Douglas Kinsella, MD, University of Calgary*
This conference will have importance to the future of research ethics boards (REBs) and research ethics in this country. My first objective is to frame an aggressive, and even pugnacious statement that demonstrates the inadequacies of the use of guidelines for REBs in research ethics. I will use the vehicle of contemporary research history in Canada and the U.S. to highlight these inadequacies. My second objective is to show the necessity of implementing some form of self-regulation in the academic research community, as has been proposed in the Tri-Council Code of Ethical Conduct for Research Involving Humans.
Many may recall the Tuskegee experiment, which began in 1932 in a small Alabama county. This study, funded by the U.S. Public Health Service, involved about 400 Black men who had acquired syphilis, and a couple of hundred Black men who served as controls. The objective of Tuskegee was to observe the "natural history" of untreated syphilis. That, in itself, is a peculiar objective in view of the fact that the natural course of syphilis had been known for many generations. Why it seemed necessary to use public money for another longitudinal study was therefore bizarre. In any event, one of the precepts of Tuskegee was that study patients were not permitted to receive any therapy to alter the natural course of their illness. As a result, many patients developed the late complications of syphilis, such as heart disease and central nervous system disease with paralysis, insanity, etc. They also passed syphilis to their spouses and children, and some of the latter developed congenital syphilis.
This experiment did not herald an auspicious beginning for contemporary clinical trials research in North America. The Tuskegee study did not end until 1972. Even though it continued during the time frame of the Nuremberg trials, it was defended by the U.S. government and U.S. Public Health Service, who claimed a "moral imperative" to continue this research. It also continued through the time frame of the 1964 Helsinki declaration. Every attempt to modify the study was resisted, such that it even continued through 1942, when penicillin became available to cure syphilis, yet the patients were still forbidden to receive any kind of antibiotic therapy that might cure their illness.
In 1966, the Buxton and Beecher Reports were published. Buxton, a lawyer who had been a social worker with the U.S. Public Health Service, was intimately aware of the details of the Tuskegee experiment. He had tried for years to bring it to public attention and have it stopped. In 1966, he was aided by the fact that Beecher, a professor of anesthesia at Harvard University, also published another in a series of papers – this time in the New England Journal of Medicine (NEJM) – about 160 research misadventures about ethical impropriety in research. The papers, dating from 1952 to 1965, had all been published in prestigious journals. The characteristic feature of these misadventures was that they ethically abused the principle of respect for persons, since many did not even know that they were in a study, and many were exposed to life-threatening harm without their knowledge and consent. Yet, all had found their way into prestigious journals, such as the NEJM, Lancet, and others. This practice was not restricted to the USA. Other reports appeared at that time. One from the UK documented similar abuses in the UK and even Canada, presumably was not involved in this kind of activity since no such reports emanated from Canada.
After the Buxton and Beecher disclosures, a series of U.S. congressional inquiries had been established to deal with the issue of ethical impropriety in scientific research. As a result, in 1972, Tuskegee was closed. Some form of financial compensation was provided for survivors or the spouses of survivors and, as you know, within the last year, President Clinton has personally apologized to the Tuskegee survivors and their families.
After 1972, the U.S. congressional inquiries continued. In 1974, it prompted legislation which led to the creation of institutional review boards (IRBs) and mandated the regulation of IRBs by the Office for Protection from Research Risks (OPRR).
A board of inquiry, known as the Belmont Group, issued a report in 1976. The Belmont Report examined all events at Tuskegee and in the Beecher Reports. It articulated a series of ethical principles to guide future research in humans. These three principles are:
- Investigators must respect the autonomy of research participants.
- Beneficence (doing good) should underlie the conduct of all human research.
- Injustice to humans in research is also an ethical transgression.
The Belmont principles continue to guide research behaviour today in an ethical sense, not only in the USA but in Canada and internationally. One addition has been a fourth principle, the principle of nonmaleficence (doing no harm), which has some particularity for biomedical research.
Canada’s first attempt to introduce some control of research ethics occurred in 1978. Both the Medical Research Council of Canada (MRC) and the Social Sciences and Humanities Research Council (SSHRC) issued guidelines, which were based on the Belmont Report.
In 1985, another series of ethical disasters in human research came to light, including the Darsee affair. This young U.S. cardiologist had published more than 60 papers in prestigious journals over a couple of years, and had carefully sought a large number of collaborators, many of whom possessed great prestige within the cardiovascular community, as co-authors. His colleagues, who were junior faculty members and graduate students, began to suspect that something was wrong since he did not seem to be doing the research on which the papers were based. An investigation, which was difficult to initiate, established that nearly all of Darsee’s papers were fabricated. He had not engaged in most of the research that was reported. His collaborators with prestigious reputations spent several years trying to dissociate themselves from Darsee and trying to explain their "participation" in his fraudulent research.
It is important to note that the Tuskegee experiment and Beecher’s reports reflected ethical abuse of research subjects. Darsee, on the other hand, abused scientific integrity by fabricating the results of fraudulent research.
The U.S. regulatory system responded, as expected, with another inquiry. And so, in 1989, new regulations were created by the Office of Scientific Integrity or Office of Research Integrity. These regulations can activate the considerable powers of criminal and civil prosecution against individuals who participate in fraudulent research.
In 1987, the MRC revised its guidelines. Justice Marshall and Francis Rolleston were the principal editors of the MRC guidelines, which were revised after an extensive national review. The 1987 guidelines essentially reiterated the Belmont Report and continued to rely upon voluntary guidelines rather than legislated regulation, as was the standard in the U.S.
The 1978 SSHRC guidelines still exist in their original form. The National Science and Engineering Research Council (NSERC) has never had any guidelines that deal with the ethics of human experimentation. Given these histories, one might conclude that Canada has been somewhat deficient in its attention to these issues.
Canada’s story of more aggressive concern about ethical misadventure in research began in 1989 with the creation of the National Council on Bioethics in Human Research (NCBHR)*. I had the honour of being the Council’s second chairperson and first president. Dr. Henry Dinsdale is the current president of NCBHR. When the Council was founded, Henry chaired the committee that initiated a series of site visits of Canadian REBs.
The primary purpose of these visits was to ascertain the extent of compliance between the activities of the REBs and MRC’s guidelines. Created by the MRC and the Royal College, the Council had some difficulty in achieving autonomy. The Council’s principal terms of reference were to interpret and promote MRC guidelines but not to revise them. Despite a wealth of wisdom and experience inherent in its membership, the Council always found it difficult to pry the MRC loose from its guidelines.
In 1993, the Canadian story of ethical misadventure in research reached a crisis. A faculty member at Concordia University, Montreal, murdered several colleagues. He accused his co-workers of fraudulent and fabricated research and claimed that conflicts of interest had led to unfair treatment. A series of inquiries documented some difficulties existed with respect to the ethics of experimentation at the institution in which NSERC-funded research was involved.
Most of us are now familiar with the Poisson affair which occurred in close proximity to the Concordia tragedy. Dr. Poisson had received funding from the U.S. National Institutes of Health (NIH) for breast cancer research. Investigations found that he had abused scientific integrity by falsifying patient records in research reports. He also abused research ethics by exposing research participants and others with breast cancer, to increased harm. In quick response to these scandals, the MRC, SSHRC, and NSERC issued Tri-Council guidelines for scientific integrity.
I will be blunt. The Tri-Council guidelines read nicely, but from personal experience in trying to apply them, they do not work. It is particularly difficult to get Councils to meet the guideline’s endpoint, i.e., the imposition of penalties for transgressors. Once again, Canadian guidelines look good on paper but not in the context of "real world" application.
In 1995, NCBHR published the results of its site visits, the findings of which undoubtedly informed Tri-Council guidelines on scientific integrity.
The NCBHR report clearly demonstrated:
- the disutility of MRC guidelines in providing a functional environment for research ethics in Canada.
- the disarray in procedures and processes that existed in Canadian REBs.
It recommended many procedural revisions, including more regulation of REBs and research ethics in Canada.
In 1994, the three federal councils established the Tri-Council Working Group, which had a mandate "to replace existing guidelines with regulations and policies". It has vigorously attempted to achieve this mandate and has proposed a Code of Ethical Conduct for Research Involving Humans. Unfortunately, in 1998, we do not know whether the proposed Code will see the light of day. It is rumoured that the Code, as such, will not be implemented. Some form of transitional guideline might be introduced for use in the Canadian scientific community over the next several years. These rumours may be false; but if not, this whole exercise could discredit the Canadian scientific community. If we do not act to change what is obviously in need of change, the academic community, research sponsors, and the thousands of Canadians who participate in research studies will pay a price.
The role of self-regulation
We must engage in some form of self-regulation in research ethics in this country, if for no other reason than to meet the Working Group’s mandate to replace guidelines with regulations and policies. We have two choices: we can stay with guidelines or we can move to regulation. I want to remind you that a guideline is nothing more than an action principle. By definition, a guideline is subjective. By experience, guidelines in Canada have been interpreted subjectively by investigators and REBs. Guidelines theoretically allow us to continue with peer overview and enforcement through REBs, but their subjectivity essentially neutralizes any national benefit that could come from peer overview and enforcement.
Two forms of regulations are relevant to our discussion: non-legislated and legislated regulation. The USA has opted for legislated regulation, which has several virtues. It is objective and has the force of law. It retains the elements of peer overview, since IRBs are composed of members from within and outside the research community. The difficulty is that legislated regulation has invited and dictated legal regulation and enforcement via a massive bureaucracy in the U.S., one which has the power to prosecute those convicted of scientific and ethical transgressions.
Non-legislated regulation shares some features of legislated regulation. Objectivity and peer overview remain. However, the focus in self-regulation remains within the community, particularly at the institutional level. Non-legislated regulation was the core of the Tri-Council Code of Conduct.
I have reviewed the history of contemporary research and research ethics in Canada and elsewhere, and characterized research misadventure as an indication for the need to develop REBs in ways that will protect the public. I have reviewed features that clearly indicate that Canadian guidelines have failed to prevent the abuse of research ethics.
I would like to close with a very personal, deeply felt request that federal funding Councils honour their commitments to the public to protect Canadians from research misadventure. Every year, tens of thousands of Canadians volunteer to participate in medical research. But the history of research regulation in Canada has clearly demonstrated that they have not been protected under the current system of guidelines. Therefore, I hope that you will impress upon our political and bureaucratic "masters" the need for change, and the need to adopt substantive portions of the Tri-Council Code of Ethical Conduct as the means of achieving enhanced protection for all research participants.
Francis Rolleston, Medical Research Council: I found myself substantially in agreement with Doug’s position, however, the statement that research subjects have not been protected may be overstated. The NCBHR document explicitly refers to process issues and talks about distinct variations in process within, among, and between REBs. The NCBHR report does not focus on cases that show strong evidence of bad ethical practice in this country. Nonetheless, it clearly points out that process is inadequate.
Dr. Kinsella challenges the councils to carry out the Code and highlights the excellent interdisciplinary scholarship work of the Tri-Council. That document, published in June-July 1997, was subjected to peer review, admittedly within the academic institutions listed here. The Code itself has been carefully reviewed by a large number of people, and members of the Working Group are actively involved in those discussions. Presidents of the councils have noted both the document and discussions, and a process is now in place for the editing and review of the document in light of input from various peer reviewers and interested groups. A document should be submitted for the councils’ approval within the first months of 1998.
This document will not be called a "code", because this word has a strong legislative connotation. Parts of the research community have made overly strong statements against legislation and the implications of the word "code" are strongly felt. Nonetheless, it will not be called a guideline. The document will be a policy statement by the councils. It will contain clear lines in the sand that, if transgressed, the councils will regard as a condition for withdrawal of funds.
The work of the Tri-Council Working Group has been well-recognized and strongly supported. There is feeling among the councils that the document, as submitted, is not yet ready for implementation as a policy statement. The work of the Tri-Council Working Group has been published, is, and will remain in the public domain. That work will not be lost and will clearly continue to be part of the councils’ final policy statement.
Douglas Kinsella: As Mordicai Richler once said, when someone turned one of his books into a movie script, a certain element of flavour and substance is always lost in the process.
More important than the name "code" is the content. While we dither, many provinces are introducing bits and pieces of legislation that chop up the whole sphere of research regulation. For example, in Alberta, two bills – one of which has been passed, the other of which is before the legislature – specifically inhibit the conduct of research in many important populations who should receive the benefit of contemporary research: patients who are disadvantaged because of physical injury or incompetent because of mental illness. In that province, legislation may conflict with any federal regulation in this area. Similar legislation has already been enacted in Newfoundland and may soon follow in other provinces. By the time the federal agencies develop their document, so many conflicts may exist at the provincial level that they will not be able to protect the public, researchers, or sponsors in an orderly manner. Again, my plea is for immediate action.
Jean Joly, Chair of Tri-Council Working Group on Ethics & University of Montreal: As chair of the Working Group, I am not aware of any consultation process that involved the Working Group.
Kenneth Jones, Leo Laboratories Canada Ltd.: The pharmaceutical industry is probably the most regulated industry in the world. Although it whines and complains about the burden imposed by those regulations from time to time, I would encourage the adoption of regulations for research ethics in Canada. Other countries, e.g., the USA, have regulations. We are required to abide by regulations that exist in every country worldwide. To do so, we adopt a system that will conform to the most rigorous regulations that exist for multinational clinical trials.
There are major problems in Canada. It is difficult to abide by ethics codes that differ from one institution to another, one province to another, etc. A national code would be logistically simpler to apply. Sometimes, it is almost impossible to comply with international regulations. We are required to abide by the International Conference of Harmonization Guidelines, which have been formally adopted by Canada’s Health Protection Branch (HPB). To do so, we must obtain certain things from REBs. Certain statements must appear in the informed consent form. It is like pulling teeth to get these statements from some institutional ethics boards, e.g., when we request information from the ethics board, but it is denied on the basis of "confidentiality". It is difficult to deal with this situation now.
For international trials, ethical guidelines require audits and site inspections, but local REBs often disallow access to their procedures, constitution, and minutes. The international auditing body will conclude that informed consent was not properly obtained and that no appropriate ethics board is in place to supervise that trial. That is very serious, and may ultimately impose limits on where clinical trials will occur in Canada. We must be able to demonstrate that REBs meet international guidelines.
I would encourage the adoption of uniform regulations across Canada that meet current international guidelines and the regulations in some countries. There is a movement in some European countries to do so, and this action would certainly encourage more research in Canada.
Melody H. Lin, OPRR, NIH: What do you think would improve the situation or suffice to protect humans in clinical research?
Douglas Kinsella: The ICHGCP guidelines are a starting point. They are primarily process-oriented and outline the minimal standards that ought to exist in order to have internationality in the exchange of research protocols in the approval process. In addition, elements for expression of national identity exist within the guidelines. At present, Canada’s national identity at the level of REBs is one of confusion. We do not have a cohesive picture of research regulation, from an ethical perspective, in Canada.
Michael Schunk, Pasteur Mérieux Connaught Canada: In the realm of animal research, laws and added bureaucracy facilitate the ease of paperwork and conducting trials but do not necessarily demonstrate a higher standard or less deviation from ethical standards than well-enforced guidelines with consistent procedures and one auditing body. Have you compared different jurisdictions?
Douglas Kinsella: From the perspective of animal research, in Canada, about $1.5 million is generated by various agencies, including federal agencies, to ensure that animal research is ethical and appropriate. I would defy anyone to find a similar contribution to Canadian research that involves humans. Animals are more likely to have better protection as research participants than humans.
I have examined some jurisdictions, and that is the reason why the focus is on non-legislative interventions rather than legislated interventions, which exist in the USA. After working on the University of Chicago’s IRB, I can agree that legislation is not everything. Other things are necessary to make it work. But if nothing exists, then difficulties arise.
The National Council on Bioethics in Human Research (NCBHR) is now known as the National Council on Ethics in Human Research (NCEHR).
*Dr. Douglas Kinsella passed away June 15, 2004.