Stem cell trials present novel issues for IRBs

Hopkins group to examine potential risks

The furor surrounding the derivation and collection of embryonic stem cells has eclipsed the many other ethical, legal, and social issues that should be examined before these therapies move from the laboratory to human clinical application, say researchers working at Johns Hopkins University in Baltimore.

"By focusing on the derivation of stem cells from embryos and fetuses, the discussion of the ethics of stem cell research has, in large part, become tied to the ongoing debate over the moral meaning and significance of early human life and the beginning of life," says Ruth Faden, PhD, MPH, professor of biomedical ethics and director of the university’s Phoebe R. Berman Bioethics Institute.

"These polarizing issues aren’t amenable to solution by political fiat or by discovering some fact of the world through scientific inquiry. And we are in a situation where the other pressing ethical issues raised by stem cell research are neglected or totally ignored because the attention that is focused on seemingly intractable disagreements," she notes.

With experts predicting the first human trials of stem cell within the next five years, institutions need to begin examining these other issues now in order to have the ethics advance with the science, Faden tells IRB Advisor.

At Hopkins, members of the bioethics faculty have formed a collaborative program with faculty from the university’s Institute of Cell Engineering to attempt to anticipate the moral and policy challenges that stem cell science and cell engineering will pose and provide the opportunity for careful, interdisciplinary analysis of these challenges to assist both policy-makers and the public.

The Program in Cell Engineering, Ethics, and Public Policy (PCEEPP) was created in March 2002, and is a formal, ongoing collaboration.

"Prior to the program’s creation, there was an existing relationship between the faculty of the two institutes, with individuals jointly involved in projects examining ethical issues in stem cell science and research; however, through the program, this effort was formalized," Faden explains.

PCEEPP recently published a report, "Safety issues in cell-based intervention trials," in the November 2003 issue of the journal Fertility and Sterility.1

According to their findings, clinical trials of stem cell therapies will present a number of novel issues in terms of risks to human subjects and questions of justice and access to new treatments.

Safety concerns

First, there are serious safety concerns that must be addressed before stem cell therapies can be tested in human subjects, Faden says.

For instance, the program members agree with the National Academy of Sciences that the presence of mouse feeder cells in the culture upon which current stem cell lines are maintained raises the specter of cross-species disease transmission should those cells be reintroduced into a human.

Although work currently is under way to develop new mouse-free feeder lines, all of the stem cell lines approved for federally funded research under the Bush administration’s policy have been in contact with mouse feeder cells.

"The risk [of disease transmission] is a theoretical risk, but it isn’t a necessary risk," Faden says. "New lines will be mouse-free, and that’s the fact that led us to say it would be unethical to use the extant cell lines in humans."

Another safety issue is the need for some kind of suicide switch that could control the functions of the stem cells once transplanted into subjects, she continues.

"One of the big hurdles that remains to be overcome with stem cells is the possibility that, after transplantation, they go somewhere other than where they were intended to go, or they start producing the wrong cell types," she says. "In both of these scenarios, we need some way to deactivate the cells so that they don’t harm the individuals who received the transplant."

There also will be complex issues involving justice and appropriate selection of research subjects, she adds. By their very nature, stem cell-based therapies will be suitable for use in some humans and not in others.

"This variability tracks — to some degree — ethnicity, so it appeared very important to us to flag the downstream justice concerns that may arise," Faden notes.

Stem cell transplants will be fairly similar to some types of solid organ transplants in that the subjects will face the possibility of immune rejection. As such, recipients of stem cell transplants will likely face the same scenario as persons who receive solid organ transplants in that they must be appropriately matched to their type of stem cell to avoid immune rejection.

This will result in disparities across ethnic and ancestral groups, Faden notes. "Due to genetic variability within the African-American ancestral groups, African-Americans disproportionately have difficulty obtaining matching in solid organ transplantation, and the same would likely be true of stem cell transplants," she explains. "Unlike solid organs, however, we have a choice in which stem cells are available for transplantation. Indeed, we may even be able to engineer the genetic code of the stem cell."

Determinations about which stem cell lines are studied and, therefore, eventually evolve into treatment options should be a concern. "Given the difference, our group addressed the question of how we should select which stem cell lines become available for transplantation, and what strategy would be most just in the American context," Faden says.

Given the complex challenges involved, it may be necessary for additions or alterations to the existing oversight process for human subjects trials, the program members noted.

They believe that serious consideration should be given to the establishment of patient advisory boards, consent monitors, patient advocates, and other procedures to concentrate attention and energy on the interests of subjects and their families as the first human trials go forward.

It’s possible that a national advisory committee, similar to the Recombinant DNA Advisory Committee, which currently oversees federally funded human gene intervention research, would be needed to provide additional guidance, Faden notes.

"The pre-clinical and the first human trials of stem cell-based therapies will likely be quite difficult," she says. "Over the years, there have been many proposals for strategies to improve protections for human subjects in high-stakes, high-risk research. The first human stem cell trials certainly fit this description."

Reference

1. Dawson L, Bateman-House AS, Mueller Agnew D, et al. Safety issues in cell-based intervention trials. Fertil Steril 2003; 80:1,077-1,085.