Financial Conflicts of Interest in Research

Marion Danis, M.D.

Department of Clinical Bioethics

National Institutes of Health

Washington, DC

DISCLAIMER

The views expressed in this presentation do not represent the views of the NIH, DHHS, or any other government agency or official.

Outline

Background The Problem with Conflicts of Interest

Definition What is Conflict of Interest?

Data Analysis and recommendations for managing

COI For individual investigators For institutions and institutional officers

Does Conflict Influence You?

Would you present data differently in a lecture if a drug company were paying you R$15,000 to give the lecture?

Would you persist in conduct of a study with adverse outcomes if a company were funding your research?

What is a Conflict of Interest? A conflict of interest occurs when a secondary

interest distorts or has the potential to distort a judgment related to a primary interest

A professional’s judgment does not necessarily have to be biased in order for that researcher to have a conflict of interest — even the appearance of a conflict of interest is ethically worrisome

Primary Interests Professionals have a primary interest—the goal of

their profession

For researchers:

Producing generalizable knowledgeEnsuring the safety of research subjectsDisseminating research results

Secondary Interests Professional goals

Publishing Obtaining future research funding Gaining recognition and fame

Personal goals Spending time with his/her family Earning a good income Other personal interests such as religion, traveling,

social activities, etc. Political activism

Bad Outcomes Associated with Conflict of Interest

Recent deaths have raised the question of whether researchers were more concerned about financial matters than patient safety Gelsinger case at University of Pennsylvania Fred Hutchinson Cancer Center

Research Funding in the United States

0%

25%

50%

75%

100%

1980 2000

Government

Industry

• Phase I-III Trials:-Pharmaceuticals R$65 billion

-NIH R$20 billion

Industry has dramatically increased its funding of clinical research compared to the government

32%

62%

Assessing Secondary Interests

It is important to note that secondary interests on their own are not bad or unethical

Usually these secondary interests are good and often praiseworthy Time devoted to one’s family Lobbying for a political belief Volunteering for a local charity

Assessing Secondary Interests What makes secondary interests problematic? Their ability to unduly influence decisions about

an individual’s primary interest

The key ethical issue is the relationship between a primary and a secondary interest

Focus on Financial Conflicts of Interest

Why this focus?

Money is… Multi-purposed A key motivating factor Can be quantified Relatively easy to regulate Source of public mistrust

Frequency of Financial Interests

In a survey of published randomized controlled trials, of authors that disclosed a financial interest… 30% Employment 22% Consultancies and Honoraria 18% Grants 7% Educational/Speaker’s Bureau 7% Stock ownership 5% Advisory Board 1% Patents/Licenses

Gross et al. JAMA 2003

Possible Threats Posed by Researchers’ Conflicts of Interest

Valid research design Data integrity Dissemination of results Research subject safety

Research Design

Industry-sponsored research was more likely to be double blind and to report adverse events in the experimental groups than research sponsored by non-profits

Liebeskind et al. BMJ 1999

Data Collection

Do financial interests compromise data collection and interpretation?

Data suggest that industry funded clinical research leads to positive results more frequently than non-industry funded research

Data Collection

Of 11 meta-analyses, 9 reported that industry sponsored trials were significantly more likely to yield pro-industry results

Odds ratio of having industry sponsorship and pro-industry conclusion:OR=3.60 (2.63-4.91)

Bekelman et al. JAMA 2003

Data Collection

Possible explanations: Industry commits resources only to clinical

research that is likely to yield positive results

Industry terminates large randomized studies early that are likely to have side effects and less likely to be successful or to generate huge profits

Dissemination of Results

Industry-funded clinical research studies that produce positive results are more likely to be published compared to government-funded clinical research

Dissemination of Results

Meta-analysis of data from randomized trials that evaluated an SSRI against placebo in the treatment of depression in children

Articles reviewed were published in a peer-reviewed journal or unpublished (and reviewed by the Committee on Safety of Medicines)

Whittington et al. Lancet 2004

Dissemination of Results Results:

When published data alone were considered, it appeared that there was a favorable risk-benefit profile for 5/5 drugs studied

Addition of unpublished data indicated that the risks outweigh the benefits for 4/5 drugs studied

Unknown if unpublished articles were not published due to publication bias against negative studies at major journals or the result of industry withholding negative data

Whittington et al. Lancet 2004

Patient Safety

No data

No data on overall safety of clinical research

Patient Safety

No data on overall safety of clinical research

In a bone marrow protocol at Fred Hutchinson Cancer Research Center, 80/82 enrolled research subjects died

Study investigators had R$937 million of holdings in a drug company sponsoring part of the research

Patient Safety

This does not necessarily indicate that a conflict of interest impacted researchers’ judgment or patient safety

Need to be sure we do not draw unsubstantiated conclusions from the data

Raises questions and concerns, but deaths are not necessarily due to the presence of conflicts of interest

Summary of Relationship of FCI and Researchers’ Behavior

Researcher financial interests are common: 25% to 33% of researchers

Financial interests Do appear to influence researcher judgment and

data dissemination Do not appear to influence research design Influence data collection and interpretation ? Influence patient safety ?

Protection against COI

Aim to reduce:

Likelihood of harm: Limit the possibility of a harm occurring in the first place

Magnitude of harm:Lessen the negative consequences of the harm

Protections for Individual Investigators

Disclosure To institution/IRB/COI committee To patients In journals

Management Data safety and monitoring boards (DSMBs) Independent consent monitors

Restrictions/Prohibitions Recusal Divestment Resignation Policies prohibiting types/amounts of financial interests

Creation of trial registries

Problems with Protections

No consistent standards for disclosure:

2001 US Government Accounting Office study of 5 major research institutions in the US

Rules regarding disclosure and prohibitions of financial interests varied widely

Limits of financial interests varied from R$30,000 to R$300,000

Problems with Protections

No consistent standards for disclosure:

Disclosed information is not well recorded and not readily available to the IRBs

Researchers are not aware or well-informed of disclosure policies At UCSF and Stanford, 58% of researchers could not

accurately describe the COI policy of their institution

Institutional Conflict of Interest

“An institution may have a conflict of interest in human subjects research whenever the financial interest of the institution, or of an institutional official acting within his authority, might affect - or reasonably appear to affect -institutional processes for the conduct, review, or oversight or human subjects research.”

AAMC Task Force 2002 Report

Concerns relating to Institutional COI

The agenda of a sponsoring agency may conflict with the agenda of the university

Commercial interests of a sponsor may conflict with social goals of scientific research

If the institution aligns itself with the sponsor the institution’s interests can conflict with goals of science and protection of human subjects

Concerns relating to Institutional COI

The goals of the sponsor may inappropriately affect the research environment Sponsors seek a positive outcome from

the research at an acceptable cost Sponsors seek to protect intellectual

property related to the subject matter of the research

How Institutions Benefit from Sponsored Research

Overhead payments Compensation for enrolling subjects Stock options Royalties from sale or license of

patented technologies Partnerships with industry Donations or grants from industry

Conflicts of Institutional Officials

Leaders: deans, department heads, trustees, officers who make institutional decisions are charged with making these decisions in the institution’s interest

Personal interests and financial holdings may give rise to conflicts with institutional responsibilities

Institutional leaders are sometimes given appointments to start up companies

Conflicts of Institutional Officials

Institutional Review Boards members who review proposed research may have ties to industry: Own stock Receive royalties Participate in clinical trials Receive industry support for their research

Conflicted IRB Officials

Decisions about research may be improperly influenced

Encouragement or permission for research that may not meet requirements for human subjects protection

Allocation of institutional resources such as funding, personnel, equipment, space to commercial sponsor’s research

Threats to Trainees

Encouragement of trainees to pursue research that is not in the trainee’s educational interest

Involvement of trainees in research that cannot be freely published

Threats to Human Subjects Protection

Pressure to recruit inappropriate subjects to yield large study sample quickly

Due to sponsor’s interest in completing trials quickly to gain time on exclusive patent holdings

Threats to Human Research Subjects from Institutional COI

Imperative to recruit quickly and show positive results may prompt: Subtle pressure to misrepresent the misrepresent

the true nature of the trial Failure to describe alternatives to trial participation Insufficient caution in assessing the capacity of a

research subject to consent Inclusion of subjects who do not meet enrollment

criteria Failure to monitor precisely and report adverse

events

Threats to Research Integrity

Sponsored research is more likely to report favorable outcomes Trial design may favor positive outcome Publication of negative results may be

delayed or restricted

Protections against Institutional COI

Institutions should establish administrative processes to assess and manage conflict

Cooperation between institutions and sponsors should be at a distance

Protections against Institutional COI

Disclosure policies Who should disclose What should be disclosed To whom to disclose

IRB Research subjects Publications

Protections against Institutional COI

Assignment of oversight responsibility Institutional conflict of interest committee

Members with experience, seniority, independence

Outside the line of authority for overseeing institutional research

Community representation

Independent review of research Study design, data analysis, publication

Independent investment management

Protection for Institutional Officers

Required disclosure of conflict of interest Divestiture of investment Prohibition of research by persons who

have combined roles as official and scientist

Protections for IRBs and IRB Members

Fund IRB from some other portfolio than that of the Dean of Research

Require IRB members to disclose personal finances

Have IRB review clinical trial agreements to avoid publication restrictions

Conduct educational programs on COI as requirement for IRB members

Conclusions

The opportunity to participate in research creates important obligations for individual investigators and their institutions to conduct research with integrity

Personal responsibility must be combined with institutional structures to address the conflicts of interest that inevitably arise in carrying out research.