FDA Inspections: Clinical Investigators. Lisa Hoebelheinrich, J.D. Associate Vice Chancellor, Compliance

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1 FDA Inspections: Clinical Investigators Lisa Hoebelheinrich, J.D. Associate Vice Chancellor, Compliance

2 Overview FDA s Bioresearch Monitoring (BIMO) Program Preparation for an Inspection Conduct of an Inspection Response to an Inspection Examples of Violations

3 Overview of FDA s BIMO Program

4 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.

5 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 * 553.pdf

6 The likelihood of inspection may increase based upon: Enrollment Time since last inspection Protocol violations Serious Adverse Events Subject deaths Number of studies per site/pi

7 BIMO Inspections (FDA BIMO Metrics FY 14)

8 Preparation for an Inspection

9 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.

10 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 startup meeting. Upon arrival, the FDA investigator will present ID and a Notice of Inspection Form FDA 482.

11 Conduct of an Inspection

12 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

13 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

14 The FDA investigator will Confirm: Whether IRB review was obtained (protocol, ICF s, amendments) Where specific aspects of the study were performed Whether inclusion/exclusion criteria were met Whether informed consent was obtained prior to performance of study related procedures

15 The FDA Investigator will Evaluate: Whether the protocol was followed and whether protocol deviations were documented and reported Whether authority to conduct aspects of the study was delegated and the nature clinical investigator oversight Whether adverse experiences were properly reported to the IRB and sponsor

16 The FDA Investigator will Evaluate: Whether source documentation matches CRFs, and (where applicable) whether data submitted by the sponsor matches the CRF s/source documents Whether documentation of investigational product accountability is complete (receipt, storage, use, return)

17 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.

18 Response to an Inspection

19 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.

20 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)

21 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

22 Inspection Classifications (FDA BIMO Metrics FY 14)

23 Examples of Violations

24 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

25 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

26 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

27 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

28 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

29 Additional Guidance FDA Inspections of Clinical Investigators, U.S. Dept. of Health and Human Services (June 2010): ances/ucm pdf FDA Compliance Program Guidance Manual, Clinical Investigators and Sponsor Investigators, Program (Dec. 8, 2008) For sponsor investigators, see also FDA Compliance Program Guidance Manual, Sponsors, Contract Research Organizations and Monitors, Program (March 11, 2011) ICH E:6, Guideline for Good Clinical Practice

30 KUMC Resources KUMC Research Institute KU Cancer Center KUMC Audit Checklist KUMC Human Research Protection Program KUMC Office of Compliance