Ethical principles in clinical research

by Allen Alvarez

Ongoing clinical trials in the Vancouver Coastal Health Research Institute (VCHRI) jurisdiction are listed on their clinical trials website. One can also search the database of clinical trials that Health Canada maintains on their website. Some of these are also in the Center Watch list of clinical trials in Vancouver, BC. The U.S. NIH maintains a global clinical trials registry, that includes clinical trials in Canada on their clinical trials registry website https://clinicaltrials.gov. According to the NIH registry, there are currently 14,940 clinical trials in Canada and 3,758 of these are in British Columbia.

Source: https://clinicaltrials.gov/ct2/search/map?map=NA%3ACA

A detailed list of the studies in the NIH registry can be viewed by clicking on the map on the clinicaltrials.gov site. For example, if the map of British Columbia is clicked, a list of completed and ongoing clinical trials will appear.

The International Committee of Medical Journal Editors (ICMJE) require researchers intending to publish results of their clinical trials in medical journals to register such trials in one of their approved registries, e.g. clinicaltrials.gov maintained by NIH and the ones listed on the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) platform.

An overview of how clinical trials in Canada is regulated by Health Canada is available here.

Health Canada classifies human clinical trials into four phases:

Phase I trials
Initial safety studies on a new drug, including first administration of the drugs into humans, usually conducted in healthy volunteers.

Phase II trials
Clinical trials to evaluate the efficacy of the drug in patients with medical conditions to be treated, diagnosed or prevented and to determine the side effects and risks associated with the drug.

Phase III trials
Controlled or uncontrolled trials conducted after preliminary evidence suggesting efficacy of the drug has been demonstrated.

Phase IV trials
All studies performed after the drug has been authorized by the regulator for the market, and related to the authorized indication.

Clinical researchers running these clinical trials were required to secure a number of independent approvals and fulfilled all the requirements for this type of research imposed by institutions, e.g. UBC, and as well as those relevant to sponsors, the institution funding the research and Canadian, U.S. and international laws. Details of forms needed to be completed as well as guidance notes from the UBC Clinical Research Ethics Board (CREB) are available online. These clinical trials are subject to audit and monitoring for continued compliance to the said requirements.

The key regulatory requirement is compliance with standards regarding adequate protection of research participants, their human right to be respected as free agents, their interests in relation to the greater good of society and fair selection in accordance to principles of distributive justice. These principles are oriented around the concern for research participants and society.

One other principle, which I call a 'Fourth Principle', that has been emphasized by researchers and research societies (e.g. the U.S. National Academy of Sciences, NAS 1992, 2002) but seldom by external regulatory commissions such as the one that drafted the Belmont Report (1978), is integrity of researchers and the related value of objectivity of research. The corresponding guideline for this is the requirement to disclose conflicts of interest, especially financial conflict of interest.

Conflicts of interest (COI) disclosures and the virtue of integrity as researcher-oriented ethical principle

Researchers, as individuals, have multiple motivations related to conducting clinical trials and research. Various interests may influence involvement in conducting clinical trials, including gaining more knowledge, advancing one's career, income, promoting benefits to society and fulfilling one's job as a researcher. Some of these interests may compromise one's primary commitment to objectively answer the research questions being investigated in a particular study or clinical trial.

When other commitments and interests compete with one's primary commitment as a researcher, her integrity is undermined, especially the societal trust this engenders. For this reason institutions, e.g. UBC, established policies to protect integrity and trust though preventing and managing conflicts of interests (COI). The key procedure is filing an annual conflict of commitment and conflict of interest disclosures (UBC Policy 97, Sections 1.2).

To cite an example of conflict of interest, if the safety or efficacy of a drug is being investigated and the profitability of the drug makes it enticing to the sponsor to influence the investigator to produce an evaluation that would favor approval of the drug, any financial interest of the investigator related to the sponsor, e.g.  investments in the sponsor's company, can be reasonably considered conflict of interest which must be disclosed. Further, the investigator must, for example, divest her investments in the sponsor's company to be able to objectively fulfill her task as evaluator of the drug's safety or efficacy. As Lemmens and Luther (2008: 223) stated: "The conflict resides then in the fact that commercial sponsors have a direct interest in obtaining commercially favorable results, while the goal of research is to obtain reliable and Scientifically accurate information that benefits patient care."

A similar proscription against financial conflict of interests are stated in the College of Physicians and Surgeons of British Columbia's "Conflict of Interest Arising from Clinical Research" document but with emphasis on the primary interest of the physician to objectively provide care that can be undermined by the secondary interest in financial or other personal benefits she could gain from enlisting her patient to a clinical trial.

Annual COI disclosures

In the case of UBC, applications and annual renewal applications for Research Ethics Board (REB) approval include a required question on COI (2.6 in the online application form at https://rise.ubc.ca) which asks:

* 2.6. Conflict of Interest
Do any of the following statements apply to the Principal Investigator, Co-Investigators and/or their partners/immediate family members?

• Receive personal benefits in connection with this study over and above the direct cost of conducting this study. For example, being paid by the funder for consulting.  (Reminder: receiving a "finders fee" for each participant enrolled is not allowed). 
• Have a non-financial relationship with the sponsor (such as unpaid consultant, advisor, board member or other non-financial interest). 
• Have direct financial involvement with the sponsor (source of funds) via ownership of stock, stock options, or membership on a Board. 
• Hold patent rights or intellectual property rights linked in any way to this study or its sponsor (source of funds).

   ___Yes ___No

The steps in disclosing COIs at UBC are listed here. The COI disclosure is reviewed by the Head of department first, then by the Faculty review committee if necessary, e.g. UBC Faculty of Medicine COI/COC Review Committee for those in that faculty. The UBC University Counsel updated the UBC Board of Governors on the UBC COI/COC policy on February 2014. The UBC Office of Research Ethics maintains a Financial Conflict of Interest (FCOI) webpage date June 17, 2015 http://ethics.research.ubc.ca/ore/us-financial-coi. Included on that webpage is a link to the UBC Directive on Financial Conflicts of Interest (FCOI) in Public Health Service (PHS) Funded Research. The Directive is effective August 24, 2012, according to that document, in compliance with US PHS regulations (42 CFR Part 50 Subpart F and 45 CFR Part 94). The document also has a date September 4, 2014 on the footer title.

The U.S. Federal Register has published a regulation on August 25, 2011, effective September 2011, called Responsibility of Applicants for Promoting Objectivity in Research for Which  Public Health Service (PHS) Funding Is Sought and Responsible Prospective Contractors; Final Rule and Responsible Prospective Contractors  (DHHS 42 CFR Part 50 Subpart F (grants and cooperative agreements), 45 CFR Part 94 (contracts)). This regulation is adopted by UBC and is required for all UBC affiliated researchers (as per UBC Policy 97 as well as TCPS2 2014 Article 7.3).  This U.S. policy requires that UBC complies no later than August 24, 2012 but immediately upon making its institutional Financial Conflict of Interest (FCOI) policy public.

Unless other institutions adopt stricter rules, the US FCOI regulation does not apply to that Small Business Innovation Research (SBIR)/ Small Business Technology Transfer research (SBTTR) phase I clinical trial (safety study) applications (42 CFR 50.602, 45 CFR 94.2). Phase II clinical trial applications are covered. However, it also states that 

"In those few cases where an individual, rather than an Institution, is applying for, or receives, PHS research funding, PHS Awarding Components will make case-by-case determinations on the steps to be taken, consistent with this subpart, to provide a reasonable expectation that the design, conduct, and reporting of the research will be free from bias resulting from a financial conflict of interest of the individual." (42 CFR 50.602, 45 CFR 94.2)

The title of the policy itself states the purpose of the requirement for COI disclosure, i.e. "promote objectivity" which could be undermined by conflicting interests. This is also affirmed in UBC Policy 97 Section 4.1, i.e. COI disclosure is crucial in "preserving the public’s confidence in their ability to pursue and disseminate knowledge, devoid of bias and personal interests."

There are corresponding sanctions to those who violate COI policies, including terminations of funding and/or "repayment of any financial benefit gained by the researcher" (UBC Policy 97 Article 8.3).

The 3 basic ethical principles that are research participant and society-oriented

There are clear similarities between the Belmont Report's (1978) three basic ethical principles and the TCPS2 2014 three core principles (Article 1.1).

	Belmont Report (1978)	TCPS2 2014
Principle 1	Respect for persons	Respect for persons
Principle 2	Beneficence “…making efforts to secure…well-being…  (1) do not harm and (2) maximize possible benefits and minimize possible harms”	Concern for welfare “protect the welfare of participants, and, …promote that welfare in view of any foreseeable risks associated with the research”
Principle 3	Justice	Justice

It would be interesting to review how the TCPS2 core principles were consolidated from the TCPS 1st edition list of 8 guiding ethical principles. This parallels the consolidation of 8 principles into 3 by the commissioners who drafted the Belmont Report (Jonsen 2005: 4). In this sense, TCPS is like the 'Belmont Report' of Canada drafted 20 years later (1998) than its predecessor. For Belmont Report (1978), however, the reduction to 3 principles was immediate. It took 12 years for the 8 guiding ethical principles in TCPS to be reduced to 3 in 2010.

References:

CIHR, NSERC, SSHRC (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada) (1998). Tri-Council Policy Statement: Ethical Conduct For Research Involving Humans. Tri-Council policy statement: Ethical conduct for research involving humans (TCPS, 1st edition). Available at: http://www.pre.ethics.gc.ca/eng/archives/tcps-eptc/Default/. Date modified: December 18, 2014.  

CIHR, NSERC, SSHRC (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada) (2010). Tri-Council Policy Statement: Ethical Conduct For Research Involving Humans. Tri-Council policy statement: Ethical conduct for research involving humans (TCPS2). Available at: http://www.pre.ethics.gc.ca/eng/archives/tcps2-eptc2-2010/Default/

CIHR, NSERC, SSHRC (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada) (2014). Tri-Council Policy Statement: Ethical Conduct For Research Involving Humans. Tri-Council policy statement: Ethical conduct for research involving humans (TCPS2 2014). Available at: http://www.pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/Default/. Date modified: February 13, 2015.

Jonsen, A. R. (2005). On the origins and future of the Belmont Report. In Childress, J. F., Meslin, E. M., & Shapiro, H. T. (Eds.). Belmont revisited: Ethical principles for research with human subjects. Georgetown University Press. pp. 3-11. https://books.google.ca/books?id=4U6iStmnQlYC&lpg=PP1&pg=PA3#v=onepage&q&f=false


Lemmens, T. & Luther, L. (2008). Financial conflict of interest in medical research. In  Singer, P.A. and Viens, A.M. The Cambridge Textbook of Bioethics, 222-230. Available at. https://www.law.utoronto.ca/documents/Lemmens/cambridge_conflict_of_interest.pdf

NAS (1992). Institute of Medicine, National Academy of Sciences, and National Academy of Engineering. Responsible Science, Volume I: Ensuring the Integrity of the Research Process.   Washington, DC: The National Academies Press, 199 pages. Available at: http://www.nap.edu/read/1864/. Published online: March 1, 2003. Last accessed: December 15, 2014.

NAS (2002). Committee on Assessing Integrity in Research Environments. Integrity In Scientific Research: Creating An Environment That Promotes Responsible Conduct.Washington, DC: The National Academies Press, 202 pages. Available at: http://www.nap.edu/read/10430/. Published online: October 1, 2002. Last accessed: December 15, 2015.