Into the wild—The use and abuse of stem cells in clinical practice
Authors: Luigi D. Notarangelo
Journal: American Journal of Hematology (2013)

In the past months, the lay press in Italy has reported on multiple cases in which injection of mesenchymal stem cells for the treatment of metachromatic leukodystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and other neurodegenerative disorders have been authorized or rejected by the court. This presumed therapy, proposed by the Stamina Foundation, involves inoculating the patient with autologous or heterologous cells. All patients who have received an injection of stem cells have taken advantage of the instrument of "compassionate care." In each case, the court decision to grant or reject the right to treatment has been preceded and followed by an intense, often harsh discussion that has involved families, physicians, judges, and regulatory agencies. Discrepancies in the final decision taken by different courts (or even by the same court) for various patients have been viewed as a mechanism whereby judges decide on those patients who have the right to treatment and those who do not. For many families, the treatment patented by the Stamina Foundation has been considered the only hope, and one that they have desperately defended. Access to care and hope are two fundamental rights, especially for subjects affected by progressive, degenerative disorders. However, invoking the instrument of "compassionate care" for the treatment of multiple subjects is scientifically unacceptable and ethically misleading. The requirement for a thorough pre and post hoc evaluation of each new experimental trial is one of the major achievements in medicine in recent decades. Although such evaluation is sometimes seen as a burden, in fact, it protects the patients' interest while permitting rigorous assessment of the benefits and risks of the treatment. This process is even more important in the case of injection of stem cells, which carry both known and potential unknown risks. Careful evaluation of the rationale of the treatment, of its potential risks and benefits (as assessed by preclinical studies), and meticulous reporting of clinical outcomes (including adverse events), is essential to prove or disprove the safety and efficacy of the treatment. It is also the only known way to make sure that other patients elsewhere may take advantage of the same treatment, if it proves beneficial and safe. Unfortunately, these safeguards have not been rigorously implemented in Italy. On May 15, 2012, the AIFA (Italian Drug Agency) banned the manipulation of stem cells at the hospital where treatment had been provided. This decision was based on the fact that the treatment could not be considered an experimental trial simply because no procedures had been activated at the regulatory agencies, and on the lack of published scientific data supporting its use. Moreover, the laboratory where the biological specimens were manipulated, although perfectly well suited for hematopoietic stem cell isolation and transplantation, was deemed inadequate for the extensive manipulation required by the Stamina protocol. For many months, treatment of patients has depended on decision by the court, on a case-by-case basis. The right to continuation of treatment and compassionate care have remained the foundation for such decisions. Recently, the Italian Council of Ministers has approved a decree by which all patients who have previously received stem cell treatment with the "Stamina method" can continue with such treatment. Such decision has been based on an ethical principle whereby treatments that have not led to serious adverse events cannot be discontinued. At the same time, the decree limits the prospective use of similar treatments to authorized institutes only and refers to forthcoming ministerial guidelines that will regulate the matter. Subsequently, the Senate of the Italian Republic has modified the decree by deleting reference to future guidelines. In 2008, the International Society for Stem Cell Research (ISSCR) developed the Guidelines for the Clinical Translation of Stem Cells 1. These guidelines, and an accompanying editorial 2 comment on the importance of peer review, regulation, and oversight in the assessment of biomedical research, and in interventional trials in particular, and emphasize the need for rigorous preclinical testing in animal models. While patient advocates often argue that preclinical studies may substantially delay implementation of translational trials and jeopardize access to care for patients with severe, often untreatable diseases 3, medical research has the fundamental task to pursue common interests, offering convincing evidence that the proposed translational interventions are safe 4. Importantly, the ISSCR guidelines recommend that "special emphasis be placed on the unique risks of stem-cell-based clinical research during the informed consent process." In the case of stem cells, these risks include (but are not limited to) tumor development, immune and inflammatory reactions, unexpected behavior of the cells once injected in vivo, and unknown long-term effects. That these are real, not just theoretical risks, is demonstrated by the occurrence of a brain tumor following neural stem cell transplantation in a patient with ataxia-telangiectasia 5. Therefore, informed consent is critically important to guarantee autonomy and protection of patients. Yet it is fairly obvious that the lack of a treatment protocol also implies the lack of adequate informed consent. Finally, perhaps ironically, the Commentary to the ISSCR Guidelines asks "whether it is ever permissible for clinicians to attempt medically innovative care for their patients' benefit using stem-cell-derived cellular products outside the context of a formal clinical trial," which is exactly what is happening in Italy. According to the ISSCR guidelines, while this may happen under extraordinary circumstances and in a very small number of seriously ill patients, stringent oversight criteria should be applied nonetheless, including peer review of the proposed procedure and its rationale, rigorous informed consent and close patient monitoring, timely adverse event reporting, and a commitment to move rapidly to a formal clinical trial. One year has gone by in Italy, but none of these guidelines are operational. Moving into the wild, uncertain territory ahead, the responsible translational use of stem cell research remains a goal yet to be met.