Chapter 8: Research Ethics

 

INTRODUCTION AND PREAMBLE

We owe much in the modern world to scientific research. In the systematic search for knowledge the scientific method is fundamental to progress. But even the rational and calculating scientific methodology cannot elude moral and ethical considerations. The study of research ethics is a study of those ethical considerations that impinge on the scientific method, its players and its stakeholders. This chapter is an attempt at introducing and fostering a sharper understanding of research ethics in (and outside) Canada.

The first broad topic in this chapter is a consideration of the evolution of research ethics. The world confronted the transgression of research ethics in the atrocities of World War II. A formal and normative research ethics has been evolving ever since. We find ourselves in the new and exciting landscape of fresh and innovative technology, pondering questions that were inconceivable even a few decades ago. Canada and the world have responded to this situation with a series of broad and comprehensive documents and treatises that both describe where we have been and attempt to establish a way forward.

While understanding the past is possible, and establishing a trajectory for the future is desirable, living in the present and simultaneously describing contemporary research ethics is a complicated affair. The second topic in this chapter is a survey and overview—a roadmap—of current rules, regulations, policy, and law pertaining to Canadian research ethics. Funds grants and financial concerns will be considered first, for it is here that, practically speaking, research begins. An overview of significant research guidelines and regulations will follow. With Health Canada as the government agency at the centre of oversight and policy formation, the departments and agencies that extend from here will be examined, and the ways and means of research oversight studied. This will include a necessary examination of some of the pitfalls of research ethics law and policy in Canada and the world. Research ethics boards (REBs) are central to regulation and oversight of research in Canada. Almost all research is scrutinized by REBs so their composition, their mandate and their influence will be discussed. This section will end with an examination of some of the significant legal considerations that have shaped research ethics in Canada.

The third major topic is research subjects. In contemplating ethical treatment of subjects, most considerations are for the ethics of research directly involving humans, and the Tri-council Policy Statement will be seen to be the first and final word on this account. This document, its guiding principles and its core policies, will be central to the discussion on research involving humans. But this section will not leave off without a description of some of the relevant guidelines for research involving animals—most animal research is, after all, not for the animals themselves, and proper treatment of animal subjects must be considered part of any comprehensive discussion about ethical scientific conduct.

The fourth and most extensive topic is that of responsible conduct, a topic that focuses on the ethical behaviour of researchers, sponsors, and institutions. This topic will open with an examination of competing and conflicting interests. On the topic of conflicts in the scientific world, conflict of interest, per se, is the one that first springs to mind. A discussion of the genesis and the many manifestations of conflict of interest will be examined along with the role that each of the stakeholders plays in this broad area. Also discussed, will be the codes of ethics, legal instruments, and institutional policy that impact on prevention and remedy of conflict of interest. Other competing interests, such as conflict of commitment and conflict of conscience, will also be examined.

In the research world, gathering information and generating knowledge and new technology are fundamental objectives. Raw data is not of value in and of itself, it is the interpretation and publication that gives it substance and value. Ethical considerations of publication will be discussed, and this will move into an examination of intellectual property and the ownership of research and the fruits that it bears.

Any discussion of proper research conduct must include a consideration of misconduct, and this will be the final topic in this chapter. Misconduct will be defined, but more importantly, the mechanisms for investigating, and remedying misconduct will be considered and discussed in parallel with an assessment of an archetypal legal case. Examining the ramifications of this case will lead to a consideration of the changes that have transpired, and the means by which future ethical transgressions can be monitored and prevented. Lastly, a brief survey of liability—just who can and should be made liable for poor outcomes—will conclude the chapter.

EVOLUTION OF RESEARCH ETHICS GUIDELINES

Canada has evolved its research ethics guidelines from the common stock of the world’s research ethics foundations. This common stock includes, in a rough timeline, the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, the Council of International Organizations of Medical Sciences (CIOMS) guidelines, and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. While it is beyond the scope of this discussion to elaborate on the guidelines themselves and the ethical and moral underpinnings, it is important to recognize the reasons for their development, and the means by which they evolved, in order to understand the current relevant guidelines and oversight in Canada.

What has commonly come to be known as the Nuremberg Code is in fact the third part of the decision at the military tribunal trying Nazi doctors after World War II.1 The world reacted with moral outrage at the experiments conducted on prisoners under the Nazi regime. The Nuremberg Code was the first code to explicitly outline ethical conduct in research involving human subjects, and it was the first formal attempt to explicate things that the scientific community previously did not deem worthy of formal explication. Hitherto, a reliance on common sense seemed to obviate such a formal code, but the absence of such a code represented a significant defence for the Nazi doctors on trial.2 Thus, the common sense principles of “respect for persons”, “beneficence” and “justice” found their way into the ten statements that make up the Code. The first statement is the clear and unequivocal requirement that willing and informed consent is paramount for any research conducted on humans.  This ensured that if ever again the sound moral judgement that would have to be suspended to permit such atrocious and cruel experiments, at least the requirement of informed consent would prove to be the gatekeeper of last resort. The further points go on to elaborate on the need for justification of the research, the requirement for ensuring safety and mitigating risks, and so on.3

The atrocities committed in the name of science under the Nazi regime represented, in a sense, a loss of innocence among the medical and research communities worldwide, and prompted an examination of practices among many international and national science foundations. The World Medical Association (WMA) began an examination of its practices that resulted in the first Declaration of Helsinki of 1964.4 This document was an attempt at a codified research ethic that would build on Nuremberg and instead of a reaction to atrocities, was a proactive piece that addressed present and future concerns. It attempted to reconcile the absolute need for informed consent with the notion that substitute consent could sometimes be legitimately warranted where a subject may lack capacity (for example with children), and a recognition that research could, in fact, be therapeutic as well as investigational (and that a sensitivity to the differences between therapeutic and non-therapeutic must be held in mind by researchers). The Declaration of Helsinki (DoH) has undergone several revisions and refinements that attempt to meet the challenges of research in the current socio-political climate. Currently, the latest iteration is derived from the 59th Congress of the World Medical Association held in Seoul Korea in 2008.5 The DoH continues to provide guidance for Canadian research and researchers.6

Another significant and evolving international set of guidelines relevant and influential in Canadian research is the International Ethical Guidelines for Biomedical Research Involving Human Subjects.7 This document was born of a twenty year partnership between the Council for International Organizations of Medical Sciences (CIOMS) and the World Health Organization. It represents a departure from other codes inasmuch as it is an attempt to address certain needs in the global community. While Nuremberg was a reactionary and bold first step, and the DoH and the Belmont Report (see below) are more philosophical in their guidance, the International Ethical Guidelines represent an attempt at providing a practical means of oversight and regulatory advice in an uncertain and unequal global community. These guidelines also attempt to create an even playing field for all stakeholders in multinational research endeavours.8 Diverse socioeconomic concerns, and varied socio-political circumstances among developed and developing nations creates tremendous uncertainty and significant barriers in carrying out research across multiple nations or by developed nations inside developing nations (HIV research in Africa is perhaps the most important and common example of this). Different nations have different governance and public policy yet, among the global medical community there is an acknowledged value in striving for consensus on how to conduct international research—research which still respects sound bioethical principles such as respect for persons, justice and mutual benefit. The CIOMS guidelines are an attempt to ensure the careful scrutiny of research protocols being proposed for underdeveloped nations, that the research will provide necessary generalizable knowledge, that the subjects and the general population will benefit from the fruits of this research, that the risks and benefits will be fairly distributed etc.

Yet another bold and ambitious international endeavour is the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. These are of a much more technical nature and provide detailed guidelines on the development and acceptance of new medical interventions, medical devices and medications. The ICH is composed of members from the US, Europe and Japan but many countries (Canada included) have adopted and incorporated many of their guiding doctrines, most notably, the Good Clinical Practice Guideline (see below).9 While the ICH has developed numerous guidelines on several topics, the ICH-GCP Guidelines remain a standard for industry based research in Canada and abroad. The guidelines illuminate the need for REBs (commonly known in other countries as Institutional Review Boards, or IRBs), outline the qualifications of researchers, the role of the sponsors, and the safety of the subjects. Despite any departure from previous codes and statements, even these guidelines clearly state a reliance on the principles derived from the DoH documents.

The loss of innocence that the world was forced to confront after the Nazi regime left no nation immune. The American Civil Rights Movement had tremendous influence in the first half of the 20th Century on social political and academic realms both in the US and abroad. The developments and changes that the Civil Rights Movement wrought contributed to priming the research world in academic centres throughout the US for a frank examination and overhaul of, the ways research was being conducted. By the 1960’s the United States had amassed a number of ethically questionable research endeavours. This fact was shockingly uncovered in an important paper by Henry K. Beecher, in 1966.10 Further scandalous research projects brought to light in the 60’s and 70’s prompted the formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.11 The Commission met between 1974 and 1978 and produced one of the most influential papers in codified research ethics, The Belmont Report. The principles of Respect for Persons, Beneficence, and Justice are the core values of the report and—by extension of the perceived primacy of the report—in research ethics in the United States, these remain core values dear to American researchers and research institutions. Under the core principles, derivative principles and guidelines are developed such as informed and voluntary consent (filed under respect for persons), and the requirement for taking stock of risks and benefits (filed under the principle of beneficence).12 What this document lacks in size it makes up for in scope, it is the foundation on which much of research bioethics law and policy has been formed. Another important product of the National Commission was the development of guidelines that could be incorporated into law—to that end, the commission’s proposals were shaped into the regulations for the US Department of Health and Human Services and ultimately became codified into law as 45 Code of Federal Regulations 46 (45 CFR 46) and is often referred to as “The Common Rule”.13

The US experience is mentioned for two reasons, first by virtue of the geographic proximity and the cultural similarities to the US, the American research ethics evolution is a legitimate comparative. Canadians have been the beneficiaries of this rich evolution of research ethics guidelines—both the international guidelines and the codified law of their American neighbours. Canada too recoiled in moral outrage at the experiments by the Nazi doctors, and has (in solidarity with much of the world) endorsed the principles and concepts of the Nuremberg Code and the Declaration of Helsinki. Much of the regulation and oversight of Canadian research is derived from these documents—directly or indirectly—as is discussed in the next section. Health Canada sets the regulatory standards of health related research in Canada and while Canadians do not have a “Common Rule” per se, the Canada Health Act does give Health Canada’s regulations the force of law. Many of the principles of the codes mentioned above (such as the ICH-GCP Guidelines) have been ported into the Health Canada Regulations.

Before leaving this sojourn through the evolution of research ethics and its guiding literature it is important to reveal some important new trends in the relationship between researchers (and research institutions), and the populations they serve. While the Nuremberg Code was a reaction to the atrocities of the Nazi regime and the injustices perpetrated on an unwilling and imprisoned population, there have been trends in research ethics that are born of the fact that much of the world enjoys greater freedom and growing relief from oppression. Moving beyond the Belmont Report and the Declaration of Helsinki, which were designed to protect people and populations from unscrupulous and unethical practices of scientific investigation, the new millennium is the dawn of an age of science that is not only inquiring as to the nature of biomedical phenomena, but taking an ever greater role in shaping outcomes and employing technology to bestow hitherto unknown benefits on these same people and populations. The industrialized world is a world of people who once needed protection from scientific endeavours, but now find themselves also needing fair and increasing access to scientific endeavours.14 Nowhere is this more evident than in clinical trials involving new cancer treatments and new HIV medications. Over “protection” may in these instances mean limiting access to a population in need.

In a similar way some populations have found themselves over-protected into the margins of care. Women (especially pregnant women), children,  minorities, and the impoverished have been so militantly “protected” from exploitation that there is significant risk of doing too little research in these areas and complicating segregation and marginalization with insufficient medical attention to their specific needs. Some of these issues are addressed by the Tri-Council Policy Statement, as will be discussed below. Canada, like the rest of the world, must continue to walk that very fine line in over and under regulating access to research. Canadian researchers continue to pick their way through the very murky no-man’s land between the realms of research and treatment, and the evolution of research ethics guidelines continues to navigate between protection and access.

ROADMAP OF CANADIAN RESEARCH ETHICS REGULATIONS AND OVERSIGHT

In order to gain insight into the broader aspects of Ethics in Research, an understanding of the practical ways and means of research in Canada must at first be apprehended. It is no simple task to navigate the complicated maze of research funding, oversight, policy and regulations. A detailed understanding will not be provided herein. In fact, a detailed understanding is a somewhat fluid entity that changes with time, location, and the field of research so an enduring and concrete understanding of the research infrastructure in Canada is not entirely possible. For this reason, a brief and concise discussion will be made of the topic, and it will be left to the reader to discover the finer points of this shifting structure if and when the matter becomes pertinent.

The changing nature of the “Research in Canada” concept has to do with the evolution of oversight and policy that has adapted to changes in our world and the new and increasing sensitivity to ethical concerns. Bioethics has been a rapidly developing field in the last thirty to forty years (here again recognition must be paid to the Civil Rights Movement in influencing a heightened ethical awareness) but corporate ethics, too, has undergone rapid evolution. Industry, government, and professional organizations have had to acknowledge an accountability to the broader population. This text is concerned with bioethics and so this chapter will not stray too far from issues relevant to that topic, but it must be recognized that such things as funding and regulations in a broader sense, do impinge significantly on the ethics of research in the narrow sense, so discussion will be introduced along those lines.

A)     GRANTS AND FUNDING

Research requires money, and an ever increasing amount of it. Research in Canada is funded, much like anywhere else in the developed world, in two main ways, by government or by the private sector. Research that involves human subjects, and research that has an impact on humans and society will be considered as it is these that have bioethical implications.

Government funding in Canada is, for the most part, overseen by Health Canada, the federal agency responsible for the health of Canadians. This includes immediate health concerns, but also health maintenance, preventive health, public health initiatives, and overseeing health related research. More has been said on this topic in Chapter 1, and the structure of health and welfare system will not be recounted here. The Government of Canada is closely tied to the oversight of three key organizations. The Canadian Institutes of Health Research (CIHR) receives its funds from the federal government and is accountable to parliament through the Ministry of Health. The other two agencies, Natural Sciences and Engineering Research Council (NSERC) and the Social Sciences and Humanities Research Council of Canada (SSHRC) are both departmental corporations of the government, funded by parliament, and both report to Industry Canada. These agencies connect back to the National Research Council (NRC) which was created in 1916 to advise the Canadian government on scientific concerns and to conduct research. The NRC has undergone many changes and it has spun-off several agencies that stand on their own, such as the three mentioned above. The NRC still has an interest in research activities and scientific pursuits such as in Aerospace and in emerging technologies such as nanotechnology.

Most government funding in health research and the biotechnology sphere comes from the three institutions named above, NSERC, SSHRC, and CIHR. Of these, the latter has, perhaps, the most impact on research that involves bioethical concerns. The Social Sciences and Humanities Research Council of Canada (SSHRC) is concerned with the promotion and development of largely university based research in the social sciences and humanities. In 2009-2010 it had a grant and scholarship budget of $335.3 million.15, 16 Natural Sciences and Engineering Research Council (NSERC) is a federal agency concerned with research in the natural sciences and engineering, and it too provides mostly university (undergraduate and post-doctoral) research funding. It had a grants and scholarships budget of $969.578 million in 2007-2008,17, 18 and $1.08 billion  in 2010-2011.19

In June of 2000, the Medical Research Council of Canada morphed into a new agency, the Canadian Institutes of Health Research. This was more than a name change, it was a conceptual change that involved the formation of an agency that was not a “brick and mortar” entity but a conglomerate of institutes throughout Canada that focus on a vast variety of topics and concerns from Aboriginal Peoples’ Health, to Gender Health, to Neurosciences Mental Health and Addiction. These are virtual institutes; in reality, they are networks of researchers. In 2008, the CIHR supported nearly 12000 researchers in 280 facilities across Canada and was responsible for $974.1 million in research funding.20 In 2004-2005 it was responsible for 58% of government funded health research financing in Canada.21 Each year the CIHR publishes a Grants and Awards Guide which is an exhaustive resource for the creation of grant proposals through to the dispensation of funds and the rules that apply every step of the way. This is a helpful and comprehensive document that is often consulted and appealed to for ethical guidance.

The scope of the funding by these agencies is stated not simply for the sake of interest, but to highlight the importance of these funding agencies. Because these agencies have such an important and well entrenched interest in research in Canada, their regulatory functions and their policy statements are the final word on regulation and policy in the research world; the holder of the purse strings holds sway over the disposition of the funds. The way researchers access funding through grant applications and the way they conduct their research is tightly controlled by the agencies.

The other source of research funding in Canada, as in other nations, is Non-Government Organizations (NGO’s) and industry-sponsored research. These are too numerous to list and involve several different types of organizations, the discussion of which falls outside the scope of this discourse. For example, there are large charitable and volunteer organizations such as the Canadian Heart and Stroke Foundation and the Canadian Cancer Society, which provide millions of dollars of research money throughout Canada. Finally, there are the industry sponsors of research including biotechnology companies, pharmaceutical companies, medical device companies, and natural and alternative health care products. Canada has seen tremendous growth in the biotech industry in the last decade and has witnessed a striking increase in the amount of money these companies have committed to research and development with $1.7 billion committed to research and development (R&D) in 2005.22

B)     OVERVIEW OF REGULATIONS AND GUIDELINES

Regulations and policies are derived from several sources depending on the source of the research funding. Fortunately they are largely consistent. A more detailed treatment of the evolution of these guidelines can be understood below in the discussion on research involving humans.  Here we will examine the regulations, guidelines, and oversight as part of the roadmap of research in Canada. This is a complicated subject and is herein simplified to provide an overview. The pertinent rules and procedures depend on a few variables such as whether the funding for the research is from a government body (CIHR, NSERC, etc.), or from industry; whether the research involves humans or animals; whether the research appertains to a drug or a device; and whether the research is to be conducted entirely within Canada or if it is international (such as a large multicenter trial for a new medication). Some of these considerations will now be discussed.

Government funded research must conform to strict rules and regulations that have been generated by the government agencies. The cornerstone of ethical guidance in Canada is the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS)23 and the newly revised 2nd Edition released in 2010 (TCPS2).24 This important document will be discussed in greater detail below but its origin reflects the need it fulfills. It was originally created by the CIHR (when the CIHR was still called the Medical Research Council), NSERC, and SSHRC – the three councils of its namesake. Government funded research is required to adhere to these guidelines, but it must be noted that these are guidelines that do not carry the force of law. The TCPS2 holds sway over researchers inasmuch as funding cannot be had (and hence research cannot be conducted) unless the guidelines are followed. It must be stressed, however, that private or industry sponsored research does not, strictly speaking, have to adhere to the TCPS2 guidelines. The original TCPS was intended to be constructed as a well-crafted document such that research conducted under any acceptable ethical standard would in fact conform to its recommendations, nonetheless, research does occur in the private and industry sponsored realms that eludes its influence.

Industry sponsored research involving medications, devices, or health products must adhere to Health Canada regulations. Health Canada oversees and regulates issues relating to food and drugs through its Health Products and Food Branch. This agency has regulations: the Food and Drug Regulations. The Health Products and Food Branch carries legislative authority through the Food and Drugs Act of Canada (which by extension enables said Food and Drug Regulations).25, 26 So much for regulation, but Health Canada also provides oversight: Health Canada oversees all aspects of the licensing of new health care products and medical devices, and oversees their manufacture packaging etc. Health Canada has several directorates that oversee various new products: the Therapeutic Products Directorate oversees new medical devices and pharmaceuticals, the Food Directorate is involved in food and nutrition, the Biologics and Genetic Therapies Directorate oversees new products derived from biological sources (such as vaccines) and radiopharmaceuticals (for example radionuclides for nuclear medicine imaging or treatment). So while industry and private research may not have to adhere to the TCPS2 guidelines, any new research involving drugs or products must, by law, still conform to Health Canada regulations.

The above map of the Health Canada oversight process still leaves the question open as to exactly where these Health Canada regulations come from and what they look like. Health Canada has adopted the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice guidelines (the ICH GCP). As noted above, these guidelines were developed by an international conference of regulatory bodies in Europe, Japan, and the US. Canada sits as an observer and an active participant in this unique body and Health Canada has adopted many of its guidelines into its regulations. Fortunately the guidelines such as GCP, the TCPS, and the TCPS2 are largely congruent and espouse many of the same principles. In addition to regulating, Health Canada provides guidance. It is committed to aiding research by such means as the Guidance for Clinical Trial Sponsors, a publication to aid researchers in creating and submitting clinical trials applications.27

It is also important to note that for international trials and studies, adherence to pertinent legislation in the country from which the research originated is also mandatory. For example, if the research is involving a trial of a pharmaceutical and the research is a multicenter trial originating in the US, the principal investigator must show that the research and the drug have US Food and Drug Administration approval, and similarly, research that has National Institutes of Health (similar to the CIHR in Canada) funding must adhere to the regulations of the US Department of Health and Human Services in the same way Canadian researchers adhere to the regulations of Health Canada.

Involvement in research does not end with the granting of approval for new products or the approval of research protocols. Health Canada is also charged with the oversight of research as it is being conducted. The Health Products and Food Branch Inspectorate (not the Directorate) has responsibilities for the inspection of investigations and clinical trials. In 2000 it set out to inspect 2% of trials being conducted across Canada.28 Despite this, and despite the very rapid rise in the number of clinical trials in Canada, Health Canada has been criticised for being too lax in its inspection of trials (having only accomplished inspection of 1% of trials instead of the intended 2%), and in not making the results of these inspections, or of actions taken because of them, known to the public or the research community. The inspectorate has attempted to increase transparency, and in 2004 published results of the trials it reviewed during 2003-2004.29 Canada, while it has been a leader in welcoming new research, has taken a back seat in oversight: the FDA in the US, for example, is much more proactive in its investigations and in making the results and disciplinary actions available to researchers.30 Another way Health Canada oversees research is through adverse events reporting. Any adverse events (such as drug related events or side effects, or device failures or complications) in research in Canada must be reported to Health Canada. This usually occurs once the primary investigator or sponsor (of a trial involving a new device or drug) is notified, and they in turn notify Health Canada.

Criticisms of Health Canada oversight illuminate a larger systemic problem with research involving humans, a systemic problem that affects the global research climate. Many countries and international organizations such as the World Health Organization have maintained that part of the accountability and oversight of research and researchers should involve the registration of such research and its outcomes in a central database. Health Canada has been advocating for the formation of a registry of clinical research since 2005 but as yet, Canada does not have a clinical trials registry. Health Canada does endorse the use of the American registry, ClinicalTrials.gov.31 Many journals will not publish results from a trial unless it is registered, and this does give force to the endorsed registry concept. The newly released TCPS2 is much stronger in its wording regarding registration of trials making it mandatory that all clinical trials over which the TCPS2 has jurisdiction must be registered in a recognized and easily accessible website before recruitment of participants begins.24

Another perennial problem with the conducting of research with a sound ethical basis involves the problem of industry and university partnership. Much of the above discussion about policy and oversight deals with one or the other as a sponsor, but in Canada, as in the rest of the world, there is an increasing trend toward university-industry partnership in research and increasing funding of university based researchers by industry (most notably pharmaceutical companies). While this trend is surely here to stay, many Canadian pundits view this arrangement with a jaundiced eye, and fear the potential for skewed, suppressed, or manipulated research results.32, 33 There have been attempts to generate policy to reconcile the perceived tension between industry (arguably, whose goal is primarily its own financial best interests) and academia (whose interest is the generation and preservation of knowledge).33 Real attempts at creating credible governing policy from Health Canada are ongoing. Since 2001 there have been initiatives to formulate concrete policy governing the relationship between public and private funding arrangements for research involving the CIHR.34 In 2007 the CIHR conducted a workshop on the matter, but there remains no distinct policy statement to guide researchers in navigating public-private arrangements. Researchers are directed to the Grants and Awards Guide published yearly by the CIHR.35

C)     RESEARCH ETHICS BOARDS

Regardless of the type of research or the scope of the protocol, any research involving humans (including cadavers and tissues) has to gain approval of a Research Ethics Board (REB). The nomenclature is somewhat arbitrary, with Institutional Review Boards in the US (IRB), Research Ethics Committees in the UK (REC) and other designations in other regions. The principles remain consistent regardless of the name, that the independent and objective review of a research protocol is a necessary and good thing to protect the interests of the subjects involved in research.

Research conducted in Canada has to be approved by the REB in the jurisdiction in which the research is occurring. REBs are typically thought of as being institutional organizations, and indeed they are most commonly found in institutions such as hospitals or universities. These REBs oversee the research done in that particular institution or the research done by employees of that institution. In Canada this concept is broadening, and now many colleges and professional and technical institutes are creating REBs. REBs are often connected to other institutions, for example, research done in a hospital that has some affiliation with a local university medical school may have close ties to the REB at that university or even be a subsidiary of it. Institutions that do not have an REB usually have an agreement or affiliation with a related institution and protocols are vetted there (in the previous example, if a hospital did not have its own REB, research done at that hospital would be reviewed by the associated university REB). REBs are also found in regional organizations such as health regions in any given province. These serve to examine research done in a more widespread area that is not necessarily associated with one institution (for example demographic analysis, or preventive health measures conducted in a certain geopolitical area that is not circumscribed easily by the catchment of one institution such as a hospital). Finally, Health Canada itself has an REB which it uses to examine research that is performed by Health Canada itself. REBs are becoming more common at every level of societal organization.

There are ethics advisory entities in many other areas of government and in the private sector that, while not REBs, do provide ethics oversight and insight into the activities of the institution or company. The CIHR has a “Standing Committee on Ethics” which provides advice and insight into the ethical issues pertaining to research born of the CIHR and its mandated activities. NSERC has a similar code of ethics that all members must adhere to. In a similar vein, in the private sector and in industry, most Canadian corporations that submit proposals for research involving humans have an internal mechanism for ethics review of the protocols while they are being developed and for overseeing ongoing research. These usually take the form of Independent Data Safety Monitoring Boards (or similar committees) that review all adverse events and irregularities in interim data analysis etc.

The Tri-Council Policy Statement clearly delineates the composition of REBs.

The REB shall consist of at least five members, including both men and women, of whom:

  • At least two members have broad expertise in the methods or in the areas of research that are covered by the REB;
  • At least one member is knowledgeable in ethics;
  • For biomedical research, at least one member is knowledgeable in the relevant law; this is advisable but not mandatory for other areas of research; and
  • At least one member has no affiliation with the institution, but is recruited from the community served by the institution.24

It further stipulates the necessity for a demographic that reflects the institution and the research that transpires in that institution. REBs are to be created at the highest level of authority of the institution and be as broad as possible in their jurisdiction. While in spirit this is meant to lend maximal authority to the REB, in practice precisely how this is to be interpreted and what it looks like, is hard to define.

The first task of the REB is to assess research proposals. All research applications are formally submitted to the REB whose panel reviews the protocol, the consent forms, the method of recruitment, and other documentation relating to the proposed research. They are tasked with scrutinizing the research protocol (the medications, the devices, the study design, the methodology, etc.), and weighing the risks and the benefits that the research may bestow on its subjects or on the population. It determines whether (if any) the gain in generalizable knowledge is worth the risks to the study participants. Research must have demonstrable social and scientific merit to be approved. The REB also ensures that proper recruitment and consent procedures are followed. It makes recommendations on how to improve the proposal (and sees to it that the improvements are implemented) before finally approving the study.

Research Ethics Boards in Canada bear the responsibility for monitoring research that they have approved, much as Health Canada has the responsibility on a broader scale to oversee research in Canada (as noted in the previous section). REBs must, at a minimum, review ongoing research at least annually. For research that involves humans and research that involves more than minimal risk this means the project must receive a full REB approval on an annual basis. However, the REB can, at its discretion, choose to require more frequent review based on its assessment of risk. Investigators must report any proposed changes to the approved research protocol or to the consent form to the REB for further approval if something is to change while the research is ongoing, for example, if the study is to run longer, or new lab tests are required, or subject enrolment criteria are to be changed. Adverse events, such as device failures, or poor outcomes, or drug adverse effects that are realized in research endeavours are to be reported to the REB that approved the research, and reported to the primary investigator or sponsor who then also has an obligation to report the event to Health Canada. But REBs have a broader responsibility than just adverse event reporting, they are responsible for the research subjects, and as such, must be sure that the protocols are followed in accordance with good ethical practices; for example, ensuring that subjects remain informed, and their consent is valid, and that they retain awareness of the distinction between research and health care.

 

In Canada there are two organizations that assist with the running of REBs. There is the National Council on Ethics in Human Research (NCEHR), in existence since 1995. NCEHR  receives its funding from Health Canada and from the Royal College of Physicians and Surgeons of Canada. The Royal College is the professional college for all specialist disciplines in medicine and surgery in Canada and the rationale behind it providing funding is based on the notion that, drawn from its ranks, are many or most of the researchers involved in human oriented research and clinical trials. It provides leadership in advancing knowledge of ethically conducted research and does so in advising, guiding and educating of members of REBs. NCEHR assists in resolving challenging problems that an REB may face, conducts conferences and workshops, and can conduct site visits (if requested by an REB) to assess the proper function of an REB. A new grassroots organization is taking shape, the Canadian Association of Research Ethics Boards (CAREB) that was formed to represent the interests of REBs, their members, and their perspectives. CAREB was active in such things as the providing commentary for the Second Edition of the Tri-Council Policy Statement released in 2010. It should be noted, indeed stressed, that while the above named institutions provide guidance, education and support, Canada does not have a government agency or department charged with REB oversight, and which wields the authority of law.

Legitimate concerns have been raised about REBs. Ongoing monitoring of research has been criticised as inadequate in Canada both, as mentioned above with respect to Health Canada’s role, but also with respect to the REBs role. The reason often cited for any shortcomings on behalf of REBs is the fact that REBs are very poorly funded and they operate on a largely volunteer basis.36 Laudable attempts have been made by Canadian REBs to be more involved and integrated in the ongoing review process,37 but the fact remains that REBs will continue to be hard pressed to perform their basic monitoring duties without broad changes to the funding and management of REBs across Canada.36 Being a member of an REB is an onerous undertaking, it is simply not reasonable to expect that busy academics and other professionals can continue to contribute, on a charitable basis no less, the enormous amount of time required to fulfill all the tasks necessary for an REB to function as it ideally should.

Another significant systemic problem with the REB process is the disjointed nature of the review of multicentre trials. These trials must receive REB approval at every site in which they are to be conducted, but every site has a different REB, and a different set of people deliberating and examining the protocol. Even though all the REBs use the same set of rules and principles (i.e., the TCPS2), their geographic and demographic differences complicates the protocol and does nothing to assure consistency in reforming and amending protocols. This redundancy also creates a duplication of effort and wastes time in a system that is already painfully short of these resources.

It is perhaps some of the above issues and pitfalls that have spurred the creation of private REBs. This phenomenon has a longer history in the US, but private REBs are now making their way north of the border. The first such company was Institutional Review Board Services which now has subsidiaries in Toronto, Montreal, and Vancouver (as well as Boca Raton, Florida). Another board that has made an appearance is the Canadian arm of Western IRB, also an American company. These companies are designed to review research that is being performed outside of academic settings, and research that is industry sponsored. While this concept has a chequered past, and stories of fraudulent and dubious research have hit the media in the US, these IRBs are being increasingly subscribed to by American academic institutes.38 Canada, thus far, does not share as rich a history with these companies and considerable debate continues as to their place in the Canadian research environment. Some of the issues that are raised involve the appearance of conflicts of interest as these boards have obvious direct ties to industry—it is industry sponsors that pay them to review their protocols and therefore it is at least possible that private REBs are closer to industry partnership than public protectorship.39 But it has also been countered that with increasing industry involvement and sponsorship in academic centres, academic REBs are not immune to the same criticism.40 This continues to be a heated and closely watched issue in the research ethics arena both locally and internationally, and it is likely that the nature of both private and academic REBs will be changed by their mutual existence.

There are several legal considerations in Canadian research involving humans. First and foremost is the issue of adherence to TCPS2 guidelines and REB approval. It was mentioned above but bears repeating: private or industry funded research outside of an academic or government institution does not have to conform to TCPS2 guidelines and therefore does not require REB approval. Further, the TCPS2 guidelines are just that, guidelines, and do not have the force of law like the American “Common Rule” (45 CFR 46). Any research that involves drugs or health care products or devices must conform to Health Canada regulations through the Food and Drugs Act, and this act does indeed have the force of law.

The Canadian Criminal Code41 does protect Canadians from professional misconduct, negligence and intentional harm from medical practitioners. While it has not specifically been wielded to remedy those harmed in a research setting, inasmuch as Section 216 stipulates that persons undertaking medical treatment that may endanger life must use knowledge skill and care in doing so, it should logically extend to the research environment and the context of the medical experiment.42 Section 265 of the Code also establishes and defines assault to include the application of any force without consent (or the coercive or fraudulent attainment of consent), and this, too, is consistent with the use and jurisdiction of the Code in medical practice. The various provinces also have health care consent acts that reinforce the necessity of obtaining informed consent for medical care.

There is a significant Civil Law history in the realm of research involving humans.43 Perhaps the most significant North American case is the Gelsinger case in the US. In 1999, Jesse Gelsinger was 18 years old when he died as a result of a complication with a gene therapy trial at the University of Pennsylvania (for more see Chapter 5). It was argued that there were several instances of research misconduct and a US FDA investigation confirmed this. Ultimately, the University of Pennsylvania paid an undisclosed amount to Jesse’s parents, as the case settled out of court.44 The ripple effects of this high profile case were felt around the world but felt acutely in Canada.

The first Canadian case predates Gelsinger by 35 years in Halushka v University of Saskatchewan.45 In 1965 a university student was recruited as a subject in research on a new anaesthetic at the University of Saskatchewan. After he was told the new drug was “safe” he agreed to participate but suffered a heart attack and other medical complications that left him unable to continue with his studies. The Saskatchewan Court of Appeal found that actionable trespass had occurred against Halushka inasmuch as he was not provided adequate information to constitute informed consent.45 In this, and subsequent cases, the courts have endorsed the very high expectations for complete and thorough informed consent, especially for healthy subjects undergoing research from which they cannot hope to benefit directly.42

In another case, that of Weiss v Solomon,46 the decision was made from an even broader perspective. In this case, the death of Julius Weiss on Oct 13, 1981 prompted a lawsuit against the physicians and the hospital involved in a research study on a new form of eye drop. Mr. Weiss died of a cardiac arrest stemming from a complication related to an angiogram procedure. While the consent form discussed the risks of the new drug, the form was felt to be inadequate in describing the ancillary procedures, such as the angiogram, that would also be required of the subjects. Although not named directly, the REB (as part of the hospital), was impugned for this oversight as the courts found for the plaintiff and against one of the doctors and the hospital.

RESEARCH INVOLVING HUMANS – THE TRI-COUNCIL POLICY STATEMENT

There are a great many moral and ethical issues to consider in an examination of research involving humans. Much of what follows in this section will have already been gleaned from the above discussion. That research involving humans must be carried out in a particular and principled fashion is indisputable, as was discussed above. What follows is an elaboration on the particular rules regulations and values in the Canadian conception of the proper conduct of research involving Canadian persons. This is largely a discussion of the Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans (TCPS)23 and the 2nd Edition (TCPS2);24 this document is the first and final word on research involving humans in Canada.

As noted above, the TCPS was born out of the concerted effort of the three government research funding agencies, the Canadian Institutes of Health Research (CIHR)47, the Natural Sciences and Engineering Research Council (NSERC), and the Social Sciences and Humanities Research Council (SSHRC). It replaced various guidelines and policy statements put out individually by these councils. It underwent several revisions, and the latest update was in 2005. A major revision, the TCPS2 was released in 2010 and is the product of efforts of The Interagency Advisory Panel on Research Ethics (PRE), a panel struck by the three agencies (the Tri-Council).48

While the goals of the first and second edition are similar—to guide the ethical conduct of research involving humans—the precise statement of the guiding principles has been subtly revised in the second edition. The first edition has as its guiding ethical principles: respect for human dignity, respect for free and informed consent, respect for vulnerable persons, respect for privacy and confidentiality, respect for justice and inclusiveness, balancing harms and benefits, minimizing harm, and maximizing benefit. The second edition has trimmed this rather long list to just three: concern for welfare, respect for autonomy, and respect for the equal moral status of all human beings. It is in this iteration that one can see the consistency with the Belmont Principles: beneficence, respect for persons, and justice respectively. The TCPS, past and future, as the official guiding light of research ethics in Canada is consistent with international guidelines.

It is the TCPS that establishes the primacy of the Research Ethics Board in the research process. As noted above, the TCPS outlines the manner in which a REB is to be struck and its constituents, and guidelines for its meeting and responsibilities. The TCPS outlines that research which requires REB approval. To be precise, all research involving humans or human tissue and remains requires REB approval in Canada. There are exceptions and these include such things as research relying exclusively on publicly available information (for example research that could be gathered from telephone books, or research involving persons in the public arena such as politicians) or observing non-identifiable persons in public places. REB involvement is, similarly, not necessary for the development of public policy, or evaluation of programs, or in quality assurance assessments.

The TCPS2 devotes a significant segment to consent issues. The basic tenets are, again, consistent with the guidelines discussed in previous sections. Free and informed consent is, and will remain, paramount in Canadian research. The TCPS2 gives voice several important notions surrounding consent: informed consent is a process that must be revisited at several points during the research endeavour; consent must be gained before research begins but also secured in an ongoing basis as the research continues; and further that consent can be withdrawn at any time. Few exceptions to informed consent in research will be allowed, and these include research in (or a response to) emergency medical situations. In their outline of informed consent, the guidelines enter into a discussion of competence and capacity49 which is a foreshadow of the TCPS2 commitment to the fair treatment of vulnerable populations.

Privacy and confidentiality are essential to the notion of respect for persons and the TCPS2 devotes a section to elaborating on the ways and means of maintaining the sanctity of privacy and maintaining confidentiality of subjects. This includes a discussion on accessing and recording personal information and how, and to whom this can be disseminated including protocols for anonymizing and linking data. As this has become an increasingly significant concern in research (see Biobanking in Chapter 6) the TCPS2 devotes more space to precisely defining the issues and the guidelines than the previous edition.

As was mentioned above, there is an evolving shift from concern over protection from research to concerns over inclusion in research. This involves not only consideration for the just distribution of novel and successful new innovations, but also that there be no one left behind in the development of new generalizable knowledge. The Belmont Report was one of the first documents to discuss the necessity to include research involving children; that is, the recognition that incompetent persons should still be the beneficiaries of research. This is not only a departure from such documents as the Nuremberg Code which demands informed and competent consent (a stipulation which excluded children because of their limited capacity) but it is a reflection of the necessity for fulfilling the requirement of the just distribution of the goods (including new knowledge) of research. Continuing in this trend, the TCPS2 has specific recommendations for the inclusion of women (and, importantly, pregnant women) in research, again, as a reflection of the trend of heightened awareness of the just distribution of goods to those in need. Greater inclusion of women means the inclusion of persons who had previously been left out of research as a result of an unfair risk benefit analysis.

The TCPS has carried this inclusive theme to unparalleled lengths. Both the first and second edition have an extensive section on research involving Aboriginal Peoples. The TCPS2 is not alone in identifying certain vulnerable populations for particular consideration—the Belmont Report and the 45 CFR 46 both discuss vulnerable populations—but it is perhaps a unique feature of evolving Canadian values that allows it to identify better with its First Nations peoples. These concerns are more than a recognition of the minority status of many of these vulnerable populations (and the attendant concern that they not be left out of the sampling when it comes time to choose subjects), but also a recognition that some populations have special needs that deserve principled and empirical investigation. (See Chapter 1 for more discussion surrounding issues in Aboriginal populations.)

The TCPS2 contains guidelines for the classification of research: descriptions of the phases of human research and clinical trials and a description of multicenter trials. On the topic of characterizing research, one type of research that is perennially contentious, is that which involves the use of placebos. The TCPS2 steers clear of a definite position on the use of placebos in clinical trials, and both editions make clear that placebos should only be used in circumstances in which there is no alternative and no established effective therapy to test a new treatment against. Equipoise, the genuine uncertainty about the therapeutic benefits of either arm or intervention of a trial, must be maintained, and this is rarely a place for placebo. This contentious issue has been debated hotly in the development of guidelines from Nuremberg to Helsinki to CIOMS to Belmont. The TCPS2 is relatively clear and succinct, and while it arguably does not contribute materially to a moral understanding of the use of placebos, the new edition does enumerate more clearly and precisely the legitimate and appropriate uses of placebos in research.

Additionally, there are large sections of the TCPS2 devoted to research involving stem cells, gene therapy and foetal tissue, but these topics were discussed in Chapters 5 and 6, and will not be recounted here.

RESEARCH INVOLVING ANIMALS

While this discourse largely concerns bioethics in human research, it would be incomplete if it ignored animal welfare and animals in research. By and large, most research (outside of veterinary medicine) that involves animals, is research not for those animals but, rather, for humans and human concerns. While debates over the moral standing of vivisection and the use of animals for food and clothing have, and will continue to, rage with no clear end or conclusions in sight, it is a fact that currently in Canada, as in many places in the world, animals are being used in research. Discussion will now turn to the salient policy and regulations in Canada surrounding the use of animals in research.

Canada, like much of the world, has a long history of animal abuse in the name of science; a history that goes back to the 19th century.50 Heightened awareness of the plight of research animals, and anti-vivisection movements of the latter half of the 20th century, prompted the formation of stronger committees and better oversight. The Canadian Council on Animal Care (CCAC) was created in 1963 following the recommendations of a committee set up by the National Research Council and the Medical Research Council. This council is made operational through funds from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC) as well as other federal science based organizations and private funding.51 The CCAC is responsible for developing guidelines on the use of animals in experimentation. They are also responsible for carrying out inspections on institutions that use animals for research. Their guidelines are extensive and frequently updated, the most ambitious and comprehensive perhaps being the Guide to the Care and Use of Experimental Animals.52, 53 This extensive document covers all facets of proper care of animals used for research. Another organization, the Canadian Federation of Humane Societies (CFHS) is an influential advocacy group that receives no public funding and promotes animal welfare in general, including in animal research.

Animals are protected by Canadian legislation. Animals are protected under Section 446 of the Criminal Code which prohibits the wilful causing of any unnecessary suffering of an animal. In addition, most provinces have provincial animal welfare acts that protect animals (for the most part these acts protect livestock); the exceptions being the territories (none of which have an animal welfare act), and Quebec (which uses the Criminal Code).54

Responsibility for implementing the CCAC guidelines falls to the Animal Care Committees (ACC) in each research institution.55 The CCAC stipulates that every institution conducting research with animals must create an ACC and it further outlines the composition and terms of reference of these committees (much like the TCPS2’s recommendations on the creation and composition of REBs). The ACC’s are composed of scientists, veterinarians, laypersons, and other stakeholders.56 Enforcement and implementation of animal welfare laws and regulations is not consistent across Canada. The Society for the Prevention of Cruelty to Animals (SPCA)  is the enforcer of animal welfare guidelines and laws in most provinces, but very often this duty is shared by the RCMP and occasionally by specially trained veterinarians or other professionals.54 Police (local, provincial, and national) are responsible for enforcing the Criminal Code.

RESPONSIBLE CONDUCT

Much of the above discussion centers on the ethical treatment of research subjects, but there is another facet to research ethics that focuses more on the conduct of the researchers. While care and attention to the research subjects is part of good and ethical conduct, researchers have a duty to behave ethically that extends beyond treating subjects well. There is an expectation that researchers and research institutions will conduct themselves professionally, fairly, follow proper guidelines for discovering and publishing generalizable knowledge, and avoid conflicts of interest, and so on. It is these considerations that will occupy much of the remainder of this chapter.

A)     CONFLICTING AND COMPETING INTERESTS

Conflict of interest is a broad and variably defined subject. In the context of research ethics, adopting a broader understanding of competing interests is essential to defining the scope of the way conflicting interests can impinge upon discharging one’s duties in an ethical and proper manner. Researchers, especially in the biomedical world, often wear many hats and have to fulfil many duties. They have their research to consider, but they may also have clinical duties and teaching duties as part of their contract and their academic affiliations. Conflict of commitment, conflict of effort, and conflict of conscience are real issues in the research world, and are often not considered independently, but, rather, are lumped into discussions of the term “conflict of interest”.

Conflict of interest is a term that finds its way into many spheres of modern life; there is conflict of interest considerations in the financial world, the business world, in the news and publishing world, and, of course, in the government. It is something that is often looked on as bad or evil and at all costs to be avoided, but a broader perspective and deeper understanding is called for on this count. While it is universally agreed that it should be avoided wherever possible, there is nothing inherently wrong or morally corrupt about finding one’s self in the territory of competing or conflicting interests. Researchers are whole people; they have lives that involve their partners friends and children in addition to their colleagues patients and research subjects. There is nothing inherently wrong in striving to make a good living and creating a stable future for one’s children by doing research that involves the lives of others. There is nothing wrong with finding one’s self having to balance the competing needs of patients with commitments to teaching— this is simply the reality of the modern world. Rather, it is in the disclosure of the conflict and the manner in which one manages the competing interests that are important, and what determines the rightness or wrongness of the actions of the researchers.

1)    Conflict of Interest

Navigating a discussion of conflicting interests should rightly start with a definition and a refined understanding of  conflict of interest in the research. A standard and oft quoted definition, is one by D.F. Thompson: “A conflict of interest is a set of conditions in which professional judgment concerning a primary interest (such as a patient’s welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as financial gain).”57 In the medical and research world this conflict can be made manifest in many ways (a few of these will be elaborated on below) and involve all of the stakeholders: researcher/clinician/teacher, sponsor, journals and journal editors, patient/subjects etc. Discussing conflict of interest is a difficult task and many of the issues discussed in this section on misconduct could be framed to involve conflict of interest or have competing interests as the root of the problem. That is, mismanaging resources, mistreating subjects or patients, or falsely representing data in publications are all varieties of misconduct, and they often involve conflict of interest as a component or theme.

It has been argued that the notion of conflict of interest found itself only lately in the biomedical and research world owing to a variety of factors such as the status of physicians and researchers as possessing a fundamental integrity that renders them immune to such shortcomings, and that they operate within a normative system which would mitigate chances of conflict of interest being actualized.58 In fact, researchers, and the system meant to oversee them, are both fallible, and conflict of interest does occur in Canada as elsewhere.

Conflict of interest in business or government—where one’s judgements and actions can be influenced to gain power or monetary gain (and forsake ones clients or constituents)—is more tangible than in the medical world. Yet in the medical world the appearance of conflict can have significant impact as it erodes trust among patients; the mere spectre of conflicting interests can do much to impact the fiduciary obligations of the researchers.59 It is for this reason that disclosure is the cornerstone of resolving conflicts of interest. Disclosure is often the remedy of choice as it will address many of the intangible issues and restore the damage done by the erosion of trust. But disclosure and self-censorship is hardly enough, real policy and law provide the teeth to help prevent harmful conflicts from arising, and to mitigate damage ensuing from these conflicts when they do occur.

Where industry sponsored research occurs, is precisely the place where conflict of interest in the business sense, and conflict of interest in the biomedical and research ethics sense, overlap. Big business, such as pharmaceutical companies, can find themselves in conflict of interest; the interest of making money competing with an obligation to make safe products for consumers. (The Olivieri case discussed below is a demonstration of this.) This conflict often arises when academic or non-academic health science centres receive financial rewards from industry for undertaking research.60 Canada is an attractive place to do research owing to its comparatively lower cost of living and lower operating costs (compared to the US or Europe). More significantly, the US and other international companies are attracted to Canada because of the universal health care system (which cuts costs of conducting clinical trials and treating patients).60 The ways and means of addressing and resolving conflicts in this burgeoning enterprise of Canadian health related research, leans heavily on the careful regulatory mechanisms in the “roadmap” described above. The extensive rules and regulations governing research, as implemented by Health Canada, are designed to prevent conflicts of interest before they start, or to stem conflicts once they arise. Industry is further restricted from running afoul its commitment to the safety of the general public inasmuch as it is prohibited from giving incentives and payment to subjects that could be construed as being an unfair inducement to take part in studies and trials (i.e. coercion). REBs are also charged with the assessment of this.

The sponsors of research are not the only business in the biomedical realm that can fall victim to conflict of interest. The last ten years has seen the explosive growth of Contract Research Organizations (CRO’s).60, 61 Traditionally, research is carried out in academic or non-academic health centres, but there has been an increasing trend in the US, and to a lesser extent in Canada, to outsource conducting clinical trials from these health care centers and hospitals, to privately owned and operated businesses that have their own lab and clinical facilities. CRO’s in the US have been particularly (and sometimes unethically) aggressive in recruiting subjects for trials.61 These businesses are run in an ever more competitive environment and are, arguably, one step removed from the systematic and scrupulous ethics that are employed in public hospitals and academic institutions.  The Health Canada regulatory structure outlined in detail above, is not only in place to prevent conflict of interest in industry sponsored research in public government run health centres and hospitals, but also serves to oversee CRO’s. The ability and effectiveness of this oversight is, as yet, untested in this new and growing field.

Researchers can find themselves in conflict of interest in several ways. Most of these situations involve a conflict of fiduciary duty, or obligation to scientific rigour, versus financial incentive. It has been argued that the Canadian health care system is particularly vulnerable to such things inasmuch as the system is publically funded and therefore capped— physicians are not paid by market driven remuneration, but by a government controlled fee schedule—and this makes extra revenues from industry sponsored research endeavours doubly attractive.60 Researchers can be in conflict whether the conflict is real or perceived. Even a potential competing interest, or the mere appearance of conflict of interest, is enough to undermine the integrity of a researcher/clinician among his or her patients or peers.

REBs have an important role in mitigating conflicts of interest. Researchers are required to report any conflict of interests before they begin conducting their research. The Tri-Council Policy Statement guidelines (TCPS2) stipulate that they must report any conflict of interest to both the REB in the protocol application, and furthermore this must be represented in the informed consent form for potential subjects to read before they agree to take part in a study.24 It must, however, be restated that there is no strictly legal structure guiding this process; while the REBs are charged with enforcing the TCPS guidelines and the ICH Good Clinical Practice guidelines, these are guidelines not laws, and, furthermore, there is no legal enforcement in place compelling the REB to carry out these duties nor make remedies if they fail to do so.61 Also as mentioned above, the rise of private REBs only complicates this scenario and enhances the potential for conflicts.39, 61 Before leaving the topic of REBs, it should also be noted that researchers who sit on REBs are required to state any conflict of interest they may have in any protocol presented to the board. For example a researcher cannot deliberate on a protocol in which he or she may be an investigator, nor can he or she be present in discussing a protocol if he or she reports directly to the principal investigator in his or her work outside the REB.

A particularly contentious issue in the realm of conflict of interest in medical research is the issue of inducements paid to physicians for the enrolment of study subjects—so called “finder’s fees”. These are monies paid to physicians or nurses who refer patients to be enrolled in a study. It creates a three-way conflict between clinicians (who find themselves in conflict of interest over their desire to enrol subjects, and earn more finder’s fee money); and the subjects (who desire to be appropriately referred for research that is relevant to them and society); and sponsors (who desire to have subjects referred that are relevant and suitable to the study at hand so as to ensure credible outcomes and good data). The cash incentive has, at the very least, the possibility or appearance of poisoning the integrity of this arrangement. Analyses in the US have shown that research data has been tainted by overzealous recruitment yielding biased or questionable results.61 In 2007 the Canadian Medical Association (CMA), in its policy statement on interaction with pharmaceutical companies, changed its 2001 policy which reluctantly permitted finder’s fees, to one which expressly forbids finder’s fees.62, 63 This seems to echo the explicit and unequivocal prohibition of finder’s fees made by the American Medical Association some years earlier.

As noted above Canadian physicians and researchers (as well as medical students and residents) are under the influence of their code of ethics and the Canadian Medical Association guidelines. These instruments are attempts at diminishing the odds of conflict of interest arising between physician/researchers and their patients as a result of interaction with pharmaceutical companies and other biomed industries. These guidelines stipulate that the fiduciary relationship with patients is primary and paramount, and is to be preserved no matter what form the relationship with any biomedical company takes. Furthermore, not only are finder’s fees prohibited, the payment for conducting research must be commensurate with typical patient care remuneration. There are also strict limits placed on the means by which physicians and students may participate in continuing medical education (CME) or professional development programs. Company products cannot be promoted or named by their trade names during public presentations, stipends for giving lectures must be reasonable, no gifts or other enticements from companies to the physicians or the participants are allowed, etc.62, 63 While these policy statements do not have the force of law, the threat of disciplinary actions before the College of Physicians and Surgeons of the various provinces does provide incentive to follow them. These Colleges have their own statements on conflicts of interest, as does the Royal College of Physicians and Surgeons (the body that oversees accreditation of the medical specialties). These stipulations, rules and regulations do go far in ensuring that undue influence from the pharmaceutical industry cannot be transmitted to patients and cause harm.

There is no specific legislation regarding conflict of interest between clinician/researcher and his or her patient/subjects. This is not to say that one that does not recognize or remedy such a conflict will not be reprimanded; it has been strongly argued that conflicts of interest could attract an action under several provincial statutes or the Criminal Code. As was outlined in Chapter 1, the various “medicine acts,” and “health professions acts” that exist in each of the provinces regulate the practice of medicine (and the practice of the allied professions) in the provinces and territories. They also give power to the Colleges of Physicians and Surgeons in each region to oversee physicians’ licensure and conduct, and provide for fair and equitable treatment of patients. These acts underscore and enhance the fiduciary commitment clinicians have to their patients. Beyond provincial legislation, it has been suggested that clinicians or researchers that gain financially or otherwise, through a conflict of interest, represent a significant enough departure from acceptable and responsible practice that they could invite charges of fraud under the Criminal Code.61

One other area of conflict of interest that a researcher may find him or herself in is a real or perceived financial conflict when said researcher has a financial stake in an industry or sponsoring company. For example, one who holds shares in Company XYZ could easily have a stake in the outcome of the research on XYZ’s new drug, and participating as an investigator on such research would certainly raise the spectre of bias. Once more, it is not, in and of itself wrong to hold equity in a company, or to even be an employee or contractor of such a company, but disclosing this to research subjects, REBs, and journals before publication is essential to dispelling the ill odour of conflicting interest. The disclosure of such a potentially troublesome conflict is really only a bare minimum. Examples of poor outcomes of such conflict of interest scenarios can be found in the US, which has prompted many academic institutions to specify limits to acceptable researcher-industry interaction. As an illustration, Harvard Medical School has been so precise as to suggest a financial limit of $20,000 in equity holdings for any researcher involved in research with that company.64 The Canadian system is much more limited in its proscription. The CMA in its policy statement, Guidelines for Physicians in Interaction with Industry, places no such financial limits nor specifies any other limits but is firm in stating and restating that “the primary objective of professional interactions between physicians and industry should be the advancement of the health of Canadians.”63 It further suggests that any interaction with industry must be clearly disclosed, and that any interaction should in no way influence or impede the care given to patients or considerations of research subjects best interests. While no specific legislation exists for these interactions they would certainly seem to fall under the purview of previously discussed legislation.

Scientific journals can find themselves in conflict of interest— publishing interesting research sells more journals and this in turn imposes an obligation to rigorously and scrupulously separate the credible and authentically interesting research, from the illegitimate and specious. Much more often than being embroiled in conflicts of interest, journals are seen as a remedy for conflict of interest in science; they are part of the solution, not the problem. Rigid publishing and authorship guidelines impose on researchers the complete and full disclosure of any conflicts of interest that may taint the data. Canada (as with most nations) and Canadian journals adhere to the strict guidelines set out by the International Committee of Medical Journal Editors (discussed below). While individual journals and editors create their own publication guidelines, the largest medical journal in Canada, the Canadian Medical Association Journal (CMAJ), has followed the lead of prestigious journals in the US in enforcing strong guidelines regarding authors and their ties to industry. While physician/researcher interaction with industry and physician/researcher investment in industry is scrupulously examined in public and academic settings, in the publishing world, the policies are rigid, absolute, and specifically defined even down to the dollar amount a potential author may have invested in a company related to the research being published. The CMAJ will not permit publication of an author that has more than $10,000 invested in any company or even a competitor company of a product named in the article (this is consistent also with the New England Journal of Medicine and The Lancet).65

2)    Other Competing Interests

As noted above conflict of interest, per se, is one facet of an understanding of conflict of interest, but consideration should also be given to other competing interests to complete an understanding of ethics in research. Conflict of commitment and effort are real and significant concerns in academic settings. When sponsored research provides financial incentive, or when a researcher’s goals and aspirations for discovering new information outweigh that researcher’s desires to teach or ability to attend to the administrative obligations of his or her institution, a conflict of commitment is said to arise. Canadian universities address this in formal rules and regulations regarding expectations they have for their teachers, and the degree to which competing concerns can be allowed to impact on their teaching duties. Furthermore, universities facilitate the reporting and monitoring of circumstances in which educators may find their time commitments in conflict. But it must also be noted that universities also benefit from the funds bestowed on them to conduct research, and as such, there is the danger that they may find themselves complicit in facilitating conflict of commitment and effort. The Canadian Association of University Teachers has addressed some of these concerns by creating formal guidelines on academic freedom; guidelines that restrict the degree to which researchers can find themselves beholden to the sponsors of their research. Nevertheless, while American universities and academic health science centres tightly regulate conflicts of interest, the Canadian regulation is less explicit, less formal, and much more varied and inconsistent when compared with their American counterparts.60

Conflict of commitment and conflict of effort may be born of the dual role—that of researcher and clinician—that many physicians have. Time spent in managing and conducting research may detract from patient care outside of the research setting. This is addressed informally through the stringent licensing regulations, the appropriate granting of hospital privileges and the professional codes of ethics that physicians are required to adhere to, but this conflict is one that is very difficult to define and even harder to prove. The dangers of this type of conflict is less probable and less intrusive in many of the other health care and allied professions inasmuch as contracts for professionals in other roles are usually explicit as to the role of the person being hired; other health care professionals are hired into clinical roles or research roles and they fill a position that is technical and defined, with little room to allow for competing interests. For example, a nurse hired as a research coordinator fills that technical role and does not risk betraying or neglecting clinical duties, if for no other reason than that he or she has none. Canadian physicians, however, are generally “self-employed” and they can take on many roles and many contracts and oversee the division of their effort according to their needs and their wishes. It is that latitude, and that discretion, that generates conflict of commitment and conflict of effort.

Finally, in this broad treatment of the notion of conflicting and competing interests, there is conflict of conscience. Health care providers (doctors, nurses, pharmacists, therapists etc.) may find themselves being compelled to provide therapy that they may find morally repugnant. The law and professional codes of ethics are clear on the resolution of these conflicts, if the treatment sought is an accepted, legal treatment and the indications are appropriate, the patient deserves this treatment so the health care provider is obliged to seek another provider and transfer care or responsibility to this other (for example, a pharmacist who cannot, in good conscience, dispense a “morning after pill,” is legally bound to refer the patient to someone who can provide her with this treatment). Conflicts of conscience can be manifest in research ethics in a few ways. The first is in the deliberations of the REB: if a member has a conflict of conscience (for example around a protocol that involves abortions), that member is obliged to recuse him or herself from weighing in on the protocol. Also, researchers should not be recruited or compelled to work on a research project in a field that is morally repugnant to them. Conflicts of conscience in research are, by their very nature, value laden and hard to define, but also owing to their very nature, self censure is often easily attained as people generally do not persist in doing things that are morally repugnant to them.

B)     AUTHORSHIP AND PUBLICATION

The concept of authorship is evolving in this rapidly changing world. There has always been pressure to publish in academic institutions but never more, perhaps, than the present when careers, fame and considerable amounts of money, are made on the quality and the impact of published information. As technology blooms so does the business end of discovering new and interesting things and bringing them to market. A necessary step in that process is the peer review and publication of new generalizable knowledge. The information age that we live in is also changing the nature of publication, the margin between discovery and reporting is ever narrower, and the race to publish more competitive.66 The World Wide Web is emerging as a new forum for dissemination of information. It is also emerging as a new medium of credible publication as online journals become more acceptable, and as print journals often publish either simultaneously on the web or web-based publication precedes print publication.

Defining authorship is a slippery subject especially in the age of multicenter, multinational trials that may involve dozens or even hundreds of authors. Authorship status must be agreed upon by the researchers, the sponsors, and the journals accepting the publication. Similarly, individual journals have their own criteria for publication and Canadian journals are no exception. The International Committee of Medical Journal Editors (ICMJE) is a working group of editors of major medical journals that was founded in Vancouver in 1978. This unique body meets annually, but in its 30 year existence is remarkable in that it has had no board, no chair, and has always been self-funded.67 Despite these bureaucratic absences, it has been able to derive the internationally recognized  Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication.68 This is the first and final word among many journals and journal editors for publication requirements and protocol. It discusses and defines authorship and other technical attributes of publication. The Canadian Medical Association Journal adheres to these guidelines and its editors are members of the ICMJE. Additional input into regulating authorship and defining it as a concept is another Tri-Council Policy Statement. This document, Integrity in Research and Scholarship (discussed in greater detail below), is clear about the necessity to identify and include all authors, and give recognition to all persons who contribute materially to publishable data.69

Canada is not immune to the issues that surround sponsorship of research in an ever more technologically complicated world. Biomedical products are expensive and much depends on research, indeed published research, to prove their worth. Research is expensive, and industry and private sponsorship is evermore necessary to bring ideas and products to fruition. Industry sponsorship is a sword that cuts both ways, for while it funds the research, industry can potentially influence the research and the publication of that research. So while industry can be a positive force in the scientific world by creating new information and knowledge (for example that a new cancer medication is very effective), it can be a negative force if it suppresses this new information and hampering the knowledge process (for example, hiding or delaying research that reveals that a competitor’s medication is actually more effective).

While it is generally true, in a democratic and free market country, that he who pays the piper calls the tune, the degree to which industry should be allowed to shape the scientific knowledge, and render the truth, is a prickly subject when a society’s general health is at stake. That sponsors should wield such power and influence over published literature is repugnant to Canadian journal editors.70 It is also repugnant to the CIHR as a major research funding agency. The CIHR has always been an advocate of open access to research. Beginning in January 2008, the CIHR adopted a bold policy that all research funded by CIHR published in a peer review journal must be made publically available on the publisher’s website or online in a data repository.71 These steps were taken to enhance knowledge translation of, and increase access to, Canadian research in a manner consistent with the values of the Canadian government that puts advancement of knowledge before financial gain. As noted above, the TCPS2 demands that all research be registered in a recognized and easily accessible website.24 Nonetheless, despite these bold steps, there is no assurance that research data will not be suppressed, for simply ensuring that published data is made more widely available does not prevent the suppression of publication in the first place.  Yet another group, the Canadian Association of University Teachers has proven itself to be an important player in guiding and promoting academic freedom (as is discussed below in the Nancy Olivieri case) and this is another step toward addressing the issue of research suppression.

C)     INTELLECTUAL PROPERTY

Patent law is one of the most complicated fields of legal expertise. The notion of intellectual property relates directly to patents, copyright, trademarks, and trade secrets and is, by extension, a very complicated arena, one where law and biomedical fields intersect. The ethical issues of just what can be owned in the form of intellectual property is far from resolved, it is this realm where questions such as the following are asked: “is it ethical to patent a new life form?” or “is it possible to patent a new gene?” and “who should have access to new and expensive patented technology?”. It is also the realm in which questions about the ownership of research data, and publication rights and copyright are fought over. The legal battles continue to rage, and in this day of explosive growth in the biotech world, many of these ideas and answers to the above questions are evolving rapidly. There are no clear legal answers in Canada or elsewhere in many of these areas. The moral solutions are even more tenuous, and an accepted and established normative ethical understanding is far from being realized or recorded in the bioethical canon.

In Canada the Intellectual Property Policy Directorate and the Patent Policy Directorate oversee the modification of the relevant laws and acts in this sphere. These include the three appropriately named acts: Patent Act, Copyright Act and Trademarks Act.72 Generally, research generates items of intellectual property that are patentable, trademarkable, or copyrightable, and Canada, like any industrialized country, has the means to protect this intellectual property. However, as alluded to above, there are some issues which are emerging, contentious, unclear and thus relegated to the grey zone of research ethics. While the US and other nations have endured high profile cases on issues such as the patenting of higher life forms, Canada has remained relatively free of such contentious cases, and as such, has not had to define such laws explicitly.73 Industry Canada, through the Intellectual Property Office, has studied the issues surrounding patenting genetic material, the ownership of human tissues, and other things that pose ethical challenges. By and large, the Canadian position on such matters is to defer to the international scientific community, the US patent decisions, and other relevant authorities (such as UNESCO) that have shaped the mood of these debates and delivered pertinent opinions.73-75

With respect to ownership of the fruits of research, answers are traced back to fairly typical common law doctrine that dictates that one owns the fruits of one’s labour (we can presume intellectual or otherwise) unless that labour is labour for hire; whether that labour be building a bridge or performing research, the fruits are owned by the employer and given over in exchange for monetary income.76 There have been modifications of this principle in the industrialized world in novel legislation such as the Bayh Dole Act of 1980 in the US which gives researchers (and the research institution) a stake in, and a share of, the earnings from research and patented technology generated by public funds.77 While this has had a ripple effect in Canada, the CIHR recommends researchers to tread softly in this as yet undefined realm in Canadian research.78 For industry funded or privately funded research, the fruits of the labour go to the sponsor, but the sponsor maintains responsibility (by virtue of the pertinent law and policy) to carry out the research ethically and responsibly.

There are fruits of the labour of research that extend beyond new technology and tangible outcomes—most notably the creation of generalizable knowledge. Here too there is a difference in the intricacies of intellectual property depending on the funding of the research. If the research is government or publically funded and carried out in a research institution, the data and knowledge is owned by that institution (such as a university lab). Data that is carried out by industry sponsors is owned by the sponsor. But here too (see below the case of Dr. Olivieri), proper conduct must be observed in the generation of that data, and the disposition of that data, if it has significant impacts on the health of research subjects or society (take for example, the mandatory reporting of Significant Adverse Effects of new drugs).

Data is not of value in and of itself, it generates value by spawning new technology and new knowledge and the way to actualize these things is through publication. The world is witness to something of a transformation in the copyright rules of research publication. While traditionally researchers and authors would give over copyrights of the publication to the publisher (such as a medical journal), there have emerged, in the digital age, new rules perspectives and improvements on this approach. By and large, the International Committee of Medical Journal Editors are a respected authority on this, and many journals adhere to the well-known Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication.68 In Canada the largest circulating medical journal, the Canadian Medical Association Journal uses these guidelines as the foundation of its own publication and copyright policy.79 These guidelines point out that many “open access” and online journals have no rigid copyright process, and that there are certain exceptions to copyrighting that is contingent on the journal and on other considerations—suffice it to say, publication copyright is becoming a more fluid concept, and contingent on agreements between the author and the publisher. The Canadian Association of University Teachers has been an influential force in this sphere as well. It publishes several online guidelines addressing issues of academic intellectual property and the changing nature of copyrighting material.80

D)     RESEARCH MISCONDUCT

Research misconduct is variably defined. In a narrow sense it includes plagiarism, falsification, and fabrication of data. In a broader sense it includes also such things as conflict of interest issues discussed above, poor lab technique or methodology that introduces systematic bias in results, unprofessional behaviour toward colleagues and co-workers, or other behaviour unbecoming a professional or an academic research organization. Research ethics is about proper conduct so, in this sense, an even broader interpretation would include much of the foregoing discussion on the proper conduct toward research subjects, and even proper attention to environmental and fiscal responsibilities. Proper research conduct means proper human conduct; research ethics is an extension of ethical human behaviour. A broader treatment of this issue is well beyond the scope of this discussion but a narrower treatment of the subject will be introduced with respect to salient Canadian context. The Canadian situation (as in other bioethical considerations) is placed in context often in comparison with the US situation. This has to do with more than just cultural similarities and geographic proximity but also inasmuch as research ethics law and policy is often informed by the American experience, an experience which is then recorded in the published literature, and which, in turn, informs much of the world.

The US Public Health Service and the US National Science Foundation have defined research misconduct precisely since 1989 and translated it into a legal understanding as it is encoded in the Code of Federal Regulations. Here, research misconduct is defined as plagiarism, falsification of data, or fabrication of data. Furthermore, the conditions that must be met—that the acts be intentional and deviate significantly from accepted norms—to identify a particular act as a bona fide act of misconduct, are also spelled out.81 By interpreting misconduct in this precise fashion there is some control over investigating wrongdoing, enforcing rules, and punishing or sanctioning wrongdoers.

In Canada research misconduct is not defined by legislation, it is defined on many levels but perhaps most explicitly by the Tri-Council Policy Statement, Integrity in Research and Scholarship.69 This document, as a general guideline, outlines misconduct issues in broad strokes and deals with the issues in general terms. As research misconduct is not defined by law, nor transgression enforced by the justice system, the responsibility for integrity is placed on the institutions conducting research. The policy statement puts responsibility first and foremost on the individual researchers. Next, and perhaps more importantly, the document specifically outlines the ways that research institutions must take responsibility for research integrity. Institutions receiving any funding from the CIHR, NSERC, and SSHRC (the Tri-Councils that are responsible for funding almost all government research), must have research integrity offices and means of enforcing guidelines. While this does not carry the weight of the legal system, it nevertheless ensures research integrity fairly reliably inasmuch as the research cannot occur without the funding, and the funding will not be given without the appropriate mechanisms and institutional policies in place. The Tri-Council also manages the implementation and creation of institutional policies through its policy statement: Framework for Tri-Council Review of Institutional Policies Dealing with Integrity in Research.82 Universities throughout Canada generally have academic codes of conduct and also have offices of research integrity that researchers or REBs can appeal to.

Procedures for making allegations of misconduct and for investigating misconduct are outlined by the above mentioned funding agencies. Procedures are made explicit in the Integrity in Research and Scholarship document. A more comprehensive treatment of the subject is to be found in the Tri-Council’s procedure statement: Tri-Agency Process for Addressing Allegations of Non-compliance with Tri-Agency Policies.83 This extensive procedure relies on the CIHR Act for authority and the various memoranda of understanding for the granting of federal research money to institutions (outlined above). The “procedure” first discusses and outlines its core values, and then outlines the types of allegations and how to proceed with them in the context of the organization. There is an Ethics and Policy Advisor—a person who acts as the receiver general for complaints or allegations—and that person defines the issue and the severity of the allegation before relaying it to the Research Integrity Committee (RIC). The RIC is then responsible for acting on the allegation by investigating it and imposing sanctions on the researcher or the institution. The RIC also has means in place for reviewing allegations and monitoring its performance in dealing with them, and also modifying its own procedures as necessary.

While these procedures do not impact privately or industry sponsored research per se, the Tri-Council’s Integrity in Research and Scholarship regulations stipulate that every institution doing research or receiving any government funding must have in place, structures for ensuring research integrity. And this does reach the arena where most industry sponsored research ends up playing out, i.e., in academic and public health care institutions that get government funding in addition to their industry funding. As was noted above, any research in these institutions and any research done by any researcher in these institutions must be passed by the REB of that institution and adhere to the TCPS2 guidelines.

What is conspicuously absent in the Tri-Council documents is specific protection for whistleblowers. Canada does not have specific legislation to protect those who would take risks to report misconduct or wrongdoing. The US Department of Health and Human Services has, in its Office of Research Integrity, a Whistleblowers Bill of Rights which protects reporters of fraud and misconduct. Canada does not have any such official policy. 84 The Canadian Human Rights Act provides some broad protection for whistleblowers,85 but no specific legislation exists for researchers or academic institutions.86

Any discussion of whistleblowing in Canadian research ethics brings to mind the archetypal Canadian case, that of Nancy Olivieri. Indeed this case has been described as one of the most important events to occur in research ethics internationally as well, and an occasion where Canadian bioethics has informed the rest of the world.87 Much ink has been spilled on the reporting, discussion, and analysis of the affair. These include not only the official 540 page report by the Canadian Association of University Teachers,88 but also the countless commentaries nationally and internationally, both in the lay and academic literature, and no less than four books on the scandal.89 While an in depth ethical analysis is beyond the scope of this discussion, the fallout of the affair has had significant impact on research ethics ever since.

In the briefest of summaries: Dr. Nancy Olivieri was a hematologist at Toronto’s Hospital for Sick Children (HSC) doing research on thalassemia (a blood disorder) in children. She was an investigator in a series of research protocols looking into the effectiveness of a new medication (deferiprone) from the pharmaceutical company, Apotex, which produces generic drugs. She began working in this area in 1989 and began her partnership with Apotex in the early 90’s, publishing some initially favourable data in 1995. When she began having concerns about the safety of the medication, and concerns over a loss of effectiveness in some patients, she wanted to warn her patients and inform the REB at HSC. Apotex disputed the data supporting these allegations, and when Olivieri tried to warn the patients about the new findings in the spring of 96, Apotex stopped the trial and fired Olivieri, ended her consultancy contract, and furthermore forbade her to share any of the data from the trials. Dr. Olivieri continued to present the data at meetings and in publications and furthermore continued to lobby to have the drug discontinued in trials and in treatment. Apotex, for their part, continued to promote the drug and said the data Olivieri presented was flawed and that the drug was safe. Dr. Olivieri did not receive the support of the HSC, nor of the University of Toronto and its REB, furthermore it is argued that the bioethics community stayed largely silent.90 At one point she lost her job and her academic position—for a short period in 1999—but was soon reinstated. Olivieri continued her efforts to present the data showing the dangers of the drug… and she continued to be persecuted and unsupported in her efforts, even to the point that her fiduciary and academic integrity was questioned and she was called before the College of Physicians and Surgeons of Ontario. The college found no misconduct had occurred, and finally Olivieri’s disputes with the HSC and University of Toronto were settled in 2003. She had been vindicated in 2001 in the official report by the Canadian Association of University Teachers.

It was this Olivieri Report 88 (see above) that was the instrument for some change in the research ethics world. There were several recommendations spawned by this affair, and by the detailed analysis provided by the Canadian Association of University Teachers (CAUT). The CAUT is a national association supporting post-secondary teachers. One of its fundamental roles is in promoting academic freedom, and one of the glaring ethical transgressions in the Olivieri case was the limits Apotex placed on Olivieri’s academic freedom in its insistence that she could not publish any of her data for at least one year after the end of the trial.91 This was an issue that inflamed the academic community nation-wide. In the CAUT findings it was strongly recommended that publication practices of journals should be changed, and that no such gag orders could be written into contracts between researchers and industry. Whether it was the Olivieri case, or just the changing times, this policy has become the norm in Canada and internationally.

While it has been argued that Olivieri may have been breaching her fiduciary commitments by even signing a contract that contained a gag order in the first place, it is generally agreed that she was exemplary in fulfilling her fiduciary commitments in breaking the terms of the contract and speaking out.92 The CAUT report lists among its 31 recommendations that REBs should be told to screen protocols for gag orders and warn the sponsor and researcher of the inappropriateness of them. This is not only intended to prevent publication gag orders, but to ensure unfettered reporting to study subjects, other investigators, and Health Canada (where necessary) any information pertinent to health of the subjects.88

The Olivieri report charges the Association of Universities and Colleges of Canada (AUCC) to provide leadership in implementing and enforcing policies governing industry academic relationships. Much as the CIHR has been studying this problem since 2001(as noted above), neither they nor the AUCC have any policy statement or guidelines firmly in place for governing industry-university partnerships, even though both recognize the rapid rate at which such public-private partnerships are being made. What has become clear in the last several years is that the Olivieri case was the first of several cases in which “Big Pharma” has been the focus of investigations of misconduct, and it is as a result of these cases that public trust in industry based research is eroding.89 The Olivieri case also points up the fact that it behoves research institutions in Canada and around the world to ensure that the research generated from the congress of industry and academia does not tarnish the reputations and the integrity of good  researchers when one of the parties (industry or academic institution) should stray from good ethical conduct.

E)      LIABILITY

Several cases and legal instruments have been alluded to above, but the precise question of just who is liable when things go badly, and just why that party is liable, remains obscure. The fact is that connecting liability to poor outcomes or poorly performed research is a topic in development, and neither firm understanding of the topic, nor an established history of illuminating precedents exists as yet. While the Nuremberg Code was specifically derived from the trial of Nazi physicians, this extreme example of liability has, fortunately, not been repeated.

New and novel treatments, and technical innovations have presaged the occurrence of catastrophic outcomes in such fields as gene therapy. The Jesse Gelsinger case is a classic case of this ilk. Balancing risks with the enormous potential for benefit in new and untried therapies is truly walking the knife-edge of research ethics. But it is not only new therapies that may raise problems, as alluded to above, the debate continues to rage about the continued use of a very old form of research, that involving placebos. As yet, no cases have been generated on the grounds of the inappropriate use of a placebo trial when a viable, proven, and available medication exists.93 Whether it is right or wrong to use placebos in research is an, as yet, undecided ethical problem, precisely whom to blame for carrying out such research adds an element of complexity that has not been decided in Canada or anywhere else.

The Gelsinger case described above is an instructive and unfortunate example of a poor outcome that connects back to a deficiency in the informed consent process, and to conflict of interest of the investigators and the institution. Negligence has been, and would arguably continue to be, the charge in these cases.94 But precisely who is liable is a difficult question to answer. The sponsor, the investigators, the institution in which the research is being conducted and even the REB, are the obvious suspects. Certainly in Gelsinger it was the institution (the University of Pennsylvania) that settled. In the Canadian cases of Halushka v University of Saskatchewan, the university was found at fault as well as two researchers; and in Weiss v Solomon, the researchers were found responsible, but the hospital was found partially responsible owing to deficiencies in the REB. Another significant, and as yet untried, defendant is the Canadian Government. The extent to which the Crown can be held liable for research that the government underwrites is unknown, as yet there have been no actions brought against it. It stands to reason that the CIHR and other agencies in funding research, or the Therapeutic Products Directorate in overseeing and permitting research on new products could be construed as liable in damages done in research they are connected to. Establishing this link is arguably very difficult owing to the diffusion of responsibility that has occurred through such things as the memoranda of understanding that government funding agencies have with research institutions, the oversight of REBs which are to be the screeners and invigilators, and tools such as the TCPS2 which are to prevent poor outcomes or poor research.95 It remains to be seen whether a significant challenge to this state of affairs will arise.

SUMMARY

Research, despite its rational and methodological approach to the creation of new knowledge and technology is not, indeed must not, be immune to moral and ethical considerations. Research ethics is a broad and multifaceted topic. This has been an examination of many of these facets in the Canadian setting. In a proper understanding of any subject, to understand the current situation requires an examination of the history from which the present was derived, and this was the point of embarkation in this chapter. The world had to confront research ethics when it was forced to confront ethical transgressions of the Nazi regime. While research ethics arose as a necessity and a reaction it has grown to be a much more proactive discipline. A discipline that has seen such important landmark documents as the Declaration of Helsinki, the Belmont Report, and Canada’s very own Tri-council Policy Statement: documents that anticipate and attempt to ensure an ethically sound trajectory in the pursuit of knowledge and progress in the future.

The second section of this chapter was a survey of the complicated landscape of regulations, laws and policies, as well as a snapshot of the major players in this realm. Funding and financial considerations were considered first, and then discussion turned to an exploration of the relevant government structure. Health Canada is at the centre of this structure, but oversight extends beyond this to the departments that oversee research (the directorates and the protectorates), and the agencies that fund research (the three major agencies that make up the “tri-council”). Some of the problems with this structure, and the pitfalls of the law and policy, was then explored. Almost all research in Canada is scrutinized at some point by research ethics boards so their composition, their mandate and their influence was considered in some detail. This section ended with an examination of some of the legal attributes that shape research ethics; both legislative and case law considerations.

The third topic was a discussion of research subjects, both animal and human. The Tri-council Policy Statement was discussed at length as the definitive policy statement on research involving human subjects. Its core principles include respect for human dignity (and concern for vulnerable populations), balancing benefits and harms, respect for privacy and confidentiality, primacy of informed consent, and concern with justice. The TCPS2 sets out the need for REBs and the guidelines by which these are to be formed. It is the definitive guiding document for research done in Canada. A briefer discussion then followed—a look at animal subjects. For, while research ethics often focuses on humans, justification and ethical treatment of the animals that contribute to human well-being cannot be neglected.

The most extensive section in this chapter was the fourth section on good conduct. First was a consideration of competing interests. The most significant and most obvious competing interest is conflict of interest and it was established that researchers, sponsors, institutions and publishers all play a role in the genesis and remedy of conflicts of interest. Other competing interests, such as conflicts of commitment and conflicts of conscience, were also seen to be germane to a discussion of good conduct and were also examined.

Research is important in creating generalizable knowledge and spawning new technological advances. There are several considerations that go into a contemplation of how to conduct this process ethically. Research is not of value in and of itself but rather dissemination (publication) of the research gives it substance and potential, and transforming it into technology and products gives it financial worth. An examination of the ethics of ownership and management of these processes at the various stages was made: intellectual property, copyrighting information, patenting technologies etc.

Finally, good conduct was examined through a study of misconduct. Misconduct was defined and then there was discussion about the ways and means of establishing, investigating, and remedying misconduct in the Canadian research setting.  The archetypal case of Dr. Olivieri was reviewed as a means to explore this concept and its history.  This chapter ended with a study of liability and posed questions about who could and should be liable for poor outcomes in research.

 

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26. Government of Canada. Food and Drug Regulations (C.R.C., c. 870).

27. Health Products and Food Branch. Guidance for Clinical Trial Sponsors. Clinical Trials Applications: Minister of Health; 2008: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ctdcta_ctddec-eng.pdf. Accessed 28 February 2011.

28. Health Canada. The Health Products and Food Branch Inspectorate Good Clinical Practices.  http://www.hc-sc.gc.ca/dhp-mps/compli-conform/clini-pract-prat/index-eng.php. Accessed 28 February 2011.

29. Health Products and Food Inspectorate. Summary Report of the Inspections of Clinical Trials Conducted in 2003/ 2004. 2004; http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/compli-conform/2003-2004-eng.pdf. Accessed 28 February 2011. This document cited deficiencies and deviations from protocol that were, in general, similar to those noted in other jurisdictions by other regulatory bodies: inadequate records, insufficient quality systems, problems with informed consent process, and deviation from research protocol. It took action on several of these, and while many deserved immediate action, none required cancelling a clinical trial.

30. Shuchman M. Clinical trials regulation–how Canada compares. CMAJ. Sep 23 2008;179(7):635-638.

31. This registry is part of the FDA in the US and can be accessed at the website of the same name http://clinicaltrials.gov/ .

32. Baird P. Getting it right: industry sponsorship and medical research. CMAJ. May 13 2003;168(10):1267-1269.

33. Lewis S, Baird P, Evans RG, et al. Dancing with the porcupine: rules for governing the university-industry relationship. CMAJ. Sep 18 2001;165(6):783-785.

34. Bernstein A. Toward effective Canadian public-private partnerships in health research. CMAJ. Feb 4 2003;168(3):288-289.

35. Canadian Institutes of Health Research. Grants and Awards Guide (2010-2011). 2010; http://www.cihr-irsc.gc.ca/e/805.html. Accessed 28 February 2011.

36. Emanuel EJ. Ethical and regulatory aspects of clinical research : readings and commentary. Baltimore: Johns Hopkins University Press; 2003.

37. McCusker J, Kruszewski Z, Lacey B, Schiff B. Monitoring clinical research: report of one hospital’s experience. CMAJ. May 1 2001;164(9):1321-1325.

38. Elliott C, Lemmens T. Ethics for sale: For profit ethical review, coming soon to a clinical trial near you. . Slate. 2005(13 Dec 2005). http://www.slate.com/id/2132187/. Accessed 28 February 2011.

39. Lemmens T, Freedman B. Ethics review for sale? Conflict of interest and commercial research review boards. Milbank Q. 2000;78(4):547-584, iii-iv.

40. Rolleston F, Corman J, Gauthier S, O’Hara P, Schmaltz R. Ethics Issues with Private Research Ethics Boards: A Breakout Session at the 2009 NCEHR National Conference. Journal of Academic Ethics. 2009(Published online 28 July 2009.).

41. Criminal Code of Canada. R.S.C. 1985, c C-46, as ammended.

42. Tremayne-Lloyd T, Srebrolow G. Research ethics approval for human and animal experimentation: Consequences of failing to obtain approval -including legal and professional liability. JCCA J Can Chiropr Assoc. Mar 2007;51(1):56-60.

43. Shaul RZ, Birenbaum S, Evans M. Legal liabilities in research: early lessons from North America. BMC Med Ethics. 2005;6(4). http://www.biomedcentral.com/1472-6939/6/4. Accessed 28 February 2011.

44. Gelsinger v. Trustees of the University of Pennsylvania (Phila.Cnty. Ct. of C.P. filed September 18, 2000).

45. Halushka v. University of Saskatchewan et al. 53 D.L.R. (2d) 436 (Sask. C.A.)[Halushka], (Saskatchewan Court of Appeal 1965).

46. Weiss  v. Solomon [1989] A.Q. no. 312 (Cour supérieure du Québec) (Superior Court of Quebec 1989).

47. Prior to 2001, the CIHR was known as the Medical Research Council (MRC).

48. Government of Canada. Panel on Research Ethics.  http://pre.ethics.gc.ca/eng/panel-group/about-apropos/. Accessed 28 February 2011.

49. While it is beyond the scope of this paper to digress into a discussion of the similarities and differences between the medical concept of capacity and the legal concept of competence, it is nevertheless important to note that edition 1 favoured the term competence, and edition 2 uses the term capacity.

50. Connor JT. Cruel knives? Vivisection and biomedical research in Victorian English Canada. Can Bull Med Hist. 1997;14(1):37-64.

51. Information on this council, its mandate, its funding, and its guidelines can be found at its website: http://www.ccac.ca/en/About_CCAC/About_CCAC_Intro.htm

52. Olfert ED, Cross BM, McWilliam AA. Guide to the Care and Use of Experimental Animals. In: Canadian Council on Animal Care, ed. Vol 1. 1993.

53. Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington, D.C.: National Academic Press; 2010.

54. Wepruk J. A Report on Animal Welfare Law in Canada. 2004. http://www.afac.ab.ca/lawsregs/awlcanada.pdf. Accessed 28 February 2011.

55. These are usually known as ACC’s but are sometimes referred to as Institutional Animal Care and Use Committees (IACUC’s as they are also known in the US), or as Animal Research Ethics Boards (AREB’s).

56. Canadian Council on Animal Care. Terms of Reference for Animal Care Committees. CCAC Policy Statement. 2006. http://www.ccac.ca/en/CCAC_Programs/Guidelines_Policies/PDFs/TOR_2006_en.pdf. Accessed 28 February 2011.

57. Thompson DF. Understanding financial conflicts of interest. N Engl J Med. Aug 19 1993;329(8):573-576.

58. Krimsky S. The ethical and legal foundations of scientific ‘conflict of interest’. In: Waring DWR, Lemmens T, eds. Law and ethics in biomedical research : regulation, conflict of interest and liability. Toronto: University of Toronto Press; 2006:viii, 267 p.

59. Lemmens T, Singer PA. Bioethics for clinicians: 17. Conflict of interest in research, education and patient care. CMAJ. Oct 20 1998;159(8):960-965.

60. Ferris LE, Naylor CD. Pomoting integrity in industry-sponsored clinical drug trials: Conflict of interest issues for Canadian health science centres In: Waring DWR, Lemmens T, eds. Law and ethics in biomedical research : regulation, conflict of interest and liability. Toronto: University of Toronto Press; 2006:viii, 267 p.

61. Lemmens T, Miller PB. The human subjects trade: ethical and legal issues surrounding recruitment incentives. J Law Med Ethics. Fall 2003;31(3):398-418.

62. Canadian Medical Association. CMA Policy Statement: Physicians and the Pharmaceutical Industry (Update 2001): CMA; 2001.

63. Canadian Medical Association. CMA Policy Statement: Guidelines for Physicians in Interaction with Industry: CMA; 2007.

64. Martin JB, Kasper DL. In whose best interest? Breaching the academic-industrial wall. N Engl J Med. Nov 30 2000;343(22):1646-1649.

65. Conflicts of interests and investments. CMAJ. Nov 23 2004;171(11):1313.

66. Macrina FL. Scientific integrity : text and cases in responsible conduct of research. 3rd ed. Washington, D.C.: ASM Press; 2005. pp 61-63

67. Van der Weyden M. The ICMJE and URM: Providing Independent Advice for the Conduct of Biomedical Research and Publication. Vol 52007.

68. International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. 2008. http://www.icmje.org/urm_full.pdf. Accessed 28 February 2011.

69. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada., Social Sciences and Humanities Research Council of Canada. Integrity in Research and Scholarship A Tri-Council Policy Statement. 2009. http://www.nserc-crsng.gc.ca/NSERC-CRSNG/Policies-Politiques/tpsintegrity-picintegritie_eng.asp. Accessed 28 February 2011.

70. Davidoff F, DeAngelis CD, Drazen JM, et al. Sponsorship, authorship and accountability. CMAJ. Sep 18 2001;165(6):786-788.

71. Canadian Institutes of Health Research. Policy on Access to Research Outputs: Government of Canada; 2007: http://www.cihr-irsc.gc.ca/e/documents/cihr_policy_on_access_to_research_outputs_e.pdf. Accessed 28 February 2011.

72. Information on these acts and the text of the acts themselves can be found at the Intellectual Property Office website: http://www.ic.gc.ca/eic/site/ippd-dppi.nsf/eng/h_ip00007.html .

73. Schrecker T, Elliott C, Hoffmaster CB, Keyserlingk EW, Somerville MA. Ethical Issues Associated with the Patenting of Higher Life Forms: Industry Canada; 2009: http://www.ic.gc.ca/eic/site/ippd-dppi.nsf/eng/ip00095.html. Accessed 28 February 2011.

74. Hirtle M, Knoppers B. Banking of human materials, intellectual property rights and ownership issues: International policy positions and emerging trends in the literature: Industry Canada: Intellectual Property Policy Directorate; 1997: http://www.ic.gc.ca/eic/site/ippd-dppi.nsf/eng/ip00163.html. Accessed 28 February 2011.

75. Rudolph J. A Study of Issues Relating to the Patentability of Biotechnological Subject Matter: Industry Canada: Intellectual Property Policy Directorate; 1996: http://www.ic.gc.ca/eic/site/ippd-dppi.nsf/eng/ip00190.html. Accessed 28 February 2011.

76. Macrina FL. Scientific integrity : text and cases in responsible conduct of research. 3rd ed. Washington, D.C.: ASM Press; 2005. p.213.

77. Adopted in 1980, the Bayh-Dole Act (or simply Bayh-Dole) is codified in 35 U.S.C. § 200-212 and implemented by 37 C.F.R. 401.

78. Bernstein A. New ethical requirements at the NIH: implications for CIHR and Canada. CMAJ. Aug 16 2005;173(4):353-354.

79. These guidelines can be seen at the CMAJ copyright policy web page: http://www.cmaj.ca/authors/policies.shtml#copyright .

80. The CAUT does not shape legal documents but does guide its members and advocate on their behalf. As such, many guidelines exist on their website (http://www.caut.ca/home.asp?page=432) as well as instruction and information on latest policy and law that affects researchers and teachers.

81. US Code of Federal Regulations, specifically 45CFR237 part 689.2 and 689.3.

82. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada., Social Sciences and Humanities Research Council of Canada. Framework for Tri-Council Review of Institutional Policies Dealing with Integrity in Research. 2009; http://www.nserc-crsng.gc.ca/NSERC-CRSNG/Policies-Politiques/frameworkintegrity-cadrereferenceintegrite_eng.asp. Accessed 28 February 2011.

83. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada. Tri-Agency Process for Addressing Allegations of Non-compliance with Tri-Agency Policies. 2010; http://www.nserc-crsng.gc.ca/NSERC-CRSNG/governance-gouvernance/process-processus_eng.asp. Accessed 28 February 2011.

84. The Whistleblower’s Bill of Rights is not formal legislation but it carries considerable weight by virtue of the authority of the DHSS and the ORI. The bill can be seen at the ORI website http://ori.hhs.gov/misconduct/Whistleblower_Rights.shtml .

85. The Canadian Human Rights Act, R.S.C. 1985, c. H-6, prohibits any person from threatening, intimidating, or discriminating against an individual because that individual has made a complaint, given evidence, or assisted in the initiation or prosecution of a complaint under the Act.

86. The exception may be in New Brunswick, Section 28 of the Employment Standards Act, Chap. E-7.2 provides specific whistleblower protection for employees, but does not name researchers or academic institutions specifically.

87. Viens AM, Savulescu J. Introduction to The Olivieri symposium. J Med Ethics. Feb 2004;30(1):1-7.

88. Thompson JH, Baird P, Downie JG, Canadian Association of University Teachers. The Olivieri report : the complete text of the report of the independent inquiry commissioned by the Canadian Association of University Teachers. Toronto: J. Lorimer; 2001.

89. Schafer A. Commentary: Science scandal or ethics scandal? Olivieri redux. Bioethics. Feb 2007;21(2):111-115.

90. Baylis F. The Olivieri debacle: where were the heroes of bioethics? J Med Ethics. Feb 2004;30(1):44-49; discussion 50-42.

91. Some sources quote one year and some sources quote three years after the trial end date.

92. Litman M, Sheremeta L. The report of the committee of inquiry on the case involving Dr. Nancy Olivieri: a fiduciary law perspective. Health Law Rev. 2002;10(2):3-13.

93. Waring DWR, Glass KC. Legal liability for harm to research participants: The case of placebo-controlled trials. . In: Waring DWR, Lemmens T, eds. Law and ethics in biomedical research : regulation, conflict of interest and liability. Toronto: University of Toronto Press; 2006:pp. 206-227.

94. Thomson MM. Bringing research into therapy: Liability anyone? In: Waring DWR, Lemmens T, eds. Law and ethics in biomedical research : regulation, conflict of interest and liability. Toronto: University of Toronto Press; 2006:pp. 183-205.

95. Halwani S. Her Majesty’s research subjects: Liability of the Crown in research involving humans.  . In: Waring DWR, Lemmens T, eds. Law and ethics in biomedical research : regulation, conflict of interest and liability. Toronto: University of Toronto Press; 2006:pp. 228-246.

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