HCCA Region I-Fall Conference ADVANCED RESEARCH COMPLIANCE

1. HCCA Region I-Fall ConferenceADVANCED RESEARCH COMPLIANCE F. Lisa Murtha, J.D. Vice President of Audit, Compliance and Privacy Officer The Children’s Hospital of Philadelphia murtha@email.chop.edu (215) 801-7824

2. Agenda • Important issues in research today • Risk areas in clinical research compliance • Compliance Officer’s role in research compliance • Questions?

3. Important Challenges in Research Today • OHRP staff turnover • Decentralized nature of research • Federal government funding is unstable • Increased focus of regulators • Unstable financial picture for many providers and research sites • Advances in use of technology • Increased exposure of IRB members

4. Risk Areas in Clinical Research Compliance • Human subject protections • Conflicts of interest and financial disclosures • HIPAA/Privacy • Research billing issues • Research vs. innovative care • Monitoring use of research funds (residual balances, cost sharing, time and effort reporting, etc.) • Scientific Misconduct

5. Human Subject Protections • Tuskegee study opened eyes to abuses in research • This led to the Belmont Report (respect, beneficence, justice) • Led to increased monitoring • Led to increased regulation • October 1, 2000-Required education in the protection of human subjects for all investigators submitting NIH applications for grants or proposals

6. Federal Regulations Governing Operation of IRBs • Common Rule: Policy for the Protection of Human Subjects • DHHS Regulations (45 CFR Part 46) • FDA Regulations (Title 21, CFR 50 and Title 21 CFR 56) • Other federal and state regulations • IOM statements and recommendations

7. FDA Rules • FDA regulates but does not per se, support or conduct research • FDA regulations address requirements for informed consent (21 CFR 50)and IRBs (21 CFR 56) • FDA regulates research on products, drugs, devices, and food/color additives • FDA rules apply whether research is funded by the government or not

8. FDA Sanctions • Withhold approval • Prohibit enrollment of new subjects • Terminate ongoing studies • Disqualify IRB or parent institution • Refer to OHRP or law enforcement authorities

9. Office for Human Research Protections (OHRP) • OHRP oversees compliance of government sponsored research • OHRP may: • Restrict or withdraw assurance • Require re-review or suspension of research • Mandate temporary suspensions • Recommend debarment or suspension from government contracting • Refer to FDA findings that affect FDA research

10. Institutional Review Boards • IRB is a medical staff committee with broad power in oversight of clinical research • IRB determination within an institution is considered FINAL • IRB must remain independent • IRB membership (# of members, diversity of group, community representation, lay perspective, independent perspective, scientific perspective)

11. Conflicts of Interest • Objectives of the Financial Disclosure Rules for Clinical Investigators (21 CFR 54) • Alert the IND/NDA sponsor to any potentially problematic financial interest • Minimize the potential for study bias • Facilitate collection of accurate data that may be submitted later

12. Disclosable Conflicts • Compensation arrangements that could affect objectivity of investigator • Ownership (including spouse and dependent children) interest in product under study • Equity interests in public companies that exceed $50,000 • Equity interests in the sponsor that cannot be calculated • Significant payments by the sponsor to the investigator or team (Subject of recent OIG guidance for pharmaceutical manufacturers)

13. HIPAA Privacy • From April 14, 2003 forward, all research must be specifically reviewed from the perspective of the privacy of the research subject by either an IRB or Privacy Board, per the HIPAA Privacy Rule • Providers, payors, clearinghouses and business associates of other covered entities are subject to HIPAA • Pharmaceutical companies are NOT covered entities under HIPAA nor are they business associates of covered entities

14. HIPAA Research Requirements • Uses or disclosures of “Protected Health Information” for research require: • Signed, HIPAA compliance “authorizations” from each study participant (which can be combined with the Informed Consent Document) • IRB or Privacy Board waivers of some or all of the authorization requirements • De-identification of patient data via removing all 18 HIPAA identifiers, statistical analysis or opinion, Or Limited Data Set

15. HIPAA Authorizations Must • Be written in plain language and signed by each study participant • Specify the data that will be collected and each use • Specify the persons or types of persons who will have access to the data • State the right of refusal and revocation and that existing data may still be used • State that once the data are provided to the sponsor, HIPAA will no longer protect them • Disclose any payments from the sponsor to the investigator for use or disclosure of the data

16. Allowed: Admission Dates Discharge Dates Service Dates Death Date Age (in hours, months or days Age (for those over 90) Zip Code Gender Not allowed: Names Address Telephone/fax Email address SSN# Certificate or License # Vehicle ID and Serial Number URLs and IP addresses Full face photos and comparable images Limited Data Set

17. Waivers • Use or disclosure involves no more than minimal risk to patient (similar to CR) • Alteration or waiver will not adversely affect privacy rights and welfare of individuals (similar to CR) • Research could not practicably be done with alteration or waiver or without access and use of the PHI (similar to CR) • Privacy risks are reasonable in relation to benefits • Adequate plan to destroy identifiers • Adequate plan to protect identifiers • Adequate written assurances that PHI will not be reused or disclosed for other purposes

18. Reviews or PHI Preparatory to Research • Reviews of PHI preparatory to research do NOT require authorizations or waivers • Need to consider what happens when individuals who are NOT in the workforce perform the preparatory reviews • Data collected before April 14 may be used and disclosed for research as long as the CR is followed

19. Research Billing Issues • Double billing • Residual funding could be viewed as a kickback • Finders fees or other incentives could compromise objectivity • Are $ sufficient to do study • Accounts receivable • Segregation of charges

20. National Coverage Decision • Effective for items or services furnished on or after 9/19/00 • Medicare will cover routine costs of qualifying clinical trials and reasonable and necessary items or services used to diagnose and treat complications arising from participation in all clinical trials • URL: http://www.cms.gov/quality/8d2.htm

21. What are Routine Costs? • All items or services otherwise generally available to Medicare beneficiaries that are provided in either experimental or the control arms of a clinical trial, including items and services that are: • Typically provided absent a clinical trial (medically necessary) • Required for the provision of an investigational item or service • Required for the clinically appropriate monitoring of the effects of the item or service or the prevention of complications • Items and services that are medically necessary for diagnosis or treatment of complications arising from the provision of an investigational item or service

22. Non-Covered Costs • The investigational item or service itself • Items or services for which there is no Medicare benefit or category, or which are statutorily excluded, or that fall under a national noncoverage policy • Items or services furnished solely to satisfy data collection and analysis needs not used in direct clinical management of the patient • Items and services customarily provided by the research sponsors free of charge

23. Research vs. Innovative Care • Recent OHRP actions have challenged articles in research publications • Cleveland Clinic and others have been challenged • Publications citing results from studies not going through IRB procedures could be vulnerable

24. Monitoring Use of Research Funds • The OIG and the DOJ continue to focus on cases of misuse of research funds • Northeastern University (2003) case involving misuse of funds and time and effort reporting • Areas of focus (time and effort reporting, cost sharing, cost transfers and residual balances in clinical trials)

25. Scientific Misconduct and Investigator Fraud • Why: • Increasing number and complexity of NCEs in development • Competition for clinical investigators and study sites • Gaining access to patients • Outsourcing of key clinical development functions

26. Clinical Investigator Fraud • Falsification of data • Detecting and preventing fraud • Roles of Clinical Monitors, QA, compliance officers, and others • Validation of research results

27. Compliance Officer’s Role in Research Compliance • Ensure that appropriate policies and procedures exist (updates occur regularly) • Standardize forms, templates, protocols • Improve lines of communication • Train research professionals regularly • Perform ongoing monitoring of research activities • Appoint a research compliance officer and a research compliance oversight committee

28. Research Compliance Monitoring • Assess and prioritize your risks • Use the 80/20 rule for risk assessment • Develop a research work plan • Perform testing of procedures and billing to ensure ongoing compliance • Interview investigators and members of research administration on an ongoing basis

29. A Model Research Compliance Work plan for 2003/2004 • Human Subject Protections • Identify a selection of studies to audit 80/20 rule • Review selection of IRB minutes to ensure quorum • Adverse event reporting • Review time spent on each protocol • Review IRB membership • Review completion of documentation of Informed Consents • Perform real time informed consent monitoring ensuring understanding or risks, etc. • Validate that annual OHRP required training took place • Review oversight of vulnerable subjects

30. Work plan cont. • Conflicts of Interest • Review a sample of protocol consent forms to ensure completion and appropriateness • Review EVERY institutional conflict of interest form to ensure completion and appropriateness • Review outliers with Conflicts Committee and Legal • Report on Conflict of Interest Disclosures to the Board on an annual basis

31. Work plan cont. • HIPAA/Privacy • Review minutes of IRB/Privacy Board meetings to ensure time spent on privacy review • Review IRB/Privacy Board policies and procedures for appropriateness • Review training documentation to ensure that all required individuals were trained • Review a sample of Waivers • Review to ensure accounting of disclosures under a waiver and other purposes

32. Work plan cont. • Research Billing Issues • Rationale for segregation of charges inconsistent/not documented • Study subject complaints • Procedures/systems insufficient to ensure proper segregation of research vs. non-research costs • Review sampling of clinical trial budgets to determine uses of residual balances and review closing of old accounts, transfers to discretionary accounts without review, researcher control of residual balances

33. Work plan cont. • Research vs. Innovative Care • Perform ongoing review of investigator publications to ensure IRB process is maintained and completed • Review training to ensure proper understanding of research