1 INDs and IDEs: Responsibilities of Sponsor/Investigators Sue Chase, RN, BSN M3 Clinical Research,...

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INDs and IDEs:INDs and IDEs:Responsibilities of Responsibilities of

Sponsor/InvestigatSponsor/Investigatorsors

Sue Chase, RN, BSNSue Chase, RN, BSN

M3 Clinical Research, Inc.M3 Clinical Research, Inc.

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Outline of Outline of PresentationPresentation

I.I. Roles and ResponsibilitiesRoles and Responsibilities

II.II. INDIND

III.III. IDEIDE

IV.IV. AmendmentsAmendments

V.V. Sponsor/Investigator Sponsor/Investigator ResponsibilitiesResponsibilities

VI.VI. Operationalizing the IND/IDEOperationalizing the IND/IDE

VII.VII. The Institution’s RoleThe Institution’s Role

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The ChallengeThe Challenge

David Lepay, the FDA’s senior advisor on David Lepay, the FDA’s senior advisor on clinical science states that, “Where clinical science states that, “Where problems have come in recent years, the problems have come in recent years, the majority have come in studies where the majority have come in studies where the investigator was also the sponsor.” investigator was also the sponsor.” Because the investigator now maintains Because the investigator now maintains also the responsibility of the sponsor, also the responsibility of the sponsor, there is lost a level of oversight that there is lost a level of oversight that comes from separate sponsors and comes from separate sponsors and investigators investigators

Guide to Good Clinical Practice Jan. 2005Guide to Good Clinical Practice Jan. 2005

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Roles and Roles and ResponsibilitiesResponsibilities

InvestigatorInvestigator

InvestigatorInvestigator means an individual means an individual who actually conducts a clinical who actually conducts a clinical investigation. In the event an investigation. In the event an investigation is conducted by a investigation is conducted by a team of individuals, the team of individuals, the investigator is the responsible investigator is the responsible leader of the team.leader of the team.

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

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SponsorSponsorSponsorSponsor means a person who takes means a person who takes

responsibility for and initiates a clinical responsibility for and initiates a clinical investigation. The sponsor may be an investigation. The sponsor may be an individual or pharmaceutical company, individual or pharmaceutical company, governmental agency, academic governmental agency, academic institution, private organization, or institution, private organization, or other organization. The sponsor does other organization. The sponsor does not actually conduct the investigation not actually conduct the investigation unless the sponsor is a sponsor-unless the sponsor is a sponsor-investigatorinvestigator

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

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Roles and Roles and Responsibilities Responsibilities

Sponsor-InvestigatorSponsor-InvestigatorSponsor-InvestigatorSponsor-Investigator means an individual who means an individual who

both initiates and conducts an investigation, both initiates and conducts an investigation, and under whose immediate direction the and under whose immediate direction the investigational drug is administered or investigational drug is administered or dispensed. The term does not include any dispensed. The term does not include any person other than an individual. The person other than an individual. The requirements applicable to a sponsor-requirements applicable to a sponsor-investigator under this part include both those investigator under this part include both those applicable to an investigator and sponsorapplicable to an investigator and sponsor21 CFR 312.3 (b)21 CFR 312.3 (b)

NOTE: NOTE: Corporations, agencies, or other institutions do not qualify as sponsor-investigators.

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Contract Research Contract Research OrganizationOrganizationContract Research Organization (CRO)Contract Research Organization (CRO)

means a person that assumes, as an means a person that assumes, as an independent contractor with the independent contractor with the sponsor, one or more of the sponsor, one or more of the obligations of a sponsor, e.g., design obligations of a sponsor, e.g., design of a protocol, selection or monitoring of a protocol, selection or monitoring of investigations, evaluation of of investigations, evaluation of reports, and preparation of materials reports, and preparation of materials to be submitted to the FDA.to be submitted to the FDA.

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

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Warning LettersWarning Letters

……purpose to determine whether purpose to determine whether activities as both sponsor and activities as both sponsor and investigator in clinical studies investigator in clinical studies complied with FDA regulationscomplied with FDA regulations

Failure to obtain an investigator Failure to obtain an investigator agreement from all implanting agreement from all implanting physiciansphysicians

Failure to ensure proper monitoring Failure to ensure proper monitoring Failure to maintain records of Failure to maintain records of

shipment and disposition of deviceshipment and disposition of device Failure to follow investigational planFailure to follow investigational plan

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Warning LetterWarning Letter

You failed to adequately supervise You failed to adequately supervise the conduct of the studythe conduct of the study

You failed to disclose sufficient You failed to disclose sufficient accurate financial informationaccurate financial information

You failed to provide SOPs for the You failed to provide SOPs for the conduct of the trialconduct of the trial

Failure to maintain adequate Failure to maintain adequate recordsrecords

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What is an IND?What is an IND?

Investigational New DrugInvestigational New Drug Federal law requires that a drug be the Federal law requires that a drug be the

subject of an approved marketing application subject of an approved marketing application before it is transported or distributed across before it is transported or distributed across state lines. state lines.

Because a sponsor will probably want to ship Because a sponsor will probably want to ship the investigational drug to clinical the investigational drug to clinical investigators in many states, it must seek an investigators in many states, it must seek an exemption from that legal requirement. exemption from that legal requirement.

The IND is the means through which the The IND is the means through which the sponsor technically obtains this exemption sponsor technically obtains this exemption from the FDA. from the FDA. 21 CFR 312.121 CFR 312.1

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When is an IND When is an IND Required?Required?

Sponsor intends to conduct a Sponsor intends to conduct a clinical study with an clinical study with an investigational drug.investigational drug.

Sponsor intends to conduct a study Sponsor intends to conduct a study with an approved drug, but in a new with an approved drug, but in a new indication, dose form, or dose range indication, dose form, or dose range that is not covered in the current that is not covered in the current package insert (off label).package insert (off label).

21 CFR 312.221 CFR 312.2

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When is an IND When is an IND NotNot Required?Required?

The clinical investigation of a marketed drug orThe clinical investigation of a marketed drug or

biologic does not require submission of an IND biologic does not require submission of an IND if all if all

six of the following conditions are met:six of the following conditions are met: It is not intended to be reported to FDA in It is not intended to be reported to FDA in

support of a new indication for use or to support of a new indication for use or to support any other significant change in the support any other significant change in the labeling for the drug?labeling for the drug?

It is not intended to support a significant It is not intended to support a significant change in the advertising for the productchange in the advertising for the product

21 CFR 312.221 CFR 312.2

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When is an IND When is an IND NotNot Required?Required?

It does not involve a route of administration or It does not involve a route of administration or dosage level, use in a subject population, or dosage level, use in a subject population, or other factor that significantly increases the other factor that significantly increases the risks (or decreases the acceptability of the risks) risks (or decreases the acceptability of the risks) associated with the use of the drug productassociated with the use of the drug product

It is conducted in compliance with the It is conducted in compliance with the requirements for IRB review and informed requirements for IRB review and informed consentconsent

It is conducted in compliance with the It is conducted in compliance with the requirements concerning the promotion and requirements concerning the promotion and sale of drugs sale of drugs

21 CFR 312.721 CFR 312.7 And it does not intent to invoke 21 CFR 50.24And it does not intent to invoke 21 CFR 50.24

21 CFR 312.221 CFR 312.2

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IND Regulations - 21 IND Regulations - 21 CFR 312CFR 312

Contains procedures and Contains procedures and requirements governing the use requirements governing the use of investigational new drugs and of investigational new drugs and biologicsbiologics

Applies to all clinical Applies to all clinical investigations of products that investigations of products that are subject to section 505 of the are subject to section 505 of the FD&C Act.FD&C Act.

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IND ApplicationIND ApplicationResourcesResources

Guidance DocumentsGuidance Documents IND Application ProcessIND Application Process Content and Format of INDs for Phase 1 Studies Content and Format of INDs for Phase 1 Studies

of Drugsof Drugs Information for Sponsor-Investigator Submitting Information for Sponsor-Investigator Submitting

INDsINDs Pharmacology and Toxicology GuidelinesPharmacology and Toxicology Guidelines

FormsForms http://www.fda.gov/opacom/morechoices/fdaforms/cder.htmlhttp://www.fda.gov/opacom/morechoices/fdaforms/cder.html

FDA Web SiteFDA Web Site http://www.fda.gov/cderhttp://www.fda.gov/cder

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IND ApplicationIND ApplicationResourcesResources

References and Resources:References and Resources: 21 CFR 312.23 Defines IND content 21 CFR 312.23 Defines IND content

and formatand format 21CFR 312.22 Sponsor investigators 21CFR 312.22 Sponsor investigators

may use pre-existing technical may use pre-existing technical information if authorized to do soinformation if authorized to do so

21 CFR 312.33 Annual Reports21 CFR 312.33 Annual Reports

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IND ApplicationIND ApplicationFDA Jurisdiction of FDA Jurisdiction of

ProductsProductsCDER Regulates:CDER Regulates: DrugsDrugs Monoclonal Monoclonal

antibodies for in-antibodies for in-vivo usevivo use

Proteins intended Proteins intended for therapeutic for therapeutic useuse

Growth FactorsGrowth Factors ImmunomodulatorImmunomodulator

ss

CBER Regulates:CBER Regulates: Cellular ProductsCellular Products VaccinesVaccines Allergenic Allergenic

extractsextracts Blood and blood Blood and blood

componentscomponents Gene Therapy Gene Therapy

productsproducts

www.fda.gov/cber/transfer/trawww.fda.gov/cber/transfer/transfer.htmnsfer.htm

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IND ApplicationIND ApplicationPre IND ConsultationPre IND Consultation

FDA Consultation Prior to ApplicationFDA Consultation Prior to Application Pre IND submissionPre IND submission Pre IND Consult with FDAPre IND Consult with FDA

Occurs within 60 days of receipt of Occurs within 60 days of receipt of requestrequest

Typically, only one meeting per issueTypically, only one meeting per issue Meeting packageMeeting package One hour formal meeting by telephone One hour formal meeting by telephone

unless unless unique situationunique situation FDA issues official minutesFDA issues official minutes

21 CFR 312.47 and 21 CFR 312.47 and 312.82312.82

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IND ApplicationIND ApplicationIND Content and IND Content and

FormatFormatContent of the INDContent of the IND Differs for different productsDiffers for different products Depends on Depends on

1)1) the phase of the investigation the phase of the investigation

2)2) the extent of human study the extent of human study

3)3) the duration of the investigation the duration of the investigation

4)4) the nature and source of the drug the nature and source of the drug substance, and substance, and

5)5) the dosage form of the drug product the dosage form of the drug product

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IND ApplicationIND ApplicationIND Content and IND Content and

FormatFormat1.1. Cover letter (Not required by CFR) Cover letter (Not required by CFR) 2.2. Cover Sheet (Form FDA 1571) (Road Cover Sheet (Form FDA 1571) (Road

Map)Map)3.3. Table of Contents (What’s where)Table of Contents (What’s where)4.4. Introduction Statement and General Introduction Statement and General

Investigational Plan (Where you are Investigational Plan (Where you are headed)headed)

5.5. Investigator’s Brochure (Preliminary Investigator’s Brochure (Preliminary package insert)package insert)

6.6. Protocols (Plan for collecting Protocols (Plan for collecting safety/efficacy data)safety/efficacy data)

21 CFR 21 CFR 312.23 (a)312.23 (a)

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IND ApplicationIND ApplicationIND Content and Format IND Content and Format

(cont.)(cont.)

7.7. Chemistry, manufacturing, control data Chemistry, manufacturing, control data and environmental impact statement (how and environmental impact statement (how the product was made and the testing the product was made and the testing performed)performed)

8.8. Pharmacology and toxicology data (data to Pharmacology and toxicology data (data to conclude that it is reasonably safe to conclude that it is reasonably safe to conduct the proposed study)conduct the proposed study)

9.9. Previous Human Experience (same or Previous Human Experience (same or similar products)similar products)

10.10. Additional Information (study, Additional Information (study, investigator, facilities, IRB, Form FDA investigator, facilities, IRB, Form FDA 1572)1572)

21 CFR 21 CFR 312.23 (a)312.23 (a)

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IND ApplicationIND ApplicationCross Reference Cross Reference

LetterLetter Information that has been previously submitted Information that has been previously submitted

to the FDA under other INDs/Drug Master Files to the FDA under other INDs/Drug Master Files may be incorporated by referencemay be incorporated by reference

A copy of a cross reference letter can be A copy of a cross reference letter can be included in the information in place of the included in the information in place of the information requiredinformation required

Sample text: We authorize the institution Sample text: We authorize the institution listed below to cross reference (company name) listed below to cross reference (company name) Biologics Master File (BB-MF-xxx) as described Biologics Master File (BB-MF-xxx) as described below in support of their IND application.below in support of their IND application.

21 CFR 314.42021 CFR 314.420

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When a Sponsor Signs When a Sponsor Signs a 1571;a 1571;

What does it mean?What does it mean? Wait 30 days before beginning the Wait 30 days before beginning the

studystudy Not begin or continue the study if Not begin or continue the study if

placed on clinical holdplaced on clinical hold IRB will be responsible for review and IRB will be responsible for review and

approval of the studyapproval of the study Conduct the study in accordance with Conduct the study in accordance with

all applicable regulatory requirementsall applicable regulatory requirements Transfer of ObligationsTransfer of Obligations

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When an Investigator Signs When an Investigator Signs the 1572; the 1572;

What do they commit to?What do they commit to? To conduct the study in accordance To conduct the study in accordance

with the protocolwith the protocol To personally supervise or conduct the To personally supervise or conduct the

investigationinvestigation To inform the subjects of the To inform the subjects of the

investigational status of the test articleinvestigational status of the test article To report adverse events to the sponsorTo report adverse events to the sponsor To read and understand the To read and understand the

Investigational BrochureInvestigational Brochure To inform all support personnel of the To inform all support personnel of the

investigation requirementsinvestigation requirements

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When an Investigator Signs When an Investigator Signs the 1572; the 1572;

What do they commit to?What do they commit to? To maintain adequate records and make To maintain adequate records and make

them available for inspectionthem available for inspection To assure that the IRB is in complianceTo assure that the IRB is in compliance To assume responsibility for initial and To assume responsibility for initial and

continuing review by the IRBcontinuing review by the IRB To promptly report study changes and To promptly report study changes and

unanticipated risks to the IRBunanticipated risks to the IRB Not make changes in the research Not make changes in the research

without IRB approvalwithout IRB approval To comply with the requirements To comply with the requirements

regarding the obligations of clinical regarding the obligations of clinical investigatorsinvestigators

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IND ApplicationIND ApplicationFormatFormat

3 copies (An original and 2 copies)3 copies (An original and 2 copies) Numbering: Beginning with the initial IND, serial Numbering: Beginning with the initial IND, serial

numbering with a 3 digit number numbering with a 3 digit number At least 1 ½” left margin for bindingAt least 1 ½” left margin for binding 3 hole punched paper3 hole punched paper If > 2” thickness, separate into separate volumes If > 2” thickness, separate into separate volumes

and labeledand labeled Section dividersSection dividers Sequentially number pages with table of contentSequentially number pages with table of content Outside wrapper of shipment(s) should identify the Outside wrapper of shipment(s) should identify the

contents, IND application, Notice of IND changecontents, IND application, Notice of IND changeFDA IND, NDA, ANDA, or Drug Master File Binders FDA IND, NDA, ANDA, or Drug Master File Binders

http://www.fda.gov/cder/ddms/binders.htmhttp://www.fda.gov/cder/ddms/binders.htm

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FDA Review ProcessFDA Review Process

Typical Review TeamTypical Review Team Regulatory ReviewerRegulatory Reviewer Clinical Medical OfficerClinical Medical Officer Product Reviewer(s)Product Reviewer(s) StatisticianStatistician Pharmacology/Toxicology ReviewerPharmacology/Toxicology Reviewer

A single review team will generally follow a A single review team will generally follow a drugdrug

from its IND application through the NDAfrom its IND application through the NDAapproval decision and into post-marketingapproval decision and into post-marketing

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FDA Review ProcessFDA Review Process

CDER: MAPP CDER Manual of Policies and CDER: MAPP CDER Manual of Policies and Procedures (MaPP) Procedures (MaPP)

6030.16030.1 IND Process and Review IND Process and Review Procedures (Issued 5/1/1998, Posted Procedures (Issued 5/1/1998, Posted 5/14/1998) 5/14/1998)

6030.26030.2 INDs: Review of Informed Consent INDs: Review of Informed Consent Documents (Issued 11/13/2002, Posted Documents (Issued 11/13/2002, Posted 12/11/2002) 12/11/2002)

6030.46030.4 INDs: Screening INDs (Issued INDs: Screening INDs (Issued 5/9/2001, Posted 5/14/2001) 5/9/2001, Posted 5/14/2001)

6030.86030.8 INDs: Exception from Informed INDs: Exception from Informed Consent Requirements for Emergency Consent Requirements for Emergency Research (Issued 2/4/2003, Posted Research (Issued 2/4/2003, Posted 3/17/2003) 3/17/2003)

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Clinical HoldClinical Hold

IND goes into effect (study may IND goes into effect (study may proceed) 30 days after FDA receives proceed) 30 days after FDA receives the IND, unless sponsor is notified the IND, unless sponsor is notified otherwise by FDAotherwise by FDA

21 CFR 312.4021 CFR 312.40

Order issued by FDA to sponsor to delay Order issued by FDA to sponsor to delay a proposed clinical investigation or a proposed clinical investigation or suspend an ongoing investigationsuspend an ongoing investigation

21 CFR 312.4221 CFR 312.42

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Clinical HoldClinical HoldAddressing a Clinical Addressing a Clinical

HoldHold Sponsor prepares amendment to the Sponsor prepares amendment to the

IND addressing specific issuesIND addressing specific issues The FDA response to the sponsor in The FDA response to the sponsor in

writing within 30 days of receipt of the writing within 30 days of receipt of the amendmentamendment

The Guidance for Industry: Submitting and Reviewing The Guidance for Industry: Submitting and Reviewing Complete Responses to Clinical HoldComplete Responses to Clinical Hold

21 CFR 312.42 Clinical Holds and Request for Modifications21 CFR 312.42 Clinical Holds and Request for Modifications

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IND Submissions IND Submissions Common PitfallsCommon Pitfalls

Data lacking to support dose proposedData lacking to support dose proposed Inadequate report of prior investigationsInadequate report of prior investigations Questionable scientific soundnessQuestionable scientific soundness Poorly defined stopping rulesPoorly defined stopping rules Undefined statistical analysisUndefined statistical analysis Undefined endpointUndefined endpoint InconsistenciesInconsistencies Lack of specific cross referenceLack of specific cross reference

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What is an IDE?What is an IDE?

It is a new medical deviceIt is a new medical device It is a significant risk deviceIt is a significant risk device Required by law Required by law (sec 515 FD&C Act)(sec 515 FD&C Act) Required by Regulation Required by Regulation (21 CFR (21 CFR

812)812)

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When is an IDE When is an IDE Required?Required?

Significant Risk DeviceSignificant Risk Device An implantAn implant For use in supporting or sustaining For use in supporting or sustaining

human life substantially important in human life substantially important in diagnosing, curing mitigating, or diagnosing, curing mitigating, or treating diseases, or in preventing treating diseases, or in preventing impairment of human healthimpairment of human health

21 CFR 812.321 CFR 812.3

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When is an IDE When is an IDE Not Not Required?Required?

Examples of non significant risk Examples of non significant risk device studies:device studies:

Contact lens solutionsContact lens solutions TENS units for treatment of painTENS units for treatment of pain Daily wear contact lenses and Daily wear contact lenses and

associated cleaners and solutionsassociated cleaners and solutions Jaundice monitors for infantsJaundice monitors for infants

Guidance Document for IRB and Guidance Document for IRB and Investigator/Medical DevicesInvestigator/Medical Devices

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When is an IDE When is an IDE NotNot Required?Required?

A diagnostic device, if the sponsor A diagnostic device, if the sponsor complies with the applicable complies with the applicable requirements in 809.10.c requirements in 809.10.c

A device undergoing consumer A device undergoing consumer preference testing, testing of a preference testing, testing of a modification, or testing of a modification, or testing of a combination of two or more devices combination of two or more devices in commercial distribution, if the in commercial distribution, if the testing is not for the purpose of testing is not for the purpose of determining safety or effectiveness determining safety or effectiveness and does not put subjects at risk.and does not put subjects at risk.

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When is an IDE When is an IDE NotNot Required?Required?

A device intended solely for A device intended solely for veterinary useveterinary use

A device shipped solely for research A device shipped solely for research on or with laboratory animals on or with laboratory animals

A custom device as defined in 21 A custom device as defined in 21 CFR 812.3.b, unless the device is CFR 812.3.b, unless the device is being used to determine safety or being used to determine safety or effectiveness for commercial effectiveness for commercial distributiondistribution

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IDE ApplicationIDE Application

Cover letterCover letter Name and address of sponsorName and address of sponsor Report of prior investigations to include all Report of prior investigations to include all

prior clinical, animal and lab testing of prior clinical, animal and lab testing of device device 21 CFR 812.2721 CFR 812.27

Investigational Plan Investigational Plan 21 CFR 812.2521 CFR 812.25 Description of methods, facilities and Description of methods, facilities and

controls used for the manufacture, controls used for the manufacture, processing, packing, storage and processing, packing, storage and installation of the device, and signed installation of the device, and signed investigator agreement investigator agreement 21 CFR 812.4321 CFR 812.43

21 CFR 812.2021 CFR 812.20

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IDE Application IDE Application (cont.)(cont.)

Name and address of IRB chairperson Name and address of IRB chairperson where investigation is being conductedwhere investigation is being conducted

Institution(s) name and address where Institution(s) name and address where investigation is being conductedinvestigation is being conducted

An example of the investigator An example of the investigator agreementagreement

Monitoring planMonitoring plan Amount charged for deviceAmount charged for device Labeling of deviceLabeling of device Informed consent Informed consent 21 CFR 5021 CFR 50

21 CFR 812.2021 CFR 812.20

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IDE ApplicationIDE ApplicationFormat and AssemblyFormat and Assembly

IDE Cover LetterIDE Cover Letter Statement that enclosed is “original IDE Statement that enclosed is “original IDE

submission”submission” Include applicants mailing address, phone, Include applicants mailing address, phone,

fax and email which must be in the US 21 CFR fax and email which must be in the US 21 CFR 812.18812.18

Reference device name and indication for useReference device name and indication for use Reference device manufacturer, address and Reference device manufacturer, address and

contact informationcontact information Indicate whether device is intended to be soldIndicate whether device is intended to be sold

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FDA Receipt of FDA Receipt of IND/IDEIND/IDE

Upon receipt of the application by FDA, an Upon receipt of the application by FDA, an IND/IDE number will be assigned, and the IND/IDE number will be assigned, and the application will be forwarded to the application will be forwarded to the appropriate reviewing division. The appropriate reviewing division. The reviewing division will send a letter to the reviewing division will send a letter to the Sponsor-Investigator providing notification Sponsor-Investigator providing notification of the IND/IDE number assigned, date of of the IND/IDE number assigned, date of receipt of the original application, and receipt of the original application, and address where future submissions to the address where future submissions to the IND should be sent. IND should be sent.

Studies shall not be initiated until 30 days Studies shall not be initiated until 30 days after the date of receipt of the application after the date of receipt of the application by FDA unless you receive earlier by FDA unless you receive earlier notification by FDA that studies may begin. notification by FDA that studies may begin.

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IND AmendmentsIND Amendments

Protocol Amendment Protocol Amendment (21 CFR 312.30)(21 CFR 312.30) Informational Amendment Informational Amendment (21 CFR (21 CFR

312.31)312.31) Safety reports Safety reports (21 CFR 312.32)(21 CFR 312.32) Annual Reports Annual Reports (21 CFR 312.33)(21 CFR 312.33)

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IND AmendmentsIND AmendmentsProtocol AmendmentProtocol Amendment

Reporting a new protocol using a protocol amendment is Reporting a new protocol using a protocol amendment is applicable when a sponsor would like to conduct a new applicable when a sponsor would like to conduct a new clinical study under an existing IND. No 30 day waitclinical study under an existing IND. No 30 day wait

Changes to an existing clinical protocol if the change Changes to an existing clinical protocol if the change impacts safety, the scope of the investigation of the impacts safety, the scope of the investigation of the quality of the studyquality of the study

FDA review and IRB approval may not be required FDA review and IRB approval may not be required immediately for a revision if the changes eliminates immediately for a revision if the changes eliminates apparent immediate hazards apparent immediate hazards 21 CFR 312.30 (b) (2) (ii)21 CFR 312.30 (b) (2) (ii) Requires FDA/IRB notification within 5 working days. Requires FDA/IRB notification within 5 working days. 21 21 CFR 56.104 (c)CFR 56.104 (c)

Addition of a new investigator. Notification within 30 Addition of a new investigator. Notification within 30 days of adding the investigator. days of adding the investigator. 21 CFR 312.23 (a) (6) (iii) 21 CFR 312.23 (a) (6) (iii) (b)(b)

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IND AmendmentsIND AmendmentsInformational Informational AmendmentAmendment

An informational amendment is used to An informational amendment is used to submit any pertinent additional submit any pertinent additional information to the FDA not reportable information to the FDA not reportable suing a protocol amendment, safety suing a protocol amendment, safety report or an annual reportreport or an annual report

Includes technical information or Includes technical information or responses to FDA commentsresponses to FDA comments

21 CFR 312.3121 CFR 312.31

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IND AmendmentsIND AmendmentsSafety ReportsSafety Reports

IND Safety ReportIND Safety Report The sponsor shall notify FDA and all The sponsor shall notify FDA and all

participating investigators in a written participating investigators in a written IND safety report:IND safety report:

Any adverse experience associated with Any adverse experience associated with the use of the drug that is both serious the use of the drug that is both serious and unexpected; orand unexpected; or

Any finding from tests in laboratory Any finding from tests in laboratory animals that suggests a significant risk animals that suggests a significant risk for human subjects including reports of for human subjects including reports of mutagenicity, teratogenticy, or mutagenicity, teratogenticy, or cardinogenticycardinogenticy

21 CFR 312.3221 CFR 312.32

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IND AmendmentsIND Amendments Safety ReportsSafety Reports

IND Safety ReportsIND Safety Reports Each notification shall be made as Each notification shall be made as

soon as possible and in no event later soon as possible and in no event later than 15 days after the sponsor’s than 15 days after the sponsor’s initial receipt of the informationinitial receipt of the information

Each written notification may be Each written notification may be submitted on FDA Form 3500 A or in submitted on FDA Form 3500 A or in a narrative formata narrative format

21 CFR 312.3221 CFR 312.32

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IND AmendmentsIND AmendmentsSafety ReportsSafety Reports

IND Safety ReportsIND Safety Reports Use Form 1571 to fileUse Form 1571 to file Indicate “IND Safety Report”Indicate “IND Safety Report” Initial reports, follow up reportsInitial reports, follow up reports Send to reviewing division at FDASend to reviewing division at FDA Indicate all previous similar reports Indicate all previous similar reports

filesfiles Provide follow up information, Provide follow up information,

resolution of event from subsequent resolution of event from subsequent reportsreports

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IDE AmendmentIDE Amendment

Changes in the investigational plan that Changes in the investigational plan that require prior approval:require prior approval:

Change in indicationChange in indication Change in type of nature of study Change in type of nature of study

controlcontrol Change in primary endpointChange in primary endpoint Change in method of statistical analysisChange in method of statistical analysis Early termination of study (except for Early termination of study (except for

safety reasons)safety reasons)

21 CFR 21 CFR 812.35812.35

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IDE AmendmentIDE Amendment

Changes that do Changes that do NOTNOT require FDA require FDA approval, but require notification to the approval, but require notification to the FDA within 5 working days of change:FDA within 5 working days of change:

Emergency UseEmergency Use Certain Developmental ChangesCertain Developmental Changes Changes to the Protocol that do not Changes to the Protocol that do not

affectaffect Validity of data Validity of data Scientific soundness of planScientific soundness of plan The rights, safety, or welfare of The rights, safety, or welfare of

subjectssubjects

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IDE AmendmentIDE Amendment Safety ReportsSafety Reports

IDE Safety ReportsIDE Safety ReportsReport of Unanticipated Adverse Device Effects Report of Unanticipated Adverse Device Effects A sponsor who conducts an evaluation of an A sponsor who conducts an evaluation of an

unanticipated adverse device effect shall report unanticipated adverse device effect shall report results to FDA and all reviewing IRBs and results to FDA and all reviewing IRBs and participating investigators within 10 working participating investigators within 10 working days after sponsor first receives notice of the days after sponsor first receives notice of the effecteffect

If sponsor determines adverse effect presents If sponsor determines adverse effect presents an unreasonable risk to subjects, termination an unreasonable risk to subjects, termination is to occur as soon as possible, but no later is to occur as soon as possible, but no later than 5 working days after sponsor makes than 5 working days after sponsor makes determination and not later than 15 working determination and not later than 15 working days after sponsor first receives notice of effectdays after sponsor first receives notice of effect

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IND/IDE Reporting IND/IDE Reporting Requirements Annual Requirements Annual

ReportsReportsIND Annual ReportIND Annual Report Within 60 days of the anniversary date of the Within 60 days of the anniversary date of the

IND/IDE filingIND/IDE filing Study title, protocol, objectives, status, number Study title, protocol, objectives, status, number

of subjects planned versus enrolled, completed of subjects planned versus enrolled, completed and discontinued, and description of resultsand discontinued, and description of results

Summary: narrative or tabular reporting of Summary: narrative or tabular reporting of SAEs, frequent and most serious by body SAEs, frequent and most serious by body system, summary of IND safety reports for the system, summary of IND safety reports for the year, number of subjects expired and cause of year, number of subjects expired and cause of death, revised IB, and resultant new death, revised IB, and resultant new information.information.

21 CFR 312.33 21 CFR 312.33

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ReportsReportsIDE Annual ReportIDE Annual Report IDE number; device name and indicationIDE number; device name and indication Summary of study progressSummary of study progress Number of investigational sitesNumber of investigational sites Number of devices shippedNumber of devices shipped Brief summary of resultsBrief summary of results Summary of anticipated and Summary of anticipated and

unanticipated ADEunanticipated ADE Description of any deviations from planDescription of any deviations from plan

21 CFR 21 CFR 812.150812.150

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ReportsReportsNon compliance with annual reporting Non compliance with annual reporting

requirements:requirements: Report Request LetterReport Request Letter A Pre Termination Letter if the sponsor A Pre Termination Letter if the sponsor

does not reply within 30 days of the does not reply within 30 days of the issuance of the Report Request Letter, issuance of the Report Request Letter, oror

A Termination Letter is issued sponsor A Termination Letter is issued sponsor does not reply within 30 days of the does not reply within 30 days of the issuance of the Pre Termination Letterissuance of the Pre Termination Letter

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Investigator Investigator ResponsibilitiesResponsibilities

Challenge to maintain final Challenge to maintain final accountability and yet set up accountability and yet set up systems that allow for objectivity systems that allow for objectivity and minimize bias.and minimize bias.

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Sponsor Sponsor ResponsibilitiesResponsibilities

CRO/Transfer of CRO/Transfer of obligationsobligations

Selecting qualified Selecting qualified investigators/monitinvestigators/monitorsors

Allocation of dutiesAllocation of duties Trial management, Trial management,

data handling, data handling, record keeping, record keeping, data management data management and conductand conduct

Quality Assurance / Quality Assurance / ControlControl

Investigational drugInvestigational drug Informing Informing

investigatorsinvestigators Safety reporting: Safety reporting:

FDA and FDA and investigatorsinvestigators

Monitoring/Monitoring/AuditingAuditing

21 CFR 21 CFR 312.50312.50

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Transfer of Transfer of ObligationsObligations

Sponsor may transfer any/all Sponsor may transfer any/all responsibilities set forth in part 312responsibilities set forth in part 312

Any transfers shall be in writingAny transfers shall be in writing If not all obligations are transferred, the If not all obligations are transferred, the

writing is required to describe each of writing is required to describe each of the obligations being assumed by the the obligations being assumed by the CRO. If all obligations transferred, CRO. If all obligations transferred, statement that all obligations statement that all obligations transferred is acceptable.transferred is acceptable.

21 CFR 312.52/ICH 21 CFR 312.52/ICH 5.2.15.2.1

56

Transfer of Transfer of ObligationsObligations

A CRO assuming any responsibility of the A CRO assuming any responsibility of the sponsor shall comply with the specific applicable sponsor shall comply with the specific applicable regulations and is subject to the same regulatory regulations and is subject to the same regulatory action as the sponsor for failure to comply with action as the sponsor for failure to comply with the obligation. the obligation.

Any regulations referring to “sponsor” shall Any regulations referring to “sponsor” shall apply to the CRO accepting one or more of the apply to the CRO accepting one or more of the transferred obligationstransferred obligations

21 CFR 312.52/ICH 5.2.121 CFR 312.52/ICH 5.2.1 While a CRO may assume any of the sponsor's While a CRO may assume any of the sponsor's

responsibility, it should be emphasized that the responsibility, it should be emphasized that the transfer does not relieve the sponsor from transfer does not relieve the sponsor from responsibility for the quality of dataresponsibility for the quality of data

Federal RegisterFederal Register

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Operationalizing the IND/IDEOperationalizing the IND/IDEInstitutional/Sponsor-Institutional/Sponsor-

Investigator Considerations Prior Investigator Considerations Prior to Implementationto Implementation

ResourcesResources IRB approvalIRB approval Role of Role of

Pharmaceutical or Pharmaceutical or Device CompanyDevice Company

TrainingTraining FundingFunding Administar Administar

ApprovalApproval

Financial Financial DisclosuresDisclosures

IndemnificationsIndemnifications Standard Standard

Operating Operating ProceduresProcedures

Trial RegistryTrial Registry RiskRisk

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Investigator Considerations Investigator Considerations Prior to ImplementationPrior to Implementation

Resources:Resources: Data Management/AnalysisData Management/Analysis Compliance with 21 CFR Part 11Compliance with 21 CFR Part 11 Data collection to meet safety Data collection to meet safety

reporting requirements and FDA reporting requirements and FDA annual and final reportsannual and final reports

Project ManagementProject Management TimelinesTimelines Contingency PlanningContingency Planning

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Resources: MonitoringResources: Monitoring Source verification, Investigational Source verification, Investigational

Product accountability, regulatory Product accountability, regulatory documents, overall compliancedocuments, overall compliance

IndependentIndependent Internal/OutsourceInternal/Outsource Monitoring Plan (submit with IDE Monitoring Plan (submit with IDE

application)application) Investigator-Sponsor oversight and Investigator-Sponsor oversight and

interventioninterventionFDA Guideline for the Monitoring of Clinical FDA Guideline for the Monitoring of Clinical

InvestigationsInvestigations

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Investigator Considerations Investigator Considerations Prior to Implementation;Prior to Implementation;

Training:Training: Site InitiationSite Initiation MonitorsMonitors TransitionsTransitions DocumentationDocumentation

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IRB approval:IRB approval: Parallel reviewParallel review Institutional PolicesInstitutional Polices IRB approval not obtained until IRB approval not obtained until

of FDA assignment letter is of FDA assignment letter is receivedreceived

62



Role of Pharmaceutical or Device Role of Pharmaceutical or Device Company:Company:

Define RoleDefine Role Wide range of roles/relationshipsWide range of roles/relationships Hands offHands off SupportSupport Reporting requirementsReporting requirements

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Financial Support:Financial Support: Typically partial financial support Typically partial financial support

from industryfrom industry Realistic definition of costs based Realistic definition of costs based

on processes to maintain on processes to maintain compliancecompliance

Hidden costsHidden costs

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The Office of the Inspector General has The Office of the Inspector General has indicated in its Compliance Program indicated in its Compliance Program Guidance for Pharmaceutical Guidance for Pharmaceutical Manufactures that the provision of study Manufactures that the provision of study drug free of change of funding for an drug free of change of funding for an investigator imitated study is not investigator imitated study is not prohibited so long as the study is for a prohibited so long as the study is for a legitimate purpose and the funding is tied legitimate purpose and the funding is tied to legitimate study costs. to legitimate study costs.

68 Fed. Reg.2373168 Fed. Reg.23731

The legitimacy may be suspect if the The legitimacy may be suspect if the marketing program is the approver of marketing program is the approver of funding.funding.

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Administar:Administar: Adminisar is the Medicare Fiscal Adminisar is the Medicare Fiscal

Intermediary for Medicare coverage Intermediary for Medicare coverage determination of CMS/FDA Category B determination of CMS/FDA Category B investigational devicesinvestigational devices

Must submit name of device and Must submit name of device and detailed approval letter demonstrating detailed approval letter demonstrating Category B status with number of sites Category B status with number of sites and subjectsand subjects

Approval within 6 weeks of submissionApproval within 6 weeks of submission

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Financial Disclosure:Financial Disclosure: Permitting an investigator to begin Permitting an investigator to begin

participation in an investigation, the IND/IDE participation in an investigation, the IND/IDE sponsor shall obtain financial information that sponsor shall obtain financial information that will allow an applicant to submit complete and will allow an applicant to submit complete and accurate certification or disclosure statements accurate certification or disclosure statements required under Part 54. 21 CFR 312.53 and 21 required under Part 54. 21 CFR 312.53 and 21 CFR 812.43CFR 812.43

Sponsor is also required to obtain the Sponsor is also required to obtain the investigator's commitment to promptly update investigator's commitment to promptly update this information if any relevant changes occur this information if any relevant changes occur during the course of the investigation and for during the course of the investigation and for one year following completion of the study. one year following completion of the study.

Maintain on file for all involved in trialMaintain on file for all involved in trial

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Indemnification:Indemnification: Determine if institution or funding Determine if institution or funding

agency will provide indemnification agency will provide indemnification for clinical investigationfor clinical investigation

Typically, very little indemnification Typically, very little indemnification if any is able to be securedif any is able to be secured

Limited Indemnification: donation Limited Indemnification: donation of study drug and agreement to of study drug and agreement to indemnify the sponsor-investigator indemnify the sponsor-investigator only for manufacturing defectsonly for manufacturing defects

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Standard Operating Procedures:Standard Operating Procedures:FDA: Compliance Program Guidance Manual: FDA: Compliance Program Guidance Manual:

Makes reference to sponsor SOPs in several Makes reference to sponsor SOPs in several areas, including monitoring, data collection, areas, including monitoring, data collection, and QAand QA

GCP ICH: GCP ICH: The sponsor is responsible for implementing The sponsor is responsible for implementing

and maintaining quality assurance and quality and maintaining quality assurance and quality control systems with written SOPscontrol systems with written SOPs

The sponsor should maintain SOPS for using The sponsor should maintain SOPS for using electronic trial data handling and or remote electronic trial data handling and or remote electronic trial data systemselectronic trial data systems

Monitors should follow and be thoroughly Monitors should follow and be thoroughly familiar with the sponsor’s SOPsfamiliar with the sponsor’s SOPs

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Trial registry:Trial registry:The data bank was established , as required under The data bank was established , as required under

section 113 of the FD & C Act be central resource section 113 of the FD & C Act be central resource to other members of the public and to health care to other members of the public and to health care providers and researchers. Clintrials.govproviders and researchers. Clintrials.gov

Fair Access to Clinical Trials Act 2005Fair Access to Clinical Trials Act 2005 The FACT Act would requireThe FACT Act would require Trials to be registered prior to IRB approvalTrials to be registered prior to IRB approval Objectives, eligibility, funding, timeline to be Objectives, eligibility, funding, timeline to be

discloseddisclosed Results be made availableResults be made available Enforcement mechanisms-including monetary Enforcement mechanisms-including monetary

penalties of up to $10,000/day to sponsor for non penalties of up to $10,000/day to sponsor for non compliancecompliance

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Risk:Risk: No or limited indemnificationNo or limited indemnification Investigator and Sponsor Investigator and Sponsor

requirementsrequirements Compliance with institutional Compliance with institutional

policies, reporting requirements policies, reporting requirements from funding source, state laws, from funding source, state laws, and GCPsand GCPs

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Closing an INDClosing an IND

An IND may be inactivated at the An IND may be inactivated at the request of the sponsor (clinical hold > 2 request of the sponsor (clinical hold > 2 yrs.) and may be reactivated with yrs.) and may be reactivated with proper documentationproper documentation

The FDA may terminate an IND that ahs The FDA may terminate an IND that ahs been inactive for over 5 yearsbeen inactive for over 5 years

An IND can be withdrawn at the An IND can be withdrawn at the sponsors request. The IND cannot be sponsors request. The IND cannot be reactivated, but can only be resumed reactivated, but can only be resumed with a new INDwith a new IND

FDA can terminate FDA can terminate

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IND Reporting IND Reporting RequirementsRequirements

WithdrawalWithdrawal At any time a sponsor may withdraw an effective At any time a sponsor may withdraw an effective

IND without prejudiceIND without prejudice If an IND is withdrawn, FDA shall be so notified, If an IND is withdrawn, FDA shall be so notified,

all clinical investigations conducted under the all clinical investigations conducted under the IND shall be ended, all current investigators IND shall be ended, all current investigators notified and all stocks of the drug returned to notified and all stocks of the drug returned to the sponsor or other wise disposed of at the the sponsor or other wise disposed of at the request of the sponsor in accordance with 21 request of the sponsor in accordance with 21 CFR 312.59CFR 312.59

If an IND is withdrawn because of a safety If an IND is withdrawn because of a safety reason, the sponsor shall promptly inform the reason, the sponsor shall promptly inform the FDA, all participating investigators, and all FDA, all participating investigators, and all reviewing IRBs with the reason of the reviewing IRBs with the reason of the withdrawalwithdrawal

21 CFR 312.4021 CFR 312.40

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IND Reporting IND Reporting RequirementsRequirementsTerminationTermination

A termination action may be based on A termination action may be based on deficiencies in the IND or in the deficiencies in the IND or in the conduct of an investigation under an conduct of an investigation under an INDIND

If an IND is terminated, the sponsor If an IND is terminated, the sponsor shall end all clinical investigations shall end all clinical investigations conducted under the IND and recall or conducted under the IND and recall or otherwise provide for the disposition of otherwise provide for the disposition of all unused supplies of the drugall unused supplies of the drug

21 CFR 312.4421 CFR 312.44

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IND/IDE Reporting IND/IDE Reporting RequirementsRequirementsFinal ReportFinal Report

The sponsor shall notify the FDA within The sponsor shall notify the FDA within thirty working days of completion or thirty working days of completion or termination of investigationtermination of investigation

Sponsor shall notify IRB and Sponsor shall notify IRB and participating investigations within 6 participating investigations within 6 months after completion or months after completion or terminationtermination

21 CFR 312.33/ 21 CFR 21 CFR 312.33/ 21 CFR 812.150812.150

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The Institution’s RoleThe Institution’s Role

Know when research is going on and Know when research is going on and oversightoversight

Notification by physicianNotification by physician Education (IND/IDE Assistance Program)Education (IND/IDE Assistance Program) Templates (application, protocols, annual Templates (application, protocols, annual

reports)reports) OversightOversight MentoringMentoring Prior review of all publicationsPrior review of all publications Cross reference publications with IRB Cross reference publications with IRB

recordsrecords

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Require Scientific Review and Require Scientific Review and AppropriateAppropriate

Pre-Implementation PlanningPre-Implementation Planning Well planned and coordinatedWell planned and coordinated Required Pre IND meeting with Required Pre IND meeting with

FDAFDA Notification of clinical holds and Notification of clinical holds and

auditsaudits

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Ensure the study is monitored Ensure the study is monitored objectivelyobjectivelyReview and approval of outside Review and approval of outside monitors monitors

Inclusion of DSMBInclusion of DSMB Implement measures to ensure Implement measures to ensure

adverse event reportingadverse event reporting

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ConclusionConclusion

Sufficient potential scientific benefit Sufficient potential scientific benefit should be identified and supported by should be identified and supported by both the PI and Institution prior to both the PI and Institution prior to beginning the IND/IDEbeginning the IND/IDE

Additional regulatory requirements Additional regulatory requirements significantly increase the need for significantly increase the need for resources and complianceresources and compliance

A sponsor-investigator should have A sponsor-investigator should have full knowledge of the regulations full knowledge of the regulations before consideration of holding the before consideration of holding the IND/IDEIND/IDE

1 INDs and IDEs: Responsibilities of Sponsor/Investigators Sue Chase, RN, BSN M3 Clinical Research,...

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