1 the new drug approval requirement daniel r. dwyer stacy l. ehrlich kleinfeld, kaplan becker llp...

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The New Drug The New Drug Approval RequirementApproval Requirement

Daniel R. DwyerDaniel R. DwyerStacy L. EhrlichStacy L. Ehrlich

Kleinfeld, Kaplan & Becker LLPKleinfeld, Kaplan & Becker LLPJune 14, 2004June 14, 2004

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What does FDA regulate?What does FDA regulate? DrugsDrugs DevicesDevices BiologicsBiologics FoodsFoods Dietary SupplementsDietary Supplements CosmeticsCosmetics Combination ProductsCombination Products

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What is a Drug?What is a Drug?Section 201(g)(1):Section 201(g)(1): Recognized in USP or other compendiaRecognized in USP or other compendia IntendedIntended to diagnose, cure, mitigate, treat to diagnose, cure, mitigate, treat

or prevent diseaseor prevent disease IntendedIntended to affect structure or function to affect structure or function IntendedIntended as component of these as component of these Exceptions for foods and supplementsExceptions for foods and supplements

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Intended UseIntended Use 21 CFR 201.12821 CFR 201.128 Objective intent of persons Objective intent of persons

responsible for labeling of productresponsible for labeling of product Based on, e.g.:Based on, e.g.:

• Labeling claimsLabeling claims• Advertising/promotionAdvertising/promotion• Oral or written statementsOral or written statements• Circumstances surrounding distributionCircumstances surrounding distribution• Consumer expectations/use?Consumer expectations/use?

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What is a Device?What is a Device?Section 201(h)Section 201(h) Instrument, apparatus, implement, Instrument, apparatus, implement,

machine, contrivance, implant, in vitro machine, contrivance, implant, in vitro reagent, or componentreagent, or component• Recognized in USP or other compendiaRecognized in USP or other compendia• Intended for use in diagnosis of disease or Intended for use in diagnosis of disease or

other conditionsother conditions• Intended for use in the cure, mitigation, Intended for use in the cure, mitigation,

treatment, or prevention of diseasetreatment, or prevention of disease• Intended to affect structure or functionIntended to affect structure or function

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Drug vs DeviceDrug vs Device

Device definition excludes:Device definition excludes: Products that achieve their primary Products that achieve their primary

intended purpose through intended purpose through chemical chemical actionaction within or on the body within or on the body

Products that are dependent upon Products that are dependent upon being being metabolizedmetabolized for the for the achievement of their primary achievement of their primary intended purposeintended purpose

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Drug or Device?Drug or Device? Sunscreen?Sunscreen? Microbubble ultrasound contrast Microbubble ultrasound contrast

agents?agents? Injectable lubricants?Injectable lubricants? Contact lens solution?Contact lens solution?

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What is a Biologic?What is a Biologic? Section 351 of PHS Act, 21 CFR Section 351 of PHS Act, 21 CFR

600.3(h)600.3(h) Virus, therapeutic serum, toxin, Virus, therapeutic serum, toxin,

antitoxin, vaccine, blood, blood antitoxin, vaccine, blood, blood component or derivative, allergeniccomponent or derivative, allergenic

Or any analogous productOr any analogous product Applicable to the prevention, Applicable to the prevention,

treatment or cure of disease or treatment or cure of disease or conditioncondition

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Drug vs BiologicDrug vs Biologic Definitions not mutually exclusiveDefinitions not mutually exclusive Large molecules vs small moleculesLarge molecules vs small molecules Hormones, e.g., insulin and human growth Hormones, e.g., insulin and human growth

hormone, regulated as drugshormone, regulated as drugs Intercenter agreements between CDER, Intercenter agreements between CDER,

CBER and CDRHCBER and CDRH Transfer of review responsibilities for most Transfer of review responsibilities for most

therapeutic biologics from CBER to CDER therapeutic biologics from CBER to CDER (except vaccines, blood products and gene (except vaccines, blood products and gene and tissue/cellular product therapies)and tissue/cellular product therapies)

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Combination ProductsCombination Products Section 503(g), 21 CFR Part 3 (RFD)Section 503(g), 21 CFR Part 3 (RFD) MDUFMA required establishment of Office MDUFMA required establishment of Office

of Combination Productsof Combination Products ““Primary mode of action” = “the single Primary mode of action” = “the single

mode of action of a combination product mode of action of a combination product that provides the most important that provides the most important therapeutic action of the combination therapeutic action of the combination product” (May 7, 2004 proposed rule)product” (May 7, 2004 proposed rule)

Assignment algorithm: PMOA, consistency, Assignment algorithm: PMOA, consistency, safety and effectiveness expertisesafety and effectiveness expertise

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What is a Food?What is a Food? Section 201(f) = used for food or Section 201(f) = used for food or

drink, chewing gum, componentsdrink, chewing gum, components Structure/function claims based on Structure/function claims based on

“nutritive value”“nutritive value” Prior authorization for disease-Prior authorization for disease-

related health claimsrelated health claims

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What is a Dietary Supplement?What is a Dietary Supplement?

DSHEA, Section 201(ff)DSHEA, Section 201(ff) Product (other than tobacco) Product (other than tobacco)

intended to supplement the diet that intended to supplement the diet that contains vitamin, mineral, contains vitamin, mineral, herb/botanical, amino acid, dietary herb/botanical, amino acid, dietary substance, or concentrate, substance, or concentrate, metabolite, constituent or extractmetabolite, constituent or extract

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What is a Dietary Supplement?What is a Dietary Supplement? Prior authorization for disease-Prior authorization for disease-

related health claimsrelated health claims Cannot be represented as a Cannot be represented as a

conventional foodconventional food Cannot contain ingredient approved Cannot contain ingredient approved

or authorized for investigation as or authorized for investigation as new drug prior to marketing as food new drug prior to marketing as food or supplementor supplement

Can make structure/function claimsCan make structure/function claims

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Drug vs Dietary SupplementDrug vs Dietary Supplement Reduces inflammationReduces inflammation Improves absentmindednessImproves absentmindedness Maintains cholesterol levels already in the Maintains cholesterol levels already in the

normal rangenormal range CarpalHealthCarpalHealth Supports the body’s ability to resist Supports the body’s ability to resist

infectioninfection Helps maintain intestinal floraHelps maintain intestinal flora For relief of occasional constipationFor relief of occasional constipation Dietary support during the cold and flu Dietary support during the cold and flu

seasonseason

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Drug vs Dietary SupplementDrug vs Dietary Supplement

Pharmanex casePharmanex case Street drug alternativesStreet drug alternatives OTC drug-supplementOTC drug-supplement

•Combination (Melagesic PM)Combination (Melagesic PM)•Dual use (Tums)Dual use (Tums)

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What is a Cosmetic?What is a Cosmetic? Section 201(i)Section 201(i) Rubbed, poured, sprinkled, or Rubbed, poured, sprinkled, or

sprayed on, introduced into, or sprayed on, introduced into, or otherwise applied to the bodyotherwise applied to the body

For cleansing, beautifying, promoting For cleansing, beautifying, promoting attractiveness, or altering attractiveness, or altering appearanceappearance

Except soapExcept soap

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Cosmetic vs DrugCosmetic vs Drug Wrinkle and anti-aging productsWrinkle and anti-aging products

• Face lift without surgeryFace lift without surgery• Reduce deep wrinklesReduce deep wrinkles• Stimulates collagen productionStimulates collagen production• Helps skin cells renew and repair themselvesHelps skin cells renew and repair themselves

Cosmetic-drugs (make-up with SPF claims, Cosmetic-drugs (make-up with SPF claims, antiperspirant/deodorant)antiperspirant/deodorant)

Presence of drug ingredient, e.g., fluoridePresence of drug ingredient, e.g., fluoride Concentration of ingredient, e.g., AHAs Concentration of ingredient, e.g., AHAs

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New DrugNew Drug Section 201(p): All drugs “new drugs” Section 201(p): All drugs “new drugs”

except drugs that are:except drugs that are:• GRAS/EGRAS/E = Generally recognized, among = Generally recognized, among

experts qualified by scientific training and experts qualified by scientific training and experience to evaluate the safety and experience to evaluate the safety and effectiveness of drugs, as safe and effective for effectiveness of drugs, as safe and effective for use under the conditions prescribed, use under the conditions prescribed, recommended, or suggested in the labeling recommended, or suggested in the labeling andand

• Have been used for a Have been used for a material timematerial time and to a and to a material extentmaterial extent

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GRAS/EGRAS/E Must be supported by same quantity Must be supported by same quantity

and quality of scientific evidence and quality of scientific evidence required to obtain new drug approvalrequired to obtain new drug approval

Adequate and well-controlled studiesAdequate and well-controlled studies Published scientific literaturePublished scientific literature Construed very narrowly by the Construed very narrowly by the

courtscourts

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““Old” DrugsOld” Drugs FDA has taken the position that it is very FDA has taken the position that it is very

unlikely that any currently marketed unlikely that any currently marketed product is an “old” drug (Draft CPG on product is an “old” drug (Draft CPG on Marketed Unapproved Drugs Oct. 2003)Marketed Unapproved Drugs Oct. 2003)

Enforcement Priorities (Draft CPG)Enforcement Priorities (Draft CPG)• Drugs with potential safety risksDrugs with potential safety risks• Drugs that lack evidence of effectivenessDrugs that lack evidence of effectiveness• Health fraud drugsHealth fraud drugs• Newly approved drugs (e.g., guaifenesin) Newly approved drugs (e.g., guaifenesin)

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Grandfathered DrugsGrandfathered Drugs Marketed prior to 6/25/38 Marketed prior to 6/25/38 andand no change no change

in formulation, dosage, strength, in formulation, dosage, strength, manufacture, indications, etc.manufacture, indications, etc.

Prior to 10/10/62, Prior to 10/10/62, • Used or sold commercially in USUsed or sold commercially in US• Not a new drug as defined at that timeNot a new drug as defined at that time• Not covered by an effective application ANDNot covered by an effective application AND• Composition and labeling have not changedComposition and labeling have not changed

Construed narrowly by courtsConstrued narrowly by courts FDA believes that few if any drugs on FDA believes that few if any drugs on

market are entitled to grandfather statusmarket are entitled to grandfather status

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DESI ReviewDESI Review Drug Efficacy Study ImplementationDrug Efficacy Study Implementation National Academy of Sciences-National National Academy of Sciences-National

Research Council (NAS-NRC)Research Council (NAS-NRC)• Category I (GRAS/E and not misbranded)Category I (GRAS/E and not misbranded)• Category II (not GRAS/E)Category II (not GRAS/E)• Category III (insufficient data)Category III (insufficient data)

If Category I, approved NDA or ANDA still If Category I, approved NDA or ANDA still requiredrequired

Still ongoingStill ongoing

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Who Decides?Who Decides? No mechanism for administrative No mechanism for administrative

determination of new drug status prior to determination of new drug status prior to marketingmarketing• Old “not new drug” letters revoked (21 CFR Old “not new drug” letters revoked (21 CFR

310.100)310.100)• Up to manufacturer to decide whether to Up to manufacturer to decide whether to

market as “old” drugmarket as “old” drug• Penalties if FDA determines it is a new drug Penalties if FDA determines it is a new drug

marketed without FDA approvalmarketed without FDA approval Manufacturer’s burden to prove Manufacturer’s burden to prove

grandfather status (21 CFR 314.200(e)(5))grandfather status (21 CFR 314.200(e)(5))

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Legal Standard forLegal Standard forNew Drug ApprovalNew Drug Approval

Adequate tests of safety under the Adequate tests of safety under the conditions prescribed, recommended or conditions prescribed, recommended or suggested in labelingsuggested in labeling

Substantial evidence of effectiveness Substantial evidence of effectiveness under the conditions prescribed, under the conditions prescribed, recommended or suggested in labelingrecommended or suggested in labeling

Manufacturing, processing and packing is Manufacturing, processing and packing is inadequate to assure identity, strength, inadequate to assure identity, strength, quality and purityquality and purity

-- Section 505(d)-- Section 505(d)

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Adequate Tests of SafetyAdequate Tests of Safety

Policy:Policy:• Determine the benefitDetermine the benefit• Determine the riskDetermine the risk• Weigh the benefit against the riskWeigh the benefit against the risk

Take into consideration:Take into consideration:• DosageDosage• Intended useIntended use• Patient populationPatient population

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Adequate Tests of SafetyAdequate Tests of Safety Procedure:Procedure:

• Pharmacology studiesPharmacology studies• Toxicology studiesToxicology studies

AcuteAcute SubacuteSubacute ChronicChronic CarcinogenicityCarcinogenicity Reproductive toxicityReproductive toxicity ADMEADME

• Human pharmacokinetics and bioavailabilityHuman pharmacokinetics and bioavailability• Clinical data and adverse eventsClinical data and adverse events

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Adequate Tests of SafetyAdequate Tests of Safety Current issues:Current issues:

• How to make risky drugs available:How to make risky drugs available: Patient educationPatient education Dispensing though physiciansDispensing though physicians Evaluating adverse event reportsEvaluating adverse event reports

• Pediatric usePediatric use Opening up access to therapies, while adequately Opening up access to therapies, while adequately

assuring safetyassuring safety• Children in clinical trialsChildren in clinical trials

These new issues result in constant These new issues result in constant revision of the old standard requiring revision of the old standard requiring “adequate tests”“adequate tests”

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Substantial EvidenceSubstantial Evidenceof Effectivenessof Effectiveness

“’“’Substantial evidence’ means evidence consisting of Substantial evidence’ means evidence consisting of adequate and well-controlled investigations, including adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under have the effect it purports or is represented to have under the conditions of use prescribed, recommended or the conditions of use prescribed, recommended or suggested in the labeling … thereof.”suggested in the labeling … thereof.”

““If [FDA] determines, based on relevant science, that data If [FDA] determines, based on relevant science, that data from one adequate and well-controlled clinical investigation from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, [FDA] investigation) are sufficient to establish effectiveness, [FDA] may consider such data and evidence to constitute may consider such data and evidence to constitute substantial evidence for purposes of the preceding substantial evidence for purposes of the preceding sentence.sentence.

-- Section 505(d).

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Adequate and well-controlled studies:Adequate and well-controlled studies:• Clear protocolClear protocol• Control (e.g., placebo, alternative treatment)Control (e.g., placebo, alternative treatment)• Careful selection of subjectsCareful selection of subjects• Procedures to minimize bias (e.g., blinding)Procedures to minimize bias (e.g., blinding)• Reliable means of assessing effectivenessReliable means of assessing effectiveness• Statistical analysisStatistical analysis

-- 21 CFR 314.50, 314.126

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Adequate and well-controlled Adequate and well-controlled studies:studies:• Standardized product (identity, strength, Standardized product (identity, strength,

quality, purity, dosage formquality, purity, dosage form• Must be conducted in conformance with:Must be conducted in conformance with:

IRB regulationsIRB regulations Informed consent regulationsInformed consent regulations Or, for foreign studies, the Declaration of Or, for foreign studies, the Declaration of

Helsinki or more rigorous local requirementsHelsinki or more rigorous local requirements-- 21 CFR 314.50, 314.126

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Key: Judgment of expertsKey: Judgment of experts Senate Report on 1962 Amendments:Senate Report on 1962 Amendments:

• When a drug has been adequately When a drug has been adequately tested by qualified experts, a claim tested by qualified experts, a claim should be permitted, even if there is should be permitted, even if there is preponderant evidence to the contrarypreponderant evidence to the contrary

• A claim may be made to the medical A claim may be made to the medical profession with a proper explanation of profession with a proper explanation of the basis on which it reststhe basis on which it rests

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““Relative Efficacy” – FDA may not Relative Efficacy” – FDA may not disapprove a drug on the ground that disapprove a drug on the ground that a more effective option is availablea more effective option is available

Often use “intent-to-treat” analysis:Often use “intent-to-treat” analysis:• All randomized patientsAll randomized patients• Limited exclusions may be permissible Limited exclusions may be permissible

(“modified intent-to-treat”)(“modified intent-to-treat”)• Defined in advance, based on indicationDefined in advance, based on indication

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Drugs for serious or life-threatening illnessesDrugs for serious or life-threatening illnesses FDA must grant “fast track” approval of drug ifFDA must grant “fast track” approval of drug if

• Intended for treatment of serious or life-threatening Intended for treatment of serious or life-threatening illness, and illness, and

• Drug demonstrates potential to address unmet needsDrug demonstrates potential to address unmet needs FDA may grant approval based on –FDA may grant approval based on –

• Surrogate endpointSurrogate endpoint I.e., an endpoint other than survival or irreversible I.e., an endpoint other than survival or irreversible

morbidity that is reasonably likely to predict clinical benefitmorbidity that is reasonably likely to predict clinical benefit Subject to requirement for postmarketing studySubject to requirement for postmarketing study

• Restrictions, e.g. – Restrictions, e.g. – Specially trained physiciansSpecially trained physicians Performance of specified medical proceduresPerformance of specified medical procedures

• Includes special procedures for prompt withdrawalIncludes special procedures for prompt withdrawal

-- Section 506 and 21 CFR 314.500 et seq.

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Drugs for use in treating serious or life-Drugs for use in treating serious or life-threatening conditions caused by exposure to threatening conditions caused by exposure to biological, chemical, radiological or nuclear biological, chemical, radiological or nuclear substances may be approved based on animal substances may be approved based on animal studies if human exposure would be unethicalstudies if human exposure would be unethical

Requires:Requires:• Postmarketing studiesPostmarketing studies• Approval with restrictionsApproval with restrictions• Information provided to patientsInformation provided to patients

Includes special procedures for prompt Includes special procedures for prompt withdrawalwithdrawal

-- 21 CFR 314.600 et seq.

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Types of ApplicationsTypes of Applications Full NDA, or 505(b)(1) NDAFull NDA, or 505(b)(1) NDA

• Data required:Data required: Chemistry, manufacturing, and controls (CMC) dataChemistry, manufacturing, and controls (CMC) data Nonclinical pharmacology and toxicologyNonclinical pharmacology and toxicology Human pharmacokinetics and bioavailabilityHuman pharmacokinetics and bioavailability Clinical dataClinical data Statistical analysisStatistical analysis Pediatric dataPediatric data LabelingLabeling Case report forms and tabulationsCase report forms and tabulations

• May be eligible for exclusivity, and must provide patent May be eligible for exclusivity, and must provide patent informationinformation

• Approval not delayed by patent or exclusivity rights of Approval not delayed by patent or exclusivity rights of other drugsother drugs

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Types of ApplicationsTypes of Applications

505(b)(2) NDA, or “Paper NDA”505(b)(2) NDA, or “Paper NDA”• Same as full NDA except –Same as full NDA except –

The NDA is based on “investigations … The NDA is based on “investigations … relied on by the applicant for approval of the relied on by the applicant for approval of the application [that] were not conducted by or application [that] were not conducted by or for the applicant and for which the applicant for the applicant and for which the applicant has not obtained a right of reference or use”has not obtained a right of reference or use”

Applicant can rely on:Applicant can rely on:• Published literaturePublished literature• FDA’s prior safety and effectiveness FDA’s prior safety and effectiveness

determinationdetermination

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505(b)(2) NDA, or “Paper NDA” -- continued505(b)(2) NDA, or “Paper NDA” -- continued• Same as full NDA except –Same as full NDA except –

Often used for changes to an approved drug that are not Often used for changes to an approved drug that are not eligible for approval under an ANDA, e.g.:eligible for approval under an ANDA, e.g.:

• Dosage formDosage form• StrengthStrength• Route of administrationRoute of administration• Change of active ingredientChange of active ingredient

• May be eligible for exclusivity, and must provide patent May be eligible for exclusivity, and must provide patent informationinformation

• Approval may be delayed by patent or exclusivity rights Approval may be delayed by patent or exclusivity rights of reference listed drugof reference listed drug

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• Abbreviated New Drug Application Abbreviated New Drug Application (ANDA), or 505(j) application(ANDA), or 505(j) application

Only for “generic” drugs, i.e., exact or close Only for “generic” drugs, i.e., exact or close copies of already approved drugscopies of already approved drugs

• Identical in active ingredients, dosage form, Identical in active ingredients, dosage form, strength, route of administration, conditions of strength, route of administration, conditions of use (some changes in inactive ingredients are use (some changes in inactive ingredients are permitted)permitted)

• Petition may be submitted for changes in route of Petition may be submitted for changes in route of administration, dosage form, and strength, or administration, dosage form, and strength, or substitution of an active ingredient in a substitution of an active ingredient in a combination productcombination product

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• ANDA – continued ANDA – continued Data requiredData required

• Basis for ANDA (conditions of use, active Basis for ANDA (conditions of use, active ingredients, route of administration)ingredients, route of administration)

• CMC dataCMC data• Bioequivalence dataBioequivalence data• LabelingLabeling

May be eligible for generic exclusivityMay be eligible for generic exclusivity Approval may be delayed by patent or Approval may be delayed by patent or

exclusivity rights of reference listed drugexclusivity rights of reference listed drug

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Biologics and AntibioticsBiologics and Antibiotics

• BiologicsBiologics Virus, therapeutic serum, toxin, antitoxin, or Virus, therapeutic serum, toxin, antitoxin, or

analogous productanalogous product Regulated under §351 of the Public Health Service Regulated under §351 of the Public Health Service

Act and 21 CFR Part 600 et seq.Act and 21 CFR Part 600 et seq. Biologics License Application (BLA) instead of NDABiologics License Application (BLA) instead of NDA CDER: most therapeutic biologics, with certain CDER: most therapeutic biologics, with certain

exceptions (e.g., cell and gene therapy products and exceptions (e.g., cell and gene therapy products and therapeutic vaccines)therapeutic vaccines)

CBER: blood and blood products, vaccines, cell/gene CBER: blood and blood products, vaccines, cell/gene therapy, certain human tissue for transplantation, therapy, certain human tissue for transplantation, and certain devices for use with blood productsand certain devices for use with blood products

• Antibiotics: regulated as drugsAntibiotics: regulated as drugs

1 the new drug approval requirement daniel r. dwyer stacy l. ehrlich kleinfeld, kaplan becker llp...

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