Clinical Investigator Inspections and FDA-483 Observations Nancy A. Bellamy, Investigator Bioresearch Specialist/ BIMO Coordinator FDA Detroit District Office October 2, 2013
Objectives Background on FDA assignments What to expect in an FDA audit Share examples of inspectional observations that were reinforced by Center letters. Disclaimer: These may not transfer to your specific case due to additional factors in study records. My statements do not represent the FDA, but are from my experience. 2
FDA s BIMO Program (Bioresearch Monitoring) Protect the rights, safety, and welfare of subjects in FDAregulated trials Determine the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications for new products Assess compliance with FDA s regulations governing the conduct of clinical trials, including those for informed consent, ethical review and control of research articles 3
FDA s BIMO Program Areas Good Clinical Practice (GCP) Institutional Review Boards (IRBs) Clinical Investigators (CIs) Sponsor-Monitors, CROs Good Laboratory Practice (GLP) Nonclinical (animal) laboratories In Vivo Bioequivalence (Beq) Analytical Laboratories Phase 1 clinical research facilities 4
BIMO REGULATIONS (Code of Federal Regulations) 21 CFR 50: Protection of Human Subjects 21 CFR 56: Institutional Review Boards 21 CFR 58: Good Laboratory Practice for Non- Clinical Laboratory Studies 21 CFR 361 Radioactive Drug Research Committees 21CFR 511 Animal Clinical Studies (Vets) 5
BIMO REGULATIONS (Code of Federal Regulations) 21 CFR 314: New Drug Applications (NDA) 21 CFR 312: Investigational New Drug Exemption (IND) 21 CFR 814: Pre-Market Approval Applications (PMA) 21 CFR 812: Investigational Device Exemption (IDE) 6
INSPECTION ASSIGNMENTS Routine/Surveillance: Studies conducted to support marketing permits: NDA, BLA, PMA, ANDA or under research permits: IND (drug), IDE (device) Directed/For Cause: May have questions on a certain aspect of study Data may appear unrealistic/suspicious Follow up: - to reports of possible misconduct received from outside sources (Sponsors, IRBs, employees, study subjects)(for Cause) Follow-up to previous inspectional deficiencies 7
OHRP Office for Human Research Protection OHRP Public Health Service Act (not FD&C Act) 45 CFR 46 (Informed Consent and IRBs) Research funded by DHHS NIH FWA: Federal-Wide Assurance Includes social research FDA inspections are product-related 8
FDA INSPECTIONS 9
PREPARING FOR AN FDA INSPECTION FDA will call to pre-announce the inspection Routine inspections, give about 5 days notice PDUFA and MDUFMA mandate deadlines for agency review Will provide the specific study to be inspected, records for review and time needed with the CI and/or other study staff Obtain the FDA Investigator s name and contact info Provide clear directions to your site 10
PREPARING FOR AN FDA INSPECTION Reserve workspace for the FDA Investigator Be sure the CI, Study Coordinator and others knowledgeable about the study will be available Set time aside for the duration of inspection Approximately 3-7 days Duration may depend on volume of records and/or FDA Investigator findings 11
COPIES REQUESTED BY FDA Protocol and amendments Informed Consent and revisions IRB approvals amendments/continuing Reviews CVs for primary personnel Any publications from the study List of other Clinical Studies for the past 3 years 12
PREPARING FOR AN FDA INSPECTION Have ALL records related to the study available, including: Regulatory records IRB approvals, protocols, investigator brochure, correspondence files CRFs, monitoring reports Source records clinic charts, hospital records, x- rays, lab reports, subjects diaries Test article accountability records 13
INSPECTIONAL ACTIVITIES Initial interview FDA credentials, Notice of Inspection (FDA-482) Interview PI about aspects of the study Facility walkthrough Review study records Obtain documents Daily summary Exit interview/close out meeting Inspectional findings (Form FDA-483, verbal observations) 14
INITIAL INTERVIEW and STUDY REVIEW Responsibilities of staff and training Contract Research Organizations (CRO s) labs, monitors, etc. How study data obtained and recorded Adhered to protocol and investigational plan Protocol deviations reported 15
STUDY COVERAGE: Degree of Delegation Delegation of authority Established & documented by clinical investigator (For Drug studies list primary on Form FDA-1572) Delegate to qualified and well-trained study staff CI is still responsible for the adequate supervision of study activities 16
STUDY COVERAGE: General Study subjects: Source, exist, have disease being studied, meet inclusion/exclusion criteria Study Records CRFs completed, agree with source data, consistent with protocol, electronic records (21 CFR Part 11) Drug/Device Accountability: Complete records for shipping, receiving & dispensing Disposition of unused test article (return/destruction) Stored in secure location at proper conditions 17
CRITICAL ASPECT OF INSPECTION Data validation Source documents/raw data vs. Case Report Forms vs. Summary Data submitted to the FDA 18
STUDY COVERAGE: INFORMED CONSENT FORM ICF and Procedures: ICF content: 21CFR 50.25 Basic and Additional elements. 50.25(c) www.clinicaltrials.gov statement Signed/dated ICFs on file Prior to study-specific activities Revisions Informed Consent Process (CI or delegate) 19
IRB approvals STUDY COVERAGE: IRB Communications Protocol (original and amendments) Informed Consents (all versions) Advertising/ recruitment IRB submissions Required reports submitted Timely 20
STUDY COVERAGE: Adverse Events Adverse Event Reporting: (adverse effects, unanticipated adverse device effects, etc) Assessment of relationship to test article Report to sponsor (and IRB if required) Reported within required timeframes FDA Guidance for AE Reporting to IRBs: http://www.fda.gov/downloads/regulatoryinform ation/guidances/ucm126572.pdf (Jan. 09) 21
ISSUES IDENTIFIED DURING THE INSPECTION Any deficiencies or observations found during the inspection will be discussed during the inspection and at the close-out. No surprises. The FDA-483 is tied to the regulations. Guidance document issues would be considered Discussion Points. 22
Responding to the Inspection The Clinical Investigator should respond to the 483 observations in writing within 15 days to be reviewed with the FDA s inspection report. The study site should report corrective actions for any deficiencies or plans for future studies Provide documentation of the corrective and preventive actions with the response 23
AFTER THE INSPECTION-FDA FDA Investigator will write an Establishment Inspection Report (EIR) that contains all the information collected during the inspection The EIR is sent to the Center that issued the assignment for review and final classification The assigning Center will usually send a follow-up letter to the Clinical Investigator The inspected site will receive a copy of the EIR after the inspection is classified (NAI/VAI) 24
AFTER THE INSPECTION: CLASSIFICATION The assigning Center will classify the inspection: NAI = no action indicated VAI = voluntary action indicated OAI = official action indicated 25
Common Deficiencies The following slides are examples of some of the common findings on inspections, along with references to the regulations. 26
Failure to adhere to the investigational plan 21CFR 812.100 / 110(b) (Device) and 21 CFR 312.60 (Drug) Subjects were enrolled that did not meet inclusion/exclusion criteria: age, concomitant meds, history of systemic disorders, testing. Problem areas: Protocol design, Employee training, Supervision of employees PI can t change the protocol, sponsor must revise it first and the IRB approve it 27
Protocol Deviations (21 CFR 812.100/110b and 312.60) Tests are not performed as required: tests missed, performed late, improper procedures, uncalibrated. Follow up visits are outside protocol window or incomplete. Ex: 6 month contact by phone or visit. Documentation was not kept as required: adverse events, phone calls, Samples not sent as requested plasma, blood 28
Investigational Plan deviations Failure to report serious adverse events (SAE) or Serious Adverse Device Effects (SADE) in accordance with the protocol. 21CFR 812.150 Unanticipated ADE report to sponsor and IRB within 10 working days. 21CFR 312.64(b) Promptly report AE reasonably or probably caused by drug. If AE is alarming, report immediately. 29
FDA-1572 was not completed for investigators participating in study. (Drug) 21 CFR 312.53 (C) (1) Signed Investigator statement did not list Co- Investigators with significant responsibilities. Problems found: Co-investigator enrolled subjects with exclusion criteria. Co-Investigator did not have documentation of training on research study. 30
Informed Consent Issues (21CFR 50.25) Any of the 8 basic elements missing: Statement of research: purpose, duration, procedures. Foreseeable risks or discomforts Benefits that may reasonably be expected Alternative Procedures Confidentiality and record review by FDA Compensation and injury treatment Contact for questions and injury report Voluntary participation Plus 50.25(c) Clinicaltrials.gov statement (March 2013) Plus Promotion of a Drug or Device (21CFR 312.7/812.7) 31
Failure to obtain proper informed consent: 21CFR 50.20, 812.100, 812.110, 812.140(a)(3)(i) and 312.60. Consent obtained prior to IRB approval Consent for wrong study was used to enroll Current IRB approved version not used Any of 8 primary consent points Consent form is dated by coordinator for the subject 32
Failure to personally conduct or adequately supervise clinical trial 21 CFR 312.60 General CI responsibilities (drug) 21 CFR 812.100 Device CI responsibilities Problem areas: Employee training and documentation Screening and Enrolling subjects Informed Consent issues Lab results documentation Follow-up evaluations done by staff members 33
Failure to Protect the rights, safety and welfare of subjects: 21 CFR 312.60 and 21CFR 812.100 Inclusion Criteria safety issues for subjects Example: Protocol excludes subjects with a history of GI disease, known sensitivity to aspirin or NSAIDs. Enrollment of subject with exclusion criteria resulted in GI bleed requiring hospitalization. 34
Failure to Protect the rights, safety and welfare of subjects: 21 CFR 312.60 and 21CFR 812.100 Example: Protocol excludes device implant in subjects with arthritis in area. MRI showed exclusion criteria. Subject required revision surgery and device removal. Device regs under 812.110(b) Protocol deviations 35
Failure to Protect the rights, safety and welfare of subjects: 21 CFR 312.60 and 21CFR 812.100 Protocol deviations for Safety testing: Hematology/urinalysis pre/post treatment Lab work performed outside protocol window Lab work missed Procedures to ensure compliance: Example: 12 hr / 24 hr urinalysis following surgery done by different hospital shifts. May need to flag chart if outside the standard care. 36
Failure to maintain accurate, complete and current records relating to study. 21 CFR 812.140 (a) and 312.62(b) No Source documentation to verify eligibility for a specific enrollment criteria. Study records show discrepancies between CRFs and source documents CRFs can t be verified by source documents and are not completed as source documents. 37
Failure to submit progress reports to Sponsor/IRB at regular intervals. 21CFR: 812.150(a)(3) and 312.66 Report was not made to IRB for continuing review and approval lapsed. Subjects were enrolled and devices implanted or study agents issued. Clinical Investigator assigns a staff member the duty to track dates for Sponsor / IRB submission for Continuing Review of studies 38
Study Agent Accountability Records 812.140(a)(2) and 312.62(a) Clinical Investigator s responsibility Pharmacy records incomplete Sponsor s form is inadequate/ confusing Disposition of drug or device Dates issued, Lot/Batch number, quantities Reconciliation: Amount received, used and returned to sponsor at close of study 39
Points to Consider Clinical research documentation is different from clinical practice. Higher standard for details Protocol compliance Need to be Stand Alone record. Sponsor may submit older research studies to support an application, but research employees have retired or moved on. 40
Points to Consider Keep research documents transparent Fully document any deviations and corrections Maintain correspondence files- emails, letters and records of phone conversations Don t try to reconstruct missing documents without source verification 41
Points to Consider A sponsor who discontinues an Investigator who is noncompliant shall notify FDA. 21CFR 312.56 (b). 21CFR812.150 (b)(6) A sponsor shall notify FDA, IRBs, C.I.s of any IRB s withdrawal of approval of study 21CFR 812 (b)(2). 42
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In Closing.. Keep communications open Sponsor and monitor IRB FDA Keep study records transparent Keep Originals of source documents 45
Common FDA Acronyms BIMO = Bioresearch Monitoring IND = Investigational New Drug application (allows clinical research) IDE = Investigational Device Exemption (allows clinical research) NDA = New Drug Application (allows marketing of drug) PMA = PreMarket Approval (allows medical device marketing) BLA = Blood License Application (allows biologics marketing) NADA = New Animal Drug Application (allows veterinary drug mkting) FY = Fiscal year (Oct 1 st Sept 30 th ) CI = Clinical Investigator IRB = Institutional Review Board RDRC = Radioactive Drug Research Committee GLP = Good Laboratory Practices (animal/preclinical studies) BEQ = Bioequivalence Spon/Mon = Sponsor/ monitor 46
Resources on www.fda.gov Guidance Documents (examples) Financial Disclosure by Clinical Investigators (Feb. 13) Q&A on Informed Consent Elements (Feb. 12) Electronic Source Documentation in Clinical Investigations (Nov. 12) IRB Responsibilities for CI Qualifications, Adequacy of Sites, and Whether an IND/IDE is needed (Mar. 13) Investigator Responsibilities-Protecting Rights, Safety, and Welfare of Study Subjects (Oct. 09) Adverse Event Reporting to IRBs- Improving HSP (Jan. 09) Compliance Programs: 7348.811- Clinical Investigators 7348.809- IRBs; 7348810- Sponsors; 7348.001- BEQ 47
Finding a Job with FDA www.usajobs.gov Investigator (Consumer Safety Officer) Requires 30 credit hours of science/usually B.S. minimum Other positions possible: Chemist, Biologist, Medical Officer, Statistician, Pharmacologist FY-2014 Limited Hiring possible 48