Why pay attention to conflicts of interest?

Conflicts of interest are an important issue in biomedical research and need attention because:
It may result in harm to research subjects

It may reduce public trust in research, threatening:

Recruitment of subjects in research Public financial support of research

Conflicts of interest are pervasive, may be present:

In peer review process
In selection of which treatment to investigate In selection of subjects In REB review of research projects They may be financial, institutional, systemic

Etc.

Other examples of COI

Pressures to obtain funding, publish, or even earn respect from peers can influence judgment and diminish objectivity.
Conflicts of conscience can occur when personal beliefs influence objectivity in research (e.g., a particular view on the use of stem cells could influence the review of the scientific merit of a study involving stem cells). Research participants may have an interest in gaining access to a promising new drug in a clinical trial. That may influence research subjects in taking more risks, being less critical of research

Other examples of COI

Universities have an interest in acquiring a reputation for bringing in the most research dollars, which attracts more students and top researchers. The government has an interest in attracting industry investment into research and the consequent job creation.

Definition from the US Institute of Medicine, 2009

A conflict of interest is a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest (such as the integrity and quality of research) will be unduly influenced by a secondary interest (such as personal financial gain).
IOM (Institute of Medicine). 2009. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: The National Academies Press, 46. It combines elements from: Emmanuel, E.J., Thompson, D.F., The Concept of Conflicts of Interest. The Oxford Textbook of Clinical Research Ethics, Oxford University Press, 2008, 760.

Clinical research requires large investments

Clinical research is a complex activity. Drug development, in particular, is an activity that may require years of commitment from researchers and sponsors and investments that can reach the hundreds of million of dollars.

Clinical research requires large investments

In seeking to recuperate their investments, sponsors and some researchers may at times make choices that favour financial interest over clinical interests

Subjects believe there are safeguards against conflicts of interest

Of the patients surveyed, 62% believed there was an oversight system in place to monitor financial ties. However, when asked, most could not specify a system but suggested that there must be a process during study implementation, such as an independent oversight committee to screen M.D.s credentials and relationship with drug companies. One third of the patients did not know whether there was such an oversight system.
Hampson, LA et al, Patientss Views on Financial Conflicts of Interest in Cancer Research Trials, New England Journal of Medicine, 355;22, 2006, 2334.

Little oversight of COI

Actually, there is little oversight of financial COI
Budgets for clinical trials are often reviewed only by institutions when they look at the contract, not always research ethics committees Patients are not very worried about the effect of clinical trials, think the physician will do what is best for them.

Jesse Gelsinger died four days after an innovative gene transfer experiment to correct an inherited liver disorder.

About the case

Jesse did not meet the inclusion criteria
Investigator failed to implement the safety protocol and stop study Purely altruistic reasons for participation Risks largely unknown Serious adverse events not declared in consent nor reported Investigator had financial stake

Financial COI
A conflict of interest was identified that involved the lead scientist, Dr. Wilson. As it turned out, Dr. Wilson had a financial interest in the development of the adenovirus vector being used in the gene therapy trial. If his gene therapy vector worked correctly and was successful, he could make a lot of money by using it to treat people or by selling it to other researchers.

Financial COI
This conflict of interest may have influenced the decisions made by Dr. Wilson as he continued with his experiments. Do you think a researcher can make sound decisions about an experiment when they have an important financial stake in the outcome of those experiments?
The financial interest of Dr Wilson was disclosed in the consent form. Did it make any difference?

Institutional COI
The university and several past and present officials had financial interests in the biotechnology company that developed the intervention. The company contributed $25 million to the research institutes annual budget and had exclusive rights to develop products emerging from the trial and related research. In addition, the director of the institute (Dr Wilson), who was also the lead researcher, had founded the company and maintained a financial interest in it.
IOM (Institute of Medicine). 2009. Conflict of Interest in Medical Research, Education, and Practice, 217

Potential conflicts of interest extend to government advisors. In 2005, an FDA advisory panel voted to allow the painkillers Celebrex, Bextra, and Vioxx to remain on the market, despite data showing that they increased the risk of heart attacks.
Josephine Johnston, Conflict of Interest in Biomedical research, in From Birth to Death and Bench to Clinic: The Hastings Center Bioethics Briefing Book for Journalists, Policymakers, and Campaigns, ed. Mary crowley (Garrison, nY:the Hastings center, 2008), 33.

A week later, the center for Science in the Public Interest reported that 10 of the 32 panel members had recently provided consultations to the manufacturers of the drugs, leading to speculation that if these conflicted researchers had been left off the panel, the drugs would have been withdrawn from the market.
2/2

Individual COI
The term individual financial conflict of interest in science refers to situations in which financial considerations may compromise, or have the appearance of compromising, an investigators professional judgement in conducting or reporting research. The bias such conflicts may conceivably impart not only affects collection, analysis, and interpretation of data, but also the hiring of staff, procurement of materials, sharing of results, choice of protocol, involvement of human participants, and the use of statistical methods.
American Association Universities, Report on Individual and Institutional Financial of Conflict of Interest, Washington, 2001.

An institutional conflict of interest involves a conflict between at least two substantial institutional obligations that cannot be adequately fulfilled without compromising one or both obligations. Conflicts may occur when pursuing particular goals, for instance, the pursuit of two different goods, such as an effort to obtain general infrastructure funding from a donor that conflicts with an effort to promote research that the donor does not wish to support. Institutional conflicts of interest may compromise duties of loyalty and lead to biased judgments. Conflicts may also undermine public trust in the ability of the institution to carry out its missions, operations and ethical responsibilities in research.

Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans,

Ottawa, December 2010, 90.

Institutional COI in Human Research

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

Task Force on Financial Conflicts of Interest in Clinical Research, Protecting Subjects, Preserving Trust, Promoting Progress II: Association of American Medical Colleges, Washington, D.C, 2002.

Examples of institutional conflicts of interest

The hospital will receive very expensive equipment if a protocol is allowed to be pursued in the institution. The administration pressures the REB to approve. The majority of US Universities (70%+) hold equity stakes in businesses that sponsor research on campus.

Promising Appointment
In early 2000, Dr. David Healy, a renowned psychiatrist, studying the effects of antidepressants, was hired as Professor of Psychiatry in the University of Toronto, and Head of the Mood and Anxiety Disorders Program at an affiliated institution, the Center for addiction and Mental Health (CAMH).

Dr David Healy

Coming Out Clear

During the interviews, Dr Healy made no secret of his involvement in a controversy concerning the influence of the pharmaceutical industry on medicine and academia. In particular, he had conducted studies which suggested that Prozac and SSRIs (selective serotonin re-uptake inhibitors) could lead to suicide and had been critical of the amount of ghost writing in the current scientific literature.

Clashing views: fired before he started

After he gave a conference criticizing drug companies for not undertaking research that might expose hazards of their products and pointing to the possibility that antidepressants like Prozac might be leading to suicide, he was contacted by the university to learn that he no longer had the job.
With the support of the Canadian Association of University Teachers, he launched a legal action which he won.

Even if There Is No Direct Intervention, Money Talks

Last year, 52 percent of the research dollars in that department came from drug companies, almost three times the centre's overall rate. Then there are corporate donations, including a $1.5 million gift Eli Lilly pledged to the centre's fundraising campaign last year. Such a close financial relationship inevitably comes with a close working relationship and lots of meetings between scientists including one on the very day David Healy delivered his lecture.
Dr. David Healy - Part II, Canadian Broadcasting Corporation News and Current Affairs Tue 12 Jun 2001

Primary interest of IRB

The primary interest of IRBs is to ensure that the rights and welfare of research participants are fulfilled. All other interests are secondary, including personal or institutional financial gain. When a person's financial concerns have the potential to conflict with the protection of participants, a FCOI exists.
Campbell, EG, Concerns about IRBs in the enterprise of clinical research, The Lancet Oncology, 5 (1) 2004, 326.

REC members financial COI may undermine objectivity

"Financial relationships with study sponsors create competing interests that could undermine the objectivity of the IRB process. Policies and practices regarding the disclosure and management of such relationships among IRB members need to withstand intense scrutiny, and our results suggest that we can do much better.
EG Campbell, cited in Osterweil, N. Many Clinical Trial Overseers Have Conflicts of Interest ,MedPage Today, November 29, 2006

US Regulations...
DHHS (OHRP) and FDA regulations [45CFR 46.107(e) & 21CFR 56.107(e)] prohibit members from participating in IRB reviews if they have a conflict of interest.
No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB.

Good Clinical Practice (E6)

3.2.1 Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter.

Universal Declaration on Bioethics and Human Rights 2005 Article 19

Independent, multidisciplinary and pluralist ethics committees should be established, promoted and supported at the appropriate level in order to:
(a)assess the relevant ethical, legal, scientific and social issues related to research projects involving human beings; (b) provide advice on ethical problems in clinical settings; (c) assess scientific and technological developments, formulate recommendations and contribute to the preparation of guidelines on issues within the scope of this Declaration; (d) foster debate, education and public awareness of, and engagement in, bioethics.

The Research Ethics Board (REB), as an entity, or in the persons of the members who make up the board, also hold trust relationships with participants, research sponsors, researchers and society. REB members must also be aware of their own potential for real or perceived conflicts of interest.

For example, REB members are in a conflict of interest when their own research projects are under review by their REB, when they are a co-investigator, or when they are in a supervisory or mentoring relationship with a graduate student applicant. REB members may also be in a conflict of interest situation when they have interpersonal or financial relationships with the researchers, or personal or financial interests in a company, labour union or not-for-profit organization that may be the sponsor of the research project, or that may be substantially affected by the research.
Conflicts of interest based on collaborations or disputes with colleagues, students or others may be ongoing or of limited duration. REBs have an obligation to ensure that the fairness and transparency of research ethics review is not compromised by real, potential or perceived conflicts of Interest Tri-council Policy Statement: Ethical Conduct for Research Involving Humans, 2010, 90

Conflicts of interest for Research Ethics Committees

the ethical review of research protocols is generally performed within and by employees of the very institutions in which the research will be carried out, a clear conflict of interest.
T.L. Beauchamp, The (mis)used of informed consent in medical research, Journal of Internal Medicine, 269, 2011, p. 383.

When we need to retain the services of the clinician-researcher

In the case of smaller or regional hospitals, there might occur a conflict originating in the will or need to retain the services of a difficult to recruit specialist. Very specialized surgeons for examples or anaesthetists are difficult to recruit. If the REB turns down a protocol, they may choose to go elsewhere.

Other examples of COI

REC members may find it difficult not to approve a proposal from a close colleague
REC members who do research in a certain field may find it difficult to reject a project in that area of research Pressure to do research in large groups may create COI with researchers that are not very close but close enough to influence REC members judgement

COI in IRBs: Common Practice

Relationships between IRB members and industry are common, and members sometimes participate in decisions about protocols sponsored by companies with which they have a financial relationship. Current regulations and policies should be examined to be sure that there is an appropriate way to handle conflicts of interest stemming from relationships with industry.
Cambell, EG et al., Financial relationships between institutional review board members and industry. The New England Journal Of Medicine, 2006 Vol. 355, (22)

Conflicts of interest for Research Ethics Committees

It is good practice for the Chair to ask if any member has I of the protocols under review a conflict of interest with any at the beginning of the REC meeting
It is expected that REC members will voluntarily recuse themselves from review and discussion of research protocols if they have a conflict of interest. Members of the REC must disclose to the REC Chair or Administrator any conflict of interest that may arise in the review of research or compliance matters for the REC.

Through motions from the SCE, Governing Council has been apprised of the problem of systemic conflict of interest for CIHR in its dual role of promoting and sponsoring researchers, and ensuring compliance to protect research participants. The

November 7th motion of the SCE on this issue:

The CIHR Standing Committee on Ethics supports the concerns raised at both meetings of the Institute Advisory

Board Ethics Designates with respect to the perceived

systemic conflict of interest within the governance structure of the Tri-Council Policy Statement.

The Standing Committee on Ethics is of the view that there is a systemic

conflict of interest in the dual role of the federal funding councils - CIHR,
SSHRC, and NSERC - to both promote research and regulate its ethical conduct. The Standing Committee on Ethics urges Governing Council to explore with the two others federal agencies the problem of systemic conflict

of interest with a view of making structural changes to avoid such conflict of

interest was presented to and accepted by the Governing Council.
Canadian Institutes of Health Research, Meeting Minutes - 18th Meeting of the Governing Council, November 20-21, 2002, Toronto, Ontario

(A) Identification: The first step regarding institutional CoI involves deciding on the ethical principles involved, defining CoI based on those principles, and assessing the institutions' interests and obligations. (B) Application: The criteria used to identify institutional CoI must be clearly delineated for researchers, institutions and reviewers. Also, comprehensive policies regarding CoI that guide rather than constrain behaviour must be created at the institutional level. A national CoI policy or at least template should also be developed so that there will be uniformity among institutions.

(C) Action: Institutions' financial and research management functions should be separated as much as possible. Education is necessary so that people recognize circumstances of competing interests and obligations. Every web of relationships has the potential to create different kinds of institutional obligations and interests, and training will assist in the identification of CoI. (D) Disclosure: There must be transparency regarding disclosure of real, apparent and potential COI. Financial and non-financial conflicts should be discussed on a routine basis. Full and complete disclosure of all relationships with industry, and of all advisory relationships with research regulators is a necessary first step in managing COI. Timely and complete disclosure of the results of all clinical trials is essential in order to reduce possible conflicts that can arise from the control of such information.

(E) Management: There is a need to enforce compliance with the rules regarding conflict that are already in place, and encourage a culture of compliance. Manage and review conflicts of interest using independent sources and external reviewers (e.g., through the use of institutional COI committees). Build organizational "firewalls" so that potentially conflicted parties do not interact; this can be accomplished through the use of professional investment managers. (F) Other Ideas: Create a website devoted to COI. Consider the use of advisory committees to interact with industry. Consider removing IRBs/REBs from the institutions they serve, in order to make them truly independent. Consider removing the mandate to regulate research from the funders of research. FOCUS, Report on an International Conference on Conflicts of Interest, Ottawa, NCEHR, 2004.

Conclusion
Conflicts of interests are pervasive
They threaten public trust in health research and the attainment of important public health objectives Transparency, information and education are key REC play important role; must disclose internal COI and help researches solve issues, inform and educate subjects