Exploring Determinants of Execution in Early Phase Clinical Studies with Cell Therapies in Stroke

Abstract

Background Stroke is associated with a significant disease burden across the world (1). Ischaemic stroke accounts for over 80% of the total number of strokes and specifically refers to central nervous system infarction accompanied by overt symptoms (2). Cell therapies (CTs) represent a composite of different cell types being investigated in different phases of stroke, with use of different dose and delivery regimens (2). Preliminary evidence for meaningful clinical translation is now available with CTs in stroke, as early studies have demonstrated safety and a trend towards functional improvement over a longer time window of application (2). Research Aims This research aimed to analyse study design, regulatory policy, ethical and economic considerations, as well as to describe their impact on the quality of execution of early-phase clinical CTs studies in stroke Methods The thesis is a compendium of subprojects that evaluated these considerations for efficient implementation of early phase CTs studies, using a mixed methodology approach. Results Study design considerations: a systematic review of early phase clinical studies with CTs in ischaemic stroke indicated a trend towards improvement across varied domains of functional impairment and reasonable safety and feasibility, in patients with stroke receiving CTs (2). A high level of heterogeneity was observed, in terms of differences in cell types used and route, dose and time of administration, use of randomised control design and selection of trial endpoints. Most studies reported temporal changes in global endpoints such as those measured by the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) or Modified Rankin scale (mRS). Regulatory considerations: a narrative review examined different national regulatory provisions and described standardization of research terminology and access to expertise in manufacturing as the key determinants critical to the execution of early phase studies with CTs in stroke. Ethical considerations: a qualitative study was undertaken to understand the perspective of stroke survivors on the research design of a proposed early phase clinical study with adult human dental pulp stem cells in chronic ischaemic stroke. The study found that patients considered outcomes such as recovery in social participation and decreased dependence on carers as most meaningful to them. Whilst improved motor function was important, the impact on cognition, memory, mood, pain and fatigue were bigger determinants of their perception of benefit. The perception of risk versus benefit was influenced by the time elapsed since stroke. Health economic considerations: a systematic review reported that there is limited evidence for economic evaluation at early stage of research in CTs. Only three studies have been published to date. All studies undertook a cost utility analysis of CTs versus current standard of care using decision analytical modelling and reported that CTs could provide meaningful cost savings in terms of direct costs of disease management accrued to the government (healthcare bodies and social services). Discussion Successful clinical translation of CTs in stroke requires efficient development strategies potentially comprising the use of adaptive trial designs and the use of domain specific endpoints for efficacy evaluation (8, 9). Addressing regulatory requirements and patients’ preferences in research design can significantly improve the eventual clinical relevance of data generated within these trials (11, 12). Collection of data on cost-effectiveness of their use from the early phase of research is critical, as these therapies are likely to be expensive (13). Conclusions Development of a practical framework comprising key elements of study design and regulatory policy, as well as ethical and health economic considerations that is available to different research groups can potentially accelerate clinical translation of CTs in stroke.