The Regulation of Clinical Stem Cell Research and Applications: three dynamics of global regulatory diversification (part 1)

Written by RegMedNet

In the first part of this commentary, Achim Rosemann introduces the regulatory landscape of clinical stem cell research and describes the emerging of a growing number of regulatory exceptions and exemptions.

Look out for part two, a discussion of the flexible enforcement of regulatory standards, and part three, thoughts on abandoning of the multiphase trial system and concluding remarks, which are coming soon.

Achim Rosemann1

Centre for Education Studies, Faculty of Social Sciences, University of Warwick, Coventry, CV4 7AL.

Email: [email protected]

The evolving regulatory landscape for clinical stem cell research is characterized by a conflict between the striving for international harmonization and an increasing process of global regulatory diversification1. Attempts of regulatory harmonization are exemplified, for instance, by the 2016 Guidelines for Stem Cell Research and Clinical Translation by the International Society for Stem Cell Research (ISSCR 2016), the Advanced Therapy and Medicinal Products (ATMP) Regulation of the European Medicines Agency (EMA), or by the ATMP Cluster of the US Food and Drug Administration (FDA), EMA and Health Canada (Arcidiacono 2012).

These processes of harmonization have evolved from a pharmaceutical model of drug development and the ideal of Evidence-Based Medicine (EBM), with the multiphase randomized controlled trial (RCT) system as methodological gold standard. In parallel to these developments, however, discontent with the use of the multi-phase trial system for the clinical validation of stem cell-based medicinal product has grown.

A politics of opposition has emerged that has called for the use of alternative methods and forms of evidence, to reduce the costs of clinical testing and to increase access to non-systematically proven innovative interventions at an earlier stage. Calls for international harmonization in the stem cell field have been undermined too, by practical challenges to standardize clinical and cell processing procedures in large-scale, multi-country trials, which require a complex logistical infrastructure and significant financial resources.

For academic researchers and small to mid-size biotech companies these resources are often not available (Rosemann 2014). Since industry involvement in stem cell medicine has remained at a low level, the mobilization of resources to take investigational stem cell products or therapies through rigorous multi-phase trials, remains typically a challenge.

This politics of alter-standardization has taken an increasingly global form. Many impulses for regulatory change and a shift away from multi-phase trials for stem cell-based treatments, have come from Asia, especially from Japan, India, China and South Korea (Sleeboom-Faulkner et al. 2016). But opposition to EBM and the multi-phase trial system, and calls for the emerging of new models and methodologies of clinical innovation in the stem cell field has also increasingly evolved in the European Union and the USA. These clashes have resulted in three central dynamics of regulatory diversification. These developments challenge the use of multi-phase trial methodology as the central methodological instrument for therapy development in the stem cell field in many respects.

The emerging of a growing number of regulatory exceptions and exemptions

A first dynamic is the emerging of a growing number of regulatory exceptions and exemptions, which have been introduced by regulatory authorities in high-income countries, especially in the European Union and the USA (Faulkner 2016, Knoepfler 2014). Examples from the European Union are the “hospital exemption scheme”, which has evolved as part of the EMA ATMP regulation, the “conditional approval scheme” and the “compassionate use program”.

The “hospital exemption scheme”, as has widely been documented, allows for the provision of cellular therapies and medicinal products to individual patients “under the exclusive professional responsibility of a doctor” (source). According to Salter, Zhou and Datta, this scheme has provided “the opportunity for a legal market of authorized stem cell therapy products to emerge within the province of the clinical professionalism” (Salter, Zhou and Datta 2014: 359).

The “conditional approval scheme”, on the other hand, allows for market approval of a medicinal product at a later stage of a phase III trial, when data collection for efficacy and safety has almost been completed (Faulkner 2016). Compassionate use” program, in turn, allows access to medicinal products outside of phase III premarket clinical trials (Mittra et al. 2015). The “conditional approval scheme” and the “compassionate use program” are both part of EMA’s pharmaceutical products regulation, but can also be applied to stem cell-based medicinal products (Faulkner 2016).

While the hospital exemption scheme is unique to the European Union, the US FDA has introduced a range of similar regulatory exceptions that aim (i) to speed up the transition from preclinical to clinical testing (the FDA “fast track approval” scheme), (ii) to realize more rapid authorization of phase I and II clinical trials, especially for trials that involve seriously ill patients with low life expectancy (the “accelerated approval” scheme), and (iii) to provide access to investigational new treatments parallel to FDA-approved phase II and III clinical trials (“compassionate use program”) (Knoepfler 2014).

The 21st Century Cure Act, that was approved by the US Congress in December 2016, has introduced additional options to accelerate market approval of new medicines, by offering possibilities to avoid going through rigorous, large-scale phase III trials (Kesselheim and Avorn 2016) and by promoting methodological alternatives to the multi-phase trial system such as adaptive and other new trial designs (Butler and Valentine 2016). What this growing number of regulatory exceptions and exemptions share is, that they either allow to shortcut the clinical trial process, or in some cases, permit possibilities for clinical innovation and sometimes commercial clinical applications outside of the multiphase trial system, but still within the confines and review procedures of national regulatory agencies.

Another development in the USA has been a growing number of “right-to-try” legislation, which offer patients and physicians the choice to use not-yet approved investigational drugs (including cellular medicines) entirely outside of the regulatory control of the FDA (Bianco and Sipp, 2014; Darrow et al., 2015). These right-to-try laws have now been issued in more than 30 US states (Feibel 2017).

Look out for part two, a discussion of the flexible enforcement of regulatory standards, and part three, thoughts on abandoning of the multiphase trial system and concluding remarks, which are coming soon.


  • This article has benefited from research support provided by the ERC (283219) and the ESRC (ES/I018107/1).


1. Parts of this contribution have been previously published in: Rosemann A, Bortz G, Vasen F, Sleeboom-Faulkner M. Global regulatory developments for clinical stem cell research: diversification and challenges to collaborations. Regenerative Medicine. 11(7): 647-57 (2016). Material from that article is reprinted with permission of Future Medicine.