The Regulation of Clinical Stem Cell Research and Applications: three dynamics of global regulatory diversification (part 3)

In the third and final part of this commentary, Achim Rosemann provides thoughts on abandoning of the multiphase trial system and his concluding remarks.

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Jun 19, 2017
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Read part one, an introduction to the regulatory landscape of clinical stem cell research and the emerging of a growing number of regulatory exceptions and exemptions, and part two, a discussion of the flexible enforcement of regulatory standards, now.  

Achim Rosemann1

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

Email: a.rosemann@warwick.ac.uk  

The abandoning of the multiphase trial system  

A third process of regulatory diversification in the stem cell field is characterized by the complete abandoning of the multiphase trial EBM system. This has recently happened in Japan and steps into this direction have with the 21st Century Cure Act also been initiated in the USA. In Japan, the Japanese regulators passed the Regenerative Medicine Promotion Act (RMP Act) in 2013 (Government of Japan 2013). This Act formed the beginning of a far-reaching regulatory reform.  

The RMP Act was followed by an amended Pharmaceuticals Affairs Law, which went into effect late 2014 (Government of Japan 2014). Under the amended PAL, the regulatory conditions for the clinical testing and use of stem cell-based medicinal interventions were significantly transformed (Azuma 2015). The amended law allowed for conditional, limited-term market approval of stem cell products after early-phase clinical trials. Conditional approval can occur after positive clinical data from as few as ten patients (Cyranoski 2013) provided these first-in-human trials demonstrate that the tested cell products are safe and ‘likely to predict efficacy’ (Sipp 2015).  

Once the Japanese Pharmaceuticals and Medical Devices Agency has provided conditional approval for a stem cell intervention, clinical trial sponsors have the possibility to seek conditional market approval for up to 7 years (ibid.). Clinical efficacy is then tested in this time period in the context of postmarketing procedures, which can but do not have to include rigorous, multiphase trials (source).  

According to Sipp (2015), this evolving regulatory model in Japan has dramatically relaxed the need to demonstrate the clinical utility of cellular products prior to marketing, and raises critical questions regarding the testing of safety and treatment efficacy. As Sipp has pointed out, with this new approach “Japan clearly hopes to compete and succeed in the race to build a regenerative medicine industry by flattening a few hurdles” (Sipp 2015: 355). It is not unlikely that other countries will follow the Japanese regulatory model, or at least create additional types of regulatory exceptions in which (conditional) market approval of stem cell therapies can be granted without preceding phase I‒III trials. In fact, exactly this has now happened in the USA.  

The passing of the 21st Century Cure Act in December 2016 has introduced various steps into a post-RCT world in the stem cell field, and in other emerging areas of medicine research. As Kesselheim and Avorn have stated, advocates have praised the Act as a ‘means of speeding drug development’ and to decrease ‘the cost and duration of drugs and devices development (Kesselheim and Avorn 2016).  

This has involved the provision of various provisions that have been designed to ‘reduce the amount and rigor of clinical testing before new drugs and devices can be approved for use’ (ibid.). These include the use of alternative, less rigorous forms of evidence, such as observational data and self-reporting of “patient experience” that were previously deemed as too subjective and unacceptable in the context of FDA approval procedures (Butler and Valentine 2016; Kesselheim and Avorn 2016). Many of the regulatory changes introduced by the 21st Century Cure Act will also apply to stem cell treatments, but it remains to be seen how applications for specific types of stem cell-based interventions are handled in practice.  

Conclusions  

The regulatory changes and developments introduced in the previous sections represent a gradual shift away from a pharmaceutics-oriented model of drug developments, that was based on the EBM and multiphase RCT system, and that has shaped the regulation of stem cell research in its initial phase, at least in the context of the European Union and the USA, but also in many other countries (Rosemann et al. 2016).  

Alternative methods and forms of evidence are now step-wise accepted in many parts of the word and are likely to partly replace the multiphase trial model for the approval of stem cell-based interventions, as well as approval procedures in other evolving fields of medicine research. Whether this development will be to the ultimate benefit of patients, as many advocates of the 21st Century Cure Act in the USA (and advocates of similar changes in various other countries) have claimed, remains to be seen.  

Some would probably argue that it is not, and that the current politics of alter-standardization, which is shaped by powerful economic and political interests, does misuse the desire of patients for more affordable and more rapidly to access cures, by justifying potentially dubious research and irresponsible business practices. Others would possibly say that the growing acceptance of less rigorous standards and data do in fact increase health risks for patients as well as risks for potential forms of financial exploitation. This in turn, could undermine trust in science and medicine at a broader level. Still others would probably reason that many of the regulatory changes that have been introduced in this paper, diminish hard-won ethical and methodological achievements, which have aimed to safeguard patients from potential misuse by the medical profession.  

No matter where you stand in these debates, it seems safe to say that the line between the realization of new benefits and opportunities for patients and the emerging of new risks, dangers and injustices is thin. The regulatory changes described in this paper require for that reason long-term monitoring, to obtain a clear idea of their implications for patients and health care systems.  

Read part one, an introduction to the regulatory landscape of clinical stem cell research and the emerging of a growing number of regulatory exceptions and exemptions, and part two, a discussion of the flexible enforcement of regulatory standards, now.  

Acknowledgements:

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

References

Azuma K. Regulatory Landscape of Regenerative Medicine in Japan. Current Stem Cell Reports 1(11), 118-28 (2015).

Bianco P, Sipp D. Sell Help not Hope, Nature, 510(7505), 336-337 (2014).

Butler M, Valentine J. The President Signs 21st Century Cures into Law; Highlights of Drug and Biologic Related Provisions. 2016.

Cyranoski D. Japan to offer fast-track approval path for stem cell therapies. Nature medicine 19(5), 510-510 (2013).

Government of Japan. The Regenerative Medicine Promotion Act. 2013 Act Nr. 13 (2013) [in Japanese]. 

Government of Japan. The Act on the Partial Revision of the Pharmaceutical Affairs Law. 2014 Act Nr. 84 (2014) [in Japanese].   

Indian Council of Medical Research. Guidelines for stem cell research. 2013.

ISSCR. Guidelines for stem cell research and clinical translation. 2016.

Kesselheim AS, Avorn J. New “21st Century Cures” Legislation: Speed and Ease vs. Science. JAMA 317(6): 581-582 (2017).

Rosemann A, Sleeboom-Faulkner M. New regulation for clinical stem cell research in China – expected impact and challenges for implementation. Regenerative Medicine 11(1), 5-9 (2016).

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).

Sipp D. Conditional approval: Japan lowers the bar for regenerative medicine products. Cell Stem Cell 16(4), 353-356 (2015).

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