In the current on-line issue of Stem Cells, members of UCSF's Campus Advisory Committee on Human Gamete, Embryo, and Stem Cell Research report that current practices must be amended to promote both the safety and well-being of the patients who would participate in clinical trials and the confidentiality of people who donate the embryos, oocytes (eggs) and sperm that contribute to the development of embryonic stem cells.
The recommendations address issues not examined by the National Academy of Sciences, which issued guidelines in May 2005, and go substantially beyond those addressed by the Food and Drug Administration in its May 2005 report.
"The potential use of embryonic stem cells as medical therapies presents unique ethical challenges that must be addressed before clinical trials begin," says the first author of the paper, Bernard Lo, MD, UCSF professor of medicine and director of the UCSF Program in Medical Ethics. "Lack of attention to these concerns could lead to delays of clinical trials in some cases and inappropriate clinical practices in others. Such developments, in turn, could undermine or delay progress towards stem cell therapies."
The recommendations of the team, which includes leading stem cell scientists, are aimed at ensuring the safety of biological materials being donated for the development of human embryonic stem cell lines, protecting the privacy of the people who donate the biomaterials, and promoting effective communication between clinician-researchers and patients about the nature of early-stage, or phase 1, clinical trials.
Addressing these issues would require:
- seeking consent from donors of biological materials to allow scientists to recontact them over the years to update their medical records and rescreen them
- implementing stringent measures to secure donors' confidentiality
- enhancing communication with prospective patients about:
- 1) the ethical decision of participating in a clinical trial involving the use of embryonic stem cells
- 2) the unlikelihood of receiving clinical benefit from participation in phase 1 clinical trials, which focus on safety of the therapy and drug dosage
Tracking health of donors over the years
Donated biological materials hold the key to enabling scientists to develop human embryonic stem cell (hESC) lines. However, transplanted hESCs and the proteins they produce could carry infectious diseases, such as Creutzfeldt-Jakob disease (CJD), and genetic-based diseases, such as cancer, Parkinson's and ALS.
The FDA issued regulations in May 2005 for screening and testing for communicable diseases at the time of donation and for tracking transplanted materials back to the original donors. However, the UCSF team says that these regulations are insufficient.
It is critical, they say, that the consent process ask prospective donors of biological materials to agree to be recontacted in the months or years following their donations, so that they can provide updates on their medical history and participate, as deemed necessary, in further screenings. Reestablishing contact is necessary, the team says, for determining if diseases that could have been latent at the time of donation subsequently emerged. This process would allow scientists to determine if a donor, or a number of members of the donor's family, has developed a disease with a strong genetic component that could affect the safety of transplanted cells.
These measures are necessary because there could be a gap of years between the time biological material is donated for embryonic stem cell studies and the time embryonic stem cells or their proteins would be used for transplantation.
Notably, one embryonic stem cell "line" -- a genetically identical group of embryonic stem cells derived from the same ancestral cell -- could be used to treat hundreds or thousands of patients. Thus, one cell line containing a pathogen or disease-causing genetic mutation could affect many patients.
Without permission to recontact and possibly rescreen donors, the team writes, scientists would be invading donors' privacy by recontacting them. In such circumstances, the donors might refuse to reveal their updated medical information, which would disqualify the cells for transplantation.
Securing donors' medical records
It is equally critical, the UCSF team writes, that stringent measures be implemented to ensure that donors' medical records are secured. The authors advocate steps ranging from having computer files locked in a secure room and password protected, with access limited to a minimum number of individuals on a strict "need-to-know" basis; to having files with identifiers copy-protected and double encrypted with one of the keys held by a high-ranking institutional official who is not involved in stem cell research; to having the records protected from subpoena by having the scientists who receive the donated biomaterial obtain a federal Certificate of Confidentiality.
Finally, clinician-researchers should ensure that patients who are considering participation in phase 1 clinical trials of hESC transplantation are fully counseled and able to make a truly "informed consent."
Because of the ethical issue regarding the use of human embryonic stem cells, informed consent would include clinician-researchers making clear to prospective patients that their therapy would involve the use of cells obtained from embryos.
(Human embryonic stem cells are obtained from five- to seven-day old embryos. At this stage of development, the embryo is a spherical cell mass with a fluid cavity and a cluster of cells called the inner cell mass, where the embryonic stem cells reside. To obtain the cells, the embryo is destroyed.)
Clinician-researchers must also make clear to prospective patients that phase 1 clinical trials are intended to begin the process of determining the safety of a given therapy and the appropriate dosage. Such trials rarely lead to improvement in the patient's condition.
"The crucial ethical issue about informed consent is not what researchers disclose in consent forms or discussions, but rather what the participants in clinical trials understand," the team writes.
Because consensus on informed consent practices needs to be in place by the time phase 1 clinical trials are proposed, meetings to develop such guidelines should be convened now, the team says.
A chain of events -- including funding, basic science and clinical trials -- must take place for the potential of human embryonic stem cells to be fully explored, the team concludes. The ethical issues of embryonic stem cell research form another important link, they write, and "a chain is only as strong as its weakest link."
Co-authors of the paper from UCSF were Patricia Zettler, BA, research assistant, Program in Medical Ethics; Marcelle I. Cedars, MD, professor of obstetrics, gynecology and reproductive sciences and director of the Division of Reproductive Endocrinology; Elena Gates, MD, interim chair of the Department of Obstetrics, Gynecology and Reproductive Sciences; Arnold R. Kriegstein, MD, PhD, professor of neurology and director of the UCSF Institute for Stem Cell and Tissue Biology; Renee Reijo Pera, PhD, associate professor of obstetrics, gynecology and reproductive sciences and co-director of the UCSF Human Embryonic Stem Cell Center; Richard M. Wagner, MA, associate director, Human Research Protection Program; Leslie E. Wolf, JD, MPH, assistant adjunct professor of medicine in the Program in Medical Ethics; and Keith Yamamoto, PhD, professor of cellular and molecular pharmacology and executive vice dean, UCSF School of Medicine. Two co-authors who participate on the UCSF's Campus Advisory Committee on Human Gamete, Embryo, and Stem Cell Research but are not employed by UCSF are Michelle Oberman, JD, MPH, professor, School of Law at Santa Clara University and Mary T. Weurth, BS, a community member.
The project was supported by the Greenwall Foundation.