Investigator Responsibilities Regulation And Clinical Trials
Investigator Responsibilities –Regulation and Clinical TrialsFDA’S 2013 Clinical Investigator Training CourseCynthia F. Kleppinger, M.D.Division of Good Clinical Practice ComplianceOffice of Scientific InvestigationsOffice of Compliance, CDERNovember 13, 2013
ObjectivesIdentify the federal regulations coveringclinical research and clinical investigator obligationsDiscuss specific problems seen during FDA inspectionsat clinical sitesDiscuss various methods that can be used to ensurecompliance with federal regulations and studyprotocol requirements
Who is an Investigator?An individual who actually conducts aclinical investigation (i.e., under whoseimmediate direction the drug isdispensed to a subject.)In the event an investigation isconducted by a team of individuals, theinvestigator is the responsible leaderof the team.[21 CFR 312.3]
Sponsor-InvestigatorAn individual who both initiates and conductsan investigation, and under whose immediatedirection the investigational drug is administeredor dispensed.– The term does not include any person otherthan an individual.– The requirements applicable to a sponsorinvestigator include both those applicable toan investigator and a sponsor.[21 CFR 312.3]
Question ?Does the investigator have to be a medicaldoctor?ANSWER: NO A physician can be asubinvestigator to perform those studyfunctions requiring the appropriate level ofmedical expertise.[21 CFR 312.53]
Legal FrameworkFederal Food, Drug, and Cosmetic Act (FD&CAct)– Section 505(i) is the statutory authority for FDA’soversight of clinical investigations to test safety andeffectivenessCode of Federal Regulations (CFR)– Regulations promulgated under Section 505(i)describing FDA’s authority over the conduct of clinicalinvestigations includingSponsor responsibilitiesClinical Investigator responsibilitiesGuidances– Advisory only, to assist clinical investigators andsponsors in complying with the regulations
Clinical Trial EnvironmentStudySubjectsUS Food andDrugAdministrationSponsorInvestigatorUS Office thicsCommittee
FDA Expectations of ClinicalInvestigatorsAdherence to Code of Federal Regulations– Knowledge of Clinical Investigatorregulations– Understanding of Clinical Investigatorresponsibilities
Statement of InvestigatorForm FDA 1572No investigator may participate in aninvestigation until he/she provides thesponsor with a completed, signedStatement of Investigator, Form FDA1572[21 CFR 312.53(c)].
Commitments on 1572Personally conduct or supervise investigationFollow protocol- only make changes afternotifying the sponsor unless subject at riskEnsure all persons assisting with the study areinformed of obligationsInform subjects that drugs are being used forinvestigational purposesEnsure informed consent (21 CFR Part 50) andIRB review, approval and reporting (21 CFRPart 56)Report to sponsor adverse events (21 CFR312.64); read and understand the IB.
Commitments (cont.)Maintain adequate and accurate records(21 CFR 312.62) and make them availablefor inspection in accordance with 21 CFR312.68Ensure initial and continuing review by anIRB and report all changes to researchand unanticipated problems involving risksto subjects, not make any changes withoutIRB approval except where necessary toeliminate immediate hazardsComply with other requirements in 21 CFR312
Form FDA 1572If a clinical study is conducted outside of theU.S. and is not conducted under aninvestigational new drug application (IND), thenthe investigator need not sign a 1572If a foreign clinical study is conducted under anIND, then all FDA IND regulations, including therequirement to obtain a signed 1572, must bemetIf local laws or regulations prohibit the signing ofa 1572, FDA would expect the sites to operateas non-IND sites
E6: Good Clinical Practice:Consolidated GuidelinePublished as officialguidance in U.S. FederalRegister (May 1997)– “The objective of this ICH GCPguidance is to provide a unifiedstandard for the EuropeanUnion (EU), Japan, and theUnited States to facilitate themutual acceptance of clinicaldata by the regulatory authoritiesin these jurisdictions”.
In General E6 More DetailedDifferences can especiallybe seen in the area ofSponsor responsibilities– ICH E6 more detailed formonitoring and QAHowever, FDA regulationsare more explicit in the IRBsections
Question?Do FDA regulations allow for delegation ofthe informed consent?
Answer: Not really but FDA has no regulations concerning delegation ofthis duty– Discussed in the FDA Information Sheets: “FDA doesnot require the investigator to personally conduct theconsent ion/Guidances/ucm126431.htmICH allows the delegation of the informedconsent process to a designee– “The investigator, or a person designated by theinvestigator, should fully inform the subject ”
Question ?Does the investigator have to sign theinformed consent?ANSWER: NO Signing/dating by personconducting the informed consent discussionis part of ICH-GCP but not FDA regulations
Role of Clinical InvestigatorsGood Clinical Practice(GCP) in FDA-regulatedresearch is not the same asgood clinical practice incaring for patients– For example, FDAregulations have veryspecific requirements forfollowing the protocol,recordkeeping, and drugaccountability
Important Caveat forClinical InvestigatorsStandards for clinical care of patients Standards for academic research Standards for FDA regulated research
Historical Perspective1961-1962: Thalidomide tragedyExposed loopholes in Food, Drug and CosmeticAct of 1938: Companies could distributeunapproved drugs for experimental purposes– Did not require notification to patients ofinvestigational status– Did not require companies ordoctors to keep track ofdistribution– Did not require FDA to benotified of experimental use– Did not require records to bekept– Did not require demonstration of drug effectiveness
Action1962: Kefauver-Harris Amendments– Approval based on demonstration of efficacy aswell as safety– Expanded inspectional authority - FDA can inspectcompany records regarding development andclinical testing– FDA must be notified beforeclinical trials could beconducted– Rulemaking authority over“Investigational New Drugs”– Expansive rulemakingauthority over clinical trials– Gave FDA the power to haltclinical trials
Additional ActionsIND Regulations of 1963– Created the current frameworkof clinical trials– Investigations must be“adequate” and “well-controlled”– Investigators qualified byscientific training andexperience– Recordkeeping requirements– Informed Consent
Who’s in Charge at the Study Site?The clinical investigator is in charge and heldaccountable– FDA regulations permit sponsors to delegate theirresponsibilities to contract research organizations(CROs) but do not permit clinical investigators todelegate their general responsibilities to CROs orsite management organizations, subinvestigators, orstudy staffPenalties for significant noncompliance– Warning Letters (posted on FDA website)– Disqualifications/Restrictions/Debarments (posted onFDA website)– Criminal prosecutions/prison/fines
QuestionWhat documents must be submitted to theIRB for review?
AnswerFDA: The IRB should receive and review all researchactivities– Copies of all research proposals reviewed, scientific evaluations, if any,that accompany the proposals, approved sample consent documents,progress reports submitted by investigators, and reports of injuries tosubjectsFDA Guidance: The documents reviewed should includethe complete documents received from the clinicalinvestigator, such as the protocol, the investigator'sbrochure, a sample consent document and anyadvertising intended to be seen or heard by prospectivestudy subjects.ICH specifically requires IRB submission of:–––––informed consent, protocol/amendments, and advertisementsWritten information provided to subjectsInformation about subject payment/compensationInvestigator’s BrochureInvestigator's current CV and/or qualifications
General Clinical InvestigatorResponsibilities [ 21 CFR 312.60]Ensuring that an investigation is conducted according tothe– Signed investigator statement (Form 1572)– Investigational plan– Applicable regulationsProtecting the rights, safety, and welfare of subjectsunder the investigator's careControl of drugs under investigationEnsuring that informed consent is adequately obtainedaccording to 21 CFR 50Ensuring IRB review, approval and reportingrequirements are met per 21 CFR 56
Investigator ResponsibilitiesControl of investigational drug (312.61)Record keeping and retention (312.62)– An investigator is responsible for:Maintaining adequate records of the disposition of the drugAccurate case histories that record all observations, andOther data pertinent to the investigation on each individualadministered the investigational drug or employed as a control inthe investigation– An investigator is required to maintain investigationrecords for:2 years following the date a marketing application is approved forthe drug for the indication for which it is being investigated2 years after the investigation is discontinued and FDA is notified ifno application is to be filed or if the application has not beenapproved for such indication
Responsibilities (cont.)Investigator reports (312.64)– Progress reports to sponsor– Safety reportsImmediately report any adverse event that is alarming (e.g.an unexpected event that is serious or life-threatening)Record nonserious adverse events and report them to thesponsor according to the timetable for reporting specified inthe protocol– Final report to sponsor– Financial disclosure to sponsor (21 CFR 54)Promptly update as needed during the course of theinvestigation and for 1 year following study completion
FORMS FDA 3454 (Certification of no disclosable financial interests) and 3455(Disclosure Statement [21 CFR § 54.4(a)]) are available on the Web at thefollowing Internet Forms/Forms/default.htm
Question?Significant equity interest in the sponsor of acovered study.– What is the monetary amount of stock in anonpublicly traded corporation?Any amount– What is considered for a publicly tradedcorporation? 50,000– To whom does this apply?Investigator, subinvestigator, spouses anddependent children
ClinicalTrials.govU.S. Public Law 110-85 (Food and Drug AdministrationAmendments Act of 2007 or FDAAA), Title VIII, Section801 mandates that a "responsible party" (i.e., the sponsoror designated principal investigator) register and reportresults of certain “applicable clinical trials”– Trials of Drugs and Biologics: controlled clinical investigations,other than Phase 1 investigations, subject to FDA regulation– Trials of Devices: Controlled trials with heath outcomes of devicessubject to FDA regulation, other than small feasibility studies, andpediatric postmarket ecs/fdaaa
ClinicalTrials.gov (cont’d)FDA requires a statement in the informed consentregarding cation of compliance with certain FDA submissions(Form FDA tions: Registration/Results - NLM Helpdeskhttp://clinicaltrials.gov/ct2/helpdesk?hd url s%2FfdaaaCompliance/Enforcement gcp.questions@fda.hhs.gov
Sponsor ResponsibilitiesSponsors are responsible for (21 CFR 312.50):– Selecting qualified investigators– Providing them with the information they needto conduct the investigation properly– Ensuring proper monitoring of the investigation– Ensuring that the investigation is conducted inaccordance with the general investigationalplan– Maintaining an effective IND– Ensuring that the FDA and all participatinginvestigators are promptly informed ofsignificant new adverse effects or risks
Outlines FDA expectationsfor study oversight– Delegation of study tasks– Training of study staff– Supervision of conduct ofongoing study– Oversight of third partiesinvolved in the study (e.g.SMOs, outside labsspecifically retained toconduct study M187772.pdf
Guidance (cont.)Outlines FDA expectations for protectingthe rights, safety, and welfare of subjects– Provision of reasonable medical care forissues related to study participation (e.g.to manage an adverse event)– Facilitation of care for other healthissues that might arise during the study– Avoiding exposure of subjects tounreasonable risks
Question?Can the investigator delegate the activitiesaround investigational product?
AnswerFDA has no regulation concerningdelegation of these duties– The investigator should ensure that anyindividual to whom a task is delegatedis qualified by education, training, andexperience (and state licensure whererelevant) to perform the delegated task(per FDA Investigator Guidance 2009).ICH allows the delegation of study drugdispensing, patient counselling, and drugaccountability to an “appropriate” designee
In SummaryFollow the current protocolPersonally conduct or superviseinvestigation(s)– Ensure that all persons assisting inconduct of studies are informed of theirobligationsEnsure informed consent (21 CFR 50) andIRB review, approval , and reporting (21CFR 56) requirements are met
In Summary (cont.)Obtain the informed consent of eachhuman subject to whom the drug isadministeredNotify the sponsor before making changesin the protocolNotify the IRB and obtain IRB approvalbefore making changes in the protocolReport adverse events to the sponsor
In Summary (cont.)Maintain adequate andaccurate recordsMake records available forinspectionComply with all otherrequirements in 21 CFR312Report Financial Intereststo the Sponsor
DON’TOver-delegate to non-physicians (e.g., diagnosis thatqualifies/determines eligibility for entry into the study)Erase, white-out or obliterate original data entryAccept suggested changes to study data withoutchecking the source documents or without justificationfor such changesBackdate the consent forms and signaturesForget to obtain IRB approval of consent form revisionsRevise the protocol without obtaining the sponsor’swritten concurrenceUse your staff as subjects in a study not having thecondition(s) under investigationDestroy study records
Regulatory Authority toConduct Inspections/AuditsSection 505(k)(2) of the Food, Drug, andCosmetic Act mandates that FDA shall haveaccess to and copy and verify the requiredclinical study records.21 CFR 312.68– “An investigator shall upon request from anyproperly authorized officer or employee ofFDA, at reasonable times, permit such officeror employee to have access to, and copy andverify any records or reports made by theinvestigator ”
Typical Questions in an InterviewDelegation of authority: Who, when, where:–––––Screening of subjectsInterpreting screening results/admitting to the studyInformed consent of subjectsReceipt of test article; handling; administration; returnReporting (including safety reporting) /transcribingdata– Clinical laboratory– Training– Archiving study data
Clinical Investigator Inspections*(All Centers, FY 2012)CDERCBERCDRHTotal 38193194668 *CDER numbers based on inspection start date – [OSI database as of January 24, 2013] CDRH numbers based on inspection end date, CBER numbers based on end date of classified inspections CDER Center for Drug Evaluation and Research, CBER Center for Biologics Evaluation and Research,CDRH Center for Devices and Radiological Health
Bioresearch Monitoring Program Inspections*(CDER, FY 2012)total 722*Based on inspection start date – [OSI database as of January 24, 2013]IRB includes only CDER numbers – previously reported metrics may have used combined data across CDER,CBER and CDRH
International CI Inspections by Location*(CDER, FY 2012)total 135*Based on inspection start date – [OSI database as of January 24, 2013]
Frequency of Clinical Investigator-RelatedDeficiencies Based on Post-InspectionCorrespondence Issued*(CDER, FY 2012)183 Domestic Inspections,116 Foreign Inspections*Based on letter issue date; Inspections may have multiple deficiencies, [OSI database as of January 24, 2013]Note that this does not denote number of inspections completed in FY 2012, but rather number of inspection reportsevaluated and closed in FY2012
Compliance ClassificationsNAI - No Action IndicatedInspected Entity is in complianceVAI - Voluntary Action IndicatedMinor deviation(s) from the regulationsVoluntary correction is requestedOAI - Official Action IndicatedSerious non-compliance requiring regulatory oradministrative action by FDA
Inspectional OutcomesNo Action IndicatedForm FDA 483– 15 business days to reply
Clinical Investigator InspectionsFinal Classification* (FY 2012)total 299*Based on Letter Issue date; Includes OAI Untitled Letters, [OSI database as of January 24, 2013]
ReferenceInspection ObservationsSpreadsheets summarizing the areas ofregulation cited on FDA's systemgenerated 483s by fiscal m250720.htm
ReferenceInspections Classification Databaseand Search (Oct. 2008 March 2013)Final inspection classification for inspectionsrelated to currently marketed FDA-regulatedproducts. (Some information may be withheldfrom posting as to not interfere withenforcement s/ucm222557.htm
Common mistakes –Risk factors for non-compliancePoor supervision and training of study staffInsufficient investigator involvement in studyconductInappropriate delegation of study tasks tounqualified personsFailure to adequate protect study subjectsOverworked investigator and study staff (e.g.,too many subjects, complex study with largedata collection, too many concurrent studies)
Regulatory ActionsWarning LetterNotice of Initiation ofDisqualification Proceedingsand Opportunity to Explain(NIDPOE)Disqualification of clinical investigatorCriminal Investigation by Office of CriminalInvestigations (OCI)– Debarment
Form FDA 483 ResponseEngage in verbal discussion at close-outSend written response within 15 business daysWhat not to say:– “The study monitor failed to inform the staff of IRBapproval of a new version of Protocol XX”. It is yourresponsibility as the investigator (not the monitor’sresponsibility) to ensure that the IRB has approvedany changes in the research prior to implementingthose changes.– The study coordinator miscalculated the WOMACpain subscale. Your response is inadequatebecause you have submitted no documentation ofthe retraining.
Inadequate ResponseScreening ferritin value of 881.4 ng/ml wassignificantly higher than the protocol-allowedmaximum value of 100 ng/ml.– “No deviation occurred with reference to randomizingthis subject because the subject was randomized perprotocol prior to receiving central lab results; when Ireceived the central lab results, I felt that the subjectwas stable enough to continue with the study. Imonitored the subject closely and felt my clinicaljudgment was correct”. Protocol XX does not allowenrollment of subjects based solely on the clinicalinvestigator’s judgment when the subject does notmeet required inclusion criteria.
ReferenceList of Warning /WarningLetters/default.htmRegulatory Procedures Manual Section onWarning RegulatoryProceduresManual/ucm176870.htm
Investigator Disqualification21 CFR 312.70– Repeated and deliberate failure to comply withthe requirements– FDA provides notice of matter to investigatorand provides opportunity to explain (informalhearing)– Opportunity for formal hearing– May result in ineligibility to receiveinvestigational drugs
ReferenceClinical Investigators- Disqualification ProceedingsProvides a list of clinical investigators who are or havebeen subject to an administrative clinical investigatordisqualification action and indicates the current statusof that action– A Notice of Initiation of Disqualification Proceedingsand Opportunity to Explain (NIDPOE)– The Notice of Opportunity for Hearing (NOOH)– Totally Restricted– ons/ucm321308.htm
ExampleSubmission of false information. The Center hasreceived affidavits that indicate you submitted falseinformation to the sponsor in a required report [21 CFR312.70].– A. You report that subject #7206 was enrolled in thepediatric study and completed all four required visits,but the subject's mother states that this subject didnot have an ear infection, and did not participate inthe study.– B. You report that subject #7223 was enrolled in thepediatric study and completed all four required visits,but the subject's mother states that this subject didnot have an ear infection, and did not participate inthe study.
ReferenceFDA Debarment List (Drug ProductApplications)Firms or individuals convicted of a felonyunder Federal law for conduct (by a firm)relating to the development or approval of anydrug product or abbreviated drug ions/FDADebarmentList/default.htm
Case Study: Lax SupervisionStudy coordinator enrolled ineligible subjects inoncology trialsCoordinator altered source records and createdfraudulent CRFs to make subjects appear eligibleData manipulations should have been apparent toattentive clinicianSubject who was ineligible due to poor renal andliver function was enrolled, dosed, and died as aresultStudy coordinator sentence to 71 months inprison and debarred from any future involvementin FDA regulated researchDr. Holland – 5 years probation, 500,000restitution to defrauded drug companies,disqualified
How can clinical investigators ensurehigh quality data and subject safety?Select qualified staff and ensureadequate training and supervision– Ensure staff are not performing tasks theyare not qualified to do (e.g. assessingeligibility, performing physical exams,assessing adverse events)– Ensure oversight of sub-investigators andstudy staff
Improve Process — BeProactiveAddress human factors in systems– Hire experienced, qualified staff– Avoid conflicts of interest/financialincentives– Decrease number of times data are handled– Assess ability to comply with protocol visits;laboratory testing; electronic systems fordata capture, archiving and transmission tosponsor; maintaining records, drugaccountability, inspections by FDA
Improve Process — BeProactiveCreate systems that limit opportunityfor errors– Simplify protocol and outcomes assessed– Be realistic about the amount of data to becollected– Standardize systems and formats where possible– Use validated instruments/definitions– Write down all procedures (SOPs). Use checklists.– Don’t re-invent the wheel– Keep amendments to a minimum and check theCRFs and consent form against each change
Improve ProcessDevelop an integrated framework– Data and Safety Monitoring Plan, DataManagement Plan, Quality Assurance Plan,Data Analysis Plan– Insist on training and then test it– Think very carefully about unblindingprocedures Many examples of errors!– Have a disaster plan (for staff turnover,floods, etc.)– Do beta-testing/dry-runs– Have weekly team meetings/calls– Audit yourself — be open and honest
Implement System to Detect andCorrect Errors in Real TimeDo real-time cleaning of the dataPay attention to monitoring queries andrespond promptly Close loopsAudit trail of changes should make clear whatwas changed, who changed it, and why itwas changedEvaluate need for system wide correctionsand training
Key MessagesClinical investigators play a critical role inensuring high quality studiesGood care of patients is not the same as GoodClinical Practices (GCP) in research– Ensure that all staff have a clearunderstanding of responsibilities under FDAregulationsAt stake is public confidence and participation inthe clinical trials and ultimately the availability ofsafe and effective products
The "cost of quality" isn't the price ofcreating a quality product or service.It's the cost of NOT creating a qualityproduct or service.*Principles of Quality Costs: Principles, Implementation, andUse, Third Edition, ed. Jack Campanella73
FDA Sites of Interest Running Clinical pics/RunningClinicalTrials/default.htm FDA Basics for rIndustry/default.htm Sign up for Industry/ucm234630.htm
FDA Sites of Interest Replies to Inquiries to FDA on Good ClinicalPractice– Designed to simplify the search for copies of e-mailmessages (including the original inquiry andassociated reply(ies)) that have been submitted bythe public to the Good Clinical Practice Program'sgcp.questions@fda.hhs.gov e-mail DAonGoodClinicalPractice/default.htm
Guidances of Interest FDA Inspections of Clinical InvestigatorsInformation ation/Guidances/UCM126553.pdf Guidance for Information/Guidances/UCM187772.pdf
New Webpage!Investigator-Initiated Investigational NewDrug (IND) Applications webpage– Brief explanations about various aspects ofIND application submissions and procedureswith links to guidances, references, and m343349.htm?source govdelivery&utm medium email&utm source govdelivery
Thank you for your attention
Investigator Responsibilities – Regulation and Clinical Trials FDA’S 2013 Clinical Investigator Training Course Cynthia F. Kleppinger, M.D. Divis
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