Stem Cell Trials: Lessons from Gene Transfer Research

Abstract

Since 1998, when James Thomson and John Gearhart reported the first successful derivation of human embryonic stem cells and human embryonic germ cells, respectively, the scientific community has championed the therapeutic potential of these cells. Indeed, despite the restrictions on embryo research in some jurisdictions and despite the recent controversy surrounding the validity of the stem cell research conducted by Woo Suk Hwang, stem cells may soon enter their first human trials--possibly within a year. Stem cell transplantation will not be the first biotechnology to begin trials amid revolutionary expectations and moral apprehension. More than fifteen years ago, the first experiments with gene transfer in human somatic cells inspired similar hopes and fears. Gene transfer quickly evolved into a competitive research area, but its progress was checked by ethical missteps. With embryonic stem cells poised to begin human trials, now is an opportune time for scientists and ethicists to review some of gene transfer's ethical miscues. Moving Too Quickly From the first protocol involving humans, gene transfer was caught up in ethical controversy. In 1980, hematologist Martin Cline began gene transfer trials without prior approval from his institutional review board (IRB); neither the National Institutes of Health (which supported the study) nor committees at a collaborating institution in Israel were apprised of the fact that his protocols involved recombinant DNA. The studies were faulted for their scientific prematurity, and Cline became the first clinical investigator to be formally sanctioned by the NIH for violating human subjects regulations. In 1992, another controversy erupted when the NIH recommended canceling a contract of a prominent gene transfer researcher, Steven Rosenberg, for pursuing trials without sufficient preclinical data. Episodes like these created early impressions that gene transfer researchers were moving into human studies too aggressively. There are various indications that some prominent stem cell researchers have not fully absorbed gene transfer's cautionary lessons. As this essay goes to press, cloning pioneer Woo Suk Hwang has admitted to ethical improprieties in obtaining human eggs and is under investigation for scientific fraud. Elsewhere, two different research groups (one backed by Geron, the other by ES Cell International) are reportedly nearing human studies despite concerns expressed by about the safety and prematurity of such trials. Scientific Value Gene transfer suffered another setback in 1995 when an NIH-commissioned review concluded that only a minority of clinical studies ... [had] been designed to yield useful basic information. The report emphasized that initial studies were exploratory and many clinical gene therapy studies thus far have not met [high] standards [of experimental design]. Because of their novelty, stem cell transplantation trials will necessarily involve high levels of indeterminacy regarding risks, methods, and standards. Considering such uncertainty, the move from animal to human trials requires first that the questions asked not be answerable using in vitro or animal models, and second, that the protocol be designed so as to maximize its yield of knowledge. Moreover, participants in early trials are unlikely to benefit directly. Maintaining a favorable ratio of harms to benefits, as required under all major codes of ethics, will thus demand exacting scientific and safety standards for early phase I trials and care in the selection of research participants. The Therapeutic Misconception Patient advocates have often misconstrued gene transfer trials as aimed at delivering therapy, and researchers have frequently contributed to this conflation of research and therapy. However, trials impose requirements (for example, in phase I studies, doses are administered that are anticipated to be subtherapeutic) that abrogate medicine's mandate to provide personalized care. …