BUILDING A VISION RESEARCH AT UC DAVIS Conflicts of Interest Lynne Chronister, MPA Wendi Delmendo, JD Mentored Clinical Research Training Program K 30 Summer RCR Course September 10, 2008 OFFICE OF RESEARCH
Wisdom From Disney – Elizabeth: Wait! You have to take me to shore. According to the code of the order of the brethren… – Barbossa: First, your return to shore was not part of our negotiations nor our agreement so I must do nothing. And secondly, you must be a pirate for the pirate’s code to apply and you’re not. And thirdly, the code is more what you'd call “guidelines” than actual rules. Welcome aboard the Black Pearl, Miss Turner. 2
RESPONDS TO: 1. Culture of Compliance 2. Federal Regulations 3. State of California Political Reform Act 4. University of California, Davis, PPM 230 -05 5. Organizational Recommendations from: • AAMC • AMA • IOM 6. Gift or Grant 3
HISTORICAL CONTEXT – 1980 Bayh Dole Act – Congressional Mandate (1995) – Increase in Industry Collaboration – Notable Cases – NIH/NSF Required Policies – Federal Common Rule 4
RESPONSIBILITIES & CHALLENGES – Research integrity is the umbrella for accountability – Ensure the integrity of science and research – Public accountability – Delicate balance – Culture of consciousness and promotion of integrity – Management does not ensure integrity/ equitable monitoring 5
COI Wants To Ensure: – Research is appropriate to the University – The teaching and research environment is open – Freedom to publish and disseminate results is preserved – University resources and facilities are not benefiting private sponsors 6
Gelsinger Case – Jesse Gelsinger was an 18 -year old male with a relatively mild form of OTC deficiency, controlled with diet and drugs – He had decreased liver function, but led a relatively normal life – Volunteered for a gene therapy study – toxicity testing 7
Gelsinger Case, cont. – Vector injected into liver 9/13, am – That evening, developed high fever – Next morning, disoriented and jaundiced – That afternoon, became comatose – Dialysis, ECMO begun – Declared brain dead 9/17 am 8
Gelsinger Complaint – Failed to tell NIH RAC of change in virus delivery method – Changed consent form from that approved by FDA – omitted information on monkey deaths – Failed to report liver toxicity in prior subjects – Failed to follow enrollment rules – Poor handling of vectors, causing variance in potency 9
Possible Reasons – Studies designed to favor study drug • e. g. , inadequate comparator: drug or dose – Publication bias (suppression negative results) – Discontinuation of studies in progress – Publication in symposia without peer review 10
BUILDING A VISION RESEARCH AT UC DAVIS Federal Laws OFFICE OF RESEARCH
POTENTIAL CONFLICT – Individual – Institutional – Leadership/Administration – Reviewer Bias (NIH, $10, 000, 2004) – Research Sponsors (Zerhouni, 2005) – Legislature (Rep. Greenwood, R - PA) • Biotechnology Industry Organization 12
DISCLOSURE – University – Sponsor – Patients/Subjects – Publications – Presentations 13
UNIVERSITY RESPONSIBILITY – To have a Conflict of Interest Policy and Procedure, to disseminate the policy and to provide review and oversight for any conflict of interest situation. – University must “manage, reduce or eliminate” any conflict of interest. – Must report to federal sponsor as appropriate. (NIH prior to account activation) 14
DEFINITIONS: CONFLICT OF INTEREST – Any outside interest or activity that may adversely affect, compromise or be incompatible with obligations of the employee to the University or professional norms. Includes situations where significant financial or other interests will affect the approval, design, conduct or reporting of research and other projects. 15
SIGNIFICANT FINANCIAL INTEREST – Anything of monetary value including (e. g. ): salary, consulting fees, equity interests and IP rights. Does NOT include (e. g. ): income from public/nonprofit seminars/teaching, equity interest of $10, 000 or less or not more than 5% ownership, salary, royalty etc. of $10, 000 or less aggregated over 12 months, mutual funds, physician reimbursement. 16
CONFLICT OF COMMITMENT – May occur when external activities demand excessive time conflicting with a faculty or other employee’s responsibility to the University. 17
INSTITUTIONAL CONFLICT OF INTEREST – Situations where the University’s beneficial relationship with corporate entities may place it in conflict with it’s responsibilities as a public institution of higher education. • Equity interest in companies • Certain licensing situations • Board or other leadership positions 18
IMPLICATIONS OF FEDERAL LAW – Solicitation or receipt of a gift or other compensation from a vendor. – Confidentiality agreements that could affect a students degree requirements or grade. – Sponsor interference with publication or suppression of data. – Evaluation of faculty or students based on participation in outside business activities by an involved employee. 19
BUILDING A VISION RESEARCH AT UC DAVIS California State Laws OFFICE OF RESEARCH
Government Code § 87100 – “No public official at any level of state or local government shall make, participate in making or in any way attempt to use his official position to influence a governmental decision in which he knows or has reason to know he has a financial interest. ” 21
Exception: “Making or participating in making a governmental decision shall not include: . . . (c) Academic Decisions. . . ” (2 California Code of Regs. , section 18702. 4) 22
Academic Decisions: – Teaching Decisions • Example: Selection of books – Research Decisions • Example: Applying for funds to finance research, allocating resources for research, manner or methodology of research. 23
Disclosure Required – Disclosure shall be required … in connection with a decision made by a person or persons at any institution of higher education with principal responsibility for a research project to undertake such research, if it is to be funded or supported in whole or in part [with private funds] …, (2 Cal. Code of Regs. , section 18702. 4(c)(2). ) 24
Disclosure Categories – Management positions/employment – Equity ($2, 000 or more) – Income ($500 or more in last year) – Loans ($500 or more in last year) – Gifts ($50 or more in last year) – Travel payments ($50/$500 – outside CA) 25
Disclosure Form – California Form 700 -U 26
CAUTION: Travel Payments – Complex rules for travel payments – If gift, limited to $390/year 27
Buying Advice in Biopolis A drug company has established a large biotech research and development campus in the Biopolis section of Singapore. In anticipation of receiving a proposal from a faculty researcher, it invites him to visit its facilities to review and comment on a product, to discuss their independent research projects, and to explore the potential for collaborative research. The company offers to pay all of the travel expenses for the Singapore trip. 28
Buying Advice in Biopolis If the company decides to fund the investigator’s proposal, will he need to disclose the travel expenses on the Form 700 U? – The best answer is A. The travel expenses are reasonable compensation for the time and inconvenience of the travel. No disclosure is required. B. The travel expenses are a gift and must be disclosed. 29
Buying Advice in Biopolis – Explanation of the answer Transportation outside of California is considered a gift, so the travel to and lodging in Singapore should be reported as gifts. Token advisory or consulting arrangements cannot be used to justify compensation, so the gift thresholds would apply. To avoid receiving a gift, the researcher’s department could pay for the transportation expenses. 30
Substantive Review Required – … disqualification may not be required … if the decision is substantively reviewed by an independent committee established within the institution. ” (Section 18702. 4(c)(2)) 31
BUILDING A VISION RESEARCH AT UC DAVIS University Policies and Procedures OFFICE OF RESEARCH
COI Policies – UC Compendium of COI Policies – UCD • • PPSM 82, Conflict of Interest PPM 380 -16, Conflict of Interest PPM 230 -05, Conflicts of Interest in Research APM 025, Conflict of Commitment – UCDHS • Section 1705, Conflict of Interest • Section 2204, Vendor Relationships 33
PPM 230 -05: Prohibitions – Academic Freedom Restrictions • Can’t require others to participate in outside activities • Can’t enter into agreements that § Impact evaluation of others § Allow sponsor to interfere with analysis/publication § Delay protection of IP, fulfillment of degree req’s or publication – Human Subjects Research • Can’t accept gifts from sponsors • Can’t buy/sell sponsor stock until results made public • Can’t accept payments from sponsor unless commensurate w/effort – Licensing • Can’t be involved w/licensing if have interest in entity • Can’t be on board of licensee if University holds equity 34
PPM 230 -05: Disclosure – When a research project is sponsored by private funds, PI must disclose any financial interest in sponsor of the research – When research project is sponsored by public funds, PI and key personnel must disclose any significant financial interest related to the project or that could reasonably appear to be affected by the project – When privately funded project involves human subjects research, key personnel must disclose any significant financial interest in the sponsor of the research 35
Disclosure Process – Private Sponsor • PI completes California Form 700 U – let the form and instructions be your guide • PI and key personnel complete Form 800 • If answer “yes” to any question, complete supplemental form • Confidentiality 36
Disclosure Process – Public Sponsor – PI and key personnel complete Form 800 Statement of Economic Interests – What constitutes a “financial interest related to the work to be conducted under the project”? – If answer “yes” to any question, complete supplemental form 37
Supplemental Form – Purpose – Let the form be your guide – Fill out the form yourself – “How are you keeping your interests separate? ” 38
PPM 230 -05: Review Process – Conflict of Interest Committee undertakes independent substantive review – Committee recommends whethere is a real or potential conflict of interest and, if so, whether any modifications or conditions should be imposed. – Recommendations go to Vice Chancellor – Research for final decision 39
COI Management Strategies – Public disclosure • • • 40 Departments Sponsors Students/research personnel Publications Conferences Research subjects
41
Management Strategies, cont’d – Independent monitoring – Modification of research plan – Disqualification from participation in research – Divestiture of financial interest – Severance of conflicting relationship 42
UCDHS 2204 – Vendor Relationships – Policy is based on research showing that providing gifts of nominal value may affect provider behavior and give the appearance of favoritism – Gifts from vendors to an individual are prohibited – Vendors can make gifts to a department/division – Policy regulates vendor visits 43
APM 025 – Conflict of Commitment – Time limits for outside compensated activities • Academic year appointment – 39 days • Fiscal year appointment – 48 days – Categories of activities • Category I – approval required • Category II – disclosure required • Category III – no disclosure, no time limit 44
BUILDING A VISION RESEARCH AT UC DAVIS Medical Issues OFFICE OF RESEARCH
CLINICAL INVESTIGATIONS – Any financial interest must be disclosed to the IRB and possibly research subjects. – Employee with conflict can be a PI or Co-PI only under exceptional circumstances. – NOT a Good Idea: incentive payments to individuals from sponsors — these should go into a Dept. account. – NOT a Good Idea: Consent of subjects by an employee with a conflict. 46
Funding Affects Publications – Experimental drug recommended as treatment of choice more often (5. 3 X) – Unfavorable economic analysis 8 X less likely – Second hand smoke • Industry sponsored 94% pro-industry • Non-industry sponsored 13% – Calcium channel blocker safety • 51% vs. 0% supportive 47
Outline – AMA code of ethics – AAMC guidelines – DHHS-OIG concerns 48
AMA Code Of Ethics – All members of UCDMC Medical Staff agree to abide by the principles of the AMA code of ethics – “Avoidance of real or perceived conflicts of interest in clinical research is imperative if the medical community is to ensure objectivity and maintain individual and institutional integrity. ” – Two parts • General guidelines • Clinical trials 49
General Guidelines For Research – Once a clinical investigator becomes involved in a research project for a company or knows that he or she might become involved, she or he, as an individual, cannot ethically buy or sell the company’s stock until the involvement ends and the results of the research are published or otherwise disseminated to the public. – Any remuneration received by the researcher from the company whose product is being studied must be commensurate with the efforts of the researcher on behalf of the company. 50
General Guidelines, cont. – Clinical investigators should disclose any material ties to companies whose products they are investigating including: financial ties, participation in educational activities supported by the companies, participation in other research projects funded by the companies, consulting arrangements and any other ties. – What is material? 51
Who To Disclose To? – The medical center – Organizations funding your research – Journals when publishing results • Include statement in publication disclosing the conflicts – Any other publication (e. g. , letter to the editor) 52
Specific Guidelines For Clinical Trials – “Safeguards against conflicts of interest are needed to ensure the integrity of the research and to protect the welfare of human subjects. Physicians should be mindful of the conflicting roles of investigator and clinician and of the financial conflicts of interest that arise from incentives to conduct trials and to recruit subjects. ” 53
Clinical Trials – Physicians should agree to participate as investigators in clinical trials only when it relates to their scope of practice and area of medical expertise. – When a physician has treated or continues to treat a patient who is eligible to enroll as a subject in a clinical trial that the physician is conducting, the informed consent process must differentiate between the physician’s roles as clinician and investigator. 54
Clinical Trials (2) – Financial compensation should be at fair market value and the rate of compensation per patient should not vary according to the volume of subjects enrolled by the physician and should meet other existing legal requirements. – It is unethical for physicians to accept payment solely for referring patients to research studies. – Physicians should ensure that protocols include provisions for the funding of subjects’ medical care in the event of complications associated with the research. 55
Clinical Trials (3) – The nature and source of funding and financial incentives offered to the investigators must be disclosed to a potential participant as part of the informed consent process. 56
AAMC – Institutional policies should establish the rebuttable presumption that an individual who holds a significant financial interest in research involving human subjects may not conduct such research. – In the event of compelling circumstances, an individual holding significant financial interests in human subjects research may be permitted to conduct the research. 57
AAMC – When an institution finds that financial interests in human subjects research are justified by compelling circumstances, those interests and the research in question must be managed through rigorous, effective and disinterested monitoring undertaken by individuals with no financial or professional ties to the research or direct reporting relationships to the researchers. 58
What Are “Compelling Circumstances” – Early trial of device for which the investigator has special skills others do not – Definitely not a late phase drug trial 59
Significant Financial Interest – Consulting fees, honoraria, etc. over $10, 000/year – Equity interest in non-publicly traded company – Equity interest over $10, 000 (unless < 5% of value of company) – Royalty income or right to receive patent or copyright royalties from source other than University – Payments not related to costs of research (e. g. , bonuses, milestone payments) – Officer or other fiduciary role in company 60
Implications of AAMC rule – Conflicts are inherently bad and disclosure doesn’t help much • Disclosure to University • Disclosure to subject – Active monitoring of study required – Conflicted persons should not participate if at all possible 61
DHHS – OIG – Indications of questionable research include: • Research initiated or directed by marketers or sales agents • Research that is unnecessary – Prudent manufacturers should separate the awarding of research contracts from marketing or promotion of their products – Grants must not be funded based, in any way, expressly or implicitly, on the physician’s use of the manufacturer’s product 62
Why? – Research funds being distributed as kickbacks • TAP pharmaceuticals: $875 M fine • Whistleblower offered research grants and educational grants to switch to Lupron – Switching patients to manufacturer’s drug under guise of research • Phase IV studies 63
WHEN IS A GIFT AND WHY DO I NEED TO TURN DOWN THE LUNCH, THE DONUTS AND THE PENS? 64
GIFTS AND BONUSES – Recruitment Bonuses – Gifts from Sponsors – Definitions • Primary Beneficiary • Quid Pro Quo 65
DEFINITIONS – Grant/Contract/Other: Depends on the intent of the awarding agency and the legal obligations of the awardee in accepting the award. A grant may be donative in nature, bestowed voluntarily and without expectation of tangible compensation. A contract always carries explicit quid pro quo between the source and the institution. 66
CONFLICTS OF INTEREST – Federal rules (PHS, NSF) apply only to research supported by Federal funds (American Heart Association) – University conflict of interest rules should apply regardless of whether research is funded by a gift or a grant – Gift classification should not allow “bypass” of conflict of interest review process 67
GIFT, GRANT OR GREY? – Dr. Green owns 25% equity in a start up company that is developing a new medical device. He gifts the university $50, 000 to carry out research in his laboratory. He states that there are no strings attached. 68
GIFT, GRANT OR GREY? – Dr. Harris accepts $100, 000 from ATV Pharmaceutical company for a clinical investigation. She signs the contract and puts the money into her Development account. The study cost $40, 000 to complete. The other funds are used for her independent research. 69
GREY? – Dr. Appleby consulted for Regis Inc. , a pharmaceutical and received a check for $15, 000. She donated the check to the University for her laboratory. Who is the donor and can she deduct the funds from her federal income taxes? 70
Hypothetical – The Case of the Sick Cows 71
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