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What Is An IND?What Is An IND?Loris McVittie, PhD.Loris McVittie, PhD.

OVRR/CBER/FDAOVRR/CBER/FDA

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RegulationRegulation

The regulations in 21 CFR 312 coverThe regulations in 21 CFR 312 coverprocedures and requirements forprocedures and requirements for

Investigational New DrugInvestigational New DrugApplications (INDs)Applications (INDs)

These regulations define the rolesThese regulations define the rolesand responsibilities of FDA reviewers,and responsibilities of FDA reviewers,

IND sponsors, and clinicalIND sponsors, and clinicalinvestigatorsinvestigators

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DefinitionsDefinitions

SponsorSponsor

A sponsor is an individual, company,A sponsor is an individual, company,

institution, or organization that takesinstitution, or organization that takesresponsibility for and initiates aresponsibility for and initiates aclinical study (21 CFR 312.3(b),clinical study (21 CFR 312.3(b),312.50)312.50)

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SponsorSponsor

A sponsor is responsible for:A sponsor is responsible for:

Selecting qualified investigatorsSelecting qualified investigators

Ensuring study monitoringEnsuring study monitoring Maintaining an effective IND, andMaintaining an effective IND, and

Ensuring AE risk information isEnsuring AE risk information is

provided to the FDA andprovided to the FDA andinvestigatorsinvestigators

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DefinitionsDefinitions

InvestigatorInvestigator

An investigator is an individual underAn investigator is an individual under

whose immediate direction the studywhose immediate direction the studydrug is administered or dispensed. Ifdrug is administered or dispensed. Ifa team is involved, the leader is thea team is involved, the leader is theinvestigator; other team membersinvestigator; other team members

are subare sub--investigatorsinvestigators

(21 CFR 312(b), 312.60)(21 CFR 312(b), 312.60)

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InvestigatorInvestigator

An investigator is responsible for:An investigator is responsible for:

Ensuring the study is conductedEnsuring the study is conducted

according to the planaccording to the plan Protecting the rights, safety andProtecting the rights, safety and

welfare of subjects, andwelfare of subjects, and

Control of drug under investigationControl of drug under investigation

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DefinitionsDefinitions

SponsorSponsor--InvestigatorInvestigator

A sponsorA sponsor--investigator is an individualinvestigator is an individualwho both initiates and conducts a studywho both initiates and conducts a studyand under whose immediate direction theand under whose immediate direction thestudy drug is administered or dispensed.study drug is administered or dispensed.This person must follow the requirementsThis person must follow the requirementspertaining to a sponsor and thosepertaining to a sponsor and thosepertaining to an investigatorpertaining to an investigator

(21 CFR 312(b))(21 CFR 312(b))

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The primary concern during allThe primary concern during allphases of clinical study is thephases of clinical study is the

safety and rights of studysafety and rights of studysubjectssubjects

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IND RequirementsIND Requirements

Even FDAEven FDA--licensed products arelicensed products aresubject to IND regulations if not usedsubject to IND regulations if not used

under conditions of licensure (anunder conditions of licensure (anexperiment is any use of a drugexperiment is any use of a drugexcept for the use of a marketedexcept for the use of a marketed

drug in the course of medicaldrug in the course of medical

practice 21 CFR 312.3(b))practice 21 CFR 312.3(b))

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IND Requirements (contd)IND Requirements (contd)

For a lawfully marketed product, no INDFor a lawfully marketed product, no INDsubmission is required if three specific conditionssubmission is required if three specific conditionsapply (21 CFR 312.2)apply (21 CFR 312.2)

The study is not intended to support a newThe study is not intended to support a newindication or labeling changeindication or labeling change

The study does not intend to support a changeThe study does not intend to support a changein advertisingin advertising

T

he study does not involve a route, dosage orT

he study does not involve a route, dosage orpatient population, etc. that increases riskpatient population, etc. that increases risk

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NOTE!NOTE!

The FDA may be aware of otherThe FDA may be aware of otherstudies that may affect evaluation ofstudies that may affect evaluation ofpotential risk, andpotential risk, and

the FDA is subject to confidentialitythe FDA is subject to confidentialityrequirements and by law can notrequirements and by law can notshare this specific information withshare this specific information with

othersothers

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IND Content RequirementsIND Content Requirements

21 CFR 312.2321 CFR 312.23

Format pertains to all sponsors and sponsorFormat pertains to all sponsors and sponsor--investigators and fosters efficient reviewinvestigators and fosters efficient review

Cover Sheet (and Form FDA 1571)Cover Sheet (and Form FDA 1571)

Table of ContentsTable of Contents

Introductory Statement and General Investigational PlanIntroductory Statement and General Investigational Plan

Clinical ProtocolClinical Protocol

Chemistry, Manufacturing and Control (CMC)Chemistry, Manufacturing and Control (CMC)InformationInformation

Pharmacology and Toxicology InformationPharmacology and Toxicology Information Previous Human ExperiencePrevious Human Experience

Additional InformationAdditional Information

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Introductory Content ElementsIntroductory Content Elements

Cover Sheet (Form FDA 1571)Cover Sheet (Form FDA 1571)

Table of ContentsTable of Contents

Introductory Statement (description ofIntroductory Statement (description of

product, formulation, route, broad studyproduct, formulation, route, broad studyobjectives, relevant previous use, foreignobjectives, relevant previous use, foreignexperience)experience)

General Investigational Plan (rationale,General Investigational Plan (rationale,

indication, general approach, anticipatedindication, general approach, anticipatedstudies including number of subjects andstudies including number of subjects andpossible risks)possible risks)

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Investigators Brochure (IB)Investigators Brochure (IB)

Sponsor must provide to all clinicalSponsor must provide to all clinicalinvestigators, not required for sponsorinvestigators, not required for sponsorinvestigators (21 CFR 312.55). It mustinvestigators (21 CFR 312.55). It must

include:include: Brief product descriptionBrief product description

Pharm/tox summariesPharm/tox summaries

Previous human experiencePrevious human experience

Description of anticipated risk and any specialDescription of anticipated risk and any specialmonitoring needsmonitoring needs

Updates as appropriateUpdates as appropriate

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CMC InformationCMC Information

Emphasis in Phase I is on identification andEmphasis in Phase I is on identification andcontrol of raw materials and new drug substance,control of raw materials and new drug substance,including information on any placebo as wellincluding information on any placebo as well

Even for Phase I, need enough information toEven for Phase I, need enough information to

assess safetyassess safety Extent of expected information increases as drugExtent of expected information increases as drug

development proceedsdevelopment proceeds

Throughout product development, goodThroughout product development, good

documentation of all manufacturing and testingdocumentation of all manufacturing and testingsteps is essentialsteps is essential

Deficiencies in CMC information can result inDeficiencies in CMC information can result inclinical holdclinical hold

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Pharm/Tox InformationPharm/Tox Information

Animal studies may be conducted toAnimal studies may be conducted toobtain proof of concept or tox informationobtain proof of concept or tox information

Studies should support proposed clinicalStudies should support proposed clinical

dose and regimendose and regimen

Best to get CBER concurrence on pivotalBest to get CBER concurrence on pivotaltox protocols prior to initiationtox protocols prior to initiation

Need to submit complete study reports forNeed to submit complete study reports fortox studies, including summary andtox studies, including summary andindividual animal dataindividual animal data

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Other IND ItemsOther IND Items

Previous human experience needs toPrevious human experience needs tobe included (if applicable)be included (if applicable)

Additional information such as preAdditional information such as pre--IND meeting minutes or criticalIND meeting minutes or criticalreferences should be included as wellreferences should be included as well

Serial numbering of pages of an INDSerial numbering of pages of an IND

is required (21 CFR 312.23(11)(e))is required (21 CFR 312.23(11)(e))as this facilitates reference if the FDAas this facilitates reference if the FDAhas questionshas questions

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IND Protocol AmendmentsIND Protocol Amendments

21 CFR 312.3021 CFR 312.30 A new protocolA new protocol

Safety or design related changes to anSafety or design related changes to an

existing protocolexisting protocol New investigator (notification is requiredNew investigator (notification is required

within 30 days of being added)within 30 days of being added)

These should be submitted to the FDAThese should be submitted to the FDAprior to implementationprior to implementation

IRB approval is needed prior toIRB approval is needed prior toimplementationimplementation

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IND Information AmendmentsIND Information Amendments

21 CFR 312.3121 CFR 312.31

Information amendments advise theInformation amendments advise the

FDA of:FDA of: New tox, CMC or other technicalNew tox, CMC or other technical

informationinformation

Notice of discontinuance of a clinicalNotice of discontinuance of a clinicalstudystudy

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AnnualReportsAnnualReports

21 CFR 312.3321 CFR 312.33

To be submitted within 60 days of theTo be submitted within 60 days of theanniversary of in effect dateanniversary of in effect date

Include enrollment, demographic andInclude enrollment, demographic andconduct status information for each studyconduct status information for each study

Adverse event summaries (safety reports,Adverse event summaries (safety reports,

deaths, dropouts)deaths, dropouts) Drug action informationDrug action information

Preclinical study status informationPreclinical study status information

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AnnualReports (contd)AnnualReports (contd)

CMC change informationCMC change information

Revised/updated investigatorRevised/updated investigator

brochure with revisions describedbrochure with revisions described Foreign marketing experienceForeign marketing experience

Outstanding business with the FDAOutstanding business with the FDA

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AnnualReporting ofAdverse EventsAnnualReporting ofAdverse Events

RECOMMENDATIONSRECOMMENDATIONS For solicited eventsFor solicited events tabulate by study, studytabulate by study, study

group and severitygroup and severity

For unsolicited events use a line listing by studyFor unsolicited events use a line listing by study

SAEs should be highlighted and discussedSAEs should be highlighted and discussed

Include numerators and denominatorsInclude numerators and denominators

Include cumulative crossInclude cumulative cross--study, multistudy, multi--yearyear

summariessummaries

Include all events regardless of attribution ofInclude all events regardless of attribution ofrelatedness to study drugrelatedness to study drug

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Specific Responsibilities ofSponsorsSpecific Responsibilities ofSponsors

Selecting qualified investigators and monitors (21 CFRSelecting qualified investigators and monitors (21 CFR312.53)312.53)

Obtaining investigator information (signed Form FDA 1572Obtaining investigator information (signed Form FDA 1572and CV)and CV)

Controlling shipment of drugControlling shipment of drug only to participatingonly to participatinginvestigatorsinvestigators

Obtaining clinical protocol informationObtaining clinical protocol information

Obtaining financial disclosure informationObtaining financial disclosure information

Providing each investigator an investigator brochure (21Providing each investigator an investigator brochure (21

CFR 312.55)CFR 312.55) Informing investigators of new safety observations (see 21Informing investigators of new safety observations (see 21

CFR 312.32 on IND safety reports)CFR 312.32 on IND safety reports)

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Specific Responsibilities ofSponsorsSpecific Responsibilities ofSponsors

Maintenance of adequate records (21 CFRMaintenance of adequate records (21 CFR312.57) including:312.57) including:

Tracking of drug shipment and informationTracking of drug shipment and information

Recording financial interest of investigatorsRecording financial interest of investigators

Keeping records for 2 years post approval or post lastKeeping records for 2 years post approval or post lastIND drug shipmentIND drug shipment

Retention of reserve samples and standards for certainRetention of reserve samples and standards for certainteststests

Providing FDA with records upon request (21 CFRProviding FDA with records upon request (21 CFR312.58)312.58)

Proper disposition of unused investigational drugProper disposition of unused investigational drug(21 CFR 312.59)(21 CFR 312.59)

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Specific Responsibilities ofSpecific Responsibilities of

InvestigatorsInvestigators

Control administration of investigational drug (21Control administration of investigational drug (21CFR 312.61)CFR 312.61)

Provide qualification and study conductProvide qualification and study conductinformation to sponsorinformation to sponsor

Following the protocol (commitment to thisFollowing the protocol (commitment to thisrequired per Form FDA 1572)required per Form FDA 1572)

Maintenance of records (21 CFR 312.62)Maintenance of records (21 CFR 312.62)including:including:

Drug dispositionDrug disposition Case histories (CRFs, ICFs, medical records)Case histories (CRFs, ICFs, medical records)

Keeping records for 2 years post approval or post studyKeeping records for 2 years post approval or post studydiscontinuationdiscontinuation

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Specific Responsibilities ofSpecific Responsibilities of

InvestigatorsInvestigators

Reports to sponsor (21 CFR 312.64)Reports to sponsor (21 CFR 312.64)

Providing progress reports for IND annualProviding progress reports for IND annualreportreport

Promptly reporting safety concernsPromptly reporting safety concerns Provision of final report after study completionProvision of final report after study completion

Providing financial disclosure informationProviding financial disclosure information

Assuring IRB review (21 CFR 312.66)Assuring IRB review (21 CFR 312.66)

Providing FDA with records upon requestProviding FDA with records upon request(21 CFR 312.68)(21 CFR 312.68)