Constance Lewin, M.D., M.P.H. Associate Director for Human Subject Protection Acting Branch Chief, Good Clinical Practice Branch 1 Division of Scientific

Constance Lewin, M.D., M.P.H.Associate Director for Human Subject Protection

Acting Branch Chief, Good Clinical Practice Branch 1Division of Scientific Investigations

Office of Medical PolicyCenter for Drug Evaluation and Research

University of Miami Statewide ConferenceMiami, FloridaApril 21, 2006

FDA Regulatory Requirements FDA Regulatory Requirements and FDA’s Bioresearch and FDA’s Bioresearch

Monitoring (BIMO) Program Monitoring (BIMO) Program

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Office of the Center DirectorSteve Galson, M..D.

Director

Office of Medical PolicyRobert Temple, M..D.

Director

Division of Drug Marketing,Advertising & CommunicationThomas Abrams, R.Ph., MBA

Director

Division of Scientific InvestigationsVACANT Director

Division of Scientific Investigations (DSI) Division of Scientific Investigations (DSI)

PHONE #301-594-0020 FAX #301-594-1204PHONE #301-594-0020 FAX #301-594-1204

DirectorVACANT

Deputy DirectorJoseph Salewski

GLP/BEQ BranchC. Viswanathan, PhD

Good Clinical Practice (GCP) Branch IILeslie Ball, MD

Good Clinical Practice (GCP) Branch I

C. Lewin MD, MPH

AgendaAgenda

FDA regulatory requirements for clinical FDA regulatory requirements for clinical investigators (CIs), sponsors and investigators (CIs), sponsors and institutional review boards (IRBs) institutional review boards (IRBs) involved in FDA-regulated clinical involved in FDA-regulated clinical research research

Overview of FDA’s Bioresearch Overview of FDA’s Bioresearch Monitoring ProgramMonitoring Program

Clinical Research Balance

•Scientific advancement•Product development

•Regulatory oversight•Human subject protections

Applies to:Applies to: Clinical research involving products Clinical research involving products regulated by FDAregulated by FDA

Regulatory Regulatory oversight of:oversight of:

IRBs, Sponsors, CRO/Monitors, Clinical IRBs, Sponsors, CRO/Monitors, Clinical InvestigatorsInvestigators

Relevant Relevant

CFR include (but CFR include (but not limited to):not limited to):

21 CFR 50, 5621 CFR 50, 56Part 50: Protection of Human SubjectsPart 50: Protection of Human SubjectsPart 56: IRBsPart 56: IRBs

21 CFR 312 (IND)21 CFR 312 (IND)

21 CFR 314 (NDA)21 CFR 314 (NDA)

Penalties for non-Penalties for non-compliance include compliance include (but not limited to):(but not limited to):

IRBs: 21 CFR 56.120, 56.121IRBs: 21 CFR 56.120, 56.121

Sponsors: Reject data; Clinical Holds; WL; Sponsors: Reject data; Clinical Holds; WL; Terminate IND; Application Integrity PolicyTerminate IND; Application Integrity Policy

CI: 21 CFR 312.70, Warning Letters, CI: 21 CFR 312.70, Warning Letters, NIDPOENIDPOE

FDA GCP RegulationsFDA GCP Regulations

Clinical Trials Oversight: Clinical Trials Oversight: FDA vs. OHRPFDA vs. OHRP

FDA oversightFDA oversight Sponsors, monitors, clinical investigators, contract Sponsors, monitors, clinical investigators, contract

research organizations involved in IND studies research organizations involved in IND studies IRBs reviewing clinical research involving any FDA-IRBs reviewing clinical research involving any FDA-

regulated product (IND and non-IND studies)regulated product (IND and non-IND studies)

OHRP oversightOHRP oversight Institutions where clinical research is conducted or Institutions where clinical research is conducted or

supported by HHS or supported by HHS or Institutions that agree to assume responsibility for Institutions that agree to assume responsibility for

the research in accordance with 45 CFR 46 the research in accordance with 45 CFR 46 regardless of the funding sourceregardless of the funding source

When Do I Need an When Do I Need an INDIND??

CFR 312.2 (b) ExemptionsCFR 312.2 (b) ExemptionsThe clinical investigation of a drug product that is lawfully The clinical investigation of a drug product that is lawfully

marketed in the United States is exempt from the marketed in the United States is exempt from the requirements of this part if requirements of this part if allall of the following apply: of the following apply:

(i) The investigation is not intended to be reported to FDA as a well-(i) The investigation is not intended to be reported to FDA as a well-controlled study controlled study in support of a new indicationin support of a new indication for use or not intended for use or not intended to be used to be used to support any other significant change in the labelingto support any other significant change in the labeling for for the drug;the drug;

(ii) If the drug that is undergoing investigation (ii) If the drug that is undergoing investigation is lawfully marketedis lawfully marketed as a as a prescription drug product, the investigation is not intended to support prescription drug product, the investigation is not intended to support a a significant change in the advertisingsignificant change in the advertising for the drug; for the drug;

When Do I Need an When Do I Need an INDIND??

CFR 312.2 (b) Exemptions (continued)CFR 312.2 (b) Exemptions (continued)(iii) The investigation does not involve (iii) The investigation does not involve a route of administration or a route of administration or

dosage level or use in a patient population or other factor dosage level or use in a patient population or other factor that that significantly increases the riskssignificantly increases the risks (or decreases the acceptability (or decreases the acceptability of the risks) associated with the use of the drug product;of the risks) associated with the use of the drug product;

(iv) The investigation is conducted in compliance with the (iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50; andthe requirements for informed consent set forth in part 50; and

(v) The investigation is conducted in compliance with the (v) The investigation is conducted in compliance with the requirements of CFR 312.7 (Promotion and charging for requirements of CFR 312.7 (Promotion and charging for investigational drugs).investigational drugs).

Who Do I Contact to Find Out if I Who Do I Contact to Find Out if I Need an Need an INDIND??

Contacts:Contacts:

Drugs:Drugs: Barry PooleBarry Poole (301) 827-3454(301) 827-3454

Biologics:Biologics: Robert YetterRobert Yetter (301) 827-0373(301) 827-0373

Devices:Devices:IDE StaffIDE Staff (240) 276-0125(240) 276-0125

Foods:Foods: David HattanDavid Hattan (202) 436-1293(202) 436-1293

Call, and then submit the request in writing (FAX or e-Call, and then submit the request in writing (FAX or e-mail).mail).

FDA plans to issue a guidance for this question.FDA plans to issue a guidance for this question.

DSI’s BIMO Program ResponsibilitiesDSI’s BIMO Program Responsibilities

Good Clinical Practice (GCP)Good Clinical Practice (GCP) Clinical InvestigatorsClinical Investigators Sponsor-Monitors, CROsSponsor-Monitors, CROs

Human Subject Protection Program Human Subject Protection Program (IRB)(IRB)

Good Laboratory Practice (GLP)Good Laboratory Practice (GLP) In vivo In vivo Bioequivalence Bioequivalence

GCP BIMO ProgramGCP BIMO Program

Clinical Investigator Inspection ProgramClinical Investigator Inspection Program Sponsor/Monitor/CRO Inspection Program Sponsor/Monitor/CRO Inspection Program

These two programs collectively allow the agency to These two programs collectively allow the agency to determine:determine: Adherence to applicable regulationsAdherence to applicable regulations Validity of studies in support of pending marketing Validity of studies in support of pending marketing

applicationsapplications Whether the rights and safety of subjects have been Whether the rights and safety of subjects have been

protectedprotected

DSI’s BIMO ResponsibilitiesDSI’s BIMO Responsibilities

DSI is responsible for all BIMO DSI is responsible for all BIMO inspections for CDERinspections for CDER Developing assignments, often in Developing assignments, often in

consultation with CDER review consultation with CDER review divisionsdivisions

Issuing assignments to Office of Issuing assignments to Office of Regulatory Affairs (ORA) field Regulatory Affairs (ORA) field investigators and participating on investigators and participating on inspection when scientific or medical inspection when scientific or medical expertise is requiredexpertise is required

Evaluating the results of inspections Evaluating the results of inspections from a scientific and regulatory from a scientific and regulatory perspective.perspective.

DSI’s BIMO ResponsibilitiesDSI’s BIMO Responsibilities

DSI is responsible for all BIMO DSI is responsible for all BIMO inspections for CDERinspections for CDER Recommending scientific follow-upRecommending scientific follow-up Recommending and implementing Recommending and implementing

regulatory actionsregulatory actions Providing expert advice on program Providing expert advice on program

design, policy issues and guidancedesign, policy issues and guidance Educating and informing program Educating and informing program

constituentsconstituents

What we do in the DSI GCP BranchesWhat we do in the DSI GCP Branches

For the CDER Review DivisionsFor the CDER Review Divisions DSI will arrange for routine data audit GCP inspections to DSI will arrange for routine data audit GCP inspections to

determine data integrity and safety of subjects in pivotal determine data integrity and safety of subjects in pivotal clinical trials, and provide the inspection reports to the clinical trials, and provide the inspection reports to the review division prior to the Division Action Goal Datereview division prior to the Division Action Goal Date

For the PublicFor the PublicDSI will investigate complaints related to the conduct of DSI will investigate complaints related to the conduct of

clinical trials, including arranging for directed or “for clinical trials, including arranging for directed or “for cause” GCP inspections, and take appropriate cause” GCP inspections, and take appropriate regulatory action.regulatory action.

About BIMO InspectionsAbout BIMO Inspections

BIMO inspections can be conducted at any point in the drug BIMO inspections can be conducted at any point in the drug development processdevelopment process

Inspections during Inspections during IND phaseIND phase are generally are generally “for cause = “for cause = directed”directed”

Inspections during the Inspections during the NDA phaseNDA phase are generally are generally “routine”,“routine”, but can be but can be “for cause” or “directed”“for cause” or “directed”

May include Clinical Investigator May include Clinical Investigator (CI),(CI), Sponsor/Monitoring Sponsor/Monitoring (S/M),(S/M), Contract Research Organizations Contract Research Organizations (CRO),(CRO), Institutional Institutional Review Boards Review Boards (IRB),(IRB), Good Laboratory Practice Good Laboratory Practice (GLP),(GLP), and and Bioequivalence Bioequivalence (BEq)(BEq) inspection of FDA regulated research. inspection of FDA regulated research.

About BIMO InspectionsAbout BIMO Inspections

RoutineRoutine

Inspections assigned for NDAsInspections assigned for NDAs

Directed (“for cause”)Directed (“for cause”)

Problems identified during FDA review processProblems identified during FDA review process Complaints reported to DSI fromComplaints reported to DSI from

FDA, other AgenciesFDA, other Agencies Sponsors/monitorsSponsors/monitors Institutions/IRB’sInstitutions/IRB’s Site personnelSite personnel Subjects/PublicSubjects/Public

*(Form FDA 1572: #9. Commitments)

Clinical Investigator Responsibilities*Clinical Investigator Responsibilities*

Follow the current protocolFollow the current protocol PersonallyPersonally conduct or supervise investigation(s)conduct or supervise investigation(s) Ensure that all persons assisting in conduct of Ensure that all persons assisting in conduct of

studies are informed of their obligations.studies are informed of their obligations. Ensure informed consent (21 CFR 50) and IRB Ensure informed consent (21 CFR 50) and IRB

review, approval , and reporting (21 CFR 56) review, approval , and reporting (21 CFR 56) requirements are met.requirements are met.

Obtain the informed consentObtain the informed consent of each human of each human subject to whom the drug is administered.subject to whom the drug is administered.

Clinical Investigator Responsibilities*Clinical Investigator Responsibilities*

Notify the sponsor before making changes in the protocol.Notify the sponsor before making changes in the protocol. Notify the IRB and obtain IRB approval before making changes Notify the IRB and obtain IRB approval before making changes

in the protocol.in the protocol. Report adverse events to the sponsor.Report adverse events to the sponsor. Maintain adequate and accurate records.Maintain adequate and accurate records. Make records available for inspection.Make records available for inspection. Comply with all other requirements in 21 CFR 312.Comply with all other requirements in 21 CFR 312.

*(Form FDA 1572: #9. Commitments)

What do we look for during the inspection?What do we look for during the inspection?

The FDA Inspection (Audit) comparesThe FDA Inspection (Audit) compares Source Medical Record DataSource Medical Record Data

vsvs

Case Report FormsCase Report Formsvsvs

Data Listing Submitted to NDAData Listing Submitted to NDA

Clinical Investigator InspectionsClinical Investigator Inspections

What do we look for during the inspection?What do we look for during the inspection? Clinical Investigator inspection determinesClinical Investigator inspection determines

Source of subjectsSource of subjectsDid subjects exist?Did subjects exist?Did they have the disease under study?Did they have the disease under study?Did they meet inclusion/exclusion criteria?Did they meet inclusion/exclusion criteria?Consent obtained?Consent obtained? IRB Review Obtained?IRB Review Obtained?


What do we look for during the inspection?What do we look for during the inspection? Clinical Investigator inspection determinesClinical Investigator inspection determines

Was the protocol followed?Was the protocol followed? Did the subjects receive the assigned study drug in the Did the subjects receive the assigned study drug in the

dose, route and frequency specified by the protocol?dose, route and frequency specified by the protocol? Are the case report forms complete and in agreement Are the case report forms complete and in agreement

with source data? Compare with NDA data listingwith source data? Compare with NDA data listing Are adverse experiences reported to sponsor and IRB?Are adverse experiences reported to sponsor and IRB? Adequacy and completeness of records?Adequacy and completeness of records?


Clinical Investigator InspectionsClinical Investigator InspectionsAll Centers - 2004All Centers - 2004

CDER: 351CDER: 351 CBER: 71CBER: 71 CDRH: 178CDRH: 178

Total: 600Total: 600

Criteria for Assigning International Criteria for Assigning International InspectionsInspections

International sites may be auditedInternational sites may be audited if there are insufficient domestic data;if there are insufficient domestic data;

onlyonly foreign data are submitted to support an application; foreign data are submitted to support an application;

domestic and foreign data show conflicting results domestic and foreign data show conflicting results pertinent to decision-making; orpertinent to decision-making; or

there is a serious issue to resolve, e.g., suspicion of there is a serious issue to resolve, e.g., suspicion of fraud, scientific misconduct, significant human subject fraud, scientific misconduct, significant human subject protection violations.protection violations.

Clinical Inspections - InternationalClinical Inspections - InternationalCDER, FY 1992 – 2005**CDER, FY 1992 – 2005**

0

10

20

30

40

50

60

70

80

9091-95*

96

97

98

99

2000

2001

2002

2003

2004

2005**

**FY05 to date 10/05

*

Clinical Investigator DeficienciesClinical Investigator DeficienciesCDER Inspections - FY 2005*CDER Inspections - FY 2005*

0%

10%

20%

30%

40%

50%

60%

70%

80%

Protocol NAI Record AEs Consent DrugAcct

Foreign

Domestic

51%

74%

63%57%

48%

17%

36%

11%

Foreign n = 65Domestic n = 261

10% 9% 10%5%

*FY05 to date 10/05

Prevalence of OAI Inspections (DSI Data)Prevalence of OAI Inspections (DSI Data)

Total number of FDA Total number of FDA inspectionsinspections

(1/77-9/2005*): = 7,909(1/77-9/2005*): = 7,909

Total OAI cases = 241Total OAI cases = 241

Percent OAI = 3%Percent OAI = 3%

Total Inspected

Total OAI

*FY05 to date 10/05

Prevalence of OAI Inspections (DSI data)Prevalence of OAI Inspections (DSI data)

Routine FDA inspections Routine FDA inspections (1/77-9/2005*) = 7023(1/77-9/2005*) = 7023


Percent OAI = 1.2%Percent OAI = 1.2%

Directed FDA inspections Directed FDA inspections (1/77-9/2005*) = 886(1/77-9/2005*) = 886


Percent OAI = 17.6%Percent OAI = 17.6%

Routine Inspections Total OAI

Directed Inspections Total OAI

*FY05 to date 10/05

Complaints to DSIComplaints to DSI

The number of complaints about clinical The number of complaints about clinical investigators/clinical trials continues to investigators/clinical trials continues to increaseincrease

DSI encourages such reporting (new DSI encourages such reporting (new Electronic Complaint Form)Electronic Complaint Form)

Follow-up on complaints is of vital Follow-up on complaints is of vital strategic importancestrategic importance Real-time follow-up of real-time issuesReal-time follow-up of real-time issues Public protection; Public confidencePublic protection; Public confidence

What Are They Complaining About?What Are They Complaining About?

Informed Consent Issues Informed Consent Issues FalsificationFalsification Failure to report adverse Failure to report adverse

eventsevents Failure to follow the protocolFailure to follow the protocol Inadequate RecordsInadequate Records Qualifications of persons Qualifications of persons

performing physicalsperforming physicals Failure to get IRB approval, Failure to get IRB approval,

report changes in researchreport changes in research Failure to follow FDA Failure to follow FDA

regulationsregulations

Drug accountabilityDrug accountability Recruitment PracticesRecruitment Practices Poor SupervisionPoor Supervision No active INDNo active IND Violations of GLP regsViolations of GLP regs Monitoring practicesMonitoring practices BlindingBlinding Charging for the test articleCharging for the test article Misleading advertisementsMisleading advertisements

Complaints Received: 1992-2005*Complaints Received: 1992-2005*

0

50

100

150

200

250

92 93 94 95 96 97 98 99 00 01 02 03 04 05**

*Calendar Years**FY05 to date 10/05

CI “For Cause” Inspection AssignmentsCI “For Cause” Inspection Assignments(CDER, FY 1992 – 2005*)(CDER, FY 1992 – 2005*)

0

20

40

60

80

100

120

FY 92 93 94 95 96 97 98 99 00 01 02 03 04 05*

*FY05 to date 10/05

Sponsor ResponsibilitiesSponsor Responsibilities A sponsor shall not begin a clinical investigation A sponsor shall not begin a clinical investigation

until the IND is in effect (21 CFR 312.20), which until the IND is in effect (21 CFR 312.20), which means:means:

after notification by FDA to begin investigationafter notification by FDA to begin investigation OROR

30 days after FDA receives the IND 30 days after FDA receives the IND

A sponsor shall not begin a clinical investigation if A sponsor shall not begin a clinical investigation if FDA places the study on clinical hold, which is an FDA places the study on clinical hold, which is an order to delay or suspend an investigation (21 order to delay or suspend an investigation (21 CFR 312.40)CFR 312.40)

Sponsor ResponsibilitiesSponsor Responsibilities

21 CFR 312.50 - General responsibilities of 21 CFR 312.50 - General responsibilities of sponsorssponsors Selecting qualified investigatorsSelecting qualified investigators Providing investigators with the information Providing investigators with the information

they need to conduct an investigation properly they need to conduct an investigation properly (e.g., protocol, IB, safety reports)(e.g., protocol, IB, safety reports)

Ensure proper monitoring of the investigationEnsure proper monitoring of the investigation

Sponsor ResponsibilitiesSponsor Responsibilities

21 CFR 312.50 - General responsibilities of 21 CFR 312.50 - General responsibilities of sponsorssponsors Ensure that the investigation is conducted in Ensure that the investigation is conducted in

accordance with the investigational planaccordance with the investigational plan Maintain an effective IND (e.g., annual Maintain an effective IND (e.g., annual

reports, safety reports, amendments,…)reports, safety reports, amendments,…) Ensure that FDA and investigators are Ensure that FDA and investigators are

promptly informed of significant new promptly informed of significant new adverse effects or risks (e.g., safety reports)adverse effects or risks (e.g., safety reports)

21 CFR 312.53-Selecting investigators and monitors21 CFR 312.53-Selecting investigators and monitors

(a)(a) Sponsors shall select only investigatorsSponsors shall select only investigators

qualified by training and experience as qualified by training and experience as appropriate experts to investigate the drugappropriate experts to investigate the drug

(b) Sponsors shall only ship drug to (b) Sponsors shall only ship drug to participating investigatorsparticipating investigators

(c) Sponsors shall obtain 1572, a statement of (c) Sponsors shall obtain 1572, a statement of qualifications, and financial disclosure info. qualifications, and financial disclosure info.

(d) Sponsors shall select qualified monitors(d) Sponsors shall select qualified monitors

Human Subject Protection ProgramHuman Subject Protection Program

IRB inspection programIRB inspection program Consults from review divisionsConsults from review divisions Inquiries from IRBs and publicInquiries from IRBs and public

Institutional Review Board (IRB)Institutional Review Board (IRB)

Formally designated by an institution to Formally designated by an institution to review, approve initiation of, and review, approve initiation of, and conduct periodic review of biomedical conduct periodic review of biomedical research involving human subjectsresearch involving human subjects

Primary purpose is to assure the Primary purpose is to assure the protection of the rights and welfare of protection of the rights and welfare of the human subjectsthe human subjects

Scientific considerations included but Scientific considerations included but not primarynot primary

IRB Inspections: What’s done?IRB Inspections: What’s done? Purpose: to assess compliance with 21 CFR Part 56Purpose: to assess compliance with 21 CFR Part 56 IRB and study-specific records reviewed IRB and study-specific records reviewed

Written proceduresWritten procedures Initial and continuing reviewInitial and continuing review Reporting findings and actions to CI and institutionReporting findings and actions to CI and institution Ensuring prompt reporting of Ensuring prompt reporting of

Research changesResearch changes Unanticipated problems involving riskUnanticipated problems involving risk Serious or continuing non-complianceSerious or continuing non-compliance Suspension or termination of IRB approvalSuspension or termination of IRB approval

Meeting minutes: attendance, actions taken, votes, basis for Meeting minutes: attendance, actions taken, votes, basis for requiring changes or disapproval, controverted issues and requiring changes or disapproval, controverted issues and resolutionresolution

Continuing review activitiesContinuing review activities All correspondence w/CIAll correspondence w/CI Membership list(s)Membership list(s)

IRB Inspections: What’s done?IRB Inspections: What’s done? FDA-regulated studies are selectedFDA-regulated studies are selected

Criteria for IRB approval (risks minimized, Criteria for IRB approval (risks minimized, reasonable; equitable subject selection; reasonable; equitable subject selection; informed consent; compliance with Part 50, informed consent; compliance with Part 50, Subpart D as appropriate; add’l safeguards for Subpart D as appropriate; add’l safeguards for other vulnerable populations)other vulnerable populations)

Documentation related to study approvals, Documentation related to study approvals, continuing review, suspensions/terminations, continuing review, suspensions/terminations, unanticipated problems involving risk to unanticipated problems involving risk to subjects or otherssubjects or others

Informed consent documentsInformed consent documents Use of expedited reviewUse of expedited review

IRB InspectionsIRB InspectionsCenter for Drug Evaluation & Research Center for Drug Evaluation & Research FY 2000 - 2004FY 2000 - 2004

0

50

100

150

200

250

300

00 01 02 03 04

IRB Inspections: What deficiencies are IRB Inspections: What deficiencies are commonly found?commonly found?

(FY’04: CDER assigned) (FY’04: CDER assigned)

0%

5%

10%

15%

20%

25%

30%

35%

40%

Mem

bers

Min

utes

Writ

ten

Proce

dure

s

37%

33%

17% 15%

02/05N=100R

esea

rch

Rev

iew

9%

Quo

rum

IRB inspections: PerspectiveIRB inspections: Perspective

Major differences among IRBs:Major differences among IRBs: Local vs. centralLocal vs. central Expertise and number of IRB membersExpertise and number of IRB members Number of studies reviewedNumber of studies reviewed Type of studies reviewedType of studies reviewed Potential risk to human subjects Potential risk to human subjects Trial populationTrial population

Evaluation of IRBsEvaluation of IRBs

Friend, Friend, notnot Foe Foe FDA has traditionally viewed IRBs as allies FDA has traditionally viewed IRBs as allies

in human subject protectionin human subject protection Official Action (OAI) is a last resortOfficial Action (OAI) is a last resort

What is Generated After an InspectionWhat is Generated After an Inspection

Form FDA 483Form FDA 483: : Inspectional Inspectional ObservationsObservations Left with inspected party at close of inspectionLeft with inspected party at close of inspection Immediately available under the Freedom of Immediately available under the Freedom of

Information ActInformation Act

Establishment Inspection Report (EIR)Establishment Inspection Report (EIR) Prepared by field investigator after inspectionPrepared by field investigator after inspection Includes exhibits supporting observed Includes exhibits supporting observed

deficienciesdeficiencies


DSI Review of EIRDSI Review of EIR Point-by-point review of 483 items, additional Point-by-point review of 483 items, additional

deficiencies, limitations of inspectiondeficiencies, limitations of inspection Confirmation of supporting documentationConfirmation of supporting documentation Assessment of any response from the inspected Assessment of any response from the inspected

partyparty For GCP inspections, often include assessment For GCP inspections, often include assessment

of impact on acceptability of data for the drug of impact on acceptability of data for the drug approval reviewapproval review

Final compliance classificationFinal compliance classification

Compliance ClassificationsCompliance Classifications

NAI - No Action IndicatedNAI - No Action Indicated Firm is in complianceFirm is in compliance

VAI - Voluntary Action IndicatedVAI - Voluntary Action Indicated Minor deviation(s) from the regulationsMinor deviation(s) from the regulations Voluntary correction requestedVoluntary correction requested

OAI - Official Action IndicatedOAI - Official Action Indicated Serious non-compliance requiring regulatory Serious non-compliance requiring regulatory

or administrative action by FDA; Data or administrative action by FDA; Data UnacceptableUnacceptable


Clinical Inspection Summary ReportClinical Inspection Summary Report Summary of all inspections assigned for an Summary of all inspections assigned for an

applicationapplication Provided to review division in advance of Provided to review division in advance of

PDUFA action goal datePDUFA action goal date Recommends acceptance or rejection of site dataRecommends acceptance or rejection of site data

Letter to the inspected partyLetter to the inspected party Emphasizes deviation from regulations, if any.Emphasizes deviation from regulations, if any. Copied to the review divisionCopied to the review division


Where Official Action is IndicatedWhere Official Action is Indicated Recommendation to Reject DataRecommendation to Reject Data

enforcement option for non-U.S., non-IND sitesenforcement option for non-U.S., non-IND sites Warning LetterWarning Letter Disqualification of a clinical investigator (21 CFR 312.70)Disqualification of a clinical investigator (21 CFR 312.70)

Notice of Initiation of Disqualification Proceedings and Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) letterOpportunity to Explain (NIDPOE) letter

Informal ConferenceInformal Conference Notice of Opportunity for Hearing (Formal)Notice of Opportunity for Hearing (Formal) Consent AgreementConsent Agreement Part 16 Disqualification HearingPart 16 Disqualification Hearing

Referral for criminal prosecution (OCI)Referral for criminal prosecution (OCI)

0

100

200

300

400

500

600

700

800

S-M

CI

IRB

BIOEQ

GLP

627678

BIMO Inspections Completed

*FY05 to date 10/05

549 556

683 690 723 692

553

CDER BIMO Inspections (FY 2005*)CDER BIMO Inspections (FY 2005*)

GLP

CI

BEQ

IRB

S-M

CI = 326BEQ= 84IRB = 90GLP = 34S-M = 19

Total = 553*FY05 to date 10/05

Helpful WebsitesHelpful Websites DSI Homepage: DSI Homepage: www.fda.gov/cder/offices/dsiwww.fda.gov/cder/offices/dsi

Includes links to the Clinical Investigator Inspection List Includes links to the Clinical Investigator Inspection List (NEW), Bioresearch Monitoring Information Systems (NEW), Bioresearch Monitoring Information Systems (BMIS) files (NEW), Warning Letters, NIDPOE Letters, (BMIS) files (NEW), Warning Letters, NIDPOE Letters, Lists of Disqualified or Restricted or Debarred Lists of Disqualified or Restricted or Debarred Investigators, Code of Federal Regulations, etc.Investigators, Code of Federal Regulations, etc.

FDA Homepage: FDA Homepage: www.fda.govwww.fda.gov

Includes links to the Federal Register Notices, FDA Includes links to the Federal Register Notices, FDA guidance documents.guidance documents.

Compliance Programs: Compliance Programs: www.fda.gov/ora/compliance_ref/default.htmwww.fda.gov/ora/compliance_ref/default.htm

Documents

Constance Lewin, M.D., M.P.H. Associate Director for Human Subject Protection Acting Branch Chief, Good Clinical Practice Branch 1 Division of Scientific