much of the current research is focused.
Ethical Concerns in Clinical Trials
All clinical trials present ethical concerns that must be balanced against research value. Patient safety is paramount; however, there is always risk and the acceptable amount is often determined by how devastating the illness to be treated is. Patients must be presented with the full facts about risk and benefit (both to themselves and others) in order to make an “informed consent” of participation.
To ensure study viability, placebo groups are often used, which, in and of itself, introduces ethical concerns as patients must decide if the potential benefits of the experimental treatment are outweighed by the possibility of being in the placebo group and receiving no treatment at all. In the case of severe illnesses, the placebo group is often replaced by a comparison of the trial results against traditional treatments. Risk/benefit analysis and informed consent are of special concern with iASC studies due to an ongoing controversy surrounding cancer studies in the 1990s.
Human integrity and provider conflicts of interest are real concerns, but difficult to quantify. In this discussion human integrity refers to protecting the patient’s rights and dignity throughout the course of the trial, including property rights and the use of an individual’s tissues for purposes outside the study. These concerns can frequently lead to conflicts of interest within the medical and research communities.
Of particular concern with technologies such as iASC, which show high profit potential, is the dual role held by doctors as care providers and researchers. Patients with serious illness are a vulnerable population and depend heavily on the guidance of their caregiver. Even the best-intentioned professionals can find themselves swayed by their personal enthusiasm for a project, as well as other pressures, to place candidates into a study when they might objectively be better served by traditional treatments.
Studies for “last chance” therapies are especially susceptible to human integrity violations by both physicians and patients. These studies involve patients suffering life-threatening illnesses who have not responded (or not responded well) to traditional treatments. The temptation of “new hope” can be coercing to patients and providers alike when palliative end-of-life care may realistically offer the greatest dignity and quality of life. An important factor in these cases is how much legitimate promise the treatment offers, versus the cost in human suffering. Again, potential systemic failures during early research into iASC has led some to be concerned that the efficacy of stem cell therapy may be overstated and improperly coercive to patients facing terminal illnesses.
Efficacy of iASC Therapies
Because stem cell therapies of all types are still in their infancy, it is difficult to ascertain a statistical basis for efficacy. In vitro (laboratory) tests and animal studies have shown great promise for both embryonic stems cell (ESC)- and iPSC-based therapies; however, this promise often fails to materialize when transitioned to human studies. Speculation about differences between controlled and uncontrolled manifestations of illness, age, and compliance of participants, and environmental factors are being examined to explain these discrepancies.
The trend in current literature seems to be that while stem cell therapies occasionally show statistically significant improvements in patient pathology, the benefit is often clinically insignificant (not powerful enough to elicit a noticeable improvement for the patient). This is scientifically encouraging but emphasizes ethical questions such as whether the patient benefit warrants the risks—especially considering that patients may bypass traditional therapies to participate in a study. There is the added conundrum that information about the efficacy of stem cell therapies will not be available until more clinical trials are performed.
When deciding whether to participate in an experimental treatment, patient and doctor must together determine if the study serves the patient’s best interests. This requires realistic analysis of risk to benefit, and some are concerned this analysis is not presently feasible due to undue scientific and media excitement over early SCT trials that may have been “over-hyped.” Of particular concern in critics’ eyes is what has come to be called the Bezwoda fraud. In the early 1990s, Werner Bezwoda of the University of the Witwatersrand, South Africa, conducted research using iASC in the treatment of breast cancer. His results were strongly positive, lighting a firestorm in the media and leading to heavy legislation to encourage SCT in the United States and elsewhere.
In 2000 it was discovered that Bezwoda had falsified much of his data. Some ethicists believe the lingering excitement and residual legislation his research spawned creates a false sense of efficacy for SCT, while others feel the scandal broke trust between patient and researcher, making it difficult to find enrollees for new studies. Ironically, both could lead to ethical concerns as pressures mount to fill studies and inadvertently making rational decisions about risk to benefit difficult.
Safety in iASC Therapies
Due to the relative newness of stem cell therapies, safety information is difficult to come by. Challenges by study coordinators on how to best assess benefit and harm have led to problems with statistical meta-analyses (comparisons of one study to another). Participants in all clinical trials endure increased risk with the hope of it being outweighed by benefit; however, iASC (and stem cell therapies in general) may be particularly risky due to the inherent manner in which stem cells function.
Tumorigenesis
The most readily identified potential for harm with SCT is that of tumorigenesis (secondary cancerous growths), since the cell’s inherent “stemness” is directly related to oncogenes such as cMyc, Rb, and ARF. In fact, a cell’s potential for tumorigenesis in the lab correlates directly to the cell’s stem viability ranking. While some consider it definitively impossible to separate the stem and tumorigenic character of iASC, there has been success in creating less tumor-prone mesenchymal stem cells as well as inducing adult stems cells after removal of the volatile oncogenes. Nonetheless, the possibility of secondary neoplasts remains significant. Theory suggests that iPSC/iASC might have a lesser tendency for tumor formation than embryonic stems cells; however, studies to date show both to be at roughly equal risk.
The most common tumors formed are teratomas, a generally benign encapsulated tumor resembling a normal derivative germ layer. Because teratomas are benign, risk can be mitigated based on transplant location, that is, tumor growth in cartilage is significantly less concerning than tumor growth in the central nervous system (CNS). However, recognized deaths resulting from SCT tumorigenesis have been documented, though it is unclear whether there is a generally increased mortality risk in SCT compared to other studies. Two famous cases involving the death of three Filipino legislators (treated out-of-country) and an infant treated at a private German clinic have drawn publicity to this concern; however, definitive evidence linking the congressmen’s deaths to SCT has not yet been found and the baby’s death was due to internal hemorrhaging from the procedure. The widespread proliferation of unapproved, medically unsupervised SCT may be skewing this data.
Genetic Mutation
Another risk specific to iASC therapy is genetic mutation or contamination. A benefit of using pluripotent iASC is the dramatically reduced incidence of adverse immune reaction; however, using an adult patient’s own cells also increases the risk that the aged cells contain activated oncogenes or other naturally occurring deleterious mutations. As these cells proliferate, the mutations are carried into progeny cells and the newly formed tissues.
In addition to natural genetic changes, contamination by the lab or hosting environment (in the case of SCNT or animal hosts) can lead to genetic contamination. Animal proteins in culture or animal hosts can contain viruses, which may incorporate into the cells ultimately transplanted. It is estimated that up to 30 percent of polio vaccine given in the late 1950s was contaminated by simian virus 40, a theretofore unknown virus found in the monkey kidney used for culturing the vaccine and which has since been associated with human cancers. It is important to note that although it can be difficult to monitor for unknown pathogens and contaminants,