Ethical Issues in Phase I Trials of Neurological Disorders: an Examination of the Neuralstem Als Phase I Trial

According to The Belmont Report and other key documents establishing the ethical requirements for clinical trials, trials should only proceed if risks have been minimized and determined to be proportional to benefits and if research candidates are able to give voluntary informed consent. Meeting these requirements for early phase trials of serious neurological disorders can prove challenging if there are flaws in the design and conduct of both preclinical and clinical studies. Preclinical studies can produce unreliable findings if they lack internal, external, or construct validity, if they are underpowered, if they fail to use randomization or blinding, or if they confuse a hypothesis generating study with a hypothesis confirming one. Alone or in combination, these problems increase the likelihood that published findings may be false. Regulatory bodies such as the U.S. Food and Drug Administration or the E.U. European Medicines Agency can sanction Phase I trials without detecting errors in the preclinical studies. In addition, they may also sanction studies even in the absence of preclinical efficacy studies, since their primary concern is safety. The limited scope of regulatory review combined with potentially flawed preclinical studies create a cloud of uncertainty that confounds the design of Phase I trials and the ability of ethics review committees to approve them. This uncertainty, and the implications of it, diminishes the effectiveness of informed consent. A recent ALS Phase I trial will be reviewed to illustrate the cumulative effect of these issues on the people who volunteered for it.