Overcoming Methodological Challenges for Advancing Stem Cell Therapies in Parkinson's Disease.

The quest for new and improved therapies for Parkinson's disease (PD) remains of paramount importance, despite previous trial failures. There is a current debate regarding the potential of stem cell research as a therapeutic approach for PD. The studies of dopaminergic fetal stem cells for PD treatment, their design, and the results of the initial surgical placebo-controlled trials were reviewed in this study. Some of the fundamental methodological challenges and possible strategies to resolve them were proposed. In this article, we argue that the most important impact lies in the proof-of-principle demonstrated by clinical trials for cell replacement strategies in reconstructing the human brain. While some researchers argue that the considerable technical challenges associated with cell therapies for PD warrant the discontinuation of further development using stem cells, we believe that the opposing viewpoints are instrumental in identifying a series of methodological misunderstandings. Here, we propose to expose key challenges to ensure the advancement of the field and unlock the potential of stem cell therapies in PD treatment. Overall, this review underscores the need for further research and innovation to overcome the hurdles in realizing the potential of stem cell-based therapies for PD.

The Placebo Response in Double-Blind Randomised Trials Evaluating Regenerative Therapies for Parkinson's Disease: A Systematic Review and Meta-Analysis.

In the field of stem cell technologies, exciting advances are taking place leading to translational research to develop cell-based therapies which may replace dopamine releasing neurons lost in patients with Parkinson's disease (PD). A major influence on trial design has been the assumption that the use of sham operated comparator groups is required in the implementation of randomised double-blind trials to evaluate the placebo response and effects associated with the surgical implantation of cells. The aim of the present review is to identify the improvements in motor functioning and striatal dopamine release in patients with PD who have undergone sham surgery. Of the nine published trials, there was at the designated endpoints, a pooled average improvement of 4.3 units, with 95% confidence interval of 3.1 to 5.6 on the motor subscale of the Unified Parkinson's Disease Scale in the 'OFF' state. This effect size indicates a moderate degree of improvement in the motor functioning of the patients in the sham surgical arms of the trials. Four of the nine trials reported the results of 18F-Fluorodopa PET scans, indicating no improvements of dopaminergic nigrostriatal neurones following sham surgery. Therefore, while the initial randomised trials relying on the use of sham operated controls were justified on methodological grounds, we suggest that the analysis of the evidence generated by the completed and published trials indicates that placebo controlled trials are not necessary to advance and evaluate the safety and efficacy of emerging regenerative therapies for PD.

Evidence-Based Evaluation of the Ethics of Sham Surgery for Parkinson's Disease.

The stated purpose of sham or placebo surgery is to enable the implementation of surgical placebo-controlled trials (SPTs) for evaluating the safety and efficacy of surgical interventions. Exposing the participants to the burdens and harms of sham surgery has been justified on the grounds of the absolute necessity for controlling large placebo effects and observer bias, assumed to be associated with surgical procedures. In the present review, we argue that evidence obtained from SPTs of cellular therapies for the treatment of Parkinson's disease (PD) has failed to demonstrate either large and consistent placebo effects or decisive methodological advantages for relying on sham surgical controls. We outline several alternative assessment strategies and designs available to establish the efficacy of cellular therapies. It is concluded that the evidence evaluated in the present analysis indicated that use of sham surgery in the context of developing novel surgical procedures for PD is not necessary, and therefore, unethical under a utilitarian model.

Assessing the Efficacy of Cell Transplantation for Parkinson's Disease: A Patient-Centered Approach.

BACKGROUND: Evidence from a growing number of preclinical studies indicate that recently discovered stem cell lines may be translated into viable cellular therapies for people with Parkinson's disease. OBJECTIVES: In a brief but critical review, we examine the use of primary and secondary outcome measures currently used to evaluate the efficacy of cellular therapies. METHODS: The current practice of relying on a single primary outcome measure does not appear to provide the evidence required for demonstrating the robust, life-changing recovery anticipated with the successful implementation of cellular therapies. RESULTS: We propose a 360-degree assessment protocol, which includes co-primary and composite outcome measures to provide accurate and comprehensive evidence of treatment efficacy, from the perspectives of both the researchers and the patients.

A Critical Evaluation of the Methodological Obstacles to Translating Cell-Based Research Into an Effective Treatment for People With Parkinson's Disease.

The remarkable scientific and technological advances in the field of cell research have not been translated into viable restorative therapies for brain disorders. In this article, we examine the best available evidence for the clinical efficacy of reconstructive intracerebral transplantation in people with Parkinson's disease (PD), with the aim of identifying methodological obstacles to the translation process. The major stumbling block is the fact that the potential contributions of people with neural grafts and the effects of the physical and social environment in which they recover have not been adequately investigated and applied to advancing the clinical stages of the research program. We suggest that the biopsychosocial model along with emerging evidence of targeted rehabilitation can provide a useful framework for conducting research and evaluation that will ensure the best possible outcomes following intracerebral transplantation for PD.

Composite brains: toward a systems theory of neural reconstruction.

The results of uncontrolled, open-label clinical trials indicate that reconstructive cellular therapies have the capacity to produce meaningful functional improvements in patients with brain disorders. However, the transplantation of fetal cells has not progressed to viable best practice treatment for any brain disorder. A conceptual approach, referred to as the Repair Model, has served as a useful heuristic for initiating research in the field and guiding the development of new practices. Analysis of evidence for the treatment of Parkinson's disease indicates that recovery following neural grafting is a complex process influenced by factors beyond the replacement of neurons. An alternative approach, the Composite Brain Model, is outlined to address limitations of the Repair Model. A hierarchical, open-system model is proposed, which aims to track the interactions between the grafted cells, the host brain, and the environment. The Composite Brain Model emphasizes the importance of the interactions between the patient, their physical and social environment, and the provision of rehabilitation during recovery. It is proposed that the Composite Brain Model is useful in providing an alternative perspective for research, theory building, and practice.

A critical analysis of evidence for using sham surgery in Parkinson's disease: implications for public health.

Sham surgery was introduced as a means for improving the methodological quality of surgical research and evaluation. The development of cellular-based surgical therapies for the treatment of Parkinson's disease provides an opportunity to carefully analyse the alleged methodological benefits of sham surgery. However, detailed analysis of the evidence does not support these hypothesised advantages. In this paper, we argue that sham surgery is a public health concern as vulnerable individuals are exposed to unnecessary and costly surgical procedures that have no benefits for ensuring rigorous health research.

Ethics, methodology and the use of placebo controls in surgical trials.

There is an emergent view among North American researchers and bioethicists that not only is the use of sham surgery ethical, but that it should also be mandatory when conducting trials to evaluate surgical procedures such as neural grafting. This view is based on erroneous assumptions concerning the magnitude of the placebo effects associated with surgery. A detailed analysis of four recent clinical trials failed to provide consistent evidence for pronounced and long term improvements in sham operated patients. There was no evidence that the results of the placebo control groups were necessary for identifying unsafe and ineffectual surgical procedures. We contend that the advancement of clinical science and the protection of individual patients are best guaranteed by adopting the principles of evidence-based medicine.