A stem cell scientist in a country with few scientific resources:
The government tries to create a space for stem cell research. But the rules of the American FDA or the ISSCR are problematic. For example, if you want to publish research data, you need to have GLP and GMP for translational research. You cannot use the same rules, because the equipment and assays are expensive. The regulation has to be flexible. Ordinary people cannot pay a million [xx] for treatment in a GMP facility. The government needs to find strategies: health for all is important. If it is too expensive, only the rich can afford it …. We like to make new regulation, but it depends on businessmen and politicians. Businessmen tell scientists what to do.
Introduction – Regulatory Boundary-Work
In a world of regulatory capitalism, the regulation of regenerative medicine is influenced by global competition and becomes skewed. As the epigraph above tells us, this creates dilemmas. This prohibitive clinical research regulation used in some wealthy countries may be too expensive to follow in countries with comparatively low research and health budgets. But the quick-fix solutions promised by regenerative medicine can be attractive in particular to these countries. Stem cell scientists employed by well-funded institutions also face dilemmas: they fear that without robust regulation their work will not be taken seriously, apart from companies interested in making a quick profit at the expense of patients. Depending on the situation and one’s perspective, prohibitive regulation can protect patients or rob patients of innovative stem cell cures. In this chapter, I will argue that regulatory capitalism creates regulatory conditions that are affected by other countries, where perceived competitors benefit from what they regard as beneficial regulation. The regulation in these competitor countries may be seen as rigged or influenced by industry, scientists and other players. In this sense, regulation seems to be ‘captured’ (Majone Reference Majone1994, Reference Majone1997), but such capture is far from straightforward. By exploring the international drivers and dynamics of regulatory competition, we see that regulatory capture takes place next to and entwined with struggles to regulate on the basis of what is thought to be suitable protection of patients and high-quality science in jurisdictions.
Although the above examples seem to imply that regulatory competition occurs due to a difference in wealth, I claim that in the current globalised world regulatory initiatives can no longer be attributed to hegemonic dominance alone. Given the ‘Western’ historical origin of regulatory institutions in the field of regenerative medicine and the scientific and economic domination of advanced industrialised countries, it has seemed obvious to academic authors to explain scientific developments through Western-hegemony theory. But over the last decades there are clear political, economic and regulatory signs that thinking in terms of Western hegemony under regulatory capitalism largely ignores how global power is reconfigured as a result of political strategies that use regulation as a tool to negotiate global competition.
In the field of regenerative medicine, international resistance to what are regarded as ‘elite’ regulation has grown (Zhang and Datta-Burton Reference Zhang and Datta-Burton2021). As we will see below, many stem cell clinics and researchers of stem cell science bend or ignore what are viewed as ‘international’ and ‘official’ regulations, while others formulate alternative regulatory guidelines. On an international level, this has led to discrepancies between countries’ research- and ethics-regulations.
Clinical research and biomedical products are regulated as different stages of the process of translational stem cell science. On the one hand, clinical research in regenerative medicine aims to determine the safety and effectiveness (efficacy) of stem cell interventions, devices, diagnostic products and treatment regimens intended for human use. Meant to prevent, treat and diagnose symptoms to relieve suffering from medical conditions, clinical research is expected to follow the guidelines created by regulatory authorities. Biomedical products, on the other hand, are marketable preparations of viable cells, delivered through devices, such as syringes, and they require marketing permission in most countries. The differences observed in countries’ regulatory guidelines and permissions for clinical research and biomedical products are often associated with a ‘civilised’ world dominated by advanced scientific institutions and a ‘developing’ world of ‘rogue’ and ‘fraudulent’ stem cell providers. The latter, especially during the first one-and-half decades of this century, have often been connected with stem cell practices found in Asian countries. This is tellingly captured by the title of an editorial in The Economist: ‘The East or Scientific Feast’ (Anonymous Reference Anonymous2010). The former is depicted as ethical, sophisticated and scientifically advanced, the latter as unethical, profit-motivated and uninterested in scientific advance (McMahon and Thorsteinsdóttir Reference McMahon and Thorsteinsdóttir2010; Sipp Reference Sipp2012).
But by defining differences in regulation in moral terms, critics do not do justice to the efforts of many researchers in lower- and middle-income countries (LMICs) to develop feasible regulation (Fantom et al. Reference Fantom, Fu and Prince2014). In fact, among the traditionally industrially advanced countries, too, only a few players can afford to conduct clinical trials in ways that match the ideals of the dominant international science community (Sleeboom-Faulkner Reference Sleeboom-Faulkner2014). The question remains, however, whether we can identify a global hegemonic order that defines the regulatory field in regenerative medicine. Although it is clear that an association is being made between following regulation – that of the ‘international science community’ – and behaving ethically and responsibly, what is not clear is whether ‘the West’ has hegemonic control over it. In fact, and as I will argue more explicitly in Chapter 4, countries with ‘prohibitive’ or ‘tight’ regulation do not necessarily implement them in their research and in clinical practices. Rather, a large grey area of stem cell–related activities exists in which stem cell scientists, doctors, politicians and regulators accommodate, adjust, circumvent and alter regulatory spaces to help advance clinical research in ways that suit their circumstances.
I illustrate and analyse this grey area using research materials pertaining to the period of 2001–2014. This will set the scene for my exploration of regulatory brokerage and regulatory violence under regulatory capitalism. The period saw major developments in regenerative medicine and its regulation, including, first, scientific and regulatory developments set off by former President Bush’s 2001 moratorium on federal funding for human embryonic stem cell (hESC) research, which boosted hESR and its regulation elsewhere in the world, including interests in other branches of stem cell research; second, the 2006 uncovering of the scientific fabrications by Hwang Woo-Suk and his team in South Korea, who had been publishing what were thought of as the most revolutionary developments in human cloning during the two previous years (Hong Reference Hong2008); third, the 2007 ‘discovery’ of iPSCs as viable ethical alternative to ESCs in humans; and, fourth, major regulatory changes, not just in the US and the EU, but especially in Asia, including the radical regulatory overhaul in Japan, announced in 2011. It is also the period in which the so-called rising powers enabled the fast-growing economies of Brazil, China and Russia to enter global science-competition and to send their students to countries with what were regarded as ‘state-of-the-art’ laboratories and knowledge.
The period of 2001–2014 saw an increase in regulatory competition and was accompanied by an increase in various forms of international life science collaboration, making it increasingly common for scientists to straddle two or more international positions. In the same period, the media began to report an increasing number of conflicts about regulation among scientists, especially between those belonging to well-funded elite laboratories and less well-funded ones in countries belonging to the so-called rising powers. The former viewed themselves as cosmopolitan and well-adjusted to the global international of what is regarded as ‘good science’ (Zhang Reference Zhang2012), while the latter adopted a more pragmatic stance toward what they regarded as catering to patient needs. This chapter and Chapter 3 will show how, rather than just being defined one-sidedly by hegemonic powers, regulatory changes in the field of regenerative medicine largely derive from national policies aimed at accommodating and enabling scientific innovation in their jurisdiction. It is a phenomenon that I describe below in terms of regulatory boundary-work. Regulatory boundary-work, I argue, is intimately linked to the emergence of a new international order, which is best characterised in terms of regulatory capitalism.
From Scientific Boundary-Work to Regulatory Boundary-Work
A history in which a few international organisations and countries driven by members from well-funded, cautious research laboratories set the standards forms the backdrop to the current binary characterisation of ‘our’ science as bona fide science and that of ‘others’ as snake-oil trade. Those that do not stick to ‘agreed’ ‘international’ conventions are seen as undisciplined and fraudulent (Bharadwaj and Glasner Reference Bharadwaj and Glasner2008; Sipp Reference Sipp2012). These views, widespread in many high-income-countries (HICs), has tainted a large group of under-resourced researchers and led to, often, false portrayals of their aims. Although accusations of ‘unethical’ clinical applications and research are partly a result of the spread of the rigid application of ethics guidelines, it is also encouraged structurally by scientists themselves. According to Thomas Gieryn (Reference Gieryn1983), scientists ideologically delineate themselves from the ‘science’ of other scientists through ‘boundary-work’: by contrasting their scientific integrity favourably with the non-scientific or inferior activities of others, they work to improve their public image. Disagreement and rivalry among scientists, then, can easily lead to polarisation. What I argue, however, is that, apart from scientific ‘boundary-work’ associated with the politics of scientific communities (Gieryn Reference Gieryn1983; Gilbert and Mulkay Reference Gilbert and Mulkay1984; Salter and Qiu Reference Salter and Qiu2009), we can observe boundary-work that is construed around standards and regulation on a global level, expressed in the media, conversations among scientists and in papers on ‘research ethics’ and ‘good practice’ at international scientific conferences.
The last three decades have seen a new regime of coordination of medical practices that link medicine and biology together. This has led to the increased articulation of genomic biology, multicentre clinical trials, organised patient communities and biobanks, which depend on sophisticated laboratories, reliable instruments and devices that produce exchangeable data. Standard setting, guidelines and regulation are central to this regime. Here, what is referred to as ‘regulatory objectivity’ (Cambrosio et al. Reference Cambrosio, Keating, Schlich and Weisz2006) defines the contents of what the dominant science community regard as correct practice (Birch Reference Birch2012). Even though these standards are often conventions. But what counts here is that results are compatible with other laboratories, whereby ‘truth’ and ‘accuracy’ become dependent on these conventions. In the field of regenerative medicine, the International Stem Cell Initiative (ISCI), for example, took the initiative to define pluripotency and assays and the media and reagents used to produce them (Eriksson and Webster Reference Eriksson and Webster2008). Standards do not only facilitate exchange, they can also define the clinical criteria in terms of diagnosis. Thus, scientific standards and assays for mesenchymal stem cells are critical both to the advancement of scientific development and to clinical practice (Bianco et al. Reference Bianco2013). Crucially, the exchangeability and common use of data require the deployment of similar equipment, devices and assays. This has major economic and intellectual property rights (IPR) implications to the advantage of those that set the standards, and to the disadvantage of the reputation of researchers that cannot comply with them (Birch Reference Birch2012; PRNewswire 2014).
These developments, then, put pressure on scientists all over the world to follow the standards and regulation of elite laboratories. At the elite levels, scientific knowledge is sanctioned by international peer-reviewed journals, regulation vetted by expert committees in modern bureaucracies and novelty defined by IPR. Here, political discourses on norms and values define the ethics acceptable to a small number of societies (Timmermans and Epstein Reference Timmermans and Epstein2010; Birch Reference Birch2012). International collaboration therefore requires elite laboratories in most countries, including those with few resources, to demand regulations that enforce ‘global’ standards. But, as we will see below, the necessity to purchase costly equipment and resources has also led to a resistance against regulatory norms and standards by those less well-endowed.
Insight into this friction between compliance and resistance is complicated by an ever-increasing demand for scientific leaders to be familiar with research regulation and research ethics, multiple scientific fields, IPR, methods of team management and business strategies, leading to development of ‘international entrepreneurship’ in the life sciences (Jones, Wheeler and Dimitratos Reference Jones, Wheeler and Dimitratos2011: 2). Entrepreneurial life-science networks (Sleeboom-Faulkner and Patra Reference Sleeboom-Faulkner and Patra2011) have emerged that engage in coordinative activities and methods using local knowledge resources and international connections. Here, values and methods are constantly weighed to realise a desired kind of ‘local’ model of scientific decision-making, taking into consideration local conditions, such as the costs, feasibility and aptness of the ‘right’ number of patients used in investigational studies or clinical trials, the quality of available preclinical studies and toxicity studies, the fees charged for investigational studies using unauthorised stem cell products and local ways of marketing therapy products. Further, global variability of therapy marketing and patient demand complicates the picture of compliance and resistance even further (Petryna Reference Petryna2009; Chen and Gottweis 2011). This variability has resulted in a situation in which the relationship between patients and doctors is conditioned by availability of research funding, expertise and medical facilities, as well as collaborative networks and regulatory constraints. It is here that scientific boundaries and regulatory boundaries become enmeshed in nation-state policies on biomedicine and public health.
Regulatory Boundary-Work and the State
Compared to pharmaceutical drugs, scientists have indicated that regenerative medicine is hampered by more challenging regulatory and financial difficulties (Ratcliffe et al. Reference Ratcliffe, Glen, Naing and Williams2013). Industries have been hesitant to invest due to the uncertainty of the field, the long (ten to fifteen year) gestation period from bench to bedside translation and the requirement for rigorous clinical-grade procedures. Though clinical trials for drugs are costly and do not guarantee commercial returns, regenerative medicine, which concerns live cells rather than molecules, exposes patients to risks that are harder to predict (Mason and Hoare Reference Mason and Hoare2007). Nevertheless, expectations of the potential therapeutic effect of regenerative medicine are high, forcing governments to make difficult decisions. After all, spending on the development of cell therapies takes away funding from other health causes. Nevertheless, the regenerative medicine lobby is strong. Research in regenerative medicine involves a wide range of disciplines, including molecular biology, physics, computer science, medicine and chemistry, which, together with industry, exert considerable pressure on the government to fund it. And, as the range of conditions the lobby of regenerative medicine promises to alleviate is impressively wide, patient groups add pressure too.
In addition, countries that hope to lead the field globally invest in the field so as not to lose out to international rivals: it is what I shall refer to as ‘competitive desire’, which propels investment. The more funding pumped into the field, the harder it becomes to admit disappointment. By withdrawing investment, a country would not just lose out financially, but it would also forego chances to have a say in the formulation of the field’s ‘international regulation’ through, for instance, the International Society for Stem Cell Research (ISSCR), the International Society for Cellular Therapy (ISCT) and the Alliance for Regenerative Medicine (ARM). These organisations set the regulatory parameters that competitors have to negotiate. This is important, as this global environment of competitive desire in the life sciences and the use of regulation to increase competitiveness together form a self-reinforcing mechanism. As I shall argue in later chapters, it prompts forms of regulatory boundary-work that misrecognise public values and define what are widely propagated and prioritised as ‘public needs’.
Regulatory Boundary-WorkFootnote 1
Regulatory boundary-work is a form of policy decision-making located at the intersection of the international and local governance of, in this case, stem cell science. I use the term as a heuristic device to capture modes of policy-making that respond to ‘universal’ standards, which by definition, are at least partly created ‘elsewhere’, and which are not conducive to local policies of economic, health and scientific interest. For instance, country X might decide to ‘tighten’ its clinical research regulation not just to protect patients but to improve its global reputation. I use the notion of regulatory boundary-work to shed light on the global conditions under which different players champion, shape and project the development of stem cell applications as the best and only way forward.
Avoiding, on the one hand, assumptions of all-encompassing global forces that predetermine a country’s responses to global conditions and notions of pre-existing local political pathways followed by countries, on the other, below I will investigate the dynamic interactions among international, regional and local politics. The claims I make are not so much based on the influence of political cultures of governance but build on the exploration of specific circumstances in which countries variously adopt particular regulatory policies. Rather than adopting a normative approach to global guidelines, I use the notion of regulatory boundary-work to understand how international regulatory trends are articulated with local conditions and competing interests and how new regulatory forms emerge. Like regulatory boundary-work, it links the global with the local. But whereas regulatory brokerage refers to ways in which regulation is used in science collaboration and in regulatory politics to gain competitive edge, regulatory boundary-work is about the reputation of regulation in different jurisdictions. Countries can credit or discredit other jurisdictions to the advantage of their own scientific reputation and to the detriment of others.
The research on which this chapter is based shows a link between the national development of regulatory tools mobilised in regulatory boundary-work and the national conditions they build on, which I correlate with policies aimed at enabling local development of regenerative medicine. The materials presented draw on archival research and on conversations with regulators, company managers, scientists, medical professionals and patients between 2006 and 2016 (see Appendix 1: Interlocutors). Below, I will first discuss examples of locally mobilised regulatory tools. The next section sketches the variety and flexibilities of the regulatory landscape in terms of authority, permission, space and acceleration as a background to the third section, which defines factors and show patterns in regulatory boundary-work of the countries examined. This pattern is based on the characterisation of four kinds of regulatory policies observed from 2008 to 2014: regulatory adjustment, sustained regulatory impasse, radical regulatory change and unclear/developing regulation (see Table 2.1). The identification of this pattern enabled the analysis of the similarities and differences between countries with divergent modes of regulatory boundary-work, the results of which are outlined in the third section.
Table 2.1 Modes of regulatory boundary-work
| Mode of regulatory boundary-work | Traditionally scientific leaders | Large LMICs | Scientifically advanced Asian countries | Small LMICs |
| Regulatory adjustment | US/ EU | |||
| Sustained regulatory impasse | India China | |||
| Radical changes in regulation | Japan South Korea | |||
| Unclear/developing regulation | Malaysia Vietnam Thailand |
The fourth section discusses how, as a result of the existent diversity of regulation and dissatisfaction with strategies of regulatory boundary-work, organisations and networks have emerged that champion diverse international guidelines and standards. I discuss their activities, questioning the designation of ‘international’ in this context.
Regulatory Boundary-Work and Science Policies – 2008–2014
Regulatory boundary-work directs the development of science to articulate international regulatory trends with socio-political and economic policies and home conditions. Changes in science policies, science funding and science regulation affect development in cell therapies. Such changes can be aligned with international science strategies. For instance, this may happen by assigning a particular level of authority to regulation, through funding-linked incentives, such as research review, scientific protocols and research ethics, and through permissions, such as for investigational studies/trials, experimental research spaces for research involving human subjects and marketing licenses. In this section, I discuss how global trends in the innovation of stem cell therapies are conditioned through particular regulation in Asia, the EU and the US.
The first subsection draws out the existence of diversity in regulatory authority. In the second section, I focus on the EU and the US to indicate the variety in regulatory provisions in the part of the world often associated with advanced science and technology. It also serves as a reference for discussing regulatory boundary-work in Asia in the next section. This section sketches the variety and flexibilities of the regulatory landscape in terms of authority, permission, space and acceleration.
Forms of Regulatory Authority
Regulatory boundary-work uses regulatory tools. Countries might diversely regulate the development of stem cell applications by legal means (hard law), formally sanctioning violation or through guidelines, that is, soft law. Some countries, such as Japan, until recently, have predominantly used soft law, which can be very effective when social/institutional controls are available at the ground level (Ida Reference Ida2002).Footnote 2 Other countries make use of a range of regulatory levels with varying degrees of authority. For instance, China has laws (法), administrative regulations (行政法规), departmental regulation (部门规章), ethical principles (伦理原则) and administrative measures (管理办法) (also see Wahlberg et al. Reference Wahlberg, Rehmann-Sutter, Sleeboom-Faulkner, Lu, Döring and Cong2013). New regulation usually comes out as draft (草案) or trial regulation (試行), amenable to change. In addition, police and armed forces have their own regulation for scientific research and medical treatment in hospitals and research centres.
In Europe and the US, we see major differences in the organisation of regulations and the status assigned to different forms, with traditionally a relatively high reliance on soft law in Anglo-American countries compared to continental Europe. For example, the UK is well known to have a highly regulated system but liberal laws for stem cell research, while France is the opposite. Furthermore, national authorities implement the European Medicines Agency (EMA) regulations through varying national regulatory and/or legal mechanisms. In the US, the Food and Drug Administration (FDA) regulates translational stem cell research federally, but leaves powers to the private sector and state governments. Finally, the status and authority of regulatory organs are subject to constant innovation, as will become clear below. The political and legal status of regulation is crucial in understanding its impact.
Permissions for Investigational Studies – Geographic Dimensions
Innovative stem cell treatment in most countries requires permission from a local institutional review board (IRB) or equivalent and from a higher-tier organisation at provincial or national level. Nevertheless, specific requirements can differ substantially per country. Scientists who are aware of this can decide to collaborate strategically (Sleeboom-Faulkner and Patra Reference Sleeboom-Faulkner and Patra2011) to enjoy advantageous regulatory conditions. This might require collaborative partners to comply with international guidelines, including GLP, GMP and ethics review. In some countries, local conditions for permission for clinical studies clash with national science policies, whereby the former encourages and the latter curtails clinical applications. For instance, the Guangzhou municipal government in southern China had funded translational stem cell applications discouraged by the national government after 2009, when a moratorium had been announced against any experimental stem cell applications unless authorised by the state (Deng, 25/4/2013*; Ping, 28/4/2013-Guangzhou* [pseudonyms]).
In some countries, national permission for the clinical application of stem cell products may only be necessary for marketisation. This means that hospitals can provide treatment using unauthorised stem cell products as long as they do not charge for the stem cell products; they charge for the ‘service’. Alternatively, stem cell products are applied off-label for indications without evidence for their safety and efficacy. Such methods enabled clinics in the US, China and India to continue to provide treatments that have not been recognised at home (Richer Reference Richer2011). In the US, permission could be acquired to take an experimental drug across state boundaries. Thus, through the Investigational New Drug (IND) programme in the US, a pharmaceutical company can obtain FDA permission to ship an experimental drug across states (usually to clinical investigators) before an application for marketing a drug has been approved (US FDA 2014a). This possibility opens up a large pool of potential subjects for clinical trials.
Creating Spaces for the Procurement of Innovative Treatment, Experimentation
Apart from following the pathway of clinical trials, there are other ways of making innovative treatments available. One is compassionate treatment, a term usually referring to a last-resort treatment for individuals without other options, also used by researchers who do not have permission for clinical trials. Thus, the Indian company Neurogen justified stem cell therapy provision for Duchenne muscular dystrophy (DMD) and other conditions by appealing to compassionate use as cited in section 37 of the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects (WMA 2018), which states that doctors may use experimental therapies when no other treatment is available (Sharma et al. Reference Sharma, Gokulchandran, Sane and Badhe2014: 236). The US FDA allows only a very few cases of compassionate treatment exemption, as researchers can charge patients (Cyranoski Reference Cyranoski2011), while the EU regulates compassionate treatment separately from research.
The EU’s Advanced Therapy Medicinal Products (ATMP) Regulation (Article 2[2]) provides the Hospital Exemption (HE) clause, which allows member states to facilitate ‘non-routine use’ for individual patients in the absence of a marketing authorisation (European Commission 2014). The uneven implementation of the HE due to different interpretations in European countries, however, led to a broad use of the clause, and it was feared that it deters users from applying for market authorisation for ATMP. For instance, while TiGenix developed cartilage treatment by going through the central regulations, others used the HE for similar treatment indications (House of Lords 2013: 544). The pre-existing UK’s ‘Specials scheme’, which is covered by Article 5(1) of Directive 2001/83/EC, allows for the manufacturing and provision, including import, of unlicensed medicines for the treatment of rare disease and the use of drugs for individual patients’ unmet needs (Lowdell, Birchall and Thrasher Reference Lowdell, Birchall and Thrasher2012; Mahalatchimy et al. Reference Mahalatchimy, Rial-Sebbag, Tournay and Faulkner2012). It can be scaled up and used across Europe, with the manufacturer paying for the process rather than the product (MHRA 2007; European Commission 2014).
Applications can receive extra incentives in terms of fees and priority at any stage of the development of therapeutic products through the Orphan Drug Designation (ODD) if certain ‘rare disease’ criteria are met. For instance, Multi-Stem, a US-based company, which created a graft versus host disease (GvHD) prophylaxis for leukaemia patients receiving allogeneic (from others) haemapoeitic stem cells (HSCs), has received ODD both from the FDA and EMA for its allogeneic multipotent adult progenitor cell based ‘MultiStem therapy’ (Athersys Inc. 2013). In short, apart from regulations, appeals to compassion, declarations, schemes and exemptions are used to make available experimental interventions.
Acceleration of Translational Pathways
In the EU, some stem cell products may be used clinically without marketing licence. This, however, does not mean that they are uncontrolled, as is illustrated by the ODD, HE and Specials pathways, which essentially assign spaces of development. In addition, accelerated licensing routes are possible under certain conditions. In 2012, the US Congress passed the FDA Safety Innovations Act (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to accelerate approval for drugs for serious conditions that fill an unmet medical need, using a surrogate or an intermediate clinical endpoint (also see, US FDA 2014c). Post-marketing confirmatory trials are generally required to verify and describe the anticipated clinical benefit or effect (US FDA 2014b).
In the EU, the European Medicines Agency (EMA) has integrated a number of initiatives, including adaptive trial design, named the Medicines Adaptive Pathways to Patients (MAPPs) programme, aiming to create an approval process that adapts quickly to a given patient’s response to therapies, focusing on clearly defined patient populations with unmet medical needs (Forda et al. Reference Forda, Bergström, Chlebus, Barker and Høngaard Andersen2013; EMA 2014). However, no agreement existed yet about minimal standards of scientific evidence and reimbursement, and these initiatives do not sit within EU pharmaceutical or other law. In the same vein, in the UK the MHRA had piloted the Early Access to Medicine Scheme (MHRA 2014) ‘to support access to unlicensed or off-label medicines in areas of unmet medical need’. It uses a Promising Innovative Medicine (PIM) designation, similar to the Breakthrough Therapy designation in the US, and would involve collaboration between existing institutions, such as the National Institute for Health and Care Excellence (NICE) and the National Health Service (NHS) (MHRA 2014). The data requirements for a PIM are less than those for a formal marketing application dossier.
A more fundamental approach to market acceleration took place earlier in South Korea and Japan, where Biologics License Applications (BLAs) are conditionally provided for new investigational drugs after producing evidence of safety and plausibility of efficacy (see below). Researchers in the US and in Europe, on the one hand, were highly concerned about the consequences of using ‘deviant’ standards and regulatory norms and, on the other hand, worried that they would lose competitive edge (Freeman and Swidlicki Reference Freeman and Swidlicki2014).
To summarise, some countries, notably the US and countries in the EU, have created a wide range of measures – some hard law, some soft, some within legal regimes some extra-legal – designed to enable the authorisation and mandating of innovative stem cell (and other cell) technologies. This kind of regulatory boundary-work has enabled these regions to maintain their core commitment to traditional biomedical standards and methodologies and their related regulatory and institutional cultures, which support highly innovative bio-economic stem cell science entrepreneurship.
Patterns in Regulatory Boundary-Work
Comparing regulatory boundary-work across countries allows the identification of correlations between regulatory policies and the situational conditions of countries in a global context. The intentions behind regulation can be difficult to verify. To improve our understanding of regulation performance, we therefore need to gauge its political meaning from the context of overall trends in scientific infrastructures and institutional cultures in countries (Sleeboom-Faulkner Reference Sleeboom-Faulkner2011b; Faulkner Reference Faulkner2012) in particular political contexts. Gaining knowledge of the regulatory context will shed light on the political considerations underlying regulatory decision-making.
Local regulation takes into account infrastructural factors such as the supply of working electricity, affordable reagents, training for technicians, public communication channels and a modern administration. In India, the absence of a responsive bureaucracy has frustrated scientists who have applied for National Apex Committee (NAC) permission to conduct clinical trials (Gupta, 12/11/2014*; Rahman, 12/11/2014*). In many countries, applying for permission for clinical trials is left to the individual institution. Thus, audits from the Indian Council for Medical Research (ICMR) might not reach those institutions that have not applied for permission, (Patra and Sleeboom-Faulkner Reference Patra and Sleeboom-Faulkner2017), leaving scope for un-mandated practices.
A shared scientific culture is needed to indicate what is acceptable in stem cell product applications (Barry Reference Barry2006; Zhang Reference Zhang2012). But, in LMICs such as China and India, sharp conflicts developed between local funders of stem cell product applications and the national government over the conditions under which they may be used and marketed (See Table 2.1, Chapters 3 and 4). In Thailand, Japan, South Korea and Taiwan, stem cell products were regularly (and continue to be) on offer as cosmetic cell therapy or as holistic medicine. Disagreement about the interpretation of key terms can undermine effective regulation. One example is the meaning of ‘minimal manipulation’ of stem cells. In the US, the companies RNL/Celltex and the FDA disputed whether the expansion of stem cells constitutes minimal manipulation, falling under the medical practice law (regulated by Texas), or whether it should be treated as a biological drug, regulated by the FDA (Cyranoski Reference Cyranoski2013a). Another example is the contentious interpretation of the ‘non-routine’ use of stem cell products for individual patients authorised through the EU Hospital Exemption (EBE 2011). A last example from Thailand relates to the term ‘stem cell therapy’, whereby the notion of ‘stem cell’ indicates that it requires state authorisation. To avoid criticism, companies advertised the application of unauthorised stem cell products as ‘cell treatment’ (Chaisinthop Reference Chaisinthop2014).
The 2013 overview of stem cell and genetic engineering products with marketing permission in Figure 2.1 gives a general idea of how countries make regulation work for innovation in regenerative medicine. As will become clear below, this figure does not represent so much the scientific advancement or productivity in regenerative medicine of a country, as it does the kind of regulatory policies it has adopted.
Figure 2.1 Stem cell and genetic engineering products in 2013.
Wealthy, Traditional Leaders of Scientific Development and Regulation
Until some five years ago, the US and EU have insisted on following scientific regulation for developing stem cell technology based on the traditional preclinical testing and clinical trial models. However, the requirements of randomised control trials (RCTs), in particular, have been contested by innovators in the field of regenerative medicine.
RCTs typically advance through three phases. According to the US NIH (NIH 2021), phase I usually tests a small group of healthy volunteers (20–80) for safety and side-effects and to find the correct drug dosage; phase II lasts for several years and usually tests more people (100–300) and emphasises effectiveness. It aims to obtain preliminary data on whether a drug works. Phase III gathers more information about safety and effectiveness in different populations and different dosages. It involves several hundred to about 3,000 people and might use combinations with other drugs. After phase III, the FDA decides whether to approve the drug. If it does, phase IV monitors the safety and efficacy of the drug in large, diverse populations. As it might take years to obtain clarity about possible side effects, this phase can take many years. The RCT is called ‘randomised’ as subjects are randomly assigned to a new drug and standard treatment, or if there is not standard treatment, to a control group, which means that they might only receive a placebo. The placebo is considered crucial to advance scientific knowledge about the efficacy of the trial and would justify any potential disappointment among subjects that ‘only’ receive a placebo drug. It also involves compliance with what are regarded as international best practice guidelines such as GCP (good clinical practice), GTP (good tissue practice) and GMP (Carson and Dent 2007).
Although for many years considered the gold standard of evidence-based clinical research, the RCT was increasingly criticised by clinical researchers in regenerative medicine. It was argued that the conditions researched in the field of regenerative medicine were rare and could never fulfil RCT requirements on the number of subjects. Opting for multi-centre clinical trials was no easy alternative, as they are difficult to coordinate in countries with different research cultures and medical systems (Kleiderman et al. 2015). Furthermore, the ‘good practice’ requirements for RCTs made them extremely expensive, even in relatively wealth Europe (Hauskeller et al. Reference Hauskeller, Baur and Harrington2017; Hauskeller Reference Hauskeller2018), while their lengthy pathway would not benefit desperate patients.
As described above, this translational paradigm itself is increasingly open to various, limited flexibilities. While clamping down on therapies using unauthorised stem cell products, regulatory spaces have been created for promising stem cell technologies. Some of these regulatory spaces are of a local nature and entail the high costs, bureaucracy and time needed for the pathway of RCTs, as well as investigational research using a small number of available human subjects. The following sub-sections discuss initiatives that organise and standardise stem cell research in Asia, contra the US/EU cases, whose regulatory boundary-work we have characterised above as adjusting incrementally.
Large and Scientifically Ambitious Low- and Middle-Income Countries (LMICs) (India, China)
Large and scientifically ambitious LMICs, such as India and China, pool resources to develop a life science industry, though they can afford only a limited number of high-tech laboratories per head of the population. Influential commercial actors play a leading role (e.g., Stempeutics and Reliance in India and Beike Biotech and Zhongyuan Union Stem Cell Bio-engineering Corporation in China). Apart from well-equipped commercial actors, both countries have a large body of underequipped laboratories using localised standards, skills and collaborations. Stem cell therapy enterprises linked to hospitals are readily found on the Internet. In both countries, local and national governments have invested heavily in the life science industry, and a call exists for an ‘ethics of return’ in the form of benefits to patients. In this context, stem cell researchers have been put under pressure not only to develop the ‘world’s highest-standard medicine’ but also the ‘world’s first clinical applications’. Scientists in India and China express concerns about the recognition of their work, which are heightened as local scientists see that clinical experiments they started years ago are now part of clinical trials elsewhere without recognition of their contribution. This creates a regulatory dilemma for scientists and policy-makers, as will be shown in Chapters 3 and 4 (Deng, 25/4/2013*; Ping, 26/4/2013*; Zhang and Datta-Burton Reference Zhang and Datta-Burton2021).
Small LMICs (Thailand, Malaysia, Vietnam)
Small LMICs invest relatively little into infrastructural development and translational stem cell applications and have no concerted policy directing the research (Saengpassa and Sarnsamak Reference Saengpassa and Sarnsamak2012; Pérez Velasco et al. Reference Pérez Velasco, Chaikledkaew, Myint, Khampang and Tantivess2013). For example, although Malaysia in the eight years from 2005 invested RM (Ringit Malaysia) 3.2 billion in 225 so-called BioNexus-status companies through its Malaysian Biotech Corporation (Bionexus 2014), its financial capacity is clearly inferior to that of India and China.
Although regulation for local approval by an IRB and the national authorities in Thailand, Malaysia and Vietnam had been in place for some time (TMC 2009; NIHBT 2011; MoH Malaysia 2013), presumptions of ‘loose regulation’ made these countries targets for collaboration. Examples include the University of Texas MD Cancer Anderson Centre supporting clinical trials with bone marrow transplants in Bangkok (Bionews Texas 2013; Cancer Hospital Wattanasoth 2024); Japan and India’s joint-venture Niscell, which provides autologous (from self) stem cell therapy and conducts clinical stem cell trials in Malaysia (Niscell 2013, 2024); and India’s Stempeutics’ clinical stem cell trials in Malaysia (Stempeutics 2013; Bionexus 2014). Regulation of translational stem cell applications in these host countries tends to be brief and general, so that the conditions under which authorised clinical trials take place are unclear (TMC 2009; MOH Malaysia 2013; Thomson Reuters 2015).
Scientists and medical professionals from Thailand and Malaysia expressed worry about the country’s scientific reputation and its effect on scientific development (see Chapter 5). Some clinics offer ‘stem cell therapies’ commercially, such as those attached to Beike Biotech and Wu Medical Centre (2014), while others, such as TheraVitae and SiriCell, were closed down. Even when regulation prescribes the application for permission from a National Ethics Committee, clinics offer treatment using stem cell products commercially without authorisation. Examples are Absolute Health (2013), VillaMedica (2020), Cellport (2022), HolisticMedical Centre in Thailand (2022) and PatrLife (2022) and StemCellMalaysia (2021), StemLife (2022), and WhatClinic (2022) in Malaysia. Vietnam, a late-developer in the field, has considerably invested in stem cells (Pham Reference Pham2016). Besides state-provided interventions, hospitals offer commercial treatment using unauthorised stem cell products and collaborate with South Korean, Chinese and Singaporean companies, including RNL (renamed K-Stemcell), KenCare and Asian Stem Cells (See Vietnamnet 2013; Kencare 2016; ASCI 2022). In all three countries, scientists and regulators worry that investment in regenerative medicine does not serve the interests of the majority of patients (Saengpassa and Sarnsamak Reference Saengpassa and Sarnsamak2012), who cannot afford the treatments on offer in the private sector.
Scientifically Advanced and Ambitious Medium-Sized Countries in Asia (South Korea, Japan)
Two scientifically advanced countries in East Asia, South Korea and Japan, have reorganised their regulation to speed up the process of translational research by means of fast-track pathways for certain kinds of stem cell applications. To uphold safety, a complex form of implementable regulation has been devised, including standards for ethics, GMP/GLP, banking, permissions, market licensing and follow-up treatment. South Korea’s Regulation on the Review and Authorization of Biological Products introduced ‘fast-track approval’ (KFDA 2010; MFDS 2013). Thus, the Korean Food and Drugs Administration (KFDA) has eased its regulation on the use of autologous cell products over the last few years by granting exemption from submission requirements and exemption from phase I trial when the data have been published in professional journals (Notification 2011-225, 2011). Furthermore, the Korean Ministry of Food and Drug Safety (MFDS, which replaced the KFDA in 2013) allowed post-marketing submission of evidence for the efficacy of medicinal products in cases of serious and life-threatening disease (including AIDS and forms of cancer) and where no other treatment option is available (MFDS notification 2013-238, article 58). So, not surprisingly, South Korea was the first in approving stem cell products: Hearticellgram and Cartistem for Osteoarthritis and Cupistem for Crohn’s fistula (Wohn Reference Wohn2012), followed by many others (see Figure 2.1).
Having been frustrated by its slow regulatory bureaucracy, and hoping to take iPSCs to the clinic first, Japanese regulators and scientists confirmed that they looked to South Korean regulatory efforts to revise Japan’s. In 2010, the Japanese government revised the non-legally binding ‘guidelines for clinical studies using human stem cells’ (Matsuyama Reference Matsuyama2008) and expanded its coverage to clinical studies using embryonic stem cells and iPSCs (Azuma Reference Azuma2015). In 2013, guidelines were replaced by legally binding regulations. In 2013, three new (hard) laws were introduced, of which the first, the Regenerative Medicine Promotion Act (RM Act), was enacted in May 2013. It promises to promote regenerative medicine among the Japanese population, linking state efforts with industry and devising policies in support of bringing regenerative medicine to the clinic.
The second, The Act on the Safety of Regenerative Medicines, was enacted on 25 November 2014, and uses a three-tiered system based on risk-assessment to determine the level of required research oversight. In cases of high risk (involving pluripotent cells) and medium risk (involving somatic stem cells), medical institutions need to apply for permission from a special committee for regenerative medicine identified by the Ministry of Health, Labour and Welfare (MoHLW).
The third, the revised Pharmaceutical Affairs Law (PAL), the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act), enacted on 25 November 2014, stipulates that the Pharmaceuticals and Medical Devices Agency (PMDA) and the MoHLW provide an expedited approval system for regenerative medical products. After the safety is confirmed and the results predict likely efficacy, the product would be given conditional, time-limited marketing authorisation (PMDA 2014; Azuma Reference Azuma2015). This radical regulatory reform, allowing market authorisation before the provision of scientific evidence through clinical trial (Cyranoski Reference Cyranoski2013b; Nikkei 2014), immediately attracted the interest of large companies, such as Athersys, Mesoblast and Cytori Therapeutics (Market Watch 2014). Also, companies from elsewhere in Asia, such as India’s Stempeutics, considered approaching Japanese partners (Monahan, Monhahan, 23/9/2013*). Nevertheless, considering the fear of scandal from the side of regulators, and the uncertainties around post-marketing conditions of cell products, it might take some time before new stem cell products will be given marketing permission.
An examination of the ways in which countries undertake boundary-work to harness the regulation of regenerative medicine in an international context made it possible to categorise countries according to their size, the state’s ability to accumulate resources, healthcare demands, established traditions of scientific governance and economic and scientific ambitions (see Table 2.2).
Table 2.2 Factors underpinning regulatory boundary-work
As discussed above, leading countries in the field from the EU and the US have been adjusting their regulation to the demands of regenerative medicine in piecemeal fashion. The ability of large LMICs to pool resources allowed them to catch up with elite laboratories, but simultaneously these countries faced regulatory difficulties in dealing with the needs of under-resourced players, which found other investors through local and international collaborations and who compete in the international stem cell therapy and banking market. Small LMICs, entering the stem cell science scene only gradually, developed their scientific and regulatory capacity, mainly by focusing on and protecting a few pioneering institutions, while opening up the country to foreign investors. Scientifically ambitious and advanced medium-sized countries changed the regulation of regenerative medicine radically and no longer require strict criteria before marketing. This change was pushed by the desire to see investment yield clinical applications rapidly and pulled by the competition faced by countries that hitherto have traditionally defined the conditions of innovation in regenerative medicine.
International Stem Cell Organisations and Networks
The diverging regulatory boundary-work regarding translational stem cell science discussed above has led to initiatives aimed to harmonise international regulation and standards. They not only facilitate exchanges in scientific knowledge but also funnel and discipline their membership by stipulating ethical review, scientific protocols and common scientific standards. Examples of such organisations are the Alliance for Harmonisation of Cellular Therapy Accreditation (AHCTA), the International Consortium of Stem Cell Networks (ICSCN 2004; Stemcellconcortium 2023), the ISSCR, the ISCT, the International Stem Cell Forum (ISCF) and the International Stem Cell Initiative (ISCI, affiliated to the ISCF). Regional networks, such as the Stem Cell Network (Canada), Eurostemcell (2022) and Stem cell Network Asia Pacific (SNAP 2007) also encourage standardisation, collective policy-making and collaboration. Initiatives focusing on biobanking, such as the International Stem Cell Registry (ISCR 2012), the European human Pluripotent Stem Cell Register (hPSCreg 2022), the European bank for iPSCs (EBiSC 2022) and the International Stem Cell Banking Initiative (ISCBI 2010) share these ambitions.
In reaction to dominant international scientific standards and restrictive national regulatory policies, a number of initiatives aim to legitimise stem cell treatments with high patient demands that have not been recognised by ‘international’ stem cell institutions. These initiatives are characterised by different degrees of size, ranging from global to local. I here just discuss some of these international initiatives, to give an indication of the diverse nature of rebellion against dominant modes of clinical research regulation.
The International Cellular Medicine Society (ICMS, Salem, Oregon) has 3,500 physicians and patients in 35 countries with chapters in China, Peru, Mexico, Argentina and Venezuela. ICMS developed its own guidelines, an IRB and an international physician and patient network, and it forged collaboration with AABB (American Association of Blood Banks) (Stem Cell Pioneers 2011). The ICMS announced a framework for the clinical translation of cell-based therapies, focusing on establishing standards and guidelines for studies that fall outside the jurisdiction of the FDA. However, after acrimonious debate and an FDA audit in 2012, ICMS had to close its IRB. Nevertheless, the AABB Center for Cellular Therapies continues to be highly influential as an international accreditor (AABB 2021), a service used by companies in Thailand, China and India to advertise their international reputation. For instance, Jiangsu Beike Bio-Technology Co., Ltd; Lifecell International Pvt. Ltd.; and Chennai prominently advertise their AABB accreditation for somatic cell facilities.
The China SCI-Net, largely funded by a Hong Kong charity and linked to SCI USA, involves a transnational collaboration that aims to bridge efforts across diverging regulatory requirements, scientific practices and interests. The aim of China SCI-Net was to fund spinal cord injury treatment using lithium and cord blood cells in a fast and safe way, involving more than twenty leading clinical centres in Mainland China, Hong Kong and Taiwan. It conducted trials through local hospitals whose staff were trained to follow the Net’s own protocol China SCI-Net (2017), which its director, Wise Young, used in subsequent collaborative efforts to formulate new research guidelines for neurorestorative therapies (Huang Reference Huang, Young, Skaper, Chen and Moviglia2019). The configuration of international skills, training, patient network, funding and local regulation has its own dynamics through which it develops standards that chime with the national situations it works in (Rosemann Reference Rosemann2014).
The International Association of Neurorestoratology (IANR), set up in 2004 in China, is a broad professional platform of academic exchange for scientific researchers and clinicians from over thirty countries working in the neurorestoralogical field, including neurology, orthopaedics, rehabilitation, cell transplantation, Chinese traditional medicine and psychiatry. It develops its own protocols for conducting clinical trials to evaluate the safety and efficacy of its neurorestorative therapies, the establishment of validated outcome measures and ethical treatment of patients, among which its own form of ‘self-assessment’ is one of the criteria for success (IANR 2021).
The Guangzhou Stem Cell and Regenerative Medicine Alliance, including eighteen research institutes, hospitals and companies in Guangzhou Province, aimed to further basic stem cell science, to share resources and to develop translational stem cell research activities and applications (GSCRMA 2008; China Daily 2016). In 2013, a leading scientist explained how the Alliance established its own rules for the clinical translation of stem cell products to respond to patient demands and local investors, though it later ceased treatment provision (Deng 25/4/2013*, also see Chapter 3).
Finally, the Cellular Biomedicine Group Inc. (CBMG) of Shanghai, which announced the completion of a phase II stem cell trial for knee osteoarthritis (KOA), claimed to follow ‘international’ standards in late 2014. Since the Chinese government had prohibited treatments using unauthorised stem cell products, ‘regulatory uncertainty’ (CBMG 2015: 32) led CBMG to apply for marketing permission of the autologous stem cells under medical device regulation. Although this is a relatively quick method of acquiring permission, it is limited to the hospital in which it is obtained. For this reason, a company will typically conduct multicentre trials for a disease in a group of hospitals, and if it proves safe and efficacious, receive permission to sell in these hospitals (Deng 25/4/2013*).
The exemplified organisations illustrate the existence of international organisations with contrasting aims and possibilities, which are mobilised against the regulatory politics of others. They look to international and local allies for support of their research methods and standards and seek shelter under the protective umbrellas of international professional communities and local business communities. The roots and targets of these movements lie in the regulatory boundary-work or regulatory institutions in nation-states and regions that try to that articulate international regulatory trends with workable rules for regulation, funding, infrastructures and treatment on national and regional levels.
Conclusion
This chapter has explored the international dynamics of regulatory competition in regenerative medicine over a regulatory turbulent period of six years (2008–2014), showing that wealth conditions are associated with particular preferences for clinical research regulation. At the same time, international movements of patients and research were associated with regulatory politics, one dimension of which I have described in terms of regulatory boundary-work. As demonstrated, regulatory boundary-work enables translational stem cell applications, not despite, but in full cognizance of, the policies of international authorities, such as the ISSCR. As a heuristic tool, the concept of regulatory boundary-work calls for attention to how countries formulate stem cell policies through locally available political and regulatory mechanisms to articulate circumstances at home with global regulatory trends: governments can alter the status of national and local regulation; use various kinds of permissions for stem cell studies, trials and provision; create regulatory clauses to make spaces for experimentation; allow hidden deployment of unauthorised therapies; and accelerate pathways to the marketing of stem cell products. The implementation, understanding and use of regulation are modulated by variable infrastructures and institutional cultures conditioning science production and the provision of therapies.
This study has heuristically categorised countries’ regulatory dynamics from 2008 until 2014 as adjusting, radical, beginning and impasse (Table 2.1) and it has correlated these different modes of regulatory boundary-work with a country’s ability to accumulate resources, country size, healthcare demands, established traditions of scientific governance and economic and scientific ambitions. This categorisation, in turn, embodies the differences between what can be regarded as large LMICs (China and India), small LMICs (Malaysia, Vietnam), traditionally dominant confederates (EU and US) and advanced Asian countries (Japan and South Korea).
Regulatory diversity has led to the emergence of international organisations that promote dominant forms of ethical review, scientific protocols and common scientific standards on regional and international levels. Dissatisfaction with national regulation has led to the formation of transnational scientific collaborations and networks that champion and practise ‘alternative’ therapeutic practices and evaluation methods. It is misleading to represent this friction only as a normative issue. As I will further illustrate in subsequent chapters, the conditions under which such regulation emerges often only make sense in socio-economic and political terms. Nevertheless, such experimental practices have great potential for physical and mental violence, when the risks and benefits of medical treatment for patients cannot be adequately weighed in their relevant context. After all, the infrastructures, healthcare systems and expertise available in HICs make for a very particular context crucial to experimental practices.
In contrast with studies that frame translational stem cell science in normative terms of ‘bona fide’ and ‘rogue’ practices and ‘Western’ (or ‘international’) versus ‘local’ practices of regenerative medicine, this study shows that ‘international regulation’ can be a flag proudly carried by privileged bearers, while masking extreme regulatory variation. Although notions of hegemony are relevant here, they cannot explain the differences between and within countries. Discourses that focus on the demoralising effects of neoliberalism, on the other hand, turn LMICs into followers of ‘capital’, discussing regulatory friction in terms of inferior ethics and values. By contrast, the notion of regulatory boundary-work sheds light on regulatory agency in a world characterised by regulatory capitalism, explaining the enabling and debilitating effects of regulatory stalemates experienced in China and India, the gradual regulatory reforms in the US and the EU, the radical regulatory changes in South Korea and Japan and the ‘international’ regulation adopted and violated by relative newcomers in the field, such as Malaysia, Thailand and Vietnam.
As further shown in Chapter 3, the notion of regulatory boundary-work can help us understand how some countries concurrently follow and resist international regulation in the context of transnational collaborations as well as why national governments deploy strategies that appear to follow ‘international regulation’ to some extent and at the same time violate and infringe it. Scientific competition and collaboration turn out to be two sides of the coin of regulatory capitalism.
Realising that the authority of regulation and the role of regenerative medicine in national plans for economic growth vary between countries means that tactics of regulatory boundary-work differ. In the context of regulatory capitalism, it also means that the regulatory landscape is a breeding ground for ‘regulatory brokerage’. The fact that a particular form of regulation has political currency invites brokering activities, including international collaboration for regulatory reasons, the lobbying for alternative regulation for alternative regulatory guidelines and, finally, brokering regulation with other international players. Chapter 3 will discuss such national brokerage of regulation in the context of LMICs.
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