Conflict of Interest

What happens if an SFI is determined to be related?

-Related SFIs are referred to the CISC for further review. -CISC is advisory to the Institutional Official (Vice Provost for Research) •Makes recommendations regarding whether a related SFI = an FCOI, and its management •FCOI =SFI could directly and significantly affect the design, conduct and reporting of the research •CISC will generally review SFIs involving certain $ thresholds or of a certain type (fiduciary roles, IP Interests and Clinical Trial IP) •Some SFIs may be handled administratively -Vice Provost for Research makes final determination regarding FCOI and management

What are the regulations related to FCOIs? What is Penn's final rule/regulation on FCOIs?

2 PHS regulations effective 8/24/12 - Promoting Objectivity in Research, 42 CFR 50, Subpart F - Responsible Prospective Contractors, 45 CFR 94 University of Pennsylvania Policy on Conflicts of Interest related to Research (the FCOI Policy) posted on 8/24/12 •Applicable to all research being conducted under Penn's auspices, regardless of funding source •Applicable to Investigators - any person, regardless of title or position, who is responsible for the design, conduct or reporting of research, whether externally or internally funded, or proposed for such funding. •Includes Key Personnel, Consultant-Key Personnel and Significant Contributors •May include individuals who are not paid off the award •It is unclear whether authorship = Investigator status •Authors must make substantial contributions to conception and design, or analysis or interpretation of data

What are the 3 main timepoints in which FCOIs and management must be disclosed?

-Prior to expenditure of funds -Within 60 days of identifying a new FCOI -And at least annually

How can financial ties to industry impact research?

Personal financial ties with industry might distort researcher's judgment/decisions regarding: •Validity of study design •Subject enrollment •Data Collection •Data Analysis •Data Reporting •Publication •Secrecy •Subject safety Empirical studies on FCOI show authors expressing favorable views (no increased risk) were more likely to have financial COI with manufacturers of this class of drug, and drug itself, than authors with an unfavorable view of the safety of the study drug.

Who is responsible for assessing SFI relatedess?

Responsibility of Institution to assess relatedness, but may obtain Investigator's input (Merck example?)

What is a financial conflict of interest (FCOI), and why is it problematic?

•Researcher must have: A role in the design, conduct, or reporting of research results AND Have a personal financial interest / relationship related to the research, or be a consultant for the research sponsor, or have stock in company that manufactures experimental product, or receive royalties related to IP being tested in the research, or have a fiduciary role in a company with a financial stake in the outcome of the research -The problem is not just the FCOI, but the potential for BIAS.

SFIs are related to research if...?

•SFI could be affected by the research; or •SFI is in an entity whose financial interests could be affected by the research

How are FCOIs managed while preserving industry collaborations? Are there any problems?

•Should be a reasoned approach, and disclosure has been the cornerstone thus far Problems? •Does disclosure actually mitigate the risk of bias? •Does it create "moral licensing"? •Some evidence that disclosures of financial ties by people serving in an advisory capacity may be interpreted as signs of expertise.

What other management conditions are in place for clinical trials?

•Formal Data and Safety Monitoring Plan (DSMP) approved by the IRB. •Oversight provided by an the independent, external DSMB. •Trial monitoring and pharmacovigilance provided by a Contract Research Organization as set forth in the DSMP. •Trial auditing provided in accordance with the DSMP. •Preclusion on the conduct of studies that are used to assess subject eligibility in a trial or that assess safety or efficacy outcomes.

What were the concluding thoughts from this presentation?

•Many factors influence scientific judgment •FCOIs relate to the potential for bias •Having an FCOI ≠ Research Misconduct •FCOI regulations and policies are here to stay (for now?) •Incorporate FCOI issues and management early into business negotiations and strategy •Be familiar with institution's relevant, current FCOI policies •Disclose Disclose Disclose •Obtain prior review and approval for consulting arrangements •Comply with management plan requirements

Discuss what the investigator's role should/should not include.

•May serve as the Scientific Advisor for this protocol, contribute scientific expertise and provide guidance to the Sponsor team regarding scientific, non-clinical aspects, but only upon request. May participate in study design, participate in data analysis, interpretation, and reporting of data, but only after the analytic data set is final ("locked"), with the condition that other investigators who have no financial conflicts related to this clinical trial also participate in these activities. May participate as an author on publications resulting from this study. •May not have any role in subject selection, enrollment, the consent process, or any other role or involvement in the actual conduct of the clinical trial, may not have any role in data collection, cleaning or adjudication of primary or secondary outcomes, including whether adverse events are related to the trial.

What factors are considered in developing the management plan for FCOIs?

•Nature and design of the research / degree of risk to subjects •Oversight mechanisms •Magnitude and nature of the SFI •Investigator's role •Other factors as appropriate •For preclinical research - does research involve safety studies that FDA relies on to approve testing in humans? •For the trial- is release testing of the study drug done in the investigator's lab?

Discuss the Penn Gene Therapy Trial of 1999 that led to heightened scrutiny of clinical research, the government's response, and the lessons/takeaways/remaining questions.

-An 18 year-old subject with a rare genetic metabolic disorder died 4 days after being injected with corrective genetic material as a result of an overwhelming immune response to the vector causing a cascade of organ failures - The investigator and Penn held equity in the biotech company sponsoring the study -Resulted in settlements with government and the family Government's Response: •Required the report of an Independent Panel •Recommended that University review its COI policies, especially in regard to clinical trials. Takeaways: Perceived, as well as actual COIs, make clinical trials more open to suspicion and criticism Equity positions by an investigator and/or the University may be ill advised, even if, in reality, there is no practical effect "the avoidance of conflict of interest that even remotely might detract from putting the needs of patients first becomes paramount. In that regard, investments in new therapies differ from those in other ventures, such as computer technology, which involve no responsibilities for patient care." Remaining questions: Was the investigator's FCOI the reason for this tragedy? Would more stringent FCOI policies have prevented it?

What is the Physician Payment Sunshine Act?

-Applies to manufacturers of drugs, devices, biologicals, or medical supplies. -States that manufacturers must report to the federal government: •Payments or other transfers of value made directly or indirectly from applicable manufacturer to a Teaching Hospital or Physician •Excludes PhDs without MD •Opportunity to review and dispute the accuracy of the data -Must report recipient's name, address, $ amount, form, and nature of payment -Must identify product if payment related to marketing, education, or research specific to a covered product -Penalties -$1,000 to $10,000 for each unreported payment and $10,000 to $100,000 for each knowing failure

What is motivated bias? Describe the background research to support this.

-Bias in the evaluation of conflict of interest policies Journal of Law, Medicine & eEthics -Asked physicians, financial planners, and control subjects to rate agreement or disagreement with 4 statements and to rate reasonableness of 6 objections for 2 versions of a COI policy •physician interactions with industry •financial planners and companies that market investments Objective - Determine whether physicians would evaluate the same COI policy differently in two contexts? Results - pattern was consistent with motivated bias -Physicians were: •Less favorable toward the policy in a medical context. •Much more negative toward the medical vs. the financial advice policy •Consistently endorsed objections more strongly in the medical vs. the financial context -Same findings for Financial Planners but reversed. -Controls had similar attitude to both.

Discuss the new federal FCOI regulation regarding federal funding.

-Investigators are subject to expanded financial disclosure, management, reporting and training requirements -PIs need to carefully identify Investigators vs. consultants -PHS awards with identified FCOIs will be subject to increased scrutiny •Government cannot be misled as to the % of effort being devoted to federal grants •Publications should accurately reflect federal sponsorship •Publications should only acknowledge grant support if consistent with aims of grant

What are the disclosure requirements for reimbursed or sponsored travel?

-Must disclose any reimbursed or sponsored travel for the past 12 months related to Investigator's Penn responsibilities -Must identify: •Purpose of the trip •Identity of the sponsor/organizer •Destination •Duration -Institution will request additional information needed to determine whether travel = FCOI

If an FCOI is not timely identified or managed. . . ?

-Within 120 days of Penn's determination of noncompliance, must complete a retrospective review to determine whether the research was biased

What are the 3 main solutions for FCOI Management?

1) Reduction of financial interests •Forego founder's equity, serve on SAB but decrease compensation for consulting •May keep royalties as received through Penn 2) Specific restrictions or conditions on participation in the trial and /or the research plan •Appointment of different PI •Limitation on involvement in selection, recruitment or consent process, administration of intervention •Limitation on involvement in or oversight of data collection and interpretation •Preclusion from doing toxicity or safety studies 3) Disclosure •In all publications and presentations that relate to the research •To subjects in the clinical trial in the informed consent •To all the investigators and others working on this research

What is a conflict of interest (COI)? Examples?

A conflict of interest (COI) may exist when financial or other personal considerations have the potential to compromise or bias professional judgment or objectivity. According to IOM 2009, a COI is "a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest. Examples: •Subjective "Fame" factors Publications Promotion Prestige Ego •Objective "Fortune" factors: Funding for research Personal financial gain

What is the risk of FCOIs in the news?

Could results in: •Damage to an entire research enterprise by reducing the trust and confidence of the public in research •Damage to institutional and personal reputation and career from adverse publicity •Civil and criminal liability •Negative impact on funding from sponsors •Federal regulatory sanctions •Questionable integrity of research and subject safety in clinical trials

How often must investigators receive FCOI training prior to participating in PHS-funded research?

Every 4 years

What are the provisions for consulting at Penn?

Scope of Work •May advise based on general knowledge and expertise in the subject matter -DSMB, Expert Witness, SAB, training •May advise /guide regarding an outside entity's research •Should not parallel your academic, research activities at Penn •Should not result in publications in which the individual is listed as an author Funding •May not involve flow-through or direct federal funding Clinical Trials •May assist outside entity with a study's design •May serve as a reviewer •Should not serve as the primary and/or sole author •Should not serve as national PI for a clinical trial sponsored by the outside entity Compensation •Fees should be reasonably related to the time and effort spent •Should be an agreed-upon $ amounts rather than equity •Should not be based on clinical milestones Consulting Agreements •Must be reviewed in advance by School to insure no violation of Penn policies Confidentiality obligations •Not permitted to apply to the research •May not prevent or restrict publishing research conducted in your capacity as a faculty member •May not prevent you from providing tangible research property to a University research sponsor IP provisions •General rule- may not assign IP arising under a consulting agreement to the company Exclusivity or Non-Compete Provisions Use of University's Name and other website considerations Consider personal risks or liability that might result from the consulting arrangement

What is Penn's inventorship policy for faculty/staff versus for students?

Under Penn's Patent Policy, all Inventions which are conceived or reduced to practice in the course of employment at Penn, or result from work directly related to professional or employment responsibilities at Penn, or from work carried out on University time, or at University expense, or with substantial use of University resources under grants or otherwise, are the property of the Penn. Inventors must assign all rights to Penn •Includes Inventors who are postdoctoral employees and trainees, graduate students, and undergraduate Inventions made by undergrads remain their property except when an Invention is made in the course of employment at Penn or from work or research performed under a grant or other sponsorship, or undertaken with another Inventor who has a duty to make or has made assignment to the University.

When is there a conflict of commitment?

When extramural activities are conducted: •On University Time •With University Resources (Physical - computers, supplies, reagents or Intellectual) •In line with University's Mission - education, health care services, research And sometimes when there is a conflict between academic role vs. consultant role, as well as authorship on "extramural research".

What is a bias blind spot?

When researchers do not think their conflicts affect their research, but that conflicts do affect other people's decisions.

How quickly must written requests from the public for information regarding FCOIs of Senior/key personnel be responded to?

Within 5 business days

Is the impact of FCOIs distorted?

•Academia, the government, and the public have become overly sensitive to FCOI concerns •Pervasive anti-industry bias is not founded in fact (FAKE NEWS) •The term conflict of interest only IMPLIES inappropriate behavior •Disclosure policies in place thus far have focused on financial gain and not fame-related conflicts •Studies seeking evidence of industry influence have provided well-publicized associations -94% of physicians have relationships with industry -Physicians who request a drug from the hospital formulary are more likely than other physicians to have a relationship with Pharma -Pharma-sponsored studies are more likely than government-sponsored ones to have positive results -Prescribing practice is influenced by attendance at pharma- sponsored symposia -The questions remains - Where is the evidence that any of these interactions, or efforts to curtail them, are beneficial or harmful to patients?