How can consent be informed when the "patient" is a fetus? Is it appropriate to begin clinical trials involving prenatal gene therapy when the potential risks to the mother, the fetus, and the child's possible offspring are not fully understood? And how would such trials be designed?
These and other ethical questions are being deliberated as a result of the recent proposal to the National Institutes of Health Recombinant DNA Advisory Committee to begin human trials of in utero gene transfer (See News, Oct. 21, 1998.)
For now, working groups at the third NIH Gene Therapy Policy Conference on "Prenatal Gene Transfer: Scientific, Medical and Ethical Issues" have concluded that there is insufficient preclinical data to support starting phase I clinical trials. But they made it clear that as the science presses forward, researchers and the public must be prepared to grapple with the gamut of ethical, legal, societal, scientific, and medical issues.
" Minimal" Risks
A key issue is how to define during the informed consent process the potential risks and benefits to fetuses. NIH guidelines and regulations on research involving human subjects call for "minimal" risks to the fetus.
Consensus is needed on what is considered "minimal," said RAC member Louise Markert, M.D., Ph.D., Duke University Medical Center, Durham, N.C. In defining an acceptable level of risk, researchers should consider that people can attribute to the fetus at least four different levels of moral status: none, one of increased standing as gestation lengthens, moral standing from the point when the fetus becomes a patient, and full moral standing from conception.
Attendant to all prenatal predictive diagnostic or therapeutic procedures, there are a number of risks to both the mother and fetus, such as during amniocentesis, chorionic villus sampling, or fetal blood sampling, according to Karin Blakemore, M.D., a specialist in maternal-fetal medicine at Johns Hopkins University School of Medicine, Baltimore. Associated risks can include fetal death, ruptured membranes, preterm labor or contractions, infection in the fetus, or rarely, in the mother, and bleeding of the fetus or mother.
There are also risks that are specific to different diseases and risks that are specific to gene therapy. Current in utero medical procedures suggest that the risks of gene transfer in fetuses will be related to gestational age, dose, source and type of cells, vectors and genes used, and route of administration, Blakemore said.
"There are many questions which will dictate what the risks are going to be involved in all types of gene therapy," she noted.
Risks of in utero allogeneic human stem cell transplantation include viral transmission of disease to the fetus and the risk of no engraftment to the child that is born. For prenatal hematopoietic stem cell transplantation to correct genetic defects, a key risk question is to what tissues the vectors might migrate. It is believed this process will be dose and gestational age dependent and probably dependent on cell types as well, according to Blakemore.
For direct gene transfer, it is unclear what cells are going to be transduced, but the risks also will likely be dose dependent, gestational age dependent, and vector dependent, Blakemore said. For ex vivo gene transfer, the question becomes what vectors to use, since different ones will confer different risks. This also raises the issue of in what tissues the vectors may integrate. Another unknown is the risks from transduction or expression of the genes under investigation by cells that are not intended for correction.
Informed consent must address the main issue of whether gene engraftment can occur, Blakemore said, because partial treatment could have unknown effects.
She suggested that if such trials happen, independent genetic testing counselors should conduct individual assessments that include disclosure of alternatives, the right to voluntary participation or to withdraw from the protocol, and the right to privacy. This process confers risks too, with which clinical medicine and research deal with daily during the exchange of information between patient and caregiver or investigator.
Blakemore emphasized that both obstetricians and laboratory researchers should regard the pregnant uterus as "hallowed ground" and should take the utmost care in terms of sterility in performing the procedure, as well as in the lab preparing samples. "Probably the greatest risk to the pregnant woman is going to be intrauterine infection. While rare, it is a very serious complication."
IRB Oversight
Under NIH rules, both the mother and father must be legally competent and give informed consent for research involving live fetuses. Some exceptions are made for the father's consent if his identity or whereabouts cannot be reasonably ascertained, he is not reasonably available, or the pregnancy resulted from rape. Institutional Review Boards are responsible for monitoring the informed consent process by either approving induction of each individual into the research activity, or verifying that approved procedures are being followed.
But IRBs may need to more actively scrutinize both the risk/benefit relationship of the study protocol and the parents' decisionmaking inclinations during the prenatal setting. Benjamin Wilfond, M.D., National Human Genome Research Institute, Bethesda, Md., said such times are characterized by a willingness of patients to follow through on interventions offered by their physicians and a belief in the therapeutic benefit of investigational interventions. Studies of oncologists and their patients, however, show that both tended to overestimate the potential benefits to patients in phase I trials, which primarily test for safety and toxicity.
Stretching Consent?
Informed consent historically has been limited to individuals, but the concept may need to be redefined to encompass intergenerational research. NIH research regulations are based on principles that go back to 1946 and the Nuremberg Code.
The possibility of "incidental germ line effects" challenges the current moral boundaries of acceptable research, said Jeremy Sugarman, M.D., of Duke University Medical Center. Critical here, he said, is to understand the risk to all parties the mother, the fetus, and future generations. Another issue that arises is that both the fetus and its possible offspring might require lifelong or long-term follow-up.
"You don't give consent for a fetus. You don't give consent for a child. You give permission. What you do when you give permission for someone else is use a best interest standard. You decide what's best for them," said Sugarman.
"What's a kid going to do at age 2, at age 16 . . . he may not be coming back to see whether there's germline transmission and what the question will be for future generations. We don't know about giving permission or consent for future generations. We've never thought about that."
The fetus-as-patient concept raises the protocol issue of whether clinical trials would be research or experimentation since gene interventions are not yet reliably expected to benefit the fetus, said Frank A. Chervenak, M.D., New York Hospital-Cornell Medical Center. And this should be made clear in the informed consent process.
"Unknown risks are not necessarily contraindictions to the serious sorts of lethal and
crippling conditions that are under discussion in this arena," Chervenak said. He added
that prenatal gene therapy has clear theoretical and clinical benefits but the challenge will be
balancing them against real and theoretical harms.
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