1 Pediatric Clinical Investigator Training - PowerPoint Presentation

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Pediatric Clinical Investigator Training GCP: Tips on Clinical Trial Conduct and Preparing for FDA Inspection Susan Leibenhaut, M.D.Office of Scientific Investigations (OSI) CDER/FDAFebruary 28, 2019

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Good Clinical Practice - GCPOutline of Topics

GCP: Science and Quality in Clinical ResearchRegulations and GuidancesFDA Clinical Site Inspection

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Inspection preparation begins with planning and start-up of the protocol

Frances Kelsey, PhD, MD receiving the President’s Award for

Distinguished Federal Service from President Kennedy 1962,

the same year as the passage of the

Kefauver Harris Amendment to the FD&C Act.

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Quality in Clinical Research

Clinical trial: an experiment to determine whether the product is safe and effectiveStatistical sampling (random) of a target populationUnbiased observations about product effect (endpoint) and AE collection and reporting

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Quality: Why We Care

Lack of quality can lead to underestimation or overestimation of true treatment effectQuality can influence the accuracy of safety reportingLabel: FDA/sponsor agreed communication with stakeholdersAccurate Dosing information

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Trash Quality

If YOUR data is not usable, it will be THROWN OUT

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Quality in Clinical Trials is

Good ScienceandIt’s in the Regulations!

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Science and Regulation

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General Principles of an IND Submission

21 CFR 312.22:FDA's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety.

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What is GCP?

According to the regulations 21 CFR 312.120 (a)(i)For the purposes of this section, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. See also ICH E6

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FDA Regulations

Regulatory oversight

Clinical Investigators

Sponsors, CROs and Monitors

Institutional Review Boards (IRBs)

Relevant Regulations

21 CFR

Part 50

: Protection of Human Subjects and Informed Consent

Part 54

: Financial Disclosure

Part 56

: Institutional Review Boards

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CDER Regulations

Relevant Regulations

21 CFR

SPECIFIC to DRUGS and BIOLOGICS

Part 312

: Subpart D

IND Responsibilities

312.50: Sponsors

312.60: Investigators

Part 314

: New Drug Applications

Part 320

: Bioavailability and Bioequivalence Requirements

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Elements of GCP

Well designed protocol and FOLLOW IT!DOCUMENTATIONAccurately and completely collect the dataAnalyze the data according to a prespecified planAccurately report results

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Consider these…..

Adequate resourcesWell trained staffCulture of excellence-no fraud or cutting corners Understanding of science of clinical trials

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Regulation and Guidance

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Regulation and Guidance

21CFRREQUIREDWHAT to do

Guidance

Optional or suggested

HOW

to do it

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ICH E6

Good Clinical Practice (GCP)

: A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected

https://www.fda.gov/downloads/Drugs/Guidances/UCM464506.pdf

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Definitions 312.3

Sponsor: takes responsibility for and initiates a clinical investigation; may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.Investigator: an individual who actually conducts a clinical investigationSponsor-investigator: an individual who fulfills both roles above

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Interface with FDA

Clinical investigator interacts with Sponsor Sponsor interacts with FDA CI

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Clinical Investigator Responsibilities

312.60 Protocol

Ensuring that an investigation is conducted according to:

Signed investigator statement (Form 1572)

Investigational plan

Applicable regulations

Control of drugs under investigation

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Clinical Investigator Responsibilities

312.60 Human Subject Protection

Ensuring that informed consent is adequately obtained according to 21 CFR 50

Ensuring IRB review, approval and reporting requirements are met 21 CFR 56

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Clinical Investigator

Recordkeeping and Retention21CFR 312.62

Drug disposition

Prepare and maintain adequate and accurate case histories

Record retention-2 years following the date of approval of marketing application

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Clinical Investigator

Reports to the Sponsor21CFR 312.64

Safety reports-Timely, appropriate

Financial disclosure: includes Family and Sub-Investigators

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM341008.pdf

Progress and Final reports (if applicable)

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Investigator Commitments

Form FDA 1572

Follow the

current

protocol

Personally

conduct or supervise investigation(s

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Part 50 and 56 requirements (Subject protection and IRB review)

Timely

adverse event reporting to the sponsor

Inform study staff of their obligations

Maintain records

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Guidance: “Investigator Responsibilities”FDA Expectations for Study Oversight by Clinical Investigator

Appropriate Delegation of study tasksAdequate Training Adequate SupervisionCI role in Oversight of Third Partieshttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM187772.pdf

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Guidance=Practical Advice

Delegation logDocumentation of trainingPlans for supervision and oversight-SOPsProcedure for documentation and timely correction of problemsReview of proficiency Quality control

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Sponsors & Contract Research Organizations (CROs) Responsibilities

[21CFR312.50-312.59]

Costs Protocol ComplianceProtocol Development Qualified CIsRegulatory Affairs Drug DispositionQualified Monitors Financial ReportingClinical Monitoring RecordsAE Reporting

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Investigator Initiated INDs aka “Sponsor Investigator” updated 2/22/18

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm343349.htm

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What happens in anFDA BIMO Inspection?

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What is BIMO?

Bioresearch monitoring begun by Francis Kelsey and Alan Lisook mid-1961 (see resource slide)CDER/OSI issues assignment based on review of trialOn-site inspection by ORA for compliance with regulations, data verificationCenter determines final classificationCompliance Program Guidance Manuals (CPGM) instructionshttp://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/ucm255614.htm

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Inspection procedures

Phone call-not much advanced noticePresent Form FDA 482Opening meetingInterview staff during the inspectionReview of study records/regulatory binderCollection (copy) of exhibitsClosing meeting-possible issue of “483”

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Inspection at CI site

What type/how were subjects recruited, enrolled and randomizedDid the study involve blinded and unblinded staff and who had access to treatmentWas the protocol followed and do the study documents reflect this? Control of “test article” drug/biologic

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Inspection at CI site

Inspection of site to “re-create” the trialVerification of data submitted to FDA Source CRF Data submitted to FDAProtocol adherenceSafety reporting Human subject protection: IRB review and Consenting process CRF=case report form

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Inspection at CI site

Source documents: what are they?“First put pen to paper”ALCOA-C: accurate, legible, contemporaneous, original, attributable and completeMay be defined in protocolConsider: paper office notes, EHR, direct patient data entry via web or PDA FDA Guidances and ICH E6

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What can go wrong?

Violations of the protocolSubjects not given proper instructions for PK samples: fasting, medication administrationSamples not processed correctlyTest article not stored correctlyNot technical violation: Misinterpretations of the protocolAnalytical Equipment malfunction or lack of calibration

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What to do if you receive a 483?

A response is advised but there is no regulatory requirement to respondFDA requests response within 15 business daysInclude CORRECTIVE ACTION to prevent the finding from occurring again“THE MONITOR should have caught it” is NOT an explanation!

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After the Inspection

Final classification taking into account response from Clinical InvestigatorOSI Recommendation to review division concerning reliability of dataAdditional comments concerning clinical trial conductPost inspectional correspondence (letter) issued to the inspected party

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Summary

Quality should be built into a clinical trialResources and culture of excellence are important componentsContinuous assessment of procedures and FIX the problem (CAPA)Adherence to the Regulations is requiredGuidances available for advice

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Contact Information

Susan Leibenhaut, M.D.

GCP Compliance Assessment Branch

Office of Scientific Investigations

Office of Compliance/FDA

White Oak, Bldg. 51, Rm. 5302

10903 New Hampshire Ave.

Silver Spring, MD 20993

Susan.leibenhaut@fda.hhs.gov

PH: 301-796-3626

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Resources

Regulatory Affairs at Your InstitutionCode of Federal Regulationshttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfmICH Guidanceshttps://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm219488.htm

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Resources: Training

FDA GCP Training Resourceshttp://www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/educationalmaterials/ucm112925.htmSoCRA https://www.socra.org/CTTI http://ctti-clinicaltrials.org/home

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Resources: OSI

OSI and History of FDA’s BIMO programhttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm091393.htm#historyClinical Investigator Inspection List (CLIIL) results going back to 1977http://www.fda.gov/Drugs/InformationOnDrugs/ucm135198.htm

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Resources: Inspection

CPGM: manual of instruction inspections and guidance for ORA investigatorshttp://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/ucm255614.htmBasics for Industry: What should I expect during and Inspection?http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm237624.htm

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Resources: OGCP

Office of Good Clinical Practice (FDA-wide)http://www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/default.htmGuidance Search Pagehttp://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm310704.htm

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Resources

OGCP Contacts and Mailboxhttp://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm134476.htmArchived replieshttp://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/RepliestoInquiriestoFDAonGoodClinicalPractice/default.htmSearchable archiveshttp://www.firstclinical.com/fda-gcp/

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Resources

When is an IND needed?http://www.fda.gov/forindustry/fdabasicsforindustry/ucm237990.htmDrug Development and Approval Processhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm

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Source Documents ICH E6

1.52 Source Documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial).

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Adequate and Well-Controlled Study 21 CFR 314.126

(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation.(b) An adequate and well controlled study has the following characteristics……..

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Financial Disclosure21CFR part 54

54.1 (b) PurposeFDA may consider clinical studies inadequate and the data inadequate if, among other things, appropriate steps have not been taken in the design, conduct, reporting, and analysis of the studies to minimize bias. One potential source of bias in clinical studies is a financial interest of the clinical investigator in the outcome of the study because of the way payment is arranged (e.g., a royalty) or because the investigator has a proprietary interest in the product (e.g., a patent) or because the investigator has an equity interest in the sponsor of the covered study.

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October 2009 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM187772.pdf

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May 2010 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214282.pdf

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Your

Signature

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Who is Listed on the 1572?

The investigator must sign the 1572Item 6: Names of sub-investigatorsIn general, if an individual is directly involved in the treatment or evaluation of research subjects, that person should be listed on the 1572For example, as part of the protocol or a clinical investigation, if each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the study, that internist should be listed in Block #6Hospital staff, including nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make a direct and significant contribution to the data do not need to be listed individuallyIt is not necessary to include in this block a person with only an occasional role in the conduct of the research, e.g., an on-call physician who temporarily dealt with a possible adverse effect or a temporary substitute for any research staff

http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0406-gdl.pdf

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August 2013 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf

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Why is monitoring so important?

Monitoring is a quality control tool for determining whether study activities are being carried out as planned, so that deficiencies can be identified and corrected.Monitoring Guidance page 2

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Focus on Conduct and Documentation

Informed consent

Eligibility criteria

Inclusion-target population

Exclusion-safety issues

Investigational Product (IP) accountability and administration

Section IVA-page 11

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Focus on Conduct and Documentation

Study Endpoints: Efficacy

Safety Assessments

Adverse Events

Trial Integrity

Blinding

Adjudication

DSMB

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Outcomes of FDA Inspections

Results posted on Clinical Investigator Inspection List (CLIIL), updated quarterlyEducation of study siteAcceptance or rejection of study dataProduct approval or complete response to sponsorLetter or Warning Letter or Enforcement Action (Disqualification Proceedings) for Clinical Investigator

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Definitions

Form FDA 482-Notice of Inspection Form FDA 483-Inspectional ObservationsViolation-not being in compliance with the regulationObservation-finding during inspection that may be a violation pending FDA Center reviewCAPA-corrective and preventive action plan initiated by an inspected entity

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Classifications

NAI-No action IndicatedNo objectionable conditions or practices VAI-Voluntary Action IndicatedObjectionable conditions were found and documented, but the Center is not prepared to take or recommend any further actionsOAI-Official Action IndicatedSerious objectionable conditions warranting action (advisory, administrative, or judicial)

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CPGM has Examples

NAI: following the protocolVAI: assessments not completed appropriatelyOAI: assessments not conducted AND the records are falsified to cover this upRepeated or deliberate failure to comply with the regulations

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Sponsor Responsibilities21CFR 312.50

Choosing qualified clinical investigators and monitorsMonitoring to ensure that the trial is conducted according to the investigational planReview and analysis of accumulating evidence relating to product’s safety and reporting this to FDA and clinical investigators (Investigator Brochure)Drug accountability

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Contract Research Organization (CRO) 312.52

CRO: assumes responsibility(ies) of the sponsor

A sponsor may transfer any or all obligations to a CRO

The transfer of obligations shall be described in writing

A CRO that assumes a sponsor obligation is subject to the same regulatory action as a sponsor