The
6.1 Issue of the American Journal of Bioethics Neuroscience (
AJOB Neuroscience) is now hot off the presses with two target articles highlighting ethical issues behind the use of two very different therapeutic interventions: first-in-human trials to treat Parkinson’s disease using stem-cell based therapies and prescription stimulants to enhance motivation.
The Target Article “Ethical Criteria for Human Trials of Stem-Cell Derived Dopaminergic Neurons in Parkinson’s Disease”
1 by
Samia A. Hurst et al. discusses three specific considerations of a phase I(safety)-II (efficacy) clinical trial designed to test an experimental neurorestorative stem cell therapy for Parkinson’s disease.
Parkinson’s disease is a result of the loss of dopamine-producing neurons in the substantia nigra, and significant depletion of dopamine leads to the tremors, rigidity, and difficulty initiating or halting movement that is often seen as the disease progresses. To compensate for the diminishing levels of the neurotransmitter, standard treatment relies on the drug levodopa, which is converted to dopamine in the body. Levodopa is not curative though, and for that reason, researchers are beginning to study the neurorestoration technique of dopamine-producing stem cells transplants
2. As promising and groundbreaking as stem-cell therapy is, protecting human subjects will be of utmost importance as the therapies enter clinical trials.
Parkinson’s disease is progressive, meaning that patients could exhibit a wide spectrum of mild to debilitating symptomology. After considering the risk-to-benefit ratio of enrolling patients who have either just been diagnosed or are at an advanced state of the disease, the authors suggest that only patients with approximately less than 15 years to live with “moderately advanced” Parkinson’s disease should be enrolled. Moderately advanced Parkinson’s is defined as a time when patients have been diagnosed and are responding to levodopa therapy. These patients should have minimal motor impairments and no impairment of cognitive function. Since neurosurgery is not without risks and stem-cell therapy benefit may not be obvious for a long time period, a clear informed consent process is critical. The patients must understand that the study’s purpose is not to alleviate Parkinson’s symptomatology immediately, but to instead increase understanding for the disease and the experimental, high risk nature of the procedure.
The authors conclude that a sham surgery, which involves inserting a needle into the brain, but not injecting stem cells, cannot be justified in a phase I-II clinical trial. Sham surgery is fraught with its own
ethical concerns related to the powerful placebo effect, especially when research has suggested that Parkinson’s disease patients are especially susceptible to the placebo effect
3,4. While a 2005 investigation of sham surgeries in Parkinson’s disease research suggested that the majority of clinicians support sham surgeries over unblinded controls
5, finding interventions better than placebo or sham is challenging if sham is the ultimate threshold over which novel therapy should pass
6. The authors ultimately recommend an open-label clinical trial design or a trial that compares stem-cell therapy to alternative medicines other than highly invasive surgery. The authors also remark that even if Parkinson’s disease patients are more likely to improve based on a placebo, Parkinson’s is degenerative and the placebo effect would most likely not survive declining motor function over the long-term of this study.