Proposed guidelines for embryonic stem cells: applying new ethical rules to old research.

You may have heard that the Obama administration has proposed new rules for federal funding of embryonic stem cell (ESC) research. (The proposed rules are available in draft form through the end of the public comment period; the NIH expects to finalize the rules in July).

While researchers are enthusiastic at the prospect under this administration of more funding for ESC research, not everyone is happy about the details of the proposed rules. Indeed, in a recent article in Cell Stem Cell [1], Patrick L. Taylor argues that there is something fundamentally misguided about the way the new rules would be applied to old research:

The National Institutes of Health (NIH) has just proposed draft embryonic stem cell (ESC) funding rules that, if adopted following an open comment period, few existing cell lines would meet. This constraint is due to new, specific mandates for informed consent. The proposed rules do not explicitly provide research funding for existing so-called Presidential ESC lines fundable under President George W. Bush, although some of these lines may yet be eligible under the current drafted regulations. Existing NIH grants are also not protected, raising the possibility that ongoing experiments must be interrupted, and new cell lines developed, for current research to continue. Nor do the proposed rules promise funding to the many ESC cell lines derived after 2001 according to ethical protocols approved by institutional review boards (IRBs), operating under federal regulations. Furthermore, funding for cell lines derived according to the so-called NAS guidelines (Committee on Guidelines for Embryonic Stem Cell Research, National Research Council, 2005) or the ISSCR guidelines (Human Embryonic Stem Cell Research Task Force, International Society for Stem Cell Research., 2006) will also be in jeopardy based onthe proposed NIH requirements for consent documentation. The NAS and ISSCR guidelines were developed after extensive multidisciplinary deliberation, and public consultation over several years. The resulting guidelines are considered models of self-regulation, and they have been adopted widely across the global research community. Existing IRB reviews and the established guidelines ought, therefore, to be given significant weight when assessing the ethical provenance of an ESC line.

Prospectively applied, the proposed NIH rules as they stand would present a challenge to the field. But retroactively applied, the draft regulations would create a tectonic shift: previously, only certain old lines were fundable, and now -- conceivably -- only certain new lines will be, and there will continue to be no federal funding available for research using cells created ethically since 2001. Important research will need to be repeated, and assays and data rebuilt. As currently outlined, it's as if the last 8 years of cell line creation and ethical self-regulation have just vanished, to be replaced by a new funding structure that does not give weight to the existing science, ethics, self-regulation, donor intentions, or diverse cell lines. Resolving this situation is critically important for stem cell research. But the broader principle -- should government guidance be retroactive? -- is vital for all areas of scientific research.

It's worth noting here that informed consent is not just required from a human subject who is an actual participant in research (whether a non-therapeutic or clinical trial of a drug or a device, a psychological experiment, an informant in an ethnographic study, etc.). Informed consent is also required when humans donate materials (like blood or tissue) to be used in research.

This means that for ESC research, the people whose ova and sperm were used to make the embryos need to render their consent for those embryos to be used in the research.

Rules about what counts as proper consent from human subjects -- and from donors of tissue to be used in research -- are intended to recognize the autonomy of the individual, including his or her right to make decisions about what happens to his or her body or body-parts. Scientists cannot ethically demand that you hand over a pint of blood, a square inch of skin, or a half dozen embryos for their use; they can ask you to provide the materials they need and hope that enough donors say yes.

In the process of asking, researchers also need to provide prospective donors with sufficient information about what they will be using the donated materials for -- what are the goals of the research, how exactly will the donated materials be used, and what are the potential harms and benefits of donating the requested materials. This allows donors to make an informed choice about whether to donate or to decline.

As far as risks and benefits are concerned, recently the privacy rights of donors have been high on the list of concerns in research with human-derived tissue, which means researchers have had to lay out their detailed plan for protecting the privacy of donors. Moreover, under current regulations in the U.S., humans are forbidden from selling their body parts, which means that researchers cannot offer payment to induce people to donate the needed tissue.

As with all research involving human subjects or tissue derived from them, ESC research has fallen under the supervision of the institutional review board(s) (IRB(s)) of the institution(s) under whose auspices the scientists conduct the research. The IRBs need to review and approve experimental protocols before research commences, and they periodically review ongoing research to assure that it meets the required standards to protect human subjects (including the donors of tissue used in the research).

So, what are the standards in the new proposed rules for ESC research?

The proposed rules require nine consent elements to be documented in the written informed consent form for donors who release embryos for research purposes. Some requirements are traditional, and well-established in the research community, such as that consent was voluntary and the donor was aware of alternatives. Other requisites are newer, and while they may have merit, such as prohibiting directed donation and barring donors from receiving any financial gain from patents or products, these issues have yet to be publicly debated in depth. In addition, institutions must assure compliance inapplications and progress reports and maintain the connection between noncompliance and potentially severe penalties (civil False Claims Act penalties and damages; criminal prosecution). Institutions will presumably be conservatively risk averse. Institutions must also assure that conditions in IVF clinics are documented, including at least two consents -- at the time of seeking reproductive services and at the time of donation. While full consent at the time of donation is essential, neither the NAS nor the ISSCR guidelines require, in all cases, that there have been a previous consent form that avoids mention of hESC, as required by the proposed NIH rules. Consent must also have been revocable until the time embryos were "used in research", which, while reflective of some guidelines, can be problematic for deidentified donations, depending on how "use in research" is defined. Finally, clinics must have had policies in place to ensure that medical care was unaffected by the decision to donate, and uninfluenced by researchers or inducements. In this case, the key concern is not the avoidance of influence per se, which is important, but whether that practice must be reflected in a written policy, instead of, for example, corporate or departmental separation of researchers from the IVF clinicians.

Here, Taylor suggests that the newer requirements in the proposed ESC rules ought to be explored in in-depth public debates rather than imposed prior to something like an attempt to establish societal consensus. And he worries about the proposed rules' focus on consent forms and written institutional policies. A signature on a consent form may indicate that informed consent has been given (although then again, it may not -- how many times have you signed what they hand you on the clipboard at the doctor's office without reading it carefully?). Written policies may capture institutional commitment to particular ethical standards and rules (although then again, they may not -- how many people in an institution can be counted on to closely read, understand, and be guided by policies just because they've been put in writing and distributed or posted on the institution's website?). But, it may be possible to secure proper consent with a single form, rather than two distinct ones, and it may be possible to institute ethical policies and practiced that are not explicitly captured in existing written policies.

And this is where Taylor's main argument comes in. Regardless of whether the new proposed ESC rules are reasonable and implementable going forward, if adopted, they are to be applied retroactively. This would mean that existing ESC lines that did not meet all the requirements of the new rules, including the various elements to be documented in two distinct written consent forms, and those to be spelled out in written institutional policies, would be ineligible for NIH funding -- even if these lines were created in full compliance with the recognized ethical guidelines in place at the time they were created. This is to say, ESC lines started under protocols approved by IRBs who were looking out for the autonomy and well-being of the donors of the embryos, who ensured that informed consent was secured, and so on, could be ruled out of future funding because the consent forms used (and approved by the IRBs for use) were missing one of the nine elements required by the new rules.

Needless to say, this would render a lot of scientific work in progress unfundable (which, in the current economic climate, might well render it undoable).

The interests of researchers, while important here, do not outweigh the interests of the donors. The question then becomes, would imposing the proposed rules retroactively remedy a harm done to the donors by earlier ESC research? If there were such harms that could be remedied, there might be a case for retroactive rules here. But in the absence of compelling evidence of such harms, Taylor argues that good compliance with the ethical standards at the time ought to count for a lot:

There is a justice interest in treating like cases alike going forward, so that all funding decisions (and grantees) are subject to the same rules. But not all cell lines are alike: those ESC lines created in accord with rigorous ethical rules of the time deserve to be treated differently from lines (like the Hwang lines of several years ago) created with less attention to ethical fundamentals or prevailing standards.

There is also a justice interest in keeping commitments to scientists who received grant awards. In addition, it is unjust to create new IVF consent rules to which, being retroactive, one has no opportunity to conform. Moreover, while scientists could not reasonably claim a "vested right" to funding (except under existing grants), it is not an overstatement that scientists and donors could reasonably rely, for an ethical stamp of approval, on (1) government designation of Presidential lines (recently reapproved by government); (2) federally regulated IRB review; and (3) review under NAS and ISSCR standards, standards to which the NIH has not objected and, I must believe, the NIH would not now condemn. So why can't scientists rely on lines that fall into these categories?

The public comment period for the proposed rules closes on Tuesday, May 26. To a limited extent, this public comment can provide something like the public debate to which Taylor argues new ethical rules should be subjected before they are adopted.

And it would be most useful if the public would weigh in on whether applying ethical rules retroactively -- especially to instances where contemporaneous ethical rules were followed -- is a good idea.

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[1] Patrick L. Taylor, "Retroactive Ethics in Rapidly Developing Scientific Fields," Cell Stem Cell, 14 May 2009 (doi:10.1016/j.stem.2009.05.002).