Challenges to international stem cell clinical trials in countries with diverging regulations

This chapter addresses challenges to the organization and conduct of international stem cell clinical trials in a context of regulatory pluralism. Multi-country clinical trial collaborations in stem cell medicine have the potential to speed up clinical developments and to widen access to new treatments among patients. However, the regulatory procedures through which the safety and efficacy of stem cell-based treatments are determined vary widely across countries. Internationally harmonized governance frameworks are not yet in place. In this chapter we show that this high level of regulatory variation and the absence of internationally binding standards for clinical stem cell research present important challenges to multi-country clinical trial collaborations. Four types of challenges will be highlighted. First is the need to inquire into and interact with regulatory procedures and law in multiple countries. Second, the interaction with medical authorities in multiple countries is resulting in a high level of organizational complexity. Third consists of delays, increased costs, and uncertainties that result from nonexistent, unclear, or still emerging regulatory arrangements in different countries. Fourth is that the high level of regulatory variation across countries necessitates far-reaching forms of scientific self-governance, training, and procedural adjustments in participating clinical trial sites. To illustrate this point, the chapter presents a case study of project-internal self-governance and capacity building in the context of a clinical trial infrastructure that is active across the contexts of China, Hong Kong, and the USA. The chapter concludes with a call for the creation of an international support structure that systematically addresses these problems. Five measures that may help to reduce existing difficulties will be introduced

Hysteretic Dynamics of Multi-Stable Early Afterdepolarisations with Repolarisation Reserve Attenuation: A Potential Dynamical Mechanism for Cardiac Arrhythmias

Abstract Some cardiovascular and non-cardiovascular drugs frequently cause excessive prolongation of the cardiac action potential (AP) and lead to the development of early afterdepolarisations (EADs), which trigger lethal ventricular arrhythmias. Combining computer simulations in APs with numerical calculations based on dynamical system theory, we investigated stability changes of APs observed in a paced human ventricular myocyte model by decreasing and/or increasing the rapid (I Kr) and slow (I Ks) components of delayed rectifying K+ current. Upon reducing I Kr, the APs without EADs (no-EAD response) showed gradual prolongation of AP duration (APD), and were annihilated without AP configuration changes due to the occurrence of saddle-node bifurcations. This annihilation caused a transition to an AP with EADs as a new stable steady state. Furthermore, reducing repolarisation currents (repolarisation reserve attenuation) evoked multi-stable states consisting of APs with different APDs, and caused multiple hysteretic dynamics. Depending on initial ion circumstances within ventricular myocytes, these multi-stable AP states might increase the local/global heterogeneity of AP repolarisations in the ventricle. Thus, the EAD-induced arrhythmias with repolarisation reserve attenuation might be attributed to the APD variability caused by multi-stability in cardiac AP dynamics