The Office of Human Subjects Research’s Compliance Monitoring Program Educational Seminars:

1. The Office of Human Subjects Research’sCompliance Monitoring Program Educational Seminars: Barbara Starklauf, MAS, CIP Jenna Schulcz, BA, CCRP Lea Olverson, MS, CIM Frederick W. Luthardt, MA, CCRP Projects that Do Not Involve FDA Regulated Products: Investigator Responsibilities and Compliance September 26, 2006 October 5, 2006

2. Presentation Topics • Federal Requirements of the Department of Health and Human Services (DHHS) and our Institution’s Federal Wide Assurance (FWA) responsibilities • Institutional Compliance mechanisms: Monitoring and Auditing • Organizational strategies for regulatory and applicable subject documentation

3. The Power of the FDA…What we already know • The FDA regulations are often considered the “gold-standard” for study organization, conduct, and oversight. • Researchers and Institutions are aware of what the FDA can do if the regulations are not followed. • We’ve seen the painful outcomes of bad FDA audits… fines, debarment, prison…

4. Rhetorical Question … • Should a study not subject to FDA authority be organized and conducted less rigorously or with diminished attention to research integrity and subject safety? • Answer: No. The DHHS and Institutional authorities are also authorized to regulate, oversee, and enforce requirements for research.

5. Does my study fall under FDA or HHS authority? • OHRP recommends that the process for determining whether the HHS regulations apply should address the following three questions in order: • (1) Does the activity involve research under 45 CFR 46.102(d)? (If yes, proceed to the second question.) • (2) Does the activity involve human subjects under 45 CFR 46.102(f)? (If yes, proceed to the third question.) • (3) Is the activity exempt under 45 CFR 46.101(b)? • If the answer to the first two questions is "yes", and the answer to the third question is "no", then the HHS regulations apply; otherwise, the HHS regulations do not apply. To view a chart regarding this decision-making process, see OHRP's "Human Subject Regulations Decision Charts" at [http://www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm].

6. DHHS Definitions • “Research”: a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. • “Human Subject”: means a living individual about whom an investigator conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information. • “Research Subject to Regulation” those research activities for which a federal department or agency has specific responsibility for regulating as a research activity, (for example, Investigational New Drug requirements administered by the Food and Drug Administration). • “Institution”: Any public or private entity or agency [that is engaged in research].

7. FDA vs. DHHS • Not all studies are subject to FDA Regulations, e.g. non-IND studies. • Department of Health and Human Services requires institutions to assure compliance with regulations (FWA). • Research that is neither conducted nor supported by a federal department or agency but is subject to regulation as defined in §46.102(e) must be reviewed and approved, in compliance with §46.101, §46.102, and §46.107 through §46.117 of this policy, by an institutional review board (IRB) that operates in accordance with the pertinent requirements of this policy. • Non-FDA studies must comply with 45 CFR 46: “The Common Rule.”

8. 45 CFR 46: “The Common Rule” • Subpart A: Basic HHS Policy for the protection of Human Research Subjects • Requirement for assuring compliance with Federal Regulations for research • Obtaining Informed Consent • Oversight of research by Institutional Review Board • Research institutions will assure the federal government that it will provide and enforce protections for human subjects of research. • Subpart B-D: Provide additional protections for Pregnant Women, Human Fetuses and Neonates (Part B), prisoners (Part C), and Children (Part D) who are involved in research

9. DHHS Scope at Johns Hopkins • 45 CFR 46.101: “All research involving human subjects conducted or supported by HHS or conducted in an institution that agrees to assume responsibility for the research in accordance with 45 CFR 46 regardless of the source of funding.” • The Institution maintains several Federal Wide Assurances (FWA), which indicate the above agreement that the Institution will oversee research and assure Human Subject Protection.

10. Federal Wide Assurance (FWA) Highlights of the terms of the “Agreement”? • Human Subjects Research Must be Guided by Ethical Principles • Compliance with the Federal Policy for the Protection of Human Subjects and Other Applicable Federal, State, Local, or Institutional Laws, Regulations, and Policies • Written Procedures • Scope of IRB(s)’s Responsibilities • Informed Consent Requirements • Compliance with the Terms of Assurance • Assurance Training • Education Training

11. FWAs across the Institution The Institutions had been operating under Multiple Project Assurance # M-1011 for the period of 11/01/98 to 10/31/03. The MPA was replaced by Federal-Wide Assurances associated with each of the organizations linked to the JHM IRBs. The specific Federal-Wide Assurance numbers and expiration dates are as follows:

12. Examples of Studies that must comply with HHS regulations • Studies that receive Federal funding in whole or in part from any Federal entity: • Studies receiving NIH Award • Studies funded by specified Federal agencies, e.g. DOE, DOD, etc. • Studies supported by the VA • Studies that receive no Federal funding • Investigator initiated protocols • Studies funded by private organizations • Studies receiving internal fellowships/grants

13. Specific types of studies that fall under HHS and Institutional (IRB) authority • Non-IND/IDE: e.g., comparison of approved treatment modalities • Pilot Studies: e.g., proof of concept • Observational/non-interventional: e.g., biomarker assays on stored samples • Quality Improvement: e.g., surveys of inpatients

14. Institutional Compliance • The HHS advises that institutions implement • “Internal audit procedures [to] assure the institution's administration that its policies and procedures are being adhered to and that they are proper in scope and content… [and] that reporting of noncompliance is accomplished and that appropriate follow-up measures are taken” • “…internal audit or self-assessment procedures and practices designed to assure proper protocol and consent document preparation, protocol submission, review and approval by the IRB, and timely monitoring of protocol implementation.” • Monitoring is “good policy.” http://www.hhs.gov/ohrp/irb/irb_chapter1.htm

15. Monitoring and Auditing • IRB approved studies can be audited or monitored by • A sponsor • A funding agency (NIH, DOE, etc.) • The IRB via the Compliance Monitoring Program • Per routine selection • Directed or “for-cause” • The DHHS (in response to a complaint)

16. Monitoring Authority of the IRB • Only consent forms with a valid approval stamp may be presented to subjects. All consent forms signed by subjects enrolled in the study should be retained on file. The Office of Human Subjects Research conducts periodic audits of protocol • records, and consent documentation is part of such audits.

17. What we hear… • “Why am I being monitored?” • Implying the following: • “Nobody died…” or • “My study is low-risk…” or • “I’m just collecting samples…” or • “My study is part of clinical care…” • Etc.

18. The Bottom Line If a study is IRB approved, all regulatory documents and subject records must be retained, organized, retrievable, and available for inspection.

19. 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

20. Regulatory Documentation Organization Recommendations • The IRB via the Compliance Monitoring Program can monitor or audit any study approved by the IRB • For example, an investigator initiated study testing clinical outcomes of two standard therapies: • Regulatory Binder contents (what to keep…): • IRB materials (applications, approvals, consent forms, problem reports, changes to the protocol, correspondence, etc.) to maintain a comprehensive audit trail • Site responsibility delegation table • The protocol

21. Sample Regulatory Binder Table of Contents

22. Example Responsibility Matrix Staff Name/Role Responsibilities Signature IRB Appr. 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

23. Subject Documentation Organization Recommendations • Keep and maintain documentation to verify • Consent process • Eligibility assessment • Protocol compliance • Problem and Deviation reporting to the IRB • Quality control (error detection and correction) • Data Collection and a means to verify data

24. 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

25. Eligibility Assessment Sample Checklist

26. Protocol Deviations Date IRB

27. Take Home Points • Keep everything organized • There are consequences to non-compliance • Any IRB approved study can be audited • Studies in disarray may lead to • Data rendered not evaluable • Subject Safety may be compromised • Study delays • Call the Compliance Team with questions • Keep everything organized

28. How to Get in Touch with the Compliance Monitoring Team • Please contact the JHM IRB office at 410-955-3008 if you have questions regarding regulatory guidance. • 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

29. References • DHHS: http://www.hhs.gov/ • OHRP: http://www.hhs.gov/ohrp/ • FDA: http://www.fda.gov/ora/ • FDA comparison with DHHS/OHRP: http://irb.jhmi.edu/Guidelines/FDAvsOHRP.html • FWA: http://www.hhs.gov/ohrp/humansubjects/assurance/filasurt.htm • The “Common Rule”: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm • JHM-IRB Guidance: http://irb.jhmi.edu/Guidelines/ • Monitoring:http://irb.jhmi.edu/Guidelines/MonitoringVisits.html