NJ stem cell research law sparks renewed ethics and legal debates

Investigators need to understand, navigate complexities

In January, New Jersey became only the second state in the union to pass legislation formally permitting research using embryonic stem cells.

Similar to a 2002 California law, the New Jersey measure explicitly prohibits any attempt at human reproductive cloning, but specifically permits research involving "human embryonic stem cells, human embryonic germ cells, and human adult stem cells from any source, including somatic cell nuclear transplantation."

Embryonic stem (ES) cells are primitive cells, present in human embryos at the earliest stages of development, that have the potential to develop into any type of cell found in the body. Scientists believe that, if they can learn to direct how embryonic stem cells develop, they then could grow lines of healthy cells to replace diseased cells in people with different illnesses.

However, use of ES cells in research is controversial because it involves the destruction of a human embryo, and the major source of the cells has been embryos left over from assisted reproductive procedures and discarded by fertility clinics.

In August 2001, President Bush limited the use of federal funds for stem cell research to only those studies using a set of approximately 50 preapproved cell lines, stem cells already derived from embryos prior to that date.

The language of the new state laws is much more permissive — allowing researchers to independently obtain embryos and derive new stem cell lines.

However, this means institutions and researchers in these states must carefully navigate the intersecting federal and state laws in order to undertake such studies.

Federal funding still cannot be used, meaning that institutions conducting federally funded research in other areas still may shy away.

"States, while they can control certain kinds of practices, they don’t really fund research, they don’t have any money, and they are not really a player in setting standards the same way that the National Institutes of Health [NIH] and other federal agencies can set standards," says Paul R. Billings, MD, PhD, vice president and national director of genetics and genomics for the Laboratory Corporation of America in Research Triangle Park, NC.

It’s also not completely clear how to interpret the federal restrictions, Billings adds. Whether investigators at institutions receiving federal funding also can conduct stem cell research using private funds, or whether a federally funded institution should refrain from all such research as a condition of continuing federal funding, is not clear.

"If you have a university that receives both private and federal funding, they are worried that they will lose their federal funding if they engage in research that could flaunt the federal standard," he says. "Some have set up separate, nonprofit entities to administer such studies outside the normal research track and receive private funds that way."

Institutions also may contract with private companies to conduct research on a contractual basis, so that the primary agency doing the research is not the university, and they are only a subcontractor, Billings says.

Growth in the private sector

The impact of the new laws still will be largely in the private research sector, Billings notes, and should encourage more research because companies can be confident that the research will be permitted and supported.

"In California, companies like Genron can now feel free to operate without the fear of having their business licenses revoked," he explains.

Various private companies, and well-funded infertility researchers probably will be the groups to benefit from and make the most use of the new laws, but that may still involve obtaining the approval of an institutional review board, Billings notes.

"One of the key issues in this type of research is where you obtain the materials from, and the consent process that it involves," he says. "That most likely will occur in some sort of study protocol and fall under the review of a local IRB [institutional review board]."

If researchers are going to derive stem cells from embryos left over from an in vitro fertilization (IVF) cycle, most centers will require the consent of people who created the embryos, and this may require some sort of review before the embryos can be collected.

"If the investigator is hooked up with any kind of university, or if the investigator thinks he or she might at some later time want to get some federal funding, or publish the data, most of those kinds of investigations are done with IRB approval," Billings notes. "There would be some review of how the material that is being worked on was gathered, and under what manner was it gathered, and was there consent and did the consent meet the Common Rule and other standards for disclosure of risks and benefits. They’ll be looking at where the cells come from, are they coming from public banks and resources that are well described, are they asking people for new contributions; if so, how are they consented, how are the commercial issues dealt with, all of those things."

Examining ethical and public policy issues

Aside from the regulatory issues, some experts feel that stem cell research presents unique challenges for clinical investigators as these cellular therapies move from the lab into clinical trials.

The Program in Cell Engineering, Ethics, and Public Policy at the Phoebe R. Berman Bioethics Institute at Johns Hopkins University in Baltimore has convened an interdisciplinary working group of experts in science, law, and philosophy to discuss the novel ethical and policy challenges in stem cell research, says Ruth Faden, PhD, MPH, the program’s co-director.

Although clinical applications for ES cell therapies are likely still years away, it’s important that institutions, the public and researchers begin to examine the unique issues this type of research presents, she says.

First, tension regarding the use of human embryos may complicate the development of safe and effective cell lines.

Many researchers feel, for example, that the current federally approved cell lines should not be used in clinical trials because they were initially grown on mouse cells and have the potential to harbor mouse-specific viruses, Faden says.

Given that safer alternatives would be easily available, it would be unethical to expose human subjects to these cell lines.

"Conducting a federally funded clinical trial of human embryonic stem cells under current federal policy would require using cell lines that none of us feel should be used in people, since it is now feasible to create safer lines," Faden says. "All clinical trials, and by extension the experiments leading to them, should be conducted with newer cell lines not eligible for federal funding. The likelihood of getting to a clinical trial using private funds, however, is very slim."

Second, because human stem cells were not developed in the laboratory until 1998, few safety questions relating to human application have been addressed in animal research. And, third, pre-clinical and clinical testing of biologic agents — particularly those as complex as stem cells — presents formidable challenges in terms of developing the needed standardized assays and of recruiting appropriate populations for early phase trials.

For instance, researchers believe that therapeutic use of embryonic stem cells will require that the cells match the recipients in ways that are similar to matching patients’ blood types for transfusions or for transplants of organs, bone marrow, and tissue.

With a small number of cell lines available for study, it’s likely that early trials could include only select members of the population, raising issues about whether such trials would be withstand scientific rigor and how issues of justice and access to therapies by minority populations might be addressed.

In a report published in the journal Fertility and Sterility, Faden and colleagues call for a national commission to oversee the development of ES cell research as it moves into the clinical arena.1

Education for IRBs and investigators

Guidance and education for institutions contemplating ES cell research also should be a national priority, agrees Billings.

"I think that clearly local IRBs need information resources that allow them to understand nationally where the field is going," he says. "While you want IRBs to reflect regional standards and regional sensitivities, or even local sensitivities, there ought to be a large-scale informational or even expert resource that they can go to for expert opinions about various issues that might confront them. For instance, it may very well be that an IRB reviews a stem cell protocol and doesn’t realize how commonly [adult] stem cells are used in therapeutics already."

Currently, no federal agency has responsibility for such oversight, though this could change if pressure from the states forces the research forward, Billings notes.

Investigators considering participation in a stem cell-based therapeutic trial should educate themselves about the federal and state regulations involved and be aware of the complex political and social implications this research presents, he adds.

"Clinical investigators need to understand the applicable regulatory law and that is something they frequently don’t understand," Billings says. "And be aware that if they are working with embryonic cells or the products of IVF, there are controversial issues. Some people believe that these cells are the moral equivalent of human beings," he adds. Whether an investigator agrees with that opinion or not, it is important to recognize that some people do and it will play a role in the decisions IRBs make about oversight and whether patients decide to participate.

"I am not suggesting that this be given any more weight than any other belief held by a particular group of people," Billings says. "But it is important to acknowledge that people have such feelings and to consider that in whatever review processes and review of document processes that might occur. That is simply recognizing the plurality of view that exists in the United States about this issue."

Reference

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