• Allowed patent extensions and Allowed patent extensions and exclusivities to innovator firmsexclusivities to innovator firms


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Brand Name Drug Generic DrugNDA Requirements ANDA Requirements

1. Chemistry 1. Chemistry2. Manufacturing 2. Manufacturing3. Controls 3. Controls4. Labeling 4. Labeling5. Testing 5. Testing6. Animal Studies7. Clinical Studies 6. Bioequivalence8. Bioavailability

NDA vs. ANDA Review ProcessNDA vs. ANDA Review Process


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What are the requirements for What are the requirements for a generic drug?a generic drug?

• LabelingLabeling

• Chemistry/MicrobiologyChemistry/Microbiology

• BioequivalenceBioequivalence

• LegalLegal


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How do we assure the quality How do we assure the quality of generic drugs?of generic drugs?

• First 5 steps of review process are identical First 5 steps of review process are identical to NDA processto NDA process

• Bioequivalence for complicated products is Bioequivalence for complicated products is discussed with the same staff that reviewed discussed with the same staff that reviewed the brand productthe brand product

• FDA has experience with the productFDA has experience with the product

• Scientific literature publishedScientific literature published

• Product is known to be safeProduct is known to be safe


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Generic Generic Drug Drug Review Review ProcessProcess

Bioequivalence Review

Labeling Review

Chemistry & Micro Review

Request for Plant Inspection

APPLICANT

ANDA

Acceptable &

Complete

Application Review

N Chem/Micro

OK?

Labeling

OK?Bioequivalence

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 Letter


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What are the requirements for What are the requirements for a generic drug?a generic drug?

• Same active ingredient(s)Same active ingredient(s)

• Same route of administrationSame route of administration

• Same dosage formSame dosage form

• Same strengthSame strength

• Same conditions of useSame conditions of use

Compared to reference listed drug (RLD) Compared to reference listed drug (RLD) - (brand name product)- (brand name product)


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LabelingLabeling

• ““Same” as brand name labelingSame” as brand name labeling

• May delete portions of labeling May delete portions of labeling protected by patent or exclusivityprotected by patent or exclusivity

• May differ in excipients, PK data and May differ in excipients, PK data and how suppliedhow supplied


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ChemistryChemistry

• 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


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Manufacturing Compliance Manufacturing Compliance ProgramsPrograms

• Purpose - To assure quality of Purpose - To assure quality of marketed drug productsmarketed drug products

• Mechanisms - Product TestingMechanisms - Product Testing

– SurveillanceSurveillance

– Manufacturing/Testing plant inspectionsManufacturing/Testing plant inspections

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


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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICEFOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCHOFFICE OF GENERIC DRUGS

APPROVEDDRUG PRODUCTS

WITHTHERAPEUTIC EQUIVALENCE EVALUATIONS

23rd EDITIONTHE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER

SECTION 505 OF THE FEDERAL FOOD, DRUG, ANDCOSMETIC ACT.

2003

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


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• All FDA approved drug products listed All FDA approved drug products listed (NDA’s, OTC’s & ANDA’s) (NDA’s, OTC’s & ANDA’s)

– Therapeutic equivalence codesTherapeutic equivalence codes ““A” = SubstitutableA” = Substitutable

““B” = Inequivalent, NOT SubstitutableB” = Inequivalent, NOT Substitutable

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

– Reference Listed Drugs/brand drugs Reference Listed Drugs/brand drugs identified by FDA for generic companies identified by FDA for generic companies to compare with their proposed productsto compare with their proposed products

“Orange BookOrange Book”


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Definition of BioequivalenceDefinition of Bioequivalence

Pharmaceutical equivalents whose rate Pharmaceutical equivalents whose rate

and extent of absorption are not and extent of absorption are not

statistically different when statistically different when

administered to patients or subjects administered to patients or subjects

at the same molar dose under similar at the same molar dose under similar

experimental conditionsexperimental conditions


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Purpose of BEPurpose of BE

• Therapeutic equivalence (TE)Therapeutic equivalence (TE)

• Bioequivalent products can be Bioequivalent products can be substituted for each other without any substituted for each other without any adjustment in dose or other additional adjustment in dose or other additional therapeutic monitoringtherapeutic monitoring

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


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Model of Oral Dosage Form Model of Oral Dosage Form PerformancePerformance

TherapeuticEffect

Dosage Form

Gut WallDrug in Solution

BloodSite of Activity

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurement

ln DoseDose


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Clinical/PD Dose-ResponseClinical/PD Dose-Response

Cli

nic

al/P

D R

esp

onse

Log Dose


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Plasma Concentration-DosePlasma Concentration-Dose

Dose

Pla

sma

Con

c.


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Approaches to Determining Approaches to Determining Bioequivalence (21 CFR 320.24)Bioequivalence (21 CFR 320.24)

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

• In vivo pharmacodynamic In vivo pharmacodynamic comparisoncomparison

• 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 Albuterol

Blanching StudyTopical Corticosteroid

Topicals Nasal Suspensions

Questran - Binding StudiesNasal Solutions-Sprayer EvaluationPropofol - Droplet Size


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• Single-dose, two-way crossover, fastedSingle-dose, two-way crossover, fasted

• Single-dose, two-way crossover, fedSingle-dose, two-way crossover, fed

• AlternativesAlternatives

– Single-dose, parallel, fastedSingle-dose, parallel, fasted

– Single-dose, replicate designSingle-dose, replicate design

– Multiple-dose, two-way Multiple-dose, two-way crossover, fastedcrossover, fasted

– Clinical endpoint studyClinical endpoint study

Study DesignsStudy Designs

Long Half-Life (wash-out)

Amiodarone, Etidronate

Highly Variable Drugs

Less Sensitive

Clozapine (Patient Trials)

Chemotherapy Trials

Topicals

Nasal Suspensions


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Waivers of In Vivo Study Waivers of In Vivo Study RequirementsRequirements

• DefinitionDefinition

• Criteria (21 CFR 320.22)Criteria (21 CFR 320.22)

– In vivo bioequivalence is self-evidentIn vivo bioequivalence is self-evident

– Parenteral solutionsParenteral solutions

– Inhalational anestheticsInhalational anesthetics

– Topical (skin) solutionTopical (skin) solution

– Oral solutionOral solution

– Different proportional strength of product Different proportional strength of product with demonstrated BEwith demonstrated BE


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Statistical Analysis Statistical Analysis (Two One-sided Tests Procedure)(Two One-sided Tests Procedure)

• AUC and CmaxAUC and Cmax

– 90% Confidence Intervals (CI) must fit 90% Confidence Intervals (CI) must fit between 80%-125%between 80%-125%


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Statistical Analysis Statistical Analysis 80 - 125 %80 - 125 %

• What does this mean?What does this mean?

• Can there be a 46% difference?Can there be a 46% difference?

• What is a point estimate?What is a point estimate?

• What is a confidence interval?What is a confidence interval?


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Statistical AnalysisStatistical Analysis

• Bioequivalence criteriaBioequivalence criteria

– Two one-sided tests procedureTwo one-sided tests procedure

• Test (T) is not significantly less than Test (T) is not significantly less than referencereference

• Reference (R) is not significantly less than Reference (R) is not significantly less than testtest

• Significant difference is 20% (Significant difference is 20% ( = 0.05 = 0.05 significance level)significance level)

– T/R = 80/100 = 80%T/R = 80/100 = 80%

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


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

T/R (%)80% 125%


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Narrow Therapeutic Range (NTI) Narrow Therapeutic Range (NTI) DrugsDrugs

• Drug Products that are subject to Drug Products that are subject to therapeutic drug concentration or therapeutic drug concentration or pharmacodynamic monitoringpharmacodynamic monitoring

– Examples are: Digoxin, Lithium, Examples are: Digoxin, Lithium, Phenytoin, WarfarinPhenytoin, Warfarin

• Traditional bioequivalence limit of 80-Traditional bioequivalence limit of 80-125% is unchanged for these 125% is unchanged for these productsproducts


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Contacting the OGDContacting the OGD

Contact: Contact: Office of Generic DrugsOffice of Generic Drugs

FDA/CDER (HFD-600)FDA/CDER (HFD-600)

7500 Standish Place7500 Standish Place

Rockville, MD 20855Rockville, MD 20855

phone: 301-827-5845phone: 301-827-5845

Web site: Web site:

www.fda.gov/cder/ogd/index.htmwww.fda.gov/cder/ogd/index.htm

Documents

The FDA Process for Approving Generic Drugs Gary J. Buehler, R.Ph.Dale Conner, Pharm. D. DirectorDirector, Division of Bioequivalence Office of Generic