Compliance Monitoring Program Educational Seminar: Audit Preparation Suggestions & Strategies

1. The Office of Human Subjects Research’sCompliance Monitoring Program Educational Seminar:Audit Preparation Suggestions and Strategies Barbara Starklauf, MAS, CIP Jenna Schulcz, BA, CCRP Lea Olverson, MS, CIM Frederick W. Luthardt, MA, CCRP June 16, 2006

2. Presentation Topics • Review of the Compliance Monitoring Program • What’s happening out there? • Why does the FDA audit studies? What happens in a FDA audit? What is the FDA finding? • What concerns are we observing? • How to organize regulatory and subject information, and what to do in advance of a visit from the OHSR or the FDA.

3. Overview: The Activities of the Monitoring Program • Examining IRB approved studies for compliance with applicable regulations to assure the protection of human subjects in research. • Evaluating a study’s progress in both regulatory documentation maintenance and overall study conduct. • Educating Investigators and staff about regulatory requirements and study organizational strategies.

4. Research Misconduct makes the News • “Ripped from the Headlines…” • Research Misconduct Examples… A Doctor's Drug Trials Turn Into Fraud By KURT EICHENWALD AND GINA KOLATA Published: May 17, 1999 …The Fraud - Falsifying Records, Endangering Patients Practice Manager Who Lied about Subjects in Clinical Study Gets Probation, Small Fine

5. When the FDA means business! • FDA 483 EIRs/Warning Letter

6. An FDA Audit: Are you next? The FDA may conduct announced or unannounced inspections of clinical investigator sites for various reasons such as: • Routinely to verify data that has been submitted to the Agency • As a result of a complaint to the Agency about the conduct of the study at the site [i.e., “for cause”] • In response to sponsor concerns or termination of the clinical site • At the request of an FDA review division • And related to certain classes of investigational products that the FDA has identified as products of special interest in its current work plan (i.e. targeted inspections based on current public health issues). http://www.fda.gov/oc/ohrt/irbs/investigator.pdf

7. The FDA Audit: What happens? During an inspection at the site of a clinical investigator, FDA personnel all aspects of a study, for example: • Who performed various aspects of the protocol (e.g., who verified inclusion and exclusion criteria, who obtained informed consent, etc.) • Signed and dated Informed Consent Forms • Medical and study records to confirm subject eligibility • Case-Report-Forms (study data) • Accountability for the investigational product http://www.fda.gov/oc/ohrt/irbs/investigator.pdf

8. An FDA Audit: The Aftermath… After the Inspection, the Clinical Investigator may receive one of the following: 1. A letter that generally states that FDA observed no significant deviations from the regulations. Note that a letter is not always sent when FDA observes no significant deviations. [NAI] 2.An informational or untitled letter that identifies deviations from statutes and regulations for which voluntary corrective action is sufficient. Occasionally, such letters request a response from the clinical investigator. [VAI] 3.A Warning Letter that identifies serious deviations from applicable statutes and regulations. A Warning Letter generally requests prompt correction by the clinical investigator and a formal written response to the agency. [OAI] http://www.fda.gov/oc/ohrt/irbs/investigator.pdf

9. What the FDA Typically Finds

10. What we are finding…

11. Specifically, we are observing… • Disorganized or missing regulatory documentation • Unclear study personnel responsibility delegation • Consent form signature/date anomalies • Inadequate or unverifiable Subject eligibility assessment procedures • Inadequate Drug or Device accountability

12. What do we suggest? • Develop compliance plans during study design or implement plans for corrective action, to include the following: • SOPs: Standard Operating Procedures are “written instructions to achieve uniformity of the performance of a specific function.” • CRFs: Case Report Forms are “documents designed to record all of the protocol-required information…” • Source Documentation: Maintain all the applicable original documents, data and records that correspond with the CRFs. • Checklists: A means to verify the completion of study related procedures. • Note-To-File: A means of explaining and correcting unexpected departures from the protocol. • Consider the following process steps and examples for creating a compliance plan… Source: ICH E6: Guideline for Good Clinical Practice

13. Regulatory Binder Organization Suggestions • Three-Ring Binder(s) to minimize loss • Arrange documents chronologically • Tab or divide documents by IRB Approval year • Maintain audit trail of all IRB approved and study related documentation

14. Sample Regulatory Binder Table of Contents

15. Delegation of Responsibility Process Compliance Suggestions • List all personnel involved in study procedures • Assure training and applicable certifications • Submit to IRB for approval • Check and update as necessary Source: 21 CFR 312: Code of Federal Regulations; Form FDA 1572

16. Example Responsibility Matrix Staff Name/Role Responsibilities Signature Date PI Initials • RESPONSIBILITY KEY • Consent Designee • Evaluates Subject Inclusion/Exclusion criteria • Maintains Source Documents • Completes Case Report Forms • Dispenses Study Drug • Administrative • Obtains Laboratory Values (sample collection) • Interprets Medical Reports and Laboratory Results (i.e. ECGs, MRIs, etc.) • Adverse Event Documenting and Reporting

17. Informed Consent Process Compliance Suggestions • Identify who obtained consent and when • Specify that subject comprehended the consent and all questions were addressed • Indicate that assent and/or proxy consent was obtained and when • Note Witness signature and date (if needed) • Verify that a copy was given to the subject Source: 21 CFR 50.20: FDA Code of Federal Regulations; ICH E6: Guideline for Good Clinical Practice

18. Informed Consent Process Sample Checklist INFORMED CONSENT CHECKLIST Subject initials: ________________ Date of Birth: ________________ Subject study identifier: _________ Consent Version #/Expiration Date: _________________ Consent signed and dated by subject: YES  NO  Date: ____________ Was a copy of the consent given to the subject: YES  NO  Consent signed and dated by parent: YES  NO  N/A  Date: ____________ Assent signed by minor: YES  NO  N/A  Assent NOT signed by minor; reason not obtained: ________________________________________ Verbal assent obtained and assent signed by parent, documenting this assent YES  NO  N/A  Consent/assent obtained by: __________________ ___________________________ ________ Print name Signature Date

19. Eligibility Determination Process Compliance Suggestions • Indicate that specific Inclusion and Exclusion criteria were assessed • File applicable source documentation with the I/E checklist or case report form • Report any exceptions to the IRB, sponsors (if applicable), etc. Source: 21 CFR 56: FDA Code of Federal Regulations; ICH E6: Guideline for Good Clinical Practice

20. Eligibility Assessment Sample Checklist

21. Drug AccountabilityCompliance Suggestions • Remember: it is mandatory if the IND is held by the Investigator • Develop log sheets to track drug receipt, dispensation, return • Keep shipping invoices • If applicable, submit annual FDA progress reports • Consider utilizing Investigational Drug Service Source: 21 CRF 312.50, 312.56, 312.57, 312.59-62, 312.68: Code of Federal Regulations

22. Drug Accountability Sample Worksheet Protocol Number: Drug Administered: Location Drug: Drug Administered: PI: Study Title: Recorder Initials ____Recorder Name_______________

23. Device AccountabilityCompliance Suggestions • Remember: it is required for the holder of the IDE • Develop log sheets to track the receipt, condition, dispensation, serial/lot numbers, and return of a device • Keep shipping invoices • As mandated, submit progress reports to FDA at least annually. Source: 21 CRF 812 Subpart G (812.140, 145, and 150): Code of Federal Regulations

24. Device Accountability Sample Worksheet DEVICE ACCOUNTABILITY LOG Principal Investigator: Study Title: Principal Investigator Signature: _________________________________ Date: _____________

25. How to Get in Touch with the Compliance Monitoring Team • Please contact the JHM IRB office at 410-955-3008 if you receive a notice from any federal or grant agency, including the FDA and NIH Ask for “Regulatory.” • For general questions and assistance, The Monitors may be contacted at the JHM-IRB office. Please ask for “Compliance.” • The Monitors may also be contacted directly by email: • jschulc1@jhmi.edu • lolvers1@jhmi.edu • fluthard@jhmi.edu

26. In Conclusion… • Preventative Maintenance: Or an ounce of Prevention is Worth .453 kg of Cure… • Keep in contact with IRB, sponsor, and FDA • Suggestions are pertinent for assembling a study as well as in preparation for a visit from the FDA or the OHSR

27. Reference Information & On-line Resources • JHM-IRB Guidance: http://irb.jhmi.edu/Guidelines/MonitoringVisits.html • FDA Regulations: http://www.fda.gov/cder/regulatory/default.htm • FDA Audit Details:http://www.fda.gov/oc/ohrt/irbs/investigator.pdf • FDA Information for Human Subject Safety: • http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm • ICH GCP Principles: • http://www.fda.gov/cder/guidance/959fnl.pdf • http://www.fda.gov/oc/gcp/regulations.html

29. Questions?? Suddenly, it all made sense. Late at night, in a nest of manila folders in the middle drawer of the filing cabinet, the paperwork had been mating.