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Lisa Hoebelheinrich, J.D.Associate Vice Chancellor, Compliance
FDA Inspections: Clinical Investigators
Overview
FDA’s Bioresearch Monitoring (BIMO) Program Preparation for an Inspection Conduct of an Inspection Response to an Inspection Examples of Violations
Overview of FDA’s BIMO Program
The BIMO Program’s Goal:
To protect the rights, safety, and welfare of subjects involved in FDA‐regulated clinical trials; To verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and To assess compliance with FDA's regulations governing the conduct of clinical trials.
The BIMO Program’s Focus* Inspections may be routine or “for cause”. In addition to verifying the accuracy and reliability of data, audits may be conducted: As a result of a complaint or sponsor concern Upon termination of a clinical site To provide real‐time assessment of ongoing trial At the request of an FDA review division Per the FDA’s work plan for targeted inspections
*http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf
The likelihood of inspection may increase based upon:
Enrollment Time since last inspection Protocol violations Serious Adverse Events Subject deathsNumber of studies per site/PI
BIMO Inspections (FDA BIMO Metrics FY’14)
Preparation for an Inspection
What To Do Before the Start
Upon Contact by the FDA, notify the designated research administration office at KUMCRI or KUCC, and the sponsor. See the FDA Audit Checklist. The FDA investigator will expect records to be accessible, available and organized. Identify an appropriate room with copier and phone access.
What To Do Before the Start
Determine who will be the designated escort. This person should keep a log of questions asked and documents requested. The PI should be available throughout. Determine who should be present at the start‐up meeting. Upon arrival, the FDA investigator will present ID and a Notice of Inspection Form FDA 482.
Conduct of an Inspection
When answering questions:
Be clear, concise, polite and honest Do not volunteer additional information If you do not know the answer, write the question down and refer the question as appropriate Do not argue with an FDA Investigator
The FDA Investigator will Review:
Regulatory documents, protocol, enrollment log Dates of IRB approvals, screening, consenting, first administration of investigational product, etc. CRF’s and supporting source documentation Consent forms Interview staff
The FDA investigator will Confirm:Whether IRB review was obtained (protocol, ICF’s, amendments)Where specific aspects of the study were performedWhether inclusion/exclusion criteria were metWhether informed consent was obtained prior to performance of study‐related procedures
The FDA Investigator will Evaluate:Whether the protocol was followed and whether protocol deviations were documented and reportedWhether authority to conduct aspects of the study was delegated and the nature clinical investigator oversightWhether adverse experiences were properly reported to the IRB and sponsor
The FDA Investigator will Evaluate:
Whether source documentation matches CRFs, and (where applicable) whether data submitted by the sponsor matches the CRF’s/source documentsWhether documentation of investigational product accountability is complete (receipt, storage, use, return)
At the Conclusion of the Visit:
The FDA Investigator will conduct the exit interview to discuss findings. If deficiencies are found, a written Form FDA 483 is issued. Document observations, comments, etc.
Determine with the designated research administration office who should be present for the exit interview. Include the designated HRPP/Office of Compliance contact.
Response to an Inspection
Response to a Form FDA 483 Deficiencies/deviations from the regulations are identified in the Form FDA 483. Copies of a Form FDA 438 must be provided to HRPP. While a written response is not required, it is encouraged. Contact RI or Office of Compliance for best practice information. Generally, the response is required within 15 days.
Establishment Inspection Report
An Establishment Inspection Report (EIR) is sent, along with collected materials and investigator’s response to the FDA Center for further evaluation and classification: No action indicated (NAI) Voluntary Action Indicated (VAI) Official Action Indicated (OAI)
FDA Letter to Clinical Investigator
After review and classification a letter is sent to the clinical investigator. This could include: A letter observing basic compliance with pertinent regulations An Informational or Untitled Letter A Warning Letter A Notice of Initiation of Disqualification Proceedings and Opportunity to Explain
Inspection Classifications(FDA BIMO Metrics FY’14)
Examples of Violations
Examples of Violations
Missing consent documents Omission of required elements when obtaining consent Records show failure to appropriately delegate to qualified personnel (e.g., physical exams, SAE evaluations), resulting in exposure to unreasonable and significant risk or injury, or unreliability of data
Examples of Violations
CRFs for study subjects who did not exist or did not participate in the study Falsified consents (signatures do not match) CRFs include results about protocol‐required procedures with no documentation that they were done Specimens and/or results characterized as being from a subject, that were not
Examples of Violations
Enrolling subjects who don’t meet the entrance criteria Administration of test article to persons not authorized to receive it Failure to perform protocol‐required procedures No documentation of required IRB review of study changes
Examples of Violations
No documentation of IRB continuing review Incomplete or missing subject records, e.g., evidence records discarded or destroyed Use of investigational product by unauthorized individual No or inadequate records re: receipt, preparation, use or return of investigational product
Most Common CI Deficiencies
Failure to follow the investigational plan and/or regulations
Protocol deviations Inadequate recordkeeping Inadequate accountability for the investigational product
Inadequate communication with the IRB Inadequate subject protection—failure to report AEs and informed consent issues
Additional Guidance FDA Inspections of Clinical Investigators, U.S. Dept. of Health
and Human Services (June 2010):http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf
FDA Compliance Program Guidance Manual, Clinical Investigators and Sponsor Investigators, Program 7348.811 (Dec. 8, 2008)
For sponsor investigators, see also FDA Compliance Program Guidance Manual, Sponsors, Contract Research Organizations and Monitors, Program 7348.810 (March 11, 2011)
ICH E:6, Guideline for Good Clinical Practice
KUMC Resources
KUMC Research Institute KU Cancer Center KUMC Audit Checklist KUMC Human Research Protection Program KUMC Office of Compliance