Who Cares about Consent Requirements for Sourcing Human Embryonic Stem Cells? Are Errors In the Past Really Errors Of the Past?

Abstract

Through an Access to Information Act request, we have obtained the consent forms used by the providers of every human embryonic stem cell (hESC) line approved for use by the Canadian Institutes of Health Research (CIHR), and examined them to verify whether or not they meet the consent requirements established by Canadian law and regulations. Our findings show that at least seven out of ten consent forms studied did not satisfy these minimum requirements. We then outline various options for responding to this situation in terms of: (i) remedial measures for dealing with executive problems with regulatory oversight procedures; and (ii) remedial measures for dealing with the impugned lines.

Keywords:

• consent forms
• embryos
• ethics
• government regulation and oversight
• informed consent
• legislation and jurisprudence
• policy
• stem cells

ACKNOWLEDGMENTS

We would like to thank Françoise Baylis, Michael Hadskis, Matthew Herder, and the Novel Tech Ethics research team for critical feedback on previous drafts of this article, as well as audience members who attended an oral, conference presentation on the topic at the American Society for Bioethics and Humanities (23 October 2010). We would also like to thank an anonymous reviewer from this journal for very astute criticisms and suggestions that have aided us in strengthening the final iteration of this article. Research for this project has been funded by Canadian Institutes of Health Research, MOP 77670, “Therapeutic Hopes and Ethical Concerns: Clinical Research in the Neurosciences.”

Notes

1. This analysis comes at an opportune time in the history of Canadian hESC research, with the addition of the very first hESC lines to the CIHR's National Stem Cell Registry on May 20, 2010. The Registry offers free access to these hESCs on a cost-recovery basis, and registration is mandatory for all hESC lines derived at CIHR-funded institutions. The implementation of the Registry is a milestone which can and should be viewed as an opportunity to establish Canadian hESC researchers as leaders in ethical practice, while simultaneously facilitating the growth of hESC research in Canada. A thorough review of the consent forms used in obtaining the biological source materials to create the hESC lines approved for use in Canada should help the CIHR to accomplish this task.

2. Hereinafter abbreviated as the “CIHR 2002 Guidelines.”

3. Hereinafter abbreviated as the “AHR Act.”

4. See Reference re Assisted Human Reproduction Act, 2010 SCC 61 (Supreme Court of Canada, 2010).

5. AHR Act, s. 3: “‘consent’ means fully informed and freely given consent that is given in accordance with the applicable law governing consent and that conforms to the provisions of the Human Pluripotent Stem Cell Research Guidelines released by the Canadian Institutes of Health Research in March, 2002, as detailed in the Regulations.”

6. The AHR Act explicitly incorporates the CIHR Guidelines into its definition of consent, and the argument has been made that since the AHR Act refers to the 2002 version of the CIHR Guidelines, any revisions to the Guidelines are inapplicable in the context of the legislation. This issue is explored in more detail below. Cf. Nelson (2008, p. 10).

7. For further explanation of the role of the SCOC see Nelson (2008, p. 9).

8. These agencies include: CIHR; the Natural Sciences and Engineering Research Council; and the Social Sciences and Humanities Research Council.

9. While one might also point out that research using pluripotent stem cell lines in Canada must receive local research ethics board approval as well, in most cases it would be reasonable to assume that SCOC approval would likely precede research ethics board submission. We therefore think it reasonable to focus our analysis on the SCOC approval process.

10. A full listing of stem cell lines approved for use in Canada can be found at: CIHR, Guidelines for Human Pluripotent Stem Cell Research Policy: Policy Highlights (30 June 2010), online at: <http://www.cihr-irsc.gc.ca/e/28215.html>. Accessed 12 November 2010.

11. That three of the consent forms passed the test of the CIHR 2002 Guidelines will come as comforting news to those involved in Canadian-based hESC research, as these three providers account for over 60% of the hESC lines available for use in Canada. There is currently no comprehensive list of stem cell lines approved for research use by the SCOC on the CIHR website. Stem cell lines were approved by the SCOC at five of their meetings, minutes of which can be found online at <http://www.cihr-irsc.gc.ca/e/6953.html>. Lines created at the University of Wisconsin–Madison (H1, H7, and H9), ESI International (hES1–hES6), Technion-Israel Institute of Technology (I3, I6), and UCSF (HSF-6) were approved in January 2004; those created at Mt. Sinai Hospital in Toronto (CA1, CA2) and Harvard University (HUES 1–HUES 28) were approved in January/February 2005; lines derived at the University of Calgary (CC1, CC3) and the Barcelona Centre for Regenerative Medicine (ES2–ES6) were approved in October, 2008; and lines derived at King's College in London (KCL-003-CF1) and at Cythera/Novocell in San Diego (CyT49) were approved in January of 2009. See CIHR (2010a).

12. Though there is some division in the literature on the suitability of consent forms for obtaining consent for all contexts (CIHR, NSERC, and SSHRC, 2010, Ch. 3), and though consent (regardless of context) is a process involving much more than consent forms (Kuczewski, 1996; Meisel and Kuczewski, 1996; Nelson, 2002), documentation of consent is nonetheless, as Streiffer points out, “an indispensible step in responsible oversight.” Streiffer further explains: “A satisfactory consent process requires more than a good consent form, but a bad consent form not only makes a satisfactory process unlikely, it makes documenting whether the process was satisfactory … extremely difficult” (Streiffer, 2008b, p. 6). The TCPS (1998, Art. 2.1(b)) stipulates that free and informed consent “should ordinarily be obtained in writing,” and in cases “where there are good reasons for not recording consent in writing, the procedures used to seek free and informed consent shall be documented”. See also CIHR et al., TCPS 2 (2010, Ch. 3, s. D), Shamoo and Resnik (2009, p. 339ff.) and Bhutta (2004).

13. I3, I6 had no signature field, only a line stating: “Signed by the participants, both female and male involved, and by a witness.” This is followed by blank space with no place indicated for signatures or dates, and no redactions.

14. The objection could be made that our Access to Information Act request may have been misinterpreted—that sample, unsigned consent forms might have been provided to us even though the SCOC itself reviewed signed consent forms. Were this true, it is quizzical why one of the sample forms provided to us has all signature fields redacted (Table 1: CyT49), and another has the donor signature fields redacted and a visible signature of the witness (Table 1: KCL-003-CF1). It is further puzzling that five of the sample forms (hES1–hES6, I3, I6, HSF-6, H1, H7, H9, CA1, CA2) provided to us have blank signature fields—and in one case there is no field indicated, just space for signatures (I3, I6)—while at the same time other personal information in these same forms is redacted.

15. During the time of writing, the TCPS (CIHR, NSERC, and SSHRC, 1998) has been superseded by the TCPS 2—2nd edition (CIHR, NSERC, and SSHRC, 2010) as the official human research ethics policy of the Agencies as of December 2010. We have elected to use the 1998 edition because it indicates the standards in place at the time (see specific dates given above in endnote 11) at which the stem cell lines (see Table 1) were approved for research use in Canada by the SCOC.

16. Sugarman and Siegel hold that the central question to address during the requisite deliberations “is whether the ethical principles underlying provisions of extant and current guidelines are violated by permitting use” (Sugarman and Siegel, 2008, p. 238).

17. Article 2.1(c) was adapted from Protection of Human Subjects, U.S. Dept. of Health and Human Services, Title 45; Code of Federal Regulations, Part 46.116(d).

18. See relevant discussions in Allen (2004), Clayton (2004), Evans and Meslin (2006), and Hakimian and Korn (2004). Rothstein (2005) notes that with respect to regulations for biobanks of human biological materials, “nearly all proposals relax the rules on informed consent for archival samples, especially for those that are not identifiable” (2005, p. 91).

19. Note that the TCPS 2 combines these sections now (CIHR, NSERC, and SSHRC, 2010).

20. Canada and Baird (1993, p. 628 and nt. 8) explain this as a conclusion made by the Law Reform Commission of Canada (1992).

21. These guidelines follow standards already set by the Royal Commission (Canada and Royal Commission on New Reproductive Technologies, 1993, p. 17). It bears mentioning that the TCPS (1998; see p. i5: C and s. 9) draws heavily on the final report of the Royal Commission. Our use of this report is intended to show that the benchmarks for assessing consent in the CIHR 2002 Guidelines were established long beforehand. It cannot be claimed that we are applying standards that were not in place for Canada either at the time of the SCOC approval of the lines indicated in Table 1 (see endnotes of Table 1 for specific dates of approval), or (probably) for the time of collection of the original embryos. Admittedly, we have not been able to establish the dates for collection.

22. In working group papers informing Canadian policies dating back to the Royal Commission (Canada and Baird, 1993) through to contemporary consensus policy statements from the SOGC, what has been acknowledged as a distinct matter of ethical concern are the risks to women's health involved with egg retrieval practices. These same documents have emphasized the relevant (not global) potential vulnerability of women as IVF clients and that therefore infractions of the consent process must be strongly guarded against (Baylis et al., 2003; Baylis, 2009; Baylis and McInnes, 2007; Canada and Baird, 1993, pp. 601, 640, 647; CIHR, 2002c; Nelson et al., 2008; Nisker et al., 2006; Nisker and White, 2005).

23. See Lo and colleagues who note that “Consent for donation of such materials for research should be specific, informed, and voluntary” (2009, p. 119). “Researchers would fail to respect donors as persons if donors were not informed of the proposed type of research, or if donors would have objected to it” (Lo et al., 2009, p. 121).

24. Note also general information that is deemed necessary to communicate to research subjects for consent to be valid (CIHR, NSERC, and SSHRC, 1998, Art. 2.4(a–e) and pp. 2.6–2.8).

25. See further explanation in the United States NBAC report (1999b) and Nuffield Council on Bioethics (2000, pp. 10–11) for why the relevant consent to the use of embryos for stem cell research must be specific to meet minimum standards.

26. Given that the stem cell lines were sourced from embryos collected in various countries with various cultures, not to mention that IVF clients often travel to other jurisdictions for assisted human reproductive services, it stands to reason that it could be very difficult to predict donors' probable decisions in disposing of their embryos. Note too that false positives in this regard could be interpreted as potential violations of the TCPS (1998) guiding ethical principle of respect for human dignity which states: “This principle aspires to protect the multiple and interdependent interests of the person—from bodily to psychological to cultural integrity” (p. i.5:C; see also s.10, p. 10.1).

27. See also Aalto-Setälä and colleagues (2009) and Lo and colleagues (2009, p. 121) for discussions of why respect for research participants' as persons makes this a necessary condition of the consent process.

28. It is an open question, though, as to who of the general public will have access and be able to afford these treatments.

29. See Cooper v. Hobart (2001, SCC 79), a case involving a claim of regulatory negligence against the British Columbia Registrar of Mortgage Brokers for failing to properly oversee the activities of a registered mortgage broker who had used investor funds for unauthorized purposes. In Cooper, at para. 42, Major J. stated that any duty of care held by a regulatory body must arise from the enabling statute. The SCOC may be distinguishable from the Registrar of Mortgage Brokers in Cooper, since there is no enabling statute, only the CIHR Guidelines. Moreover, even if the Guidelines were sufficient to found a duty of care, the SCOC would likely be interpreted in light of Cooper to owe a duty to the public in general, rather than to the specific group of donors that would be alleging negligence, given its broad mandate under s. 8.1.5 (Supreme Court of Canada, 2001). Prospects for recovery may thus seem remote, but not impossible.

30. Though it is true that the number of researchers and prospective beneficiaries of stem cell treatments from the general public far outnumber donors, it should be noted that stem cell science is still quite inefficient, and many donated embryos are wasted or discarded in the creation of any given stem cell line. Any given stem cell line thus represents multiple donations. See Cowan et al. (2004).

31. We have not yet found any studies that have attested to donors' experiences of harm in the wake of finding out that their embryos had been used in ways during research, or for research purposes, that they were not fully informed of in advance of donation. Given the rather common special attachments that couples feel towards their embryos detailed in Section 3, it might be expected that the outrage would be even greater than presumptuous uses of other human biological materials without voluntary, informed consent. One need only look back to the outrage expressed by Minnesota parents when finding out that stored blood samples from newborns were made available for research without the parents' informed consent (Stein, 2009 cited in Streiffer, 2009a, p. 5), or the public outcry in the United Kingdom over proposed rules to give scientists greater access to samples of blood and tissue (collected by NHS hospitals during biopsies and treatment) as well as tissue banks. While said scientists were mandated to gain explicit consent before using cells from such stores, if the samples were collected before October 1st, 2009 and the donor could not be tracked down, it was proposed that the experiments should be allowed to go ahead regardless. These proposals were met with a great deal of public resistance (Donnelly, 2009; Jones and MacKellar, 2009). Admittedly, these examples are not directly analogous for the Canadian case involving human reproductive materials; however, they do show examples of how donors can be made to feel intense harm even when that harm is indirect and mostly psychological.

32. For further discussions of donors' attitudes towards their embryos see Lyerly et al. (2006), Massey (2010), Nachtigall et al. (2005).

33. See also de Lacey (2005, 2007), Hammarberg and Tinney (2006), Lyerly et al. (2006), McMahon et al. (2003), and Nachtigall et al. (2005).

34. “Grandparenting in” stem cell lines usually means that an exception is granted to older lines that fail to meet current regulatory standards for informed consent, and as said before, this is usually justified because they nonetheless “have followed the core principles” underlying current guidelines (Leshner, 2009; Lo et al., 2009).

35. These anticipated effects of the “grandparenting” option may be mitigated if the form of discipline against the SCOC included dismissal and reconstitution of the membership.

36. See endnote 41, given below.

37. Another—perhaps also “proportionate”—remedial option would be one that allows continued use of the lines with faulty consent in research where the imperfections in consent would be judged to not have made a difference to the willingness of the (actual or reasonable) donors to donate, but that prohibits continued or future uses in more controversial areas of research. This option would have the advantage of allowing some current research with the impugned lines to proceed apace, while stopping the use of the impugned lines in research that the donors (presumably) might not have wanted to support. Some might find this option attractive because it would involve less loss of time and resources already invested in the lines, not to mention that some lines would avoid being (on some points of view) “wasted” if the re-consent option was either unavailable or not feasible. A significant difficulty with this course of action would be to determine what criteria would be used to make such an assessment, as well as who would rightfully make the necessary determinations in lieu of getting re-consent from the actual donors. See relevant discussions above in Section 3.

38. The ban would also apply to any export of these lines. The point of this measure would be to stop the sale of the impugned lines to foreign clients and to prevent the lines from being exported to jurisdictions that would permit their continued use without re-consent. Perhaps this ban would be lifted for those lines that successfully achieved informed re-consent from the donors.

39. In addition to the significant complexity of setting out a framework for the exemption for the “downstream,” perhaps “innocent” researchers,” the exemption itself is likely to come perilously close to a well-defined legal concept of the bona fide purchaser for value without reasonable notice concept in the realm of property law. This is troubling because of the significant antipathy towards categorizing human tissues as property in Canadian and other cultures; utilizing something that mimics property law in any way might be viewed with some distaste.

40. Hypothetically speaking, it is possible that not necessarily all downstream researchers are innocent just by virtue of being downstream researchers. Within a small research community, it is plausible that if some upstream researchers were knowingly overlooking consent requirements some downstream researchers may have had knowledge of these practices and nonetheless used the affected hESC lines. This claim, it must be underscored, is purely speculative.

41. This, in effect, could send a “mixed message” to all stakeholders, namely, that on the one hand, regulations regarding consent are serious enough that noncompliance will not be tolerated with impunity, but not serious enough to imply requirements for re-consent.

42. We would like to thank L. Syd M. Johnson and Andrew Fenton for bringing this point to our attention.

43. Glasner notes: “Consent is not just about evaluating a particular technology, but also about assessments of trust and risk in professionals and institutions” (2005, p. 361).

44. Matthews and colleagues note: “Scientific and ethical integrity are crucial to scientific progress, which depends not only on the replication of results, but also on the public's trust” (2006, p. 921). See also McDonald (2000, 2001) and Streiffer (2008a).