Governance and stem cell research: towards the clinic.
Our strategy in this paper is to first give an overview of the context of Canadian stem cell research as it moves toward clinical applications. In Part 1, we identify principal agents and stakeholders and then describe their interests, accountability relationships and interactions. In Part 2, we identify ethical, legal and social issues that seem novel or unique to stem cell research. Most of these involve the derivation and use of embryonic stem cells. Part 3 highlights "generic" research ethics issues that we deem most pertinent to stem cell research. Finally, in Part 4, we offer some recommendations, most prominent of which is the need to recognise the special opportunity presented by stem cell research for improving ethical governance of health research more generally.
Before turning to the context of Canadian stem cell research, it is important to say a bit about what we mean by the governance of such research and how we identified ELSI issues. One thing that we do not mean to imply is that there is or ought to be a single means of governance for all stem cell research in Canada. As noted in Part 1 below, there are multiple institutional actors and stakeholders that are involved in the movement of stem cell research from the bench to the bedside. Many of these have their own governance structures, which are intended to achieve often divergent and competitive organisational objectives. (1) Their interrelationships are complex.
We would also note that governance involves the use of various forms of power (legal, bureaucratic, financial, rhetorical, etc.) to bring about results either within an organization or in relation to other organizations. (2) Governance is not only about organizational and inter-organizational lines of authority and accountability; it is also about organizational culture and socialization. Hence, governance involves bottom-up as well as top-down considerations.
Our interest is in governance designed to achieve ethical objectives. In many cases, there is a widespread social agreement on ethical objectives. For example, with regard to the ethical treatment of human subjects in research, there is a general consensus that research subjects are volunteers, not conscripts; research should only be conducted when there is sufficient promise of social benefit, the risks to subjects are reasonable and then only with the subjects' consent (or their duly constituted representatives'). Other ethical values are contested, e.g., whether an embryo is entitled to the same protections as human subjects. We note, however, that even when there is consensus around ethical standards, there may still be significant failures in governance arrangements. One of us has argued that this is the case with human subjects protection, claiming in particular that we lack in Canada a demonstrably effective and appropriately accountable evidence-based system of protection. (3) Some of the most challenging governance issues with respect to novel technologies may well be in the most mundane and familiar areas rather than in their novel aspects. We will also argue that even for issues that seem specific to stem cell research, there are important lessons to be learned from earlier developed areas of research-based clinical practice, in particular gene transfer and solid organ transplantation.
The use of stem cells in biomedical research has been the subject of enormous, and often vociferous, public and policy debate around the world, and Canada has been no exception. The promises and hopes for this field of inquiry are substantial, but so too are the ethical, religious or social concerns and challenges. Many of these challenges relate to the nature and conduct of modern bioscience research.
As with other areas of applied science and biomedicine, such as genomics or nanotechnology, stem cell research operates as a complex, international field of inquiry in which a diversity of stakeholders is involved in a wide range of basic and applied research, e.g., understanding disease aetiology, drug development, and novel therapeutics. Scientists, clinicians and industry partners are increasingly collaborating with governments and civil society (often represented through advocacy groups or charitable organisations) in the development of and debates about the practice and goals of stem cell research. (4) Bioscientists, and for our purposes all those working on stem cells, do not conduct their research in isolation, free from the economic, social, ethical or political concerns of their colleagues or society at large. (5) Instead, these scientists, clinicians and, indeed, bioethicists are embedded, participating in the shaping of stem cell science, public discourse and policy.
Such complexity may be increasingly the norm in the biosciences--"big science" is now international, increasingly networked and often political. (6) But just because it is normal does not mean that it is stable or free from ethical concern. It is our contention that the very interconnectedness and complexity of relations between the stakeholders in stem cell research raises challenging socio-ethical issues, e.g., with relation to the sourcing of material, conflicts of interest in university-industry-government partnerships, and the framing of appropriate lines of inquiry. As such, reflection about the ethics and governance of stem cell research also needs to pay attention to the complex context and networks within which stem cell research is conducted.
a. The Stem Cell Network
In Canada, as in most other developed countries, the vast majority of stem cell research is happening in university research centres, hospitals and laboratories, although biotechnology and pharmaceutical companies are also becoming active in this field. A focal point for stem cell research in Canada is the Stem Cell Network (SCN), a non-profit corporation that began in 2001 with federal funding from a Networks of Centres of Excellence (NCE) grant. (7) The network's mandate is to facilitate the investigation and development of the therapeutic potential of stem cells to treat incurable diseases. It does so by bringing together researchers at 24 university and hospital research centres, with partners in industry, government and non-governmental organizations (NGOs). The major partners in the SCN can be grouped into roughly five categories: 1) universities and research centres; 2) for-profit corporations; 3) professional and medical groups; 4) government departments, agencies and funding councils; and 5) NGOs, disease and charitable foundations and advocacy groups. The network is thus an organisation that brings together stakeholders interested in basic and applied sciences, commercialization and economic development in order to capitalise on the potential of stem cell research to produce novel medicines and treatments.
Apart from its core NCE funding ($5 million/year), the SCN obtains the bulk of its support from disease advocacy groups or charitable foundations. Governmental support for the SCN comes largely from federal and provincial agencies or departments involved in economic development. Some of the partners receive funding from Canada's major banks (e.g., Toronto Dominion Bank, Scotiabank, Bank of Montreal, RBC Royal Bank), as well as the private sector, especially pharmaceutical companies. The Heart and Stroke Foundation (HSF) and the Juvenile Diabetes Research Foundation (JDRF) are key funders of stem cell research in Canada and active in lobbying for stem cell research, as are many other not-for-profits and foundations. Through these key stakeholders, the SCN is able to mobilise a diverse set of influential interest groups and is becoming an important actor itself in the organisation and development of stem cell research in Canada. As such, it is also a key locus for the examination of the socio-ethical and governance issues in stem cell research. In Figure 1, we provide a concept map of SCN relationships.
[FIGURE 1 OMITTED]
One of the major challenges of such networked and socially embedded science is the management of conflicts of interest and conflicting interests. Conflicts of interest (COI) arise when competing interests unduly influence or bias the judgment of a decision-maker who has a fiduciary responsibility to a third party--for example, when a patient advocacy group lobbies government on behalf of a corporate research sponsor in order to achieve various objectives, including ensuring funding for their group. (8) But while COIs receive much attention, they can often be managed through various mechanisms, such as disclosure to ensure transparency of interests, or the removal of interested parties from the decision making process. (9) Conflicting interests, however, may be more difficult to manage because they do not necessarily involve interests that bias a decision maker, but instead arise with the often legitimate competition between different agendas and interests, e.g., differences between stakeholders involved in basic science, commercialization, economic development or disease treatment.
Whether we are dealing with conflicts of interest or conflicting interests, a key ethics and governance question is, how or should various and often divergent interests be aligned? While all the stakeholders involved in stem cell research--and more specifically those partners and collaborators in the SCN--may agree on the ultimate objective of using stem cells to significantly improve patients' health, their short to medium term goals and interests will likely vary. Given such differences, it is critical to reflect on what the power relations are between the various stakeholders: who decides the direction of research, what should be given priority and what criteria (if any) should be used for setting priorities? These questions are particularly important for a group like the SCN, which fosters productive collaboration. How are partners and collaborators "enrolled" and kept "onside" with the larger mission? Is the decision making process consensual, democratic, competitive or autocratic? Are divergent views or interests tolerated? How do these various interests cohere or conflict, especially when situated in the larger national and international debates about the potential promises of and threats from stem cell research?
These questions present important challenges, but also opportunities, that the SCN is well structured to respond to because of the foresight to include an ELSI component in the network. This involves not only an ELSI research component, but also a commitment to the integration of ELSI considerations into other network activities such as annual meetings and educational programs. Thus members of the network are already reflecting on many of the socio-ethical issues in stem cell research, the role of science and commerce, etc., as evidenced by this paper and other publications and events. Importantly, integration of ELSI into stem cell research creates the possibility for ethics and science to co-exist and profit from a close interaction by simultaneously exploring the emerging science and associated socio-ethical and governance issues of bioscience research and technology development.
b. A Complex Competitive Environment
Whatever possibilities there are for successfully integrating ethical and scientific considerations into Canadian and international stem cell research, it has to be said that the stem cell research context is driven by high hopes for health, social and economic benefits for both consumers and producers of stem cell research and its clinical applications. But the field is nonetheless marked by fears about potential ill effects. Naturally enough, significant competition arises amongst producers of stem cell research. Potential clinical applications (push factors) are fuelled by demand from direct and indirect consumers (pull factors), including patients and health care professionals. Push and pull factors do not exist in isolation from each other; producers can and do work to stimulate demand. Thus, researchers working on stem cells, including ELSI researchers, have a vested interest in securing public and private sector support for their research.
As with other areas of competitive research, intellectual property issues loom large. From a public utility perspective, it is fair to ask, what is the right balance to be struck between intellectual property and public domain knowledge? (10) Similar balancing acts have to be conducted in terms of access to the information that is essential for stem cell research and its clinical applications (e.g., patenting of stem cell lines, patient records, basic scientific knowledge).
As in other areas of health research, the diversity of domestic and international governance structures adds complexity and creates opportunities and threats. Countries with less restrictive rules and practices around stem cell research have a potential competitive advantage over those with more restrictive regimes. Countries like Canada, with a wide range of different practices with respect to access to health information, face a competitive disadvantage compared to countries with more uniform practices. Our intent, however, is not to offer an assessment of which governance practices are ethically superior; we note simply that ethical decision-making is more complicated for agents who have to cope with divergent governance regimes. A common case in point is the movement of genetic materials across jurisdictions. In the absence of cross-jurisdictional protocols and practices, senders of such materials have to ask themselves whether or not equivalent protection (of individual or collective privacy) will be afforded to donors under the prevailing regime at the recipient institution. (11) For example, Canadian Research Ethics Boards (REBs) are now struggling with issues raised when health information is shared with researchers at US institutions subject to the US Patriot Act.
2. Unique Issues?
In Part 2, we identify some ethically sensitive issues that appear, at least at first blush, to be unique to stem cell research as it moves toward clinical applications. We then ask what governance tools are in place to meet ethical standards, and whether they are effective and provide sufficient accountability to primary stakeholders. (12)
If we contrast stem cell research with other promising contemporary areas of research such as genomics or nanotechnology, one obvious difference is with respect to one major source of stem cells--embryos. The moral status of the embryo is an issue particular to stem cell research. The status and use of embryos for stem cell research and clinical applications is contested, more so in the US than in most other countries, including Canada. Stem cell research also generates special issues related to the methods used to derive embryos for implantation or research. Such issues affect first and foremost the women who contribute embryos; secondly, their biological partners and significant social others (families and friends); and, thirdly, society as a whole, concerned about commodification and the like. With respect to these issues we believe that there is more social consensus. For example, few if any would deny the necessity of donor consent for the removal of human eggs for implantation or research.
Canadian law (e.g., the Assisted Human Reproduction Act (AHR)) (13) and policy (e.g., CIHR's recently updated Guidelines for Human Pluripotent Stem Cell Research), (14) which set restrictions around the derivation and use of embryonic stem cells, represent acts of governance designed to achieve ethical objectives. For example, rules forbidding cloning, the production of human-animal chimeras and the use of materials derived from parthenogenesis represent important value choices and set significant objectives for Canadian research and clinical governance structures. Important governance choices are also presented in the AHR and the CIHR Guidelines with respect to who, how and when donation for research purposes is solicited and what incentives (if any) are appropriate, e.g., reduced payment for IVF treatment. There are also important issues dealing with the role of clinician-researchers as they interact with patients or potential donors to research in discussions about fresh or frozen egg donation. (15)
With such governance issues, it is fair to consider how well given ethical objectives are achieved. Does respect for egg donors require action on the part of the medical profession and its regulatory bodies, as Nisker seems to suggest? (16) Will improvements occur without any deliberate governance interventions? For example, in an ideal free market, informed consent of donors would not be a problem, though payment for donation would.
This leads us to ask what mechanisms are in place to deal with the unique, as well as non-unique, aspects of stem cell research? There is of course law with the AHR, but as yet no regulations have appeared. Were such regulations to be deployed, how would one assess whether they met criteria for effective and accountable governance? (17) Consider the one draft regulation that has been posted on written informed consent. On a positive note, it seems reasonable to assume that standard audit methods by Health Canada should be able to determine if there is appropriate documentation of informed consent. Yet this leaves open the substantive question of whether donors really did understand what they were doing, and whether they were free from undue influence and manipulation. These are not questions that will be answered by paper audits, and indeed this is acknowledged in the Regulatory Impact Analysis Statement. (18) While the statement lists a number of factors that are believed to mitigate the risks of negligence or abuse of written informed consent, there is no evidence offered that the factors are real or that they sufficiently mitigate the risks of uninformed or coerced consent. We would suggest adopting the additional mitigating strategy of more substantive monitoring of informed consent and sponsoring empirical research on the experiences of donors. (19)
Given that debate around stem cell research has focused on embryonic donation and derivation of stem cell lines, it is unsurprising that stem cell governance tends to be conceived in these terms. Thus, in the Canadian context, governance may be seen through the lens of the AHR and CIHR Stem Cell Oversight Committee (SCOC) as the top-down imposition of rules and regulations on a specific area of conduct. We find this problematic for a number of reasons. First, rules and regulation tend to be rigid. Caulfield, Knowles and Meslin make an important point about stem cell research governance when they argue that legal prohibitions "do not have the flexibility essential to regulate an area as rapidly evolving and scientifically complex as reproductive genetics." (20) Second, this perspective ignores the possibilities for developing more flexible governance mechanisms that are responsive to scientific and societal change and to the diverse and changing interests of stakeholders. One such mechanism could be professional self-regulation. (21)
3. Generic Issues in Ethics and Governance
Having discussed features that are particular to stem cell research and clinical applications, we now turn to areas where researchers and stakeholders would do well to learn from other areas of health research. These we label as "generic issues" in ethics and governance. We focus on three areas: a) lessons from gene therapy; b) tissue and transplantation issues; and c) governance work in research ethics.
a. Lessons from Gene Therapy: A Cautionary Tale
The experiences of the various research, policy and ELSI communities in Canada, the US and Europe with gene therapy and human genetic engineering research can provide important lessons for stem cell research.
Gene therapy research in the 1990s was, as with many of the biosciences, a very competitive and expensive field. While governments started dedicating infrastructure and financial resources for researchers in this field, these dollars were clearly finite. At the same time, there was growing interest from the private sector in exploring opportunities to commercialise the products of gene therapy research, and thus there was the potential for academic scientists to collaborate with and seek financing from industry. (22) With growing emphasis and encouragement from governments for universities to partner with industry, and a hope that universities would become important engines for supporting if not driving national economies, (23) stem cell research and the other biosciences have become intimately linked into various public-private partnerships.
In order to secure research funding, scientists must make promises to funding councils and/or industry about the potential for developing the science of genetic engineering--or for our purposes stem cell research--and translating it into functional therapeutics. Tying into the larger public, government and industry interest in and hopes for gene therapy, many scientists and science funders played up or hyped the possibilities of the field: e.g., gene therapy would be available in the near future (10 years) and able to cure the most challenging diseases, such as cystic fibrosis or the rare autoimmune disorders. Similar rhetoric in public and policy discussions is all too apparent with stem cell research. (24)
Such rhetoric gives rise to exaggerated hopes and expectations that are difficult to substantiate in practice. Enormous pressure is then brought to bear on researchers to make scientific breakthroughs that will lead quickly to phase 2 and phase 3 clinical trials and result in marketable health care products and services. But while science does occasionally have dramatic and unexpected breakthroughs that revolutionize an area and quickly result in products that make a real difference to consumers or patients, the vast majority of scientific discoveries are the result of many years of patient incremental research. (25) The translation of bioscience research from bench to bedside often takes decades or more. Success rates tend to be low--the majority of products entering phase 1 clinical trials do not make it to market. The fact is, then, that medical scientists will be hard pressed to make good on their promises and meet the over inflated expectations for revolutionary treatments. However, if promises of useful research are not made, then it becomes difficult if not impossible to secure the funding needed to conduct the research that may one day lead to actual working treatments--scientists are in a catch 22 situation.
The tendency to be overly positive, especially in media presentations, and not to qualify the early stage or experimental nature of scientific research is exacerbated by an increasing audit culture in academia, where scientists are required to meet frequent and more demanding measures of productivity, often over very short time frames. It is no longer sufficient to write a grant with a clear objective, methods, and reasonable outcomes; short and medium term deliverables are required. From the point of view of research sponsors, it should be standard practice to determine if milestones are met and deliverables produced. While it is reasonable for private and public research sponsors to assess whether their investments in research are justified, audit measures can have diverse effects beyond measuring research productivity. Such measures may drive the types of research that are conducted and if the auditing is too onerous or the measures chosen wrong headed, can create perverse incentives. Longer term research, with more meaningful but harder to measure results, may be marginalised or abandoned in favour of research that will lead quickly to results that are easily quantified.
We have already said that it is an important and legitimate part of the scientific endeavour for scientists to promote their ideas to colleagues and research sponsors. But if the promotion is overblown it will eventually undermine long term support and cause scepticism about the value of research in that field. (26) This happened with gene therapy. When legitimate promotion became hype, followed by very public failures of clinical trials, venture capital and government sponsors withdrew from the field. The result was that scientific research suffered, and the public and other stakeholders were left holding an empty bag of promises. There is an important lesson here for stem cell research--too much self-promotion can be dangerous to a field, especially one that is so promising but still at a very early stage of development.
Worse yet, in a very competitive and hyped research environment, there is a real danger that some scientists and clinicians will bow to various pressures and interest groups, buy into their own hype and public expectations, and move too quickly from basic science to human subjects research and clinical trials before sufficient safety and efficacy data are available. When coupled with financial and reputation interests, the potential for conflicts of interest and unethical behaviour becomes significant. (27) In the case of gene therapy research, there have been many public occurrences of COI and unethical research practices, some of which resulted in the failure of researchers to protect trial participants, occasionally with fatal results as exemplified by the death of Jesse Gelsinger. (28) Kimmelman and colleagues provide a pertinent observation: "As the curtain rises on stem cell transplantation trials, the field will at least have enjoyed a luxury available only to understudies: extra time to review its script and learn from its predecessors' missteps." (29)
b. Tissue and Transplantation Issues
In a recent article, Kahn has suggested that there are important lessons for stem cell research to be drawn from the early days of solid organ transplantation:
Those working in the early years of organ transplant faced many questions that have recognizable parallels in the stem cell research debate: (1) where would organs come from [read embryos for stem cells]; (2) how would our understanding of human life and its definitions be affected by the desire to perform transplants [read moral status issues of human embryos]; and 3) what policies were needed and how would society responsibly oversee this new and controversial area of research and medicine [with obvious parallels to the stem cell debate]? These and other questions arose in the context of a public that was at turns shocked, amazed, and concerned by news of the ability to take a beating heart from the body of one person and successfully transplant it into the chest of another, prompting reactions ranging from existential angst to repugnance. (30)
Kahn notes the importance of stakeholder acceptance of a definition of death that was consistent with transplant aims; he suggests that there needs to be similar stakeholder engagement with regard to the status of early stage embryos. He further argues that disputes around the ownership and control of solid organs can provide lessons for the use of stem cells. In terms of governance, Kahn notes that "[t]he lesson for stem cell research is that there are almost always unforeseen circumstances and unintended consequences produced by legislated attempts to oversee controversial biomedicine, however well intentioned." (31) Hence he recommends the judicious use of sunset clauses and other review mechanisms in legislation to ensure appropriately flexible oversight.
While many of the ethical issues that arise from research involving tissues and in transplantation research have been addressed in the bioethics literature, many still remain unresolved in practice. These issues could be especially sensitive for stem cell research as it moves toward clinical applications. Above, in Part 1, we have already said that ethical issues become much more complex when tissues and associated health information are sent from one governance regime to another. (32) Their relevance to stem cell research and clinical applications is fairly clear given discrepant national sensitivities with respect to the derivation and use of embryonic stem cells. Quasi-regulatory bodies such as the CIHR SCOC thus have to wrestle with the ethical complexities of stem cells imported from countries that adhere to standards that may be at significant variance with the CIHR Guidelines. Adding to this complexity is the inevitable question of whether practices in another jurisdiction are in accord with that jurisdiction's own rules.
For those familiar with debates around transplantation ethics, and in particular xenotransplants, the concerns raised by Lo (33) and Greely (34) about phase 1 clinical trials involving stem cells have a familiar ring. Lo argues that for the protection of human subjects it will be necessary to re-contact the original donors in order to "update their medical history and screening." (35) Greely suggests that the "US Food and Drug Administration will want as much information as possible about the donor's health, not only with regard to pathogens that may infect the donated cells, but also about diseases with genetic or family links." (36) This would potentially involve re-contacting donors years after transplantation has taken place. Neither author mentions the possibility that this could lead to significant donor reticence. It would also involve a significant departure from accepted norms in solid organ transplantation or clinical genetics research. We wonder too if this is really required for the ethical treatment of volunteers for phase 1 trials or subsequent phases. Be that as it may, we see this as an important issue for structuring governance for stem cell research as it moves toward clinical trials.
It is important to ask how stem cell research may transform transplantation and its ethics. Waldby argues that stem cell research has the potential to transform our current "tissue economy," which is one of high demand and organ scarcity, to a new tissue economy with high supply and much better health results. (37) This, she claims, is likely to involve unsettling challenges to our conceptions of what it is to be human, the nature of reproduction, and life itself. Whether this claim is correct or not, we do agree with her comment that "stem cell technologies promise to transform the way that healthy tissues for transplant are sourced and circulated; from a social economy in which citizens donate whole organs to others, to one in which embryos are a major source of therapeutic tissues." (38)
More generally, we see in the evolution of stem cell research to clinical applications the need to pay more attention to the interests and rights of potential recipients, who in the first instance will be research subjects in various phases of clinical trials. This does not mean neglecting the interests and rights of donors, which have heretofore received the most attention on the part of bioethicists studying stem cell research. From a governance perspective, some issues relating to recipients will be easier to deal with than others given current practices. Consider, for example, potential recipient objections to implantation with embryonic stem cells. This can presumably be dealt with through fully informed consent. There may be the need, however, to add to the process of informed consent access to information about the ethics of accepting embryonic stem cell implants. Picture a recipient who feels a religious obligation not to accept any clinical application that involved embryonic stem cells. If this potential recipient could access a variety of perspectives current in their religious tradition, their objections might be strengthened or actually disappear; the net result would be a decision that was much more in line with their considered values. Such considerations take us to our next category of "generic" governance lessons for stem cell research--research ethics.
c. Research Ethics
To focus concerns for this section, we present the following scenario. A team of Canadian stem cell scientists in concert with international collaborators believes that it has identified a highly promising therapeutic modality for treating Parkinson's disease. Some testing has been done on animals and the results have been very encouraging. The researchers are eager to move to human testing. The research sponsors, including industrial partners and a charitable foundation, are supportive. A rival group of researchers based in the UK also appears to be ready to move to human testing.
For this hypothetical (but we believe, realistic) scenario, we ask a number of questions. The first set of questions centres on first-order ethical issues:
1. According to generally accepted norms for ethical research involving humans, what are the conditions that must be met for testing on human subjects to begin phase 1 clinical trials?
2. What conditions would have to be met to move to phase 2 and 3 clinical trials?
3. Under what conditions would such research on humans be stopped or modified?
4. What would constitute ethically acceptable ways for moving from successful research involving humans to the clinical use of the new stem cell therapy?
Our next set of questions is directed to second-order governance issues:
1. What do we have in place in Canada (and, where relevant, internationally) in terms of standards and processes for addressing the first-order ethical questions?
2. Are existing Canadian and international standards and processes ethically adequate?
3. How would we know that our standards and processes are ethically adequate? How would we demonstrate this to various stakeholders, including research subjects, those suffering from or at risk for developing Parkinson's disease, and the general public? That is, what is the evidence-base for showing that governance arrangements are ethically adequate?
In presenting our questions about the scenario as first-order or second-order questions, we follow the conceptualization of governance that was introduced by one of us in a report to the Law Commission of Canada on The Governance of Health Research Involving Human Subjects: (39)
Governance can be described as an organization's second-order (or level) activities for controlling, guiding, organizing and in general overseeing its own first-order (or level) activities--whether these are directed internally to the organization's own members or externally to outside institutions. Thus, governance represents in organizations a kind of reflexive capacity--a capacity to rationally determine the direction of lower activities. (40)
Governance then represents a way in which those charged with oversight responsibilities ensure things go well on the ground. Managers or overseers are concerned with governance of ethics, both within their organizations and in relation to other organizations and individuals. For the ethical governance of research involving humans, three objectives have been identified:
1. The promotion of socially beneficial research;
2. Respect for the dignity and rights of research subjects; and
3. As an overarching aim, the maintenance of trust between the research community and society as a whole. (41)
In a widely cited article, Emmanuel and colleagues offer seven conditions for determining if clinical research is ethical:
(1) value -- enhancements of health or knowledge must be derived from the research;
(2) scientific validity -- the research must be methodologically rigorous;
(3) fair subject selection -- scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects;
(4) favourable risk-benefit ratio -- within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks;
(5) independent review -- unaffiliated individuals must review the research and approve, amend, or terminate it;
(6) informed consent -- individuals should be informed about the research and provide their voluntary consent; and
(7) respect for enrolled subjects -- subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored. (42)
The list provides a useful overview, although we have some criticisms of this analysis--particularly of condition (5), which confuses a means to human research protection with the end, i.e., ethical clinical research. We would also call special attention to the fact that condition (6) informed consent, is only one of several conditions for ethical clinical research. All too often researchers act as if informed consent were the sole condition for ethical research, aside from REB approval. (43) Even worse, they conflate signed consent forms with actual informed consent--so paper documentation replaces ethical substance. The important lesson for stem cell research is that many conditions need to be met before anyone is asked to give informed consent to participation in a stem cell therapy clinical trial.
With respect to second-order governance questions for human research protection, the following overview is useful:
1. The complexity and fragmentation of Canadian governance arrangements poses major ethical challenges and is inadequate to withstand the major pressures on health research today (globalization, privatization, competition and rapid scientific and technological development).
2. Current policies (such as Tri-Council Policy Statement and the International Convention on Harmonization Good Clinical Practice) and processes (viz., the REB system and current oversight mechanisms) suffer from "ethical tunnel vision." The net result is that REBs and researchers become too focused on paperwork--the bureaucratic processing of research proposals and the administration of consent forms--and not enough on substantive protection.
3. While major oversight responsibilities are placed on REBs, they lack knowledge of what happens after research proposals are approved. This is in large part due to the lack of monitoring and auditing processes for on-going and completed research. In short, Canadian human research protection lacks "the virtuous learning loops" which provide quality assurance and quality improvement.
4. Research subjects are treated as passive rather than active participants in the research process and its governance.
5. Little attention has been paid to the culture of research and the ethics education of researchers and REB members. At local and national levels there are systemic conflicts of interest due to absence of arm's length oversight for human research protection. Evidence-based research and experimentation on effective modes of human research protection are missing. (44)
We note as well that reports on governance in other jurisdictions, particularly the US, echo similar concerns about the lack of good evidence for the effectiveness of current governance arrangement for human research protection. (45)
4. Conclusions and Recommendations
One conclusion we would draw is that the governance of stem cell research in Canada (and probably many other countries) is now and is likely to remain "messy" with multiple centres of power and authority. To be sure, one could view Canadian governance through the lens of the AHR, but that would be to miss multiple realities--scientific and clinical developments here and abroad; the role of professional groups and associations like the SCN and Canadian physician-researchers (to name but two); and demands from multiple interested publics.
A second conclusion is that "legitimacy"--a prime objective for governance--will come from the activities of stakeholders in stem cell research (including donors and recipients) developing working consensuses around central issues unique to stem cell research. In areas where issues are more generic (such as human subjects' research), stem cell researchers and their supporters will see governance issues played out against the larger backdrop of health research.
Third, Canadian governance of health research involving human subjects lacks "virtuous learning loops" by which the various actors involved can learn from their successes and failures. If we transpose these learning loops to the governance of stem cell research, we see five possible loci for improvement (Figure 2).
Loop #1: Culture of research: Discussion between research centers, hospitals, universities, and bioscience and ELSI researchers.
Loop #2: Evidence-based research ethics: Discussion between bioscience and ELSI researchers, the public, SCOC, and the funding agencies.
[FIGURE 2 OMITTED]
Loop #3: Promoters, funding agencies and governmental involvement: Discussion between promoters and funding agencies.
Loop #4: Gamete donation and embryos related issues: Discussion of the work of fertility clinics, research centers and the Canadian government.
Loop #5: Normative and regulatory: Discussion between foreign governments and Canada's government (federal and provincials).
1. Current oversight arrangements for stem cell research provide a unique opportunity for innovative and flexible models of governance that are relevant to stem cell research and other areas of health research.
2. The SCN could play a leading role in identifying and addressing key ethical issues in stem cell research as well as fostering a positive culture of research ethics.
3. The SCN could serve as a venue for bringing together stem cell research scientists, bioethicists, regulators and stakeholders for developing consensus statements around such crucial issues as the movement from bench and animal studies to clinical trials on humans, and assuring that the benefits of stem cell research are equitably distributed.
4. For ELSI researchers, more attention needs to be focussed on generic research ethics and governance issues associated with the movement of stem cell research to clinical applications. As well, the focus needs to widen to include potential recipients of stem cells in clinical trials.
5. Despite the presence of federal regulation and guidance, governance for stem cell research is likely to remain somewhat decentralised. This may well be desirable and fit more with the Canadian context. (46) However, if it is going to both be, and be perceived as, effective and trustworthy, much more attention needs to be paid to developing an evidence-based approach to research ethics and governance. This will require an empirically based research effort to determine, inter alia, what are the actual experiences of donors and recipients of stem cells. (47)
Michael McDonald is the Maurice Young Chair of Applied Ethics at the W. Maurice Young Centre for Applied Ethics, College of Interdisciplinary Studies, University of British Columbia. Bryn Williams-Jones is an Assistant Professor in the Departement de medecine sociale et preventive, Faculty of Medicine, at the Universite de Montreal.
We gratefully acknowledge the help of Guillaume Pare, who conducted a comprehensive literature review and prepared the concept maps (two of which are here included) that contributed enormously to the development of this paper. We also thank Vural Ozdemir and Tim Caulfield for their insightful comments and suggestions on the final draft. Finally, we thank Maria McDonald for her incredible generosity and hospitality in making Williams-Jones' visit to Vancouver such a delightful and productive experience! This research was supported by a grant from the Canadian Stem Cell Network.
1. Michael McDonald, "The Governance of Health Research Involving Human Subjects: Reflections on Ethical Policy for Scientific Research" (2000) Series VI, Volume XI Transactions Science and Ethics: Royal Society of Canada Special Issue 49.
2. Fern Brunger & Michael Burgess, "A Cultural Understanding of Research Ethics Governance" (2005) 13:2-3 Health Law Rev. 69.
3. Supra note i; Michael McDonald, "Canadian Governance of Health Research Involving Human Subjects: Is Anybody Minding the Store?" (2001) 9 Health Law J. 1; Michael McDonald, "Introduction: Canadian Governance for Ethical Research Involving Humans" (2005) 13:2-3 Health Law Review 4; Brenda Beagan & Michael McDonald, "Evidence-Based Practice of Ethics Review" (2005) 13:2-3 Health Law Rev. 62.
4. Stem Cell Network, online: Stem Cell Network <http://www.stemcellnetwork.ca>.
5. Helga Nowotny, Peter Scott & Michael Gibbons, Re-Thinking Science: Knowledge and the Public in an Age of Uncertainty (Cambridge: Polity Press, 2001).
6. Janet Atkinson-Grosjean, Public Science Private Interests: Culture and Commerce in Canada's Networks of Centres of Excellence (Toronto: University of Toronto Press, 2006).
7. Supra note iv.
8. Michael Davis, "Conflict of Interest" in Ruth Chadwick, ed., Encyclopedia of Applied Ethics vol. 1 (San Diego: Academic Press, 1998) 589; Chris MacDonald, Michael McDonald & Wayne Norman, "Charitable Conflicts of Interest" (2002) 39:1-2 Journal of Business Ethics 67.
9. AAMC Association of American Medical Colleges Task Force on Financial Conflicts of Interest in Medical Research, Report on Individual Financial Interest in Human Subjects Research (Washington D.C.: Association of American Medical Colleges, December 2001), online: <http://www.aamc.org/members/coitf/firstreport.pdf>; AAMC Association of American Medical Colleges Task Force on Financial Conflicts of Interest in Medical Research, Protecting Subjects, Preserving Trust, Promoting Progress--Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research (Washington D.C: Association of American Medical Colleges, December 2001).
10. Paul A. David, "A Tragedy of the Public Knowledge 'Commons'? Global Science, Intellectual Property and the Digital Technology Boomerang" (2000) WP 04 Electronic Journal of Intellectual Property Rights 1, online: <http://www.oiprc.ox.ac.uk/EJWP0400.pdf>; Timothy Caulfield & Barbara von Tigerstrom, "Globalization and Biotechnology Policy: The Challenges Created by Gene Patents and Cloning Technologies" in Belinda Bennett & George F. Tomossy, eds., Globalization and Health: Challenges for Health Law and Bioethics, International Library of Ethics, Law, and the New Medicine (New York, NY: Springer, 2006) 129.
11. James V. Lavery, Michael McDonald, & Eric M. Meslin, "Research Ethics across the 49th Parallel: The Potential Value of Pilot Testing "Equivalent Protections" In Canadian Research Institutions" (2005) 13:2-3 Health Law Review 86.
12. R. Edward Freeman, "A Stakeholder Theory of the Modern Corporation" in Tom Beauchamp & Norm Bowie, eds., 6 ed., Ethical Theory and Business (Upper Saddle River, N.J.: Prentice-Hall, 2000) 56; Archie B. Carroll, "The Pyramid of Corporate Social Responsibility: Toward the Moral Management of Organizational Stakeholders" Business Horizons 1991) 39.
13. Bill C-6, "An Act Respecting Assisted Human Reproduction and Related Research," Statutes of Canada 2004, Third Session, Thirty-seventh Parliament, 52-53 Elizabeth II, 2004 ed. (2004), online: <http://www.hc-sc.gc.ca/hl-vs/alt_formats/hpb-dgps/pdf/reprod/C-6_4_RA.pdf>.
14. CIHR, Updated Guidelines for Human Pluripotent Stem Cell Research, June 28, 2006 (June 28, 2006), Canadian Institutes for Health Research, online: CIHR <http://www.cihr-irsc.gc.ca/e/28216.html>.
15. Henry T. Greely, "Moving Human Embryonic Stem Cells from Legislature to Lab: Remaining Legal and Ethical Questions" (2006) 3:5 PLoS Medicine e143, online: <http://dx.doi.org/10.1371/journal.pmed.0030143>; Jeffrey Nisker & Angela White, "The CMA Code of Ethics and the Donation of Fresh Embryos for Stem Cell Research" (2005) 173:6 Canadian Medical Association Journal 621.
16. Nisker, ibid.
17. Michael McDonald, The Governance of Health Research Involving Human Subjects (Ottawa, Ontario: Law Commission of Canada, October 2000), online: <http://www.ethics.ubc.ca/people/mcdonald/lccmacdonald.pdf>.
18. Department of Health, "Regulatory Impact Analysis Statement" Canada Gazette 2005, online: <http://canadagazette.gc.ca/partI/2005/20050924/html/regle1-e.html>.
19. J. Nisker et al., "Development and Investigation of a Free and Informed Choice Process for Embryo Donation to Stem Cell Research in Canada" (2006) 28:10 Journal of Obstetrics and Gynaecology Canada 903.
20. Timothy Caulfield, Lori Knowles, and Eric M. Meslin, "Law and Policy in the Era of Reproductive Genetics" (2004) 30 Journal of Medical Ethics 414 at 416.
21. J. Nisker, "Physician Obligation in Oocyte Procurement" (2001) 1:4 American Journal of Bioethics 22.
22. Paul A. Martin, "Genes as Drugs: The Social Shaping of Gene Therapy and the Reconstruction of Genetic Disease" (1999) 21:5 Sociology of Health and Illness 517.
23. Bryn Williams-Jones & Vural Ozdemir, "Enclosing the 'Knowledge Commons': Patenting Genes for Disease Risk and Drug Response at the University-Industry Interface" in Christian Lenk, Nils Hoppe, and Roberto Andorno, eds., Ethics and Law of Intellectual Property: Current Problems in Politics, Science and Technology (London: Ashgate Publishing, 2007) at 137; Henry Etzkowitz et al., "The Future of the University and the University of the Future: Evolution of Ivory Tower to Entrepreneurial Paradigm" (2000) 29 Research Policy 313.
24. Alan Petersen, Alison Anderson, and Stuart Allan, "Science Fiction/Science Fact: Medical Genetics in News Stories" (2005) 24:3 New Genetics & Society 337.
25. Timothy A. Caulfield, "Underwhelmed: Hyperbole, Regulatory Policy, and the Genetic Revolution" (2000) 45:2 McGill Law Journal 437; Paul Nightingale & Paul Martin, "The Myth of the Biotech Revolution" (2004) 22:11 Trends in Biotechnology 564.
26. Nik Brown, "Hope against Hype--Accountability in Biopasts, Presents and Futures" (2003) 16:2 Science Studies 3; Bryn Williams-Jones & Oonagh P. Corrigan, "Rhetoric and Hype: Where's the 'Ethics' In Pharmacogenomics?" (2003) 3:6 American Journal of Pharmacogenomics 375.
27. Steven Lewis et al., "Dancing with the Porcupine: Rules for Governing the University-Industry Relationship [Commentary]" (2001) 165:6 Canadian Medical Association Journal 783; David B. Resnik & Adil E. Shamoo, "Conflict of Interest and the University" (2002) 9:1 Accountability in Research 45.
28. Sheryl Gay Stolberg, "The Biotech Death of Jesse Gelsinger" New York Times (28 November 1999), online: <http://www.gene.ch/gentech/1999/Dec/msg00005.html>.
29. Jonathan Kimmelman, Francoise Baylis & Kathleen Cranley Glass, "Stem Cell Trials: Lessons from Gene Transfer Research" (2006) 36:1 Hastings Center Report 23 at 26.
30. Jeffrey Kahn, "Organs and Stem Cells: Policy Lessons and Cautionary Tales" (2007) 37:2 Hastings Center Report 11 at 1.
31. Ibid. at 12.
32. Greeley, supra note 15.
33. Bernard Lo et al., "A New Era in the Ethics of Human Embryonic Stem Cell Research" (2005) 23:10 Stem Cells 1454, online: <http://stemcells.alphamedpress.org/cgi/content/abstract/23/10/1454>.
34. Greeley, supra note 15.
35. Supra note xxxiii.
36. Greeley, supra note 15.
37. Catherine Waldby, "Stem Cells, Tissue Cultures and the Production of Biovalue" (2002) 6:3 Health 305.
38. Ibid. at 305.
39. Supra note xvii.
40. Ibid. at 23.
41. Ibid. at v.
42. Ezekiel Emanuel, David Wendler & Christine Grady, "What Makes Clinical Research Ethical?" (2000) 283:20 Journal of the American Medical Association 2701.
43. Oonagh P Corrigan, "Empty Ethics: The Problem with Informed Consent" (2003) 25:7 Sociology of Health and Illness 768.
44. McDonald 2005, supra note iii at 11.
45. Supra note xi; IOM Institute of Medicine, Responsible Research: A Systems Approach to Protecting Research Subjects (Washington DC: Institute of Medicine, 2002); E.J. Emmanuel et al., "Oversight of Human Participants Research: Identifying Problems to Evaluate Reform Proposals" (2004) 141:4 Annals of Internal Medicine 282; OIG Office of the Inspector General, Institutional Review Boards: A Time for Reform (Washington DC: Department of Health and Human Services, June 1998).
46. Gilles Paquet, "Innovations in Governance in Canada" (1999) 29:2/3 Optimum 71.; supra note xx.
47. Beagan, supra note iii.