what is an ind?

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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 cover The regulations in 21 CFR 312 cover

procedures and requirements for procedures and requirements for Investigational New Drug Investigational New Drug Applications (INDs)Applications (INDs)

These regulations define the roles These regulations define the roles and responsibilities of FDA reviewers, and responsibilities of FDA reviewers, IND sponsors, and clinical IND sponsors, and clinical investigatorsinvestigators

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DefinitionsDefinitions

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

institution, or organization that takes institution, or organization that takes responsibility for and initiates a responsibility for and initiates a clinical 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 is Ensuring AE risk information is

provided to the FDA and provided to the FDA and investigatorsinvestigators

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InvestigatorInvestigator An investigator is an individual under An investigator is an individual under

whose immediate direction the study whose immediate direction the study drug is administered or dispensed. If drug is administered or dispensed. If a team is involved, the leader is the a team is involved, the leader is the investigator; other team members investigator; other team members are sub-investigators are sub-investigators (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 conducted Ensuring the study is conducted

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

welfare of subjects, andwelfare of subjects, and Control of drug under investigationControl of drug under investigation

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Sponsor-InvestigatorSponsor-Investigator A sponsor-investigator is an individual who A sponsor-investigator is an individual who

both initiates and conducts a study and both initiates and conducts a study and under whose immediate direction the under whose immediate direction the study drug is administered or dispensed. study drug is administered or dispensed. This person must follow the requirements This person must follow the requirements pertaining to a sponsor and those pertaining to a sponsor and those pertaining to an investigatorpertaining to an investigator(21 CFR 312(b))(21 CFR 312(b))

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The primary concern during all The primary concern during all phases of clinical study is the phases of clinical study is the

safety and rights of study safety and rights of study subjectssubjects

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IND RequirementsIND Requirements

Even FDA-licensed products are Even FDA-licensed products are subject to IND regulations if not used subject to IND regulations if not used

under conditions of licensure (“an under conditions of licensure (“an experiment is any use of a drug experiment is any use of a drug except for the use of a marketed except for the use of a marketed

drug in the course of medical drug in the course of medical practice” 21 CFR 312.3(b))practice” 21 CFR 312.3(b))

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IND Requirements (cont’d)IND Requirements (cont’d) For a lawfully marketed product, no IND For a lawfully marketed product, no IND

submission is required if three specific conditions submission is required if three specific conditions apply (21 CFR 312.2)apply (21 CFR 312.2)• The study is not intended to support a new The study is not intended to support a new

indication or labeling changeindication or labeling change• The study does not intend to support a change The study does not intend to support a change

in advertisingin advertising• The study does not involve a route, dosage or The study does not involve a route, dosage or

patient population, etc. that increases riskpatient population, etc. that increases risk

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NOTE!NOTE!

The FDA may be aware of other The FDA may be aware of other studies that may affect evaluation of studies that may affect evaluation of potential risk, and potential risk, and

the FDA is subject to confidentiality the FDA is subject to confidentiality requirements and by law can not requirements and by law can not share this specific information with share this specific information with othersothers

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IND Content RequirementsIND Content Requirements21 CFR 312.2321 CFR 312.23

Format pertains to all sponsors and sponsor-Format 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) InformationChemistry, Manufacturing and Control (CMC) Information• 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 of Introductory Statement (description of

product, formulation, route, broad study product, formulation, route, broad study objectives, relevant previous use, foreign objectives, relevant previous use, foreign experience)experience)

General Investigational Plan (rationale, General Investigational Plan (rationale, indication, general approach, anticipated indication, general approach, anticipated studies including number of subjects and studies including number of subjects and possible risks)possible risks)

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Investigator’s Brochure (IB)Investigator’s Brochure (IB)

Sponsor must provide to all clinical Sponsor must provide to all clinical investigators, not required for sponsor investigators, not required for sponsor investigators (21 CFR 312.55). It must investigators (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 special Description of anticipated risk and any special

monitoring needsmonitoring needs• Updates as appropriateUpdates as appropriate

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Clinical ProtocolClinical Protocol

The clinical protocol must contain the The clinical protocol must contain the following elements:following elements:

• A statement of objectivesA statement of objectives• Investigator, subinvestigator, site and IRB Investigator, subinvestigator, site and IRB

informationinformation• Inclusion/Exclusion criteriaInclusion/Exclusion criteria• Study size and designStudy size and design• Dosage informationDosage information• Monitored parametersMonitored parameters• Clinical procedures and lab testsClinical procedures and lab tests

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CMC InformationCMC Information Emphasis in Phase I is on identification and Emphasis in Phase I is on identification and

control 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 to Even for Phase I, need enough information to assess safetyassess safety

Extent of expected information increases as drug Extent of expected information increases as drug development proceedsdevelopment proceeds

Throughout product development, good Throughout product development, good documentation of all manufacturing and testing documentation of all manufacturing and testing steps is essentialsteps is essential

Deficiencies in CMC information can result in Deficiencies in CMC information can result in clinical holdclinical hold

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Pharm/Tox InformationPharm/Tox Information Animal studies may be conducted to Animal studies may be conducted to

obtain proof of concept or tox informationobtain proof of concept or tox information Studies should support proposed clinical Studies should support proposed clinical

dose and regimendose and regimen Best to get CBER concurrence on pivotal Best to get CBER concurrence on pivotal

tox protocols prior to initiationtox protocols prior to initiation Need to submit complete study reports for Need to submit complete study reports for

tox studies, including summary and tox studies, including summary and individual animal dataindividual animal data

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Other IND ItemsOther IND Items Previous human experience needs to Previous human experience needs to

be included (if applicable)be included (if applicable) Additional information such as pre-Additional information such as pre-

IND meeting minutes or critical IND meeting minutes or critical references should be included as wellreferences should be included as well

Serial numbering of pages of an IND Serial numbering of pages of an IND is required (21 CFR 312.23(11)(e)) as is required (21 CFR 312.23(11)(e)) as this facilitates reference if the FDA this facilitates reference if the FDA has 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 an Safety or design related changes to an

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

within 30 days of being added)within 30 days of being added) These should be submitted to the FDA These should be submitted to the FDA

prior to implementationprior to implementation IRB approval is needed prior to IRB approval is needed prior to

implementationimplementation

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IND Information AmendmentsIND Information Amendments

21 CFR 312.3121 CFR 312.31Information amendments advise the Information amendments advise the

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

informationinformation Notice of discontinuance of a clinical Notice of discontinuance of a clinical

studystudy

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Annual ReportsAnnual Reports

21 CFR 312.3321 CFR 312.33 To be submitted within 60 days of the To be submitted within 60 days of the

anniversary of “in effect” dateanniversary of “in effect” date Include enrollment, demographic and Include enrollment, demographic and

conduct 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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Annual Reports (cont’d)Annual Reports (cont’d) CMC change informationCMC change information Revised/updated investigator Revised/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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Annual Reporting of Adverse EventsAnnual Reporting of Adverse Events

RECOMMENDATIONSRECOMMENDATIONS For solicited events – tabulate by study, study For solicited events – tabulate 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 cross-study, multi-year Include cumulative cross-study, multi-year

summariessummaries Include all events regardless of attribution of Include all events regardless of attribution of

relatedness to study drugrelatedness to study drug

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Specific Responsibilities of SponsorsSpecific Responsibilities of Sponsors

Selecting qualified investigators and monitors (21 CFR Selecting qualified investigators and monitors (21 CFR 312.53)312.53)

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

Controlling shipment of drug – only to participating Controlling shipment of drug – only to participating investigatorsinvestigators

Obtaining clinical protocol informationObtaining clinical protocol information Obtaining financial disclosure informationObtaining financial disclosure information Providing each investigator an investigator brochure (21 Providing each investigator an investigator brochure (21

CFR 312.55)CFR 312.55) Informing investigators of new safety observations (see 21 Informing 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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Review ongoing investigations (21 CFR 312.56)Review ongoing investigations (21 CFR 312.56) Monitor study progress for compliance with Monitor study progress for compliance with

protocolprotocol Dealing with noncompliant investigatorsDealing with noncompliant investigators Review and report to FDA safety and Review and report to FDA safety and

effectiveness data (annual reports and IND safety effectiveness data (annual reports and IND safety reports)reports)

Discontinuance of unsafe investigations and Discontinuance of unsafe investigations and informing the FDA, IRBs and investigators of informing the FDA, IRBs and investigators of these actionsthese actions

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Maintenance of adequate records (21 CFR Maintenance of adequate records (21 CFR 312.57) 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 last Keeping records for 2 years post approval or post last

IND drug shipmentIND drug shipment• Retention of reserve samples and standards for certain Retention of reserve samples and standards for certain

teststests Providing FDA with records upon request (21 CFR Providing FDA with records upon request (21 CFR

312.58)312.58) Proper disposition of unused investigational drug Proper disposition of unused investigational drug

(21 CFR 312.59)(21 CFR 312.59)

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Specific Responsibilities of Specific Responsibilities of InvestigatorsInvestigators

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

Provide qualification and study conduct Provide qualification and study conduct information to sponsorinformation to sponsor

Following the protocol (commitment to this Following the protocol (commitment to this required 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 study Keeping records for 2 years post approval or post study

discontinuation discontinuation

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Specific Responsibilities of Specific Responsibilities of InvestigatorsInvestigators

Reports to sponsor (21 CFR 312.64)Reports to sponsor (21 CFR 312.64)• Providing progress reports for IND annual Providing progress reports for IND annual

reportreport• 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 request Providing FDA with records upon request

(21 CFR 312.68)(21 CFR 312.68)

what is an ind?

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