Kathleen Glass, LLB, BCL, LLD, Biomedical Ethics Unit, and Departments of Human Genetics & Pediatrics
Regardless of circumstance, we all have an interest in whatever works to our advantage and betters our profits. In the academic world, conflicts of interest (CI) are an integral part of the review process. In grant, promotion, and publication reviews, we have opportunities to promote or censor our competition. We are expected to use our best professional judgment and not to subordinate it to private or personal interests.
I will talk about the potential for CI in relationships between investigators and other parties in the research endeavour. I will not talk about scientific misconduct or fraud, which is not ethically questionable but clearly wrong. I will discuss the potential for subordinating professional judgment to private or personal interests. I am speaking from an academic perspective and as an REB member, who also has some experience as a research subject in a clinical trial.
There are many individuals and groups with an interest in research. Clinical investigators share an interest in developing safe, effective, and accessible treatment and diagnostic methods. They are primarily interested in scientific or clinical truth, i.e., valid answers to research questions, but they may also be interested in enhancing their clinical reputation, academic promotion through publication, and fair compensation for their work.
Patients are interested in accurate diagnosis, accurate and complete information, effective treatment, and a low risk:benefit ratio. They want any risks minimized to the greatest possible extent. Patients in clinical trials are particularly interested in finding an effective treatment that may benefit them or the specific group with whom they share a particular condition.
In a clinical trial, recruiting physicians or other health-care professionals may be interested in receiving some remuneration for the time that they spend in this endeavour. They may have an interest in reciprocity; if they recruit for other investigators’ trials, their colleagues may do the same for them.
Sponsors, particularly commercial sponsors, are interested in relevant and prompt research findings with marketable results. They are interested in minimizing research costs and protecting other interests, such as patentable discoveries or the future commercial use of tissue samples. In addition, they are interested in maintaining a good reputation.
Host institutions value good research, because it adds status and enhances their reputation. They are, of course, interested in financial subsidies that clinical trials may bring to their institutions.
The scientific community wants to maintain a good public reputation, respect for the enterprise, and medical progress. Access to research findings lies within the interest of the scientific community. Traditionally, scientists have shared results at conferences, where they have a strong interest in maintaining the academic freedom to say and publish what they wish in the proceedings.
Society has a shared interest in safe and inexpensive prevention, diagnostic, and treatment strategies.
These interests influence clinical research. Their impact has and will continue to change over time. In the pre-WWII era, research was largely a laboratory-based endeavour. There were few sizable clinical studies. Funding was mostly provided by host institutions, medical schools, and private foundations. Medical research was not enormously expensive. It was primarily based on case studies, observation, and simple laboratory investigations.
The success of government-funded, war-related research led to increased government funding for basic and clinical research. With a great deal of financial support, medical research entered an era of immense activity. Today, there is less public funding but more private support from pharmaceutical, biotechnology, and medical equipment firms. These companies have looked to health-care institutions and universities for expertise in basic and clinical research and for access to patients to enroll in clinical trials.
Which interests may influence an investigator’s behaviour? For those coping with shrinking budgets or reduced grants, financial interests may be paramount for personal reasons or to aid in establishing a successful research program by enabling investigators to buy supplies, support research fellows, travel to conferences, etc.
It is difficult for investigators to be unbiased about their work, but when they have an economic interest in the outcome, objectivity is even more difficult to achieve. Care must be taken to ensure that investigators do not erode scientific objectivity or public trust, i.e., not only to try to prevent impropriety but the appearance of it.
No one disagrees with the notion of compensation for work in clinical trials; however, the issues of fair compensation and payment distribution can raise ethical questions. For example, direct payments to an investigator for per-capita enrollment of subjects could cause some concern about bias. Support for laboratory facilities, corporate or equity interests in the sponsoring company, and a potentially profitable patent-licensing arrangement create the potential for conflict of interest.
Noncommercial interests may conflict with the competitive pressures of academic or commercial life. If it were true that the order of names on a certain National Cancer Institute paper is based on the number of patients that investigators were able to recruit into the trial, that could be a cause for concern. Similarly, a commercial sponsor’s interest in controlling the publication of results may result from competitive pressures and negatively influence the investigator’s or the research subject’s interests. Concerns about research funding, peer recognition, "publish or perish", community recognition, academic advancement, and promotion of research has sometimes had superior status in the medical faculties.
Aside from these interests, a number of other issues may potentially lead to inappropriate decisions about the design and conduct of clinical trials. They may result from investigator input into trial design or the investigator’s implementation of the trial. Some design features can affect the bottom line. For example, the choice of what treatments to test and whether or not to use a placebo will affect the size and cost of clinical trials. What the investigator picks as a favourable or adverse endpoint may affect how long the trial will last and how much it costs. Subject inclusion and exclusion criteria and the quality and quantity of care for subjects are other issues. Disclosure to subjects, i.e., the informed consent process, raises many questions. Who will begin the consent process? Will those involved be trained to undertake it? Will the sponsor cover this expense or will the investigator invest this time at personal cost?
Will the trial develop communication tools, such as video presentations, or conduct repeat presentations in the case of trials in children, adolescents, or patients with fluctuating competencies and cognitive impairments? Will trial stopping or modification rules be influenced by monetary interests?
We would hope that these decisions are made in the interests of posing a good and valid research question, looking for an accurate answer, and providing maximum protection for patients.
What safeguards or policies can help investigators to avoid potential conflicts of interest? Certainly, a long tradition of professional self-regulation exists among medical researchers and within the scientific community. This practice may foster some resentment when outsiders, especially non-scientists, are in a position of oversight or even regulation. Whether government regulations or professional guidelines, such as the Tri-Council Policy Statement, come into play, we will still have to rely on the honesty of investigators.
The publication of vested interests is another possibility. The Tri-Council publicity test states: "If information on the motives and incentives of the researcher were to be accurately presented to the general public, would the trust relationship between that researcher and all relevant parties be maintained?" The answer to that question may indicate when an investigator has crossed the line between ethical and unethical behaviour.
This example of a suggested amendment to a consent form comes from a U.S.-based IRB. Although it seems fairly harmless, the investigators at their institution did not like it. The amendment reads: "The physician and/or this institution will be compensated by the study sponsor for each patient enrolled as well as for record-keeping and administrative services. You are free to ask about the compensation."
When I read this statement, I recalled when my son discovered that his school teachers were paid for their work. He was so disillusioned when he realized that they were not teaching just because they loved him. I explained that teachers have families to support. They have to pay for food, clothing, and a place to live. Research subjects would probably understand these needs, although they may be a little disillusioned at first by the thought that their physician or investigator is not only interested in their welfare.
Here are few, more stringent suggestions for published statements of conflict of interest:
- The investigator/physician has an equity interest in the company sponsoring this clinical trial.
- The investigator/physician is a paid consultant of the company sponsoring this clinical trial.
Often, the host institution or local ethics review board, rather than the patient or research subject, reviews the publication of interests. The philosophy is to allow the research ethics board or another institutional mechanism to assess the likelihood that an investigator’s judgment may be influenced by any of these factors. That body can decide whether or not to prohibit that interest.
Another strategy is to eliminate conflicts of interest – to prohibit them directly. For example, many institutions have prohibited direct personal payment or reimbursement on a per-capita basis for subject enrollment. These funds are not directly distributed to investigators but are funnelled into some institutional mechanism. Institutions can prohibit investigators from having a commercial interest in the sponsoring corporation or trial result or from accepting consultancies from the sponsor. Gifts and other sponsor-derived benefits can be prohibited. Most institutions strongly oppose sponsor-imposed publication bans or other kinds of unreasonable controls of trial results.
The Tri-Council suggests publication as an initial solution with prohibitions as a backup measure, when publication appears to be insufficient to prevent conflicts of interest.
As investigators, we should recognize that conflict of interest extends beyond commercial relations. No matter what policies are developed to prevent conflicts, professional self-regulation will always play an important role.
When reviewing research protocols, REBs and institutions must be aware of potential conflicts of interest. They must choose to follow regulatory mechanisms that incorporate relevant codes of ethics, such as the Tri-Council Policy Statement. Although no code of ethics can ensure 100% propriety, it can help to assure it to the greatest extent.