Based on ICH E6 GCP Guidance Sections124 amp 6 and 45 CFR 46 Protection of Human Subjects Purpose To provide an overview of Investigator Responsibilities and GCP to study sites ID: 904587
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Tool:Training Presentation: Investigator Responsibilities and Good Clinical Practice (GCP)Based on ICH E6 GCP Guidance (Sections1.24 & 6) and 45 CFR 46: Protection of Human Subjects Purpose:To provide an overview of Investigator Responsibilities and GCP to study sitesAudience/User:NIDCR study staff, including PIs, Sub-Is, and Site Study CoordinatorsDetails:This training presentation provides information pulled directly from ICH E6 (Section 1.24 and Section 6) and 45 CFR 46; sections are identified in the header of each slide. Additional information is provided as “Information Sidebars” that are identified with the following icon: Speaker notes provide the actual text from ICH. Best Practice Recommendations:Delete the slide containing this Tool Summary Sheet before presenting or providing this presentation to a study site.Customize the amount and type of information that is provided verbally based on the type of study (e.g., interventional, observational), the experience level of study site personnel, and the time allotted for the presentation.Speaker Notes:Text from the speaker notes that may be of special interest to the audience is in bold underline.Alert the audience that they will have access to the slide deck, which includes the direct wording from ICH in the speaker notes.
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Tool Summary
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Slide2v2.0 - 2013-03-26NIDCRNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthCROMSClinical Research Operations and Management SupportRho, Inc., Federal DivisionICH E6 Good Clinical Practice Guidance and 45 CFR 46: Protection of Human SubjectsInvestigator Responsibilities and Good Clinical Practice (GCP)
Slide3Note that this is a general slide presentation designed for a broad audience of clinical researchers.Accordingly, some sections may not apply to your protocol. Information that may not be applicable for all studies is indicated via blue italics. Disclaimer3
Slide44Examples include references to:Investigational Product (IP), the Investigator’s Brochure (IB), or a study pharmacistSafety reporting and adverse eventsRandomization and unblinding proceduresRegulatory authoritiesClinical treatment (for a behavioral or study or a registry)Information that may be helpful but does not come directly from ICH or 45 CFR 46 is identified by this icon.Disclaimer (continued)
Slide5Good Clinical Practice (GCP) Guidelines (ICH-E6)Widely accepted international research standardsTitle 45 Code of Federal Regulations (CFR) Part 46 Applies to federally funded researchFederal regulations to protect human subjectsSubpart A: The Common RuleIRB roles and responsibilities/Informed ConsentBasis for Research Roles and Responsibilities: Guidelines & Regulations5
Slide6Additional sections of the Code of Federal Regulations apply to clinical trials 21 CFR 11: Electronic Records/Electronic Signatures21 CFR 50: Protection of Human Subjects21 CFR 54: Financial Disclosure by Clinical Investigators21 CFR 56: Institutional Review BoardsAdditional GuidanceFDA Information SheetsBasis for Research Roles and Responsibilities: Guidelines & Regulations (continued)6
Slide7A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials [studies],that provides assurance that the data and reported results are credible and accurate,and that the rights, integrity, and confidentiality of study subjects are protected.What is GCP? ICH 1.247
Slide88Sets minimum quality standards for the conduct of clinical researchCompliance with GCPEnsures that the rights, safety, and well-being of study participants are protectedEnsures the integrity of the data submitted for approvalSets standards for a system of mutual accountability among sponsors, regulatory authorities, investigators, and IRBsWhy is GCP Important?
Slide99The regulations and guidelines concerning the establishment of good clinical practice apply to all studies involving human subjectsApplies to Interventional studies, including studies without an investigational productObservational studies (specimen collection studies, natural history, etc.)Device studiesRealm of GCP in NIDCR Studies
Slide1010Specific to research involving human subjects conducted or funded by the DHHSFederal Policy for the Protection of Human SubjectsDesigned to make uniform human subject protection across all federal agencies and departmentsThe Common Rule: 45 CFR 46 Subpart A45 CFR 46
Slide11Properly qualified to assume responsibility for conduct of the studyThoroughly familiar with the investigational product (IP), and its appropriate useWilling to comply with GCP and applicable regulations and be prepared for audits and monitoringMaintain a Delegation of Responsibilities logPI Commitments: Investigator Qualifications and Agreements ICH 4.111
Slide12Ability to recruit in sufficient numbers and on timeSufficient time to complete the studyAdequate number of qualified staff and adequate facilities to complete the studyStaff who are well informed about the protocol, the IP, and their study responsibilitiesPI Commitments: Adequacy of Resources ICH 4.212
Slide13Ensure that all trial-related medical decisions are made by an investigator who is a qualified physicianProvide adequate medical care for participants who experience adverse eventsNotify the participant’s primary physician of his/her participation (as appropriate)Make an effort to learn why participants withdrawPI Commitments: Medical Care of Trial Participants ICH 4.313
Slide14Obtain written approval before the study beginsProvide the IRB with the current Investigator’s BrochureProvide the IRB/IEC with all documents subject to its review throughout the trialPI Commitments: Communication with the IRB/IEC ICH 4.414
Slide15Conduct the trial in compliance with the protocolDeviate only with agreement from the sponsor and prior review/approval from the IRB/IEC There can be exceptions – see next slide!Document and explain all deviationsPI Commitments: Compliance with the Protocol ICH 4.515
Slide16The investigator may deviate from the protocol before obtaining agreement from the sponsor and review/approval from the IRB/IEC only:When the changes are logistical/administrative, orTo eliminate an immediate hazard to study subjects. This requires immediate submission to:the IRBthe sponsorregulatory authorities (if required)PI Commitments: Compliance with the Protocol ICH 4.516
Slide17Responsible for the product, its usage, and its storageMay delegate to a Pharmacist under the PI’s supervisionMaintain IP recordsStore as specified by the sponsor and in accordance with applicable regulatory requirement(s)Use IP in accordance with the protocolPI Commitments: Investigational Products (IP) ICH 4.617
Slide18Follow the study randomization proceduresEnsure that the randomization code is only broken in accordance with the protocolPromptly document and notify the sponsor of any unblinding (for blinded trials)PI Commitments: Randomization and Unblinding Procedures ICH 4.718
Slide1919These require the same basic elements of consent.Regulations and GuidanceICH 4.845 CFR 4645 CFR 46 must be followed for research involving human subjects that is conducted, supported, or otherwise subject to regulation by any federal department or agency.PI Commitments: Informed Consent Process
Slide20Adhere to GCP and the ethical principles that have their origin in the Declaration of HelsinkiUpdate consent document when new information becomes availableAvoid:Coercion or undue influenceLanguage that causes the participant to waive any legal rightsPI Commitments: Informed Consent ICH 4.820
Slide2121Fully inform participant of all pertinent aspects of the trialUse lay and non-technical language Should be understandable to the subject8th grade reading levelTranslated to native language as applicable (IRB must approve translations)Provide enough time for participant to review the consent document and ask questionsPI Commitments: Informed Consent ICH 4.8
Slide2222The consent document must be signed and datedObtain consent prior to start of any study-related activities. Initial phone screening can precede consenting.If a participant or representative is unable to read, a witness should be present during the consenting processProvide the participant with a copy of the signed and dated consent formPI Commitments: Informed Consent ICH 4.8
Slide23The informed consent discussion and the consent document should include all essential and additional elementsEssential elements include:Statement that the study involves researchStatement that participation is voluntaryInformation about purpose, duration, and proceduresPI Commitments: Informed Consent ICH 4.823
Slide24Essential elements (continued):Number of subjects involved in the studyDescription of risks, benefits, and alternativesInformation about compensation/care for injuryStatement regarding confidentiality of recordsDescription of possible unforeseen risksPI Commitments: Informed Consent ICH 4.824
Slide25Essential elements (continued):Circumstances for termination without subject consentConsequences of withdrawing from the studyAdditional costs that may result from participationStatement that new research findings will be sharedContact information for questions/concernsPI Commitments: Informed Consent ICH 4.825
Slide26Additional elements from Title 45 CFR 46:Subpart B: Additional protections for pregnant women, human fetuses, and neonatesSubpart C: Additional protections for prisonersSubpart D: Additional protections for childrenPI Commitments: Informed Consent 45 CFR 4626
Slide27Explain the study to the extent it can be understood by participants who can only be enrolled with the consent of a legally acceptable representative (LAR)Follow guidelines for nontherapeutic trials (trials in which there is no anticipated direct clinical benefit to the participant)If participant and LAR can’t provide consent, follow measures described in the protocol PI Commitments: Informed Consent ICH 4.827
Slide28ICH 4.9 (Records and Reports)ICH 4.10 (Progress Reports)PI Commitments: Records and Reports28
Slide29Data must be ALCOA (Accurate, Legible, Contemporaneous, Original, and Attributable) and completeHow and where the data is recorded is key!If it is not documented, it does not existData on CRFs should match the source documents (raw data)PI Commitments: Records and Reports ICH 4.929
Slide30All changes to a CRF must be dated and signed such that the original data is not obscuredRetain essential documents for at least 2 years after the last approval of a marketing applicationProvide monitors, auditors, IRB/IEC, or regulatory authorities with direct access to trial recordsPI Commitments: Records and Reports ICH 4.930
Slide3131Record UP/SAE events thoroughlyMeets criteriaPI to determine causality Follow-up informationMake records available to monitors, auditors and inspectorsRecord retentionInstitutional requirementsICH GCP – 2 years after last approval of marketing application in an ICH regionFollow protocol, NIH, and local institutional requirements Longest requirement should be followedRecords and Reports
Slide3232Essential DocumentsPermit evaluation of the conduct of the study and the validity of the dataICH GCP E6 section 8.0 provides a table of essential documents, the purpose of the document, and the location broken down according to the stage of the studyApproved documents maintained at centralized location with copies (protocol, MOP) at satellite locationsReviewed for completeness and accuracyRecords and Reports
Slide3333Essential Documents (Examples)Investigator of Record (IoR) or 1572CVs for PI and Sub-InvestigatorsLicenses, as appropriateTraining records for all study personnelProtocol / amendment signature pageIRB membership list or roster IRB approvals – of protocol, consents, ads, handoutsCommunication – with IRB, sponsor, CRO, if applicableRecords and Reports
Slide34Submit a written report at least annually and in accordance with the IRB’s requestSubmit a written report if there are changes that might significantly change the conduct of the trial and/or increase risk to subjectsPI Commitments: Progress Reports to Sponsor/IRB/IEC ICH 4.1034
Slide35ICH 4.11 (Safety Reporting)ICH 4.12 (Premature Termination or Suspension of a Trial)PI Commitments: Safety and Safety Reporting35
Slide36Immediately report all SAEs to the sponsor; follow-up with a written reportEXCEPTION: SAEs identified in protocol as not requiring immediate reportingIdentify study participants using codes rather than personal identifiersComply with applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IECPI Commitments: Safety Reporting ICH 4.1136
Slide37Report AEs and/or lab abnormalities critical to safety evaluations to the sponsor per protocolProvide the sponsor and IRB with additional requested information Autopsy report in the event of a deathEKG or other supporting documentationPI Commitments: Safety Reporting ICH 4.1137
Slide3838* Notify in writingConditionNotifyStudy terminated/suspendedAll participantsPI terminates studyInstitution, sponsor, IRB*Sponsor terminates studyInstitution, IRB*IRB terminates studyInstitution, sponsor*PI Commitments: Premature Termination or Suspension of a Study ICH 4.12
Slide3939*Where applicable DocumentationProvided toNotification of study completion Institution*Summary of the trial’s outcomeIRB/IECAny required report(s)Regulatory Authority(ies)At study completion, the investigator should provide:PI Commitments: Final Report(s) ICH 4.13
Slide4040Insufficient evidence of Investigator involvement/oversightNo documented delegation of responsibility/scope of workFailure to adhere to protocol requirementsInadequate source documentsChanges made to original records without audit trail of when, why, by whomFailure to report UPs/SAEs appropriatelyParticipants not signing most current version of consent formInadequate product accountability recordsExamples of Common Non-Compliance
Slide4141Non-compliance runs the gamut from simple mistakes to fraud.Even simple mistakes can be costly! ConsentSpecimen handling and processing (labeling, etc.)Consequences can range from:Loss of data (Subject, Site, or Study data considered invalid)Professional/reputational risk for PI and institutionConsequences of Non-Compliance
Slide4242Understanding is key to protecting subject safety and integrity of dataMonitoring and quality management help ensure complianceUltimately, it is the PI’s responsibilityApplying GCP to Your Study
Slide43Q&AResourcesNIDCR FormsWrapping It All Up43
Slide44Questions?44
Slide4545Electronic Code of Federal Regulationshttp://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&tpl=%2Findex.tplOffice for Human Research Protections (OHRP)http://www.hhs.gov/ohrp/ICH E6 Guidelinehttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdfResources
Slide4646Objective ResourceProtection of human subjects45 CFR 46Staff qualifications/training ICH E6, Sec 4.1, Sec 4.2Research resources ICH E6, Sec 4.2Protocol adherenceICH E6, Sec 4.5Record keepingICH E6, Sec 4.4.1, Sec 4.9, Sec 8FAQs (OHRP Investigator Responsibilities)http://answers.hhs.gov/ohrp/categories/1567Resources
Slide47NIDCR Investigator of Record AgreementDelegation of Responsibilities LogTraining LogSite Screening and Enrollment LogSubject Code ListAdverse Event FormsMonitoring Visit LogThese forms and other tools are available through NIDCR’s Toolkit for Clinical Researchers: http://nidcr.nih.gov/research/toolkitNIDCR Forms47