The theoretical importance of the notion of regulatory capitalism to today’s global trade-flows cannot be overestimated (Jordana and Levi-Faur Reference Jordana and Levi-Faur2004; Braithwaite Reference Braithwaite2008). Many scholars regard ‘neoliberalism’ as the culprit of most of what is socially, economically, politically and culturally wrong with the world. But it is regulatory capitalism that sets the rules and norms of economic exchanges, which is especially crucial to the development of innovative biomedicine. The dynamics of regulatory capitalism crosses the boundaries of all jurisdictions, no matter what political systems rulers defend.
Regulatory capitalism forms the backdrop to my discussion of regulatory brokerage and regulatory violence in the field of regenerative medicine. Regulatory capitalism does not just account for an epidemic of national, professional and global regulations in terms of market mechanisms. Rather, its global reach makes possible the brokering of regulation among market economies, whether socialist, democratic, autocratic or other for economic gain. As a result, regulatory measures are introduced that are biased by illegitimate interests, the consequences of which are played out on the bodies of patients.
From Neoliberalism to Regulatory Capitalism
Under regulatory capitalism, the economic compatibility of trade is shaped and defined, not by financial security and innovation but by regulation and standards. In today’s global scenario, Hobbesian visions of a world ruled by free-market competition are outdated. Rather, the globalised economy is a consumer-targeted market regulated by countless guidelines and standards for safety, security, quality, sustainability, fairness, health, the environment, climate and, of course, research. In our globalised world, compatibility is not just based on the price and quality of a product but also on how you can shape, ignore, use and manipulate the rules that underlie its trade. The difference with what is usually understood as neoliberalism is that it is not the invisible hand of the market that determines what and who may be ‘fit’ for purpose, but the geopolitical activities of the nation-state. This is why any country that wants to compete internationally needs a set of regulations, whether guidelines or laws, to enable competition on an international level. But how does this tally with the idea that we live in a world of neoliberalism?
Sociologist Lawrence Busch describes in Standards (2011) how Old School liberals such as Adam Smith emphasised the importance of individual liberty and the need to separate the state from the market and to delimit its powers. Neoliberal theory, developed since the 1930s by Henry Simons, Walter Lippmann and others, criticised national-plan economies. Both Simons and Lippman sought to minimise state powers, but they gave it regulatory functions instead. The former believed in a state that would maintain adequate rules for money, eliminate monopolies and minimise subsidies and protective tariffs, while the latter argued that the market was built on law, such as property law and contract, and their enforcement (Busch Reference Busch2011: 180–182). These ideas were followed up by a group of leading advocates of liberalism, including Lippman, Michael Polanyi, Alfred Schutz and Friedrich A. Hayek, who were resolved to create a ‘Road Code’ for the market. In this view, economic monopoly and oligopoly were not a result of the concentration of capital, as argued by Marxists, but by state protectionism. The power of the state, then, was to be limited to the maintenance of a competitive price system, and state funds curtailed to support national defence, education, social services and scientific research.
After the Second World War, this neoliberal project resumed its quest against central planning, including Keynesian policies. It became especially associated with the neoliberalism of Hayek and Milton Friedman, who argued that free markets should be promoted, as they can distribute goods and services without recourse to a central authority; the social order must be reorganised such that it meets the conditions established by the formal mathematical models underlying the free market; and, the power of the government is mainly limited to regulating economic, social and political affairs through the market mechanism (Busch Reference Busch2011: 182–187). An increase in regulation is not usually associated with neoliberal policies, as the power of the state to regulate is supposed to be limited in this view. Nevertheless, in the post-war period, when countries started to stimulate production internationally, regulation was developed to support global expansion.
Global capitalism required an increase in regulation to guarantee the standards and regulations used by the international dominant, ‘advanced’ industrial nations (Braithwaite Reference Braithwaite2008), and it was the intensification of globalisation in the 1970s that warranted global regulation of international free trade. The expansion of the regulatory functions of the state and international corporate and professional networks led to a mushrooming of regulatory agencies since the 1990s on both global and national levels (Vogel Reference Vogel1996; Levi-Faur, Jordana and Gilardi 2005). More so than the notion of neoliberalism, which is confusingly applied to characterise various political regimes and geographical areas (Kipnis 2007), an exploration of regulatory capitalism, originally developed by political scientists David Levi-Faur and Jacint Jordana, can shed light on changes in the standards and norms of social, economic and political legitimacy and effectiveness (Jordana and Levi-Four Reference Jordana and Levi-Faur2004). For theories of regulatory capitalism claim that the increase in regulation in the United States, Western Europe and Japan since the 1980s was not a mere matter of home-politics but a trend more broadly inherent to the expansion of global capitalism (Levi-Faur Reference Levi-Faur2005b; Braithwaite Reference Braithwaite2008).
The acceleration of the global expansion of production in the post-war era meant a change in the ways in which standards and norms were set. Sociologist Manuel Castells showed how Fordist hierarchical production management transformed into transnational networks that straddled the market with varying dynamics prevalent in different geopolitical regions of the world through international mergers, collaborations and agreements (Castells Reference Castells2000). Crucially, within these horizontal links, collaborative private and public networks started to define the standards of excellence. Lobbying among competitors led to a blurred line between regulators and the ‘players’ of the game. This is important, as the global playing field was not one of free trade and equal opportunity but one of a reconfigured playing field of unequal players. Many players that cannot live up to the benchmarks set stay on board through intricate systems of collaboration and regulatory manipulation. Those who cannot afford to keep up this game feel forced to operate at the ‘margins’ and develop their own rules. A large majority, however, develop practices that fall somewhere between ‘global’ and ‘marginal’ standards, a grey area with an enormous scope for regulatory brokering of the rules as will be explained and illustrated in this book. But first, we discuss what it means to be in a world characterised by regulatory capitalism.
Criminologist John Braithwaite in Regulatory Capitalism (2008) argued that the realisation of the neoliberal ideal of privatisation, deregulation and a diminished public sphere is a myth: deregulatory policies in both the US and Europe were limited in the 1960s and 1970s, and many of the policies cut were reintroduced through the G10 after the banking crisis in the mid-1980s (Braithwaite Reference Braithwaite2008). Similarly, after the Asian financial crisis of 1987, some Asian countries survived by protecting their regulation. Ignoring the International Monetary Fund’s (IMF) advice to liberalise and deregulate their financial markets helped them recover faster than those that had followed it (Stiglitz Reference Stiglitz2002). Political protectionism and the promotion of particular industries were conceived as ‘unfair’ and counter to global economic integration and market liberalisation. To many, it appeared that the promotion of international economic governance through the World Trade Organisation’s (WTO) Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS), the Agreement on Trade Related Investment Measures (TRIMS) and the General Agreement on Trade in Services (GATS) served to fend off competition from developing economies (Wade Reference Wade2003; Salter Reference Salter2007). Even arch-liberal Milton Friedman admitted that the 1990s had been more about law than about privatisation (Fukuyama Reference Fukuyama2004: 28). The political question was not so much whether to regulate but how to regulate and to what extent. In regulatory capitalism, then, in contrast with ‘the neoliberal schema of markets as the antithesis of regulation’ (Braithwaite Reference Braithwaite2008: 8), regulation does not level international markets but it skews them.
Regulation and the Reputation of Biomedical Products
But how do global markets become skewed? Regulations are a matter of compromise, for they are meant to coordinate the actions of producers to work in a compatible way. Regulators combine knowledge from different fields of expertise (Braithwaite Reference Braithwaite2008). For instance, regulatory standards and procedures for regenerative medicine draw on expertise from a number of fields, including chemistry, bioinformatics, biomedicine, public health and economics. Regulation impacts production in various ways: producers have to adjust their ways of doing things by using new ingredients, different formulae, different suppliers. In the life sciences, Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) are examples of standards for clinical research and manufacturing that are expensive to attain and maintain. Those that follow the regulations meticulously will feel disadvantaged compared to those who profit by not doing so. Producers who are close to regulators may have an advantage, as they can try to influence the regulation through lobbying. Reputation also matters: those whose ‘ways of doing things’ are perceived to be ‘inferior’ may not be able to compete, whether these perceptions are correct or not. The regulations will affect the playing field in general, as those with the technological expertise, scientific, managerial and financial capacity to integrate regulatory requirements in the production process will have an advantage compared to competitors that do not. Also, users of regenerative therapy products can refer to regulation when purchasing products or services and when lodging complaints.
Under regulatory capitalism, then, regulation regulates competition (Kingsbury et al. Reference Kingsbury, Malone, Mertenskötter, Stewart, Streinz and Sunamin2019): it sets the rules for compatibility. Science innovation is especially vulnerable to regulatory capitalism, as its regulation also involves the innovation of society and its values, which may differ from society to society. Such competition, as I will show, goes beyond one or the other interest group dominating or capturing regulation, involving complex dynamics of interactions between norms and values, material conditions and international relations, no longer headed by a global authority, be it in the shape of a country, region, institution or power. For conflict occurs where no common international rules have been agreed upon but also where regulation is introduced to harmonise global practices (Abraham Reference Abraham2002; Görg and Brand Reference Görg and Brand2006). This is not surprising, as regulation can divide those that have the means to follow them from those who do not. Apart from being a matter of financial affordability, scientific knowledge and technological expertise, regulatory reputation is of great importance in scientific competition (Carpenter Reference Carpenter2010). I use the notion of regulatory reputation to refer to how a jurisdiction’s regulation and its implementation are subjectively rated in other jurisdictions. Regulatory reputation is important in the context of international competition, where scientific products and services in one country or area are avoided when aspersions of ‘unreliability’ have been cast. Such ‘boundary-work’, as we shall see, can have devastating consequences for scientists in entire parts of the world, as was the case when Asia was referred to as the ‘Wild East’, implying that ‘international’ rules were systematically flaunted (Bionet 2007; Zhai et al. 2020).
It is in this context that Chapters 2 and 3 will introduce the notion of regulatory boundary-work. The makers of scientific products, scientists, make political distinctions between their own work and that of others through what sociologist Thomas Gieryn calls scientific boundary-work. Gieryn argues that scientists draw up boundaries ‘between the realm of science and non-science’ in order to claim and defend their own territory: Such boundary-work is useful in the light of scientists’ pursuit of professional goals, such as the ‘acquisition of intellectual authority and career opportunities, denial of these resources to ‘pseudoscientists’ and protection of the autonomy of scientific research from political interference’ (Gieryn Reference Gieryn1983: 781). According to Gieryn, scientists deploy an ideological style to create a public image for science by contrasting it favourably to what they portray as non-scientific intellectual or technical activities (Gieryn Reference Gieryn1983). Apart from scientific boundary-work, we can also speak of regulatory boundary-work, which I define as the politics of regulatory reputation.
Chapters 2 and 3 show how regulatory capitalism shapes a multitude of regulatory hegemonies as a result of power reconfigurations in the world of science innovation. These trends, I will argue in Chapter 2, create the structural spaces for activities of regulatory boundary-work and regulatory brokerage practiced by individual enterprises and regulators alike. Neither global hegemony approaches nor approaches that emphasise the scientific rationale of regulations are sufficient to explain the global dynamics of regulatory development in the field of regenerative medicine. Chapter 3 illustrates how the nation-state plays a central role as main shaping agent of regulatory boundaries at provincial, national and global levels of organisation. The nation-state also plays an important role in developing a regulatory framework appropriate to the country’s scientific capacity and economic aspirations. Adapting ‘foreign’ regulations requires compromising between ‘the ideal’ models used by the laboratories of the global elites and standards aimed at home. And as the aims and aspirations of regulatory regimes within a country differ, the state plays an important role in channelising, managing and policing them.
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.
Dr S thinks that the regulation in his country is permissive, and that it needs a law for non-hematological stem cell research. During a conversation with Dr T about international science collaboration, Dr S explains that his country needs decent regulation: ‘without the basics, ‘no one wants to collaborate with us’. Dr T smiles, ‘Even if there is no regulation, we will follow it! Any regulation in the world!’
If viewed as a global arena, it seems that the regulation of regenerative medicine is steered hegemonically by powerful countries. But coming across a cynical ‘anything goes’ attitude towards scientific regulation, like the one expressed by Dr T in the epigraph above, might give us the impression that regulation is merely part of a game and that it is really all about finding the right technological solutions for biomedical problems. This chapter illustrates how it is neither the one nor the other.
In Chapter 2, we saw that under the global dynamics of regulatory capitalism, LMICs have been under pressure to engage in particular forms of regulatory boundary-work when regulating regenerative medicine. Nevertheless, Chapter 3 argues that notions of Western hegemonic power are becoming outdated as a main analytical tool for understanding global regulation: changing global reconfigurations of power and scientific institutions in the global life-sciences have created structural spaces for both enterprises and regulators to negotiate new regulation. As discussed in Chapter 1, in regenerative medicine, brokerage activities empower an increasingly diverse range of actors, including scientists, entrepreneurs and regulators. Theories of world hegemony too easily assume that national catching-up policies in LMICs are automatically directed at mimicking modes of governance prevalent in HICs.
In this chapter, I use two examples of regulatory boundary-work from the PRC and India. Both are large LMICs with the ability to centrally mobilise resources for expensive scientific programmes, such as regenerative medicine, to examine how international pressures condition regulatory construction with the desire to compete for global leadership in the field. Their ‘catching-up’ policies have been linked to economic growth targets, so that the adoption of regulatory templates from abroad is by no means straightforward. Nevertheless, such emulation is presumed by two approaches: the global hegemony approach, which critically suggests that LMICs are forced to adjust to ‘global requirements’ by building the regulatory capacity attractive to global investors (e.g., Bharadwaj and Glasner 2009; Salter et al. Reference Salter, Zhou and Datta2015; Zhang and Datta-Burton 2022), and by some science and technology studies (STS) approaches, such as biomedical platform theory, which maintains that regulation is contingent upon the technological requirements of biomedical platforms.
Below, two case studies on regulatory capacity building in China and India from approximately 2005 to 2010 show that any global notion of regulatory hegemony should be understood as dynamic and modulated by conflicting local needs and developments especially in large LMICs (Petryna Reference Petryna2009; Harmon and Kale Reference Harmon and Kale2015). Rather than thinking in terms of the wholesale import of guidelines, we need to think in terms of regulatory capacity building, which I view as the ability to develop regulatory requirements to cater to the local dilemmas that obtain as a result of regulatory differences, both internationally and at home. The first case study shows how China’s regulators have needed to negotiate clashing local and global interests through regulatory capacity building. The second case study on the Indian company Stempeutics illustrates the considerations involved in regulatory capacity building, indicating that technological factors cannot provide the sole rationale for building a biomedical platform (Keating and Cambrosio Reference Keating and Cambrosio2000, Reference Keating and Cambrosio2003). Rather than focusing on the adoption of regulations and standards that fit the technological rationale of advanced biomedical platforms, we need to take into account the temporal advantages of pioneering industries and the resource-limited settings of LMICs. We will then discover how standards and guidelines are both emulated and adapted to the current needs of countries through contested claims over technological potential and its economic viability, over time creating new international spaces for gaining competitive edge.
Regulatory Capacity Building and the Governance of Clinical Stem Cell Research in China
Although, as we saw in Chapter 2, international organisations, such as the ISSCR and the International Society for Cellular Therapy (ISCT), and many countries and regions have developed guidelines for regenerative medicine, the international, national and regional guidelines for clinical stem cell research differ and are subject to continual revision. International authority has been ascribed to the guidelines of the ISSCR (2008) and the ISCT (2015), and many countries treat the standards of drug regulatory authorities in the US and the EU as a basis for collaborative research. But in some LMICs, including China and India, the articulation of ‘international guidelines’ with local practices has led to sustained regulatory dilemmas. In China, life science innovation is earmarked as a main driver for economic progress, and bioscience and biotechnology have become key areas for government support and funding for scientific research over the last decades (CURE 2009; China National Center for Biotechnology Development 2011; Wang Reference Wang2011; MoST 2013). But global pressures to follow international guidelines left governments squeezed between elite laboratories, keen to be seen as ‘cosmopolitan’, and other interest groups with their own regulatory preferences. In China, the initial regulatory reforms of 2009, aimed at policing and enabling the field of clinical stem cell applications, clashed with the interests of established communities of practice. This effort of national regulatory harmonisation led to a prolonged regulatory stalemate until 2015.
In China, various sets of regulation have been issued in the years between 2000 and 2015. They include the ‘Drug Administration Law’ issued by the Ministry of Health (MoH 2001) – now part of the National Health and Family Planning Commission (NHFPC) – the ‘Quality Control Standards for Clinical Drug Trials’ (China Food and Drug Administration [CFDA] 2007) and the ‘Interim Regulations on the Ethical Review of Biomedical Research Involving Human Subjects’ (MoH 2007). Regulations directly pertaining to clinical stem cell science only appeared in 2009, 2012, 2013 and 2015.
In 2009, the MoH promulgated the Management Measures for the Clinical Use of Medical Technologies. This regulation classified a range of new medical technologies and procedures into three categories where stem cell transplants were classified as ‘Category 3’. This category of medical technologies involves serious ethical problems and safety and efficacy issues that still need to be resolved through clinical trials. The regulation stipulated that clinical applications of stem cell technology had to be halted by 31 October 2009, if they had not applied for or passed auditing (MoH 2009). But though stem cell interventions required MoH approval before clinical application, for-profit clinics and a number of hospitals continued to provide ‘stem cell therapy’.
In January 2012, the MoH issued the ‘Notification on Self-Evaluation and Self-Correction Work regarding the Development of Clinical Stem Cell Research and Applications’ (MoH 2011). It gave stem cell research institutions a period of six months for self-evaluation and self-correction. Clinical stem cell research and clinical trials came to a virtual standstill in most laboratories and hospitals of academic institutions, although there were exceptions, including military and police academies, private hospitals and some lower-tier academic and medical institutions.
In March 2013, the MoH published three interrelated draft regulations for public comments: ‘Administrative Measures for Clinical Stem Cell Research Trials’, ‘Administrative Measures for the Research Base of Clinical Stem Cell Trials’, and ‘Guiding Principles for the Quality Control of Stem Cell Research Preparation and Preclinical Research’ (MoH 2013). These draft-regulations prepared the way to the regulation of clinical stem cell research and applications in China (Sui and Sleeboom-Faulkner Reference Sui and Sleeboom-Faulkner2015). It was not until August 2015 that the MoH published the trial administrative measures for clinical research for stem cells (CFDA 2015). It affirmed that stem cell technologies would be regulated as pharmaceutical products, with the exception of routine treatment with hematopoietic stem cells (HSCs). The CFDA published standards and technical procedures for the collection, manufacture and storage of stem cells for clinical use, and it also specified the required criteria for safety and efficacy assessment in preclinical studies. Only the highest-level hospitals (tier-three) were permitted to conduct stem cell clinical trials. Applications for these trials were to address provincial branches of the NHFPC and CFDA, and to be assisted by expert committees, while the NHFPC and CFDA jointly review the projects. Clinical trials needed to be registered online at the Chinese Medicine Registry and Management System (see Rosemann and Sleeboom-Faulkner Reference Rosemann and Sleeboom-Faulkner2016).
Despite these regulatory efforts, the regulatory framework had not allowed clinical stem cell researchers from state laboratories to formally register new clinical procedures and products (Rosemann Reference Rosemann2013). Even after the announcement of the draft regulations, in 2015 there were still many loose regulatory threads pertaining to market permissions, international collaboration, ‘compassionate interventions’ and the implementation of regulatory rules for for-profit and other unauthorised stem cell procedures. Nevertheless, the purpose of the government in this period of regulatory strife had not necessarily been to conform to ‘hegemonic Western ethics’. For, it was not a secret that the implementation of guidelines was half-hearted and allowed a wide variety of stakeholder efforts, such as those of private hospitals, companies and military hospitals, to forge ahead with clinical stem cell research (Sipp Reference Sipp2009; Cyranoski Reference Cyranoski2012). As a result, elite laboratories saw themselves as casualties of a regulatory regime that was selectively implemented to their disadvantage: their translational research was subject to close regulatory oversight through the funding they received.
But rather than ascribing normative motives to the government, I will here discuss the regulatory orientations that have shaped regulatory capacity building in China.
Regulatory Orientations
In China, stem cell communities have emerged that each in their own way have adapted to China’s science policies on regenerative medicine and its regulatory policies, as well as local needs and opportunities. Examples can give us an idea of why different attitudes towards regulation have developed. I have identified five regulatory orientations on the basis of over fifty visits to state laboratories, public and private hospitals and enterprises in the period of 2006–2015, including those described below. I use the notion of ‘regulatory orientations’ to refer to the different political attitudes of scientific communities towards national regulatory institutions. I delineated the five regulatory orientations on the basis of organisational closeness to the political centre, financial independence and business strategy. Stem cell institutions in China have been allowed to develop their own regulatory dynamics for a sustained period. Their path-dependent and locally entrenched nature means that communities of practice have emerged that have formed their own regulatory orientations, some more impervious to the power of the national regulatory regimes than others. Detailing the complexity of networks may shed light on the regulatory challenges in a large LMIC.
Beijing’s Chinese Academy of Medical Sciences: Close to Power
The Chinese Academy of Medical Sciences (CAMS) relies heavily on state support and illustrates how the state has affected its standards of protocol creation, safety and efficacy. At CAMS, Professor Zhao Chunhua, an early leader in immunology and foetal stem cell research (Eurekalert 2009), led research on clinical applications of hematopoietic stem cells (HSCs). He complemented these with what are controversially known as bone marrow–derived mesenchymal stem or stromal cells (BM-MSC) (cf. Bianco Reference Bianco2014). Zhao was the first in China to receive support from China’s Food and Drug Administration (CFDA) (the current China Food & Drug Administration [CFDA]) to start a clinical trial for patients with graft-versus-host disease (GvHD). GvHD has been a priority area, as it is widespread among China’s Thalaseamia patients that have received hematopoietic stem cell transplantation.
In 2003, when Zhao first asked permission to use BM-MSC in a clinical trial, no clear guidelines were available for the use of allogeneic cells, defined by the CFDA as category-3 drugs in need of research review. Zhao’s group provided regulators with basic explanations of the procedures and helped to create the very regulation that gave them permission to go ahead with the BM-MSC trial in patients with GvHD in 2004 (Cha, 15/5/2007*, also see Chen 2009). In December, Zhao began to collaborate with another CAMS team in Tianjin, which had access to patients in the People’s Liberation Army (PLA) 307 Hospital (People’s Daily 2005). In 2006, phase II of the GvHD clinical trial commenced, but in 2009, when phase II was close to completion, the then-CFDA put a general halt to clinical stem cell applications. Nevertheless, Zhao was able to continue recruitment for clinical trials for biliary cirrhosis (ClinicalTrials.gov 2016), and for GvHD, in collaboration with CAMS, Zhejiang University and various military hospitals, which are regulated separately (ClinicalTrials.gov 2016b). In 2012, Zhao’s study was the first ‘pilot’ case to receive permission to conduct clinical trials ‘to test the new regulatory system’ (Cai, 28/10/2012*).
Being close to the corridors of power is advantageous: first, it helps in acquiring state support. In 2004, the Ministry of Science and Technology (MoST) invested approximately 40m RMB (some US$ 4.8m) into the research (People’s Daily 2005). Second, Zhao could help create the regulation from which his own research would benefit as standard model, and third, Zhao had access to a network of hospitals and state supported academies. Most elite laboratories of well-known academies and universities receive state funding through which they are tied to state policies. Usually, such elite laboratories develop a regulatory orientation of toeing the official regulatory policy-line. However, CAMS, by being close to power, was able to adopt a proactive orientation by contributing to regulatory developments.
Tianjin’s Stem Cell Cluster: Stem Cell Industrialisation
The entrepreneurial cluster around Tianjin Municipality exemplifies the hybridisation of state-supported higher educational institutions that have been able to attract private funding. Such clusters combine funding received from state institutions, local governments and private companies. Their institutional complexity provides them with the leverage to carve out developmental pathways that are not always supported by the central government. In 2000, Tianjin set up the National Stem Cell Engineering (NSCE) Industrialization Base, where its Research Center developed a technological platform (2002), which was to serve the development of the life sciences. Professor Zhongchao Han, a successful scientist who had spent eleven years in Paris, was asked to run the famous Institute of Hematology of the CAMS /Peking Union Medical College (PUMC). The Institute of Hematology received major funding from the state (IH 2014) and from private sources for the construction of buildings in the TEDA development zone. Han co-created the company Union Stem Cell & Gene Engineering (USCGEN) and, together with Zhao Chunhua, he set up the Tianjin Umbilical Cord Blood Bank in 2001. The local government invested over 10 billion RMB in the Tianjin Huayuan Hi-tech Park, where the Tianjin UCB was established. Claiming to meet international standards, it obtained a license from the MoH (IH 2014).
Under Han’s direction, fifty-odd hospitals in Tianjin started sending umbilical cord blood (UCB) to the bank. Soon, USCGEN managed and owned the entire process of UCB collection and research: recruitment, banking, cryopreservation, clinical application of stem cells, R&D, manufacture and the distribution of monoclonal antibodies and gene chips. In June 2002, USCGEN set up the University for Pregnant Women to persuade couples to donate UCB (Union Stem Cell 2014). With the support of the National Development and Reform Commission and the Tianjin City Government, the Cell Product National Engineering Research Center was set up in 2004. In the same year, however, Han pulled out his shares from USCGEN and established Tianjin Amcell Gene Engineering Co., Ltd., producer of human umbilical cord MSCs, adipose-derived MSCs, placenta-derived MSCs and amniotic membrane-derived MSCs. Its projects were financially supported by Tianjin City and backed by the work of the Institute of Hematology. In January 2007, Han also set up Hanshi or Huaxia Ganxibao Lianmeng (translated as ‘The Beijing Health and Biotech Group’), which specialised in placenta UCB banking (HanShi Lianhe Reference HanShi2011). In 2008, the Tianjin City UCB Bank and the China Bone Marrow bank linked up with Tianjin Xiehe hospital, which had opened in May 2007 and started to specialise in stem cell transplantation and genetic diagnosis in 2008. It has become a large-scale centre for stem cell storage, research and applications (Li, 5/11/2012*).
While receiving considerable state funding for the Institute of Hematology and the Cell Products & National Engineering Research Centre, Han’s network was mainly indebted to local investors. Links between this industrialisation hub, the country’s largest UCB bank, the placenta bank and the Institute of Hematology have yielded both wealth and fame. Han had built long-term international collaborations with laboratories in France and with Amcell and occupied important national positions as regulator, as respected academician, as ‘father of family banking in China’, as one of the initiators of a licensed UCB bank and as advocate of ethical research. The dense interlacing of powerful state and commercial institutions was a major challenge to regulatory oversight. Clamping down on one of these networks can affect the services of others, as financial and personal relations connect them. By contrast, elite laboratories that advocate ‘international’ procedures question the standards of the MSCs banked and used in clinical applications by Han. In their view, only transparency could lead to harmonised standards, which they regard as essential to safeguarding their reputation (Hou, 17/10/2012*).
The Military and Stem Cell Activities: A Separate World
China has a diverse network of military hospitals and research institutes, which can be found in all major Chinese cities. From 2005 to 2015, as today, they form a special category of medical service provision, which, together with university hospitals, are seen as the best in the country. Military hospitals have their own set of rules and regulations for clinical stem cell procedures and are overseen by military bodies such as the People’s Liberation Army – separate from the Ministry of Health – which answer to the Central Military Commission (cf. Art. 109 in MOJ 2021). Military research institutes provided stem cell therapies without state authorisation, including the Academies of Military Medical Sciences (AMMS 2014), and Peoples’ Liberation Army (PLA) universities, such as military police hospitals, PLA hospitals (Lyn Reference Lyn2011; Shizhentang 2014), navy hospitals (Intec 2014) and armed forces hospitals (B&D 2014; Sinostemcells 2015). Its simultaneous closeness to and regulatory isolation from the state has given the military advantages above other stem cell enterprises. Despite the announcement of the new 2015 draft regulation, military hospitals continued to provide unauthorised treatment through arrangement with small private clinics operating on hospital’s premises and under its license (Song Reference Song2011; Jourdan Reference Jourdan2016; Zhang Reference Zhang2017).
The military hospitals were early providers of stem cell interventions. According to An Yihua, director of the stem cell transplant department at Beijing’s General Hospital of the Chinese People’s Armed Police Forces, Chinese hospitals have been using foetal brain cells to treat patients since the 1980s. An’s hospital alone has treated thousands of patients with neural stem cells since 2003, including foreign patients from twenty countries (Tam Reference Tam2011). Many small hospitals followed suit. Top tier military hospitals, though relatively autonomous from a regulatory point of view, collaborate also with international contract research organisations (CROs) in multicentre clinical trials, such as the collaborative study of a phase I/II ischemic stroke trial by Neuralstem and BaYi Brain Hospital (Neuralstem 2014), and with hospitals and research institutes at home. Both CAMS and AMMS have close research links with the military hospitals to further translational research. The military provide therapies, not so much for profit but to study their efficacy rather. As such, the publication of research results at home is thought to be invaluable as a source of experience with stem cell procedures and as a basis for making research progress. In addition to state research institutions, there are also private research centres and hospitals that collaborate with the military by providing cell-processing services (Dan, 30/11/2012*).
Due to their exceptional status, the military hospitals have remained well-financed, closed pockets for research and the provision of stem cell procedures for a sustained period. The military have set up a solid research basis and publish widely, especially in Chinese journals. Despite the January 2012 Notification (MOH 2011), the military continued to collaborate with both private hospitals and prestigious academic research institutions such as CAS, providing them with access to patients at least until our visit later in the autumn of that year.
The Guangzhou Alliance: Mutual Self-help
The Guangzhou Alliance exemplifies university-linked alliances active in translating regenerative medicine into clinical applications. On 19 June 2008, twelve research institutes, hospitals and companies involved in regenerative medicine in the Guangzhou area forged a collaboration to set up the Guangzhou and Regenerative Medicine Alliance to facilitate clinical applications (Guangzhou Shengwu-Yiyaowang 2014). This collaborative network illustrates how it has been possible for a regional organisation to formulate its own standards for safety, efficacy, scientific protocols and ethics. Six stem cell science institutes in Guangzhou started developing clinical applications for the Guangzhou City Large S&T Expert Program (Guangzhou Shengwu-Yiyaowang 2014). The Alliance, headed by Professor Pei Duanqing from the Guangzhou Institute for Biomedicine and Health (GIBH), aimed, first, to further basic stem cell science, technological innovation and design industrialisation strategies, second, to provide technological training, contribute technical equipment to Guangzhou’s development and sharing of resources and, third, to develop clinical stem cell procedures.
One example is the Alliance, referred to in Chapter 2. This collaboration among a tissue-engineering centre (TEC) with various hospitals transplanted MSCs into thirty patients with GvHD, reporting progress in twenty-two patients (Guangzhou Shengwu-Yiyaowang 2014). Although TEC received funding from the Ministry of Education for basic stem cell research in 2007, it also received funding from the local government in Guangdong for translational research. In 2000, the research team found that administering BM-MSCs to rats decreases immunological rejection in GvHD, compared to transplantation of BM alone. The team leader (Deng, 25/4/2013*) told me that he had not considered clinical applications until he heard about a Japanese researcher using a mother’s BM-MSCs for her child’s GvHD and about Osiris conducting clinical trials on GvHD. As his university did not have enough funding for clinical trials, and funding from local government covered clinical studies alone, TEC started collaborating with hospitals from the Alliance using small amounts of funding, initially for two to three years. They planned to apply for a state license after the basics had been put in place. To the team leader, this research was not about making money, but about ‘returning the favor to the taxpayer’ (Deng, 25/4/2013*).
The Alliance had the following labour division: GIBH would provide technology, two women’s hospitals biomaterials, the Centre for Cells and Tissue Engineering, Southern Medical University, Guangdong Province People’s Hospital, the Third Affiliated Hospital of the Guangzhou Medical Academy and Guangzhou City’s First People’s Hospital would form the clinical research basis, while the companies Hanshi, Seer and Guangzhou Huanhuang were to commercialise. The Alliance used its own rules for conducting research and clinical translation to accommodate the high patient demand and to fulfill expectations of local investors: researchers were to have institutional review board (IRBs) permission before starting clinical research and register the research with the Guangzhou Hygiene Department. But after the government denounced unregulated experimental stem cell applications in May 2009, the Alliance started to invite staff from the CFDA as visiting professors to stay in the know about the ever-changing standards and regulations and to coordinate its activities with the CFDA. This, then, was to facilitate future applications for marketing licenses (Deng, 25/4/2013*).
The research orientation of the Alliance was incentivised by local needs and local research funding, which made use of alternative regulation until in 2009 it started to toe the official line. And after the publication of the 2015 draft-regulation, the research institutes related to the Alliance have started to operate on certified hospital premises as registered experimental interventions may be used as last resort treatment (CFDA 2015; Rosemann and Sleeboom-Faulkner Reference Rosemann and Sleeboom-Faulkner2016). In the meanwhile, local governments still exert funding pressures to provide stem cell interventions for GvHD and to start clinical trials.
Semi-dependent Enterprises from Changsha: In Anticipation of Guidelines
Semi-private life-science enterprises that have close links to the state, even though largely operating independently, tend to collaborate with the state in developing new guidelines in accordance with state rules. Xiangya Reproductive Hospital exemplifies this. Xiangya’s biomedical research in Changsha goes back three generations: Director Lu Guangxiu followed in her father’s footsteps, and her son followed in hers. In 1984, she opened China’s first in vitro fertilisation (IVF) clinic, and in 2003, she became president of the Institute of Reproduction & Stem Cell Engineering (Central South University) and president of the Reproductive & Genetic Hospital CITIC-Xiangya. CITIC (China International Trust and Investment Corporation) funded the initial commercialisation of the research.
The case of Lu’s ‘family enterprise’ illustrates that close state collaboration here meant conforming to official guidelines and a turn from applied to basic research. In 2004, the National Development and Reform Commission decided to fund a second national centre for stem cells, the National Centre for Human Stem Cell Research Engineering (NC-SCRE) in Changsha, and asked Professor Lu to lead it. The committee invested 20m RMB, while Lu had to raise an additional 90m RMB, which was partly provided by the Changsha local and Hunan Provincial governments (Li, 5/11/2012*). In 2009, Lu formed an enterprise, the Hunan Guangxiu Biological Science Co., Ltd., to build the National Centre and the Hunan Guangxiu Hospital next door. Apart from the clinically graded embryonic stem cell bank, CITIC-Xiangya and the NC-SCRE have an umbilical cord bank, a cord blood bank, a placenta bank and an induced pluripotent stem cell (iPSC) bank. Although CITIC-Xiangya have both a private and a public UCB bank, they now want to focus on the public bank to develop clinical stem cell interventions for patients with cerebral palsy, spinal cord injury, ischemia (for diabetes), cirrhosis of the liver and pancreatitis. The head of the UCB emphasised, however, that no clinical applications had yet been made: ‘Patients keep ringing to ask for help. But it would be a violation of state regulation, and we have no evidence for safety yet’ (interview Zhang). Lu and her team were the first researchers to engage with and publish on bioethics issues in practice. As soon as the new regulation is promulgated, the Changsha group hopes to receive funding for their UCB projects. Among their contacts in Beijing are Zhao Chunhua, who had permission to use BM-MSCs, and Wu Zuke, a famous academician from AMMS, who works with military hospitals (Li, 5/11/2012*). While Zhao and Wu continue their research, Changsha is waiting for the green light.
Although largely independent, this Changsha-based research hub, like many others, needs the support of regulators, licenses and collaborators in Beijing (CAMS/PUMC) to continue their lucrative IVF hospital. Ethics and research authorisation are crucial to their ability to conduct business and to their general credibility. This enterprise is known for its provision of training courses, ethics activities and publications and charity. Although regulatory stasis hampered its aspiration for translational research, toeing the official regulatory line was thought to be ‘ethical’ and rewarded in the long-run.
The Research Orientations described above can be summarised in Table 3.1, which illustrates that institutions with different interest and background are not easily governed.
Table 3.1 Research orientations
| Medical institutions | Researchorientations | |
| 1. | Close to government | Have influence on state regulation and tended to follow it |
| 2. | Military and police hospitals | Follow their own independent regulation |
| 3. | Commercial/financially independent | Tried to avoid state regulation |
| 4. | Regional collaborative initiatives | Created their own regulations |
| 5. | Dependent on state-finance/support | Abided by state regulations |
Regulatory Capacity Building and Regulatory Orientations
Building regulatory capacity in China requires juggling international and local opportunities, possibilities and requirements. Although the research institutions exemplified above (see Table 3.1) are discrete in some ways, they are also involved in alliances and organisations that are tied in with networks adhering to different scientific norms and regulations. These cross-cutting linkages can be found across China and beyond. Thus, we saw that Hanshi in Tianjin was a member of the Guangzhou alliance; Beijing’s CAMS operated a biobank with Tianjin’s Institute of Hematology; Changsha works closely with Beijing’s PUMC, CAMS, but also Lu Daopei hospitals, which works closely with military hospitals (Dan 30/11/2012*); and, besides having links to the cord blood banks of various provincial capitals, Beike has close links with Sun Yat-Sen University in Guangzhou. The networks are also sustained by myriad collaborations with research institutions abroad.
The sustained cultivation of life-science networks with their own communities of practice and the emergence of local regulatory orientations, summarised in Table 3.1, made the creation of an effective national regulatory infrastructure a major challenge. In the past, standards used in clinical stem cell practices developed by local investors and the stem cell industry contrasted with those vetted in official regulatory announcements. The 2015 draft regulation promised to eliminate this inconsistency. But local stem cell research communities had already invested in material and intellectual resources, patient recruitment, research networks, commercial relations and collaborative agreements with municipal, provincial and national governments over a sustained period of time, which entailed particular ways of dealing with standards and regulation in clinical stem cell research. They display a range of regulatory orientations regarding standards for safety, efficacy, scientific protocol, licensing and ethics, shaped variously through local, regional, public, private and state institutions. It is through these diverse regulatory orientations that the Chinese government had to balance the building of regulatory capacity with its international life-science strategy.
Regulatory Struggles and Responsible Innovation in India
A second example of regulatory boundary-work of an LMIC illustrates how the desire to economically compete and international reputation shape the development of a regulatory framework for regenerative medicine. India’s regulatory development, as embodied in the development of the company Stempeutics, illustrates that the importation of ‘ideal’ regulation from abroad is not independent from local conditions and economic ambitions and not determined by the standards set by its biomedical platform. When adapting regulations from abroad, compromises were made between ‘the ideal’ models used by the laboratories of the global elites and the standards aimed for at home.
In under a decade, policy-makers transformed the image of India as a land of commercial provider of stem cell transplants into a country of ‘responsible’ production of cell-based products. This effort is illustrated by the transformation of the regulatory orientation of Stempeutics Research Private Limited. Stempeutics was a trend-setting and leading ‘biomedical platform’ in the development of stem cell–based medical devices and therapeutic products, with facilities in Bangalore and Manipal (India) as well as in Kuala Lumpur (Malaysia). This case study shows how Stempeutics’ transformation created the conditions for a major shift in stem cell research and cell-based product development in India.
This shift in the organisation of a biomedical platform is often represented as a technological development. In the STS literature, biomedical platforms are assumed to spread through the dynamics of scientific and technological requirements of the biomedical products concerned (e.g., Keating and Cambrosio Reference Keating and Cambrosio2000, Reference Keating and Cambrosio2003). The notion of platform refers to both the equipment and technology and to the implementation and coordination of biomedical interventions (Keating and Cambrosio Reference Keating and Cambrosio2003: 345). For instance, instruments that count the number of CD4 cells in HIV-patients need to serve AIDS control activities. The order created by the platform results from a consistency of purpose between the various parts, such as the match between measurement and diagnosis. Platforms, then, rather than for political or commercial aims, generate configurations of techniques/instruments for certain (biomedical/technical) purposes (Keating and Cambrosio Reference Keating and Cambrosio2003: 348). Forming both technological support and a springboard for action, platform dynamics are not incentivised by the politics of scientific and technological change but are the result of it.
Functionalist approaches to research platforms can easily draw attention away from the role of turf struggle in their development. Rather than tracing the scientific and technological dynamics of the biomedical platform, the case of Stempeutics illustrates the contentions and political considerations in moving from a platform of commercial stem cell provision to one of ‘responsible’ producer of stem cell products. The evolution of Stempeutics’ biomedical platform in India shows that in a globalising world with scientific and technological pioneers and followers, the shift between platforms is dominated by international and national entrepreneurial considerations, political interests, regulatory limitations and resource constraints. Pioneering a novel biomedical platform in India, Stempeutics altered protocols, procedures and standards reconfigured to suit its own situation, product requirement, institutional capacity, available expertise, collaboration, equipment and so on. Accordingly, it developed its own regulatory orientation.
Stempeutics regulatory orientation regarding stem cell research, clinical trials and product-development changed radically in the period between 2006 and 2014. These changes were driven by the introduction of new regulations (see below). Enquiring about the radical changes in company strategy, the Company’s CEO welcomed Prasanna Kumar Patra, my co-researcher, and me to talk with personnel about the history of Stempeutics and its stem cell–based products in September and October 2013 and between May and June 2014. The story of Stempeutics illustrates what happens when an enterprise decides to develop biomedical products similar to those in pioneering countries – but on the basis of adapted methods of protocol writing and regulation from abroad and with limited intellectual and material resources. It shows how political incentives create spaces for the regulatory orientation that skews the relation between biomedical product and biomedical need, for instance, by privileging biomedical products according to regulatory convenience and following the path of least regulatory resistance.
Regulatory Capacity Building
In 2007, the Indian Council of Medical Research (ICMR) and the Department of Biotechnology (DBT) jointly released the Guidelines for Stem Cell Research and Therapy. The regulation would guarantee safe and efficacious stem cell research and treatment using the three categories of Permitted, Restricted and Prohibited. The notion of ‘therapy’ in the title of the Guidelines had created much confusion, as it has the positive connotation of medicine that works. So why restrict or prohibit it? The 2013 National Guidelines for Stem Cell Research (2013) retained the earlier classification of stem cell research but with an additional layer of oversight, besides the Institutional Ethics Committee (IEC), in the form of an Institutional Committee for Stem Cell Research (IC-SCR) and the National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT). Crucially, and following practices abroad, it omitted the word ‘therapy’ from the Guidelines, emphasising that there could be no guidelines for therapy until its efficacy was actually proven. The guidelines included both basic research and translational applications, but not therapy, making applications contingent upon permissions. This development was reflected in Stempeutics’ shift from therapy provision to translational research and its role as ‘model’ for the development of stem cell applications in India.
Following regulatory changes in the United States, the Guidelines further emphasised that the use of any stem cells in patients, other than hematopoietic stem cells for approved indications, had to be investigational. Investigational, following regulatory developments in the US, refers to experimental research that has been authorised. Accordingly, any stem cell applications in humans were to take place within the purview of an approved and monitored clinical trial with the intent to advance science and medicine: the use of stem cells in patients outside an approved clinical trial was to be considered as malpractice (ICMR-DBT 2013). The amendment in the Drugs and Cosmetics Act (DCA) mandates that all stem cells and cell based products that can be used for therapeutic purposes shall be referred as Stem Cell and Cell Based Products (SCCPs) and that all activities related to their usage, that is, manufacture, isolation, collection, storage and transplantation into patients required a license granted by the Drug Controller General of India (DCGI)/ Central Drugs Standard Control Organisation (CDSCO 2013). This regulation inaugurated the development of a sharp discursive divide between the leading elite laboratories, such as Stempeutics, and the sea of unauthorised stem cell clinics (Tiwari and Raman Reference Tiwari and Raman2014), a phenomenon further discussed in the next chapters. Important in the current study, however, is the assumption, held by both scientists and managers, that the elite laboratories had imported regulation solidly built on the scientific and functional requirements of their biomedical platform. As will become clear below, the importation of regulation, also when adapted, conditioned not just technological necessities but also altered the biomedical possibilities.
Stempeutics’ Shift in Stem Cell Business
Stempeutics in 2007 changed its business plan from a lucrative clinical provider of stem cells to a mainly research-based allogeneic stem cell product development corporation. The stories behind Stempeutics’ new regulatory orientation personnel narrate as an epic of ‘responsible innovation’.
Stempeutics was established by the Manipal Group in 2006 in Bangalore in the midst of India’s biotech boom, of which Bangalore was a vibrant hotspot. The Manipal Group or Manipal Education and Medical Group (MEMG) is one of India’s largest private institutions in education, research and healthcare, active at home and abroad. In 2006, MEMG appointed a scientist, Dr Ratan Pal (pseudonym*), as the first director and scientific head of Stempeutics. By then, Dr Pal had spent over four years at Reliance Life Sciences in Mumbai, another frontline private stem cell company in India, and before that he was with a public-sector research institute named National Institute of Immunology (NII), in New Delhi. Dr Sanjay Singh, a scientist who until recently was in charge of Stempeutics’ Malaysian branch first sets Stempeutics’ decision to reorganise in a national regulatory context. He explained that, in 2006, Dr Pal was utilised by Stempeutics and the Manipal Group to generate revenue through stem cell therapy related services. But after the introduction of the 2007 ICMR-DBT and stem cell guidelines, he realised that the activities of Stempeutics and Manipal were not going to remain lucrative (Singh, 24/5/2014*).
Next, Dr Singh set the decision to reorganise in a global economic and scientific context, explaining that, at the time, there were many stem cell companies in the West, especially in the US and Canada, that were getting encouraging results from mesenchymal stem cells, and many were engaged in allogeneic stem cell product development (Singh, 24/5/2014*). Dr Pal impressed upon the Manipal Group the marketing advantages of the strategy of changing the enterprise from therapy provision to stem cell–based product development grounded on research. Dr Pal then recruited young scientists from reputed institutes such as the Indian Institute of Science (IISc), Bangalore, including Dr Uday, Dr Jyothi and Dr Rakhi. The parallel exercise of translational research at Stempeutics and the provision of clinical stem cell applications at Manipal Hospital continued until 2008, after which Stempeutics decided to stop therapy provision altogether and focus entirely on stem cell research and product development. Dr Pal and Stempeutics’ management decided to focus on allogeneic stem cell products.
In 2007–2008, Dr Pal moved to Stempeutics’ Malaysian branch at Kuala Lumpur as the head of the unit, and after a few years he left Stempeutics to open his own company in Mumbai called Kanishka (pseudonym*). Subsequently, there was a structural shift in Stempeutics’ entrepreneurial activities. The organisational set-up of Stempeutics was rewired in pursuit of linking up basic research, cell processing, industrialisation and therapy provision. This set-up resembles the heterogeneity and interconnected nature of the biomedical platform described by Keating and Cambrosio (Reference Keating and Cambrosio2000), where it is ‘less of a thing than a way of arranging things’ that characterises its network-activities (Keating and Cambrosio Reference Keating and Cambrosio2000).
After Dr Pal moved out of Stempeutics, Mr M. Kumar, the current CEO, an engineer by training and a close aid of MEMG, was asked to lead Stempeutics’ business side. He joined Stempeutics in August 2008 and was made responsible for generating funding and looking for partners that could support Stempeutics’ research activities. Dr Singh described the importance of entrepreneurial networking across national boundaries that took shape under Mr Kumar’s leadership. By this time, only the Manipal Group was investing in Stempeutics, and their earlier revenue from clinical applications and stem cell processing had already dried out. Then, Cipla became collaborator in 2009 and it agreed to fund the research by giving Rs. 50 crore (US$8 million) every year towards research. The scientific team of Cipla (an Indian multinational pharmaceutical and biotech company) became convinced by the proposal of Stempeutics for allogeneic stem cell product development (Kumar, 24/5/2014*).
Stempeutics’ development of stem cell–based products using allogeneic MSCs now only focused on eight indications: ischemic cardiomyopathy (ICM), acute myocardial infarction (AMI), (liver cirrhosis (LC), critical limb ischemia (CLI), CS, chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM) and OA (osteoarthritis). Financial constraint influenced the selection of indications. Stempeutics’ scientist, Dr Chaturvedi (pseudonym*) explained that the expenses per disease condition, from basic, to pre-clinical to clinical, are huge, so that focusing on many disease conditions was not financially viable (Kumar, 28/5/2014*).
The shift from exclusively ‘therapy’-provision to the simultaneous practice of research and clinical interventions and, finally, to stem cell-based product development, led Stempeutics to expand and reshape its networks and to develop a new scientific infrastructure and functional regulatory approval mechanism. This socio-scientific network structure brought public-sector research institutes, clinical research organisations (CROs), pharmaceutical companies, corporate hospitals and small clinics together, forging a new collaborative biomedical platform. Advanced technological and scientific infrastructures were created around the stem cell–based product development process at Stempeutics with the support from the Manipal Group and Cipla pharmaceuticals.
Regulatory Capacity Building and the Biomedical Platform
Regulatory capacity was central to Stempeutics’ threefold plan of ethical standardisation, protocol development and clinical data generation. Forming institutional review boards (IRBs), managing and educating board members capable of evaluating a project application and providing technical recommendation required, according to Stempeutics, immense resource mobilisation. Its role in regulatory capacity building eventually led to Stempeutics’ invitation to play an advising role in India’s regulatory efforts of regenerative medicine. CEO Mr Kumar explained that, along with the regulatory and policy-making bodies, they tried to address the regulatory concerns and to make scientific practices meaningful, accountable and transparent (Kumar, 27/5/2014*).
Regulatory capacity building, then, was seen as key to both scientific and business development. To Stempeutics, the opportunity to co-create research regulation meant that it could more easily comply with the new regulation, handle regulatory knowledge and build scientific research on a nationally and internationally acknowledged basis. In other words, it had the regulatory authorities to vouch for the legitimisation of its scientific research, as it had helped build it.
It was then that Stempeutics decided to develop a biomedical platform for three stem cell–based products that were destined for the market: Stempeucel, Stempeutron and Stempeucare. Stempeucel is a stem cell product based on cultured adult allogeneic mesenchymal stromal cells. Stempeucel was targeting various degenerative disorders as an on-demand off-the-shelf product available to clinics and hospitals. It uses cryopreservation techniques to attain higher numbers of viable cells after thawing and without losing their multi-potent differentiation and cytokine production capacity. Stempeutics had regulatory approval for clinical trials on three indications: Liver Cirrhosis (LC) in India, Osteoarthritis (OA) in India and Malaysia, and Critical Limb Ischemia (CLI) in India. For Acute Myocardial Infarction, Stempeucel was in phase I in India, and for Ischemic Cardiomyopathy it was in the pre-clinical stage in Malaysia. It had received phase 2 approval from the DCGI for Diabetes Mellitus Type 2 and for COPD in India, and Phase ½ approval for Cerebral Stroke from NPCB in Malaysia (Stempeutics webpage 2015).
Stempeutron is a point-of-care, fully automated stem cell isolation device for the isolation of autologous stromal vascular fraction (SVF) from fat tissue, intended for cosmetic and reconstructive procedures. This device can be used for breast reconstruction/cosmetic breast augmentation, facial restructuring, deformity correction and scar and wrinkle reduction (Stempeutics webpage 2015). Kumar, its CEO comments:
Compared to other similar products worldwide, Stempeutron was to be cost-effective and more flexible. Its uniqueness lies in the use of the ‘filtration method’ (rather than a ‘centrifugal method’, used by Cytori), ‘robotic arms’ and being ‘tubeless’.
Kumar explained that the product was expected to be one-fifth of the price charged by multi-national companies, such as Cytori (Kumar, 27/5/2014*).
Stempeucare is a conditioned medium derived from BM-MSCs for cosmetic applications. The conditioned medium contains more than 200 growth factors and cytokines, of which Stempeutics had quantified about 30. They are claimed to play an important role in tissue regeneration and repair (Stempeutics webpage 2015). Some of these factors would possess biological activity for skin repair and rejuvenation. One skin health product in the Stempeucare range has passed the phases of pre-clinical efficacy and safety. According to Stempeutics’ CEO, ‘it has received the Karnataka Government’s approval for a human volunteer study. Its launch was expected within six months; while a Stempeucare product for hair growth was expected to reach the market soon, too’ (Kumar, 27/5/2014*).
These three products developed at Stempeutics target different categories of clients, follow different regulatory pathways – in India or Malaysia – and cater to different market logics (Figures 3.2–3.4). Stempeutics attaches importance to developing three quite different products for strategic reasons. Dr Singh reasoned that:
As a cell-based allogeneic product, Stempeucel will have a long gestation period and it is [to go] through an uncertain regulatory approval process. One is not sure when it would come to the market and one can get back his money.
Economic and regulatory considerations clearly play an important role in the decision about therapy targets. The other two products, Stempeutron and Stempeucare, are relatively less capital-intensive and have a shorter gestation period. According to Dr Singh, they have a market waiting for them:
The global market for cosmetic surgery services were $31.7 billion in 2008, a figure that was expected to reach $40.1 billion in 2013, with a compound annual growth rate (CAGR) of 5.2 per cent.
The International Society of Plastic Surgeons survey ranks India fourth in the number of cosmetic surgical procedures (850,000) performed per year (compared to 3,100,000 in the number one ranking US). India also ranks fourth in the number of breast augmentation surgeries performed annually, which is market valued at US$ 600 million market (PharmaBiz 2012). Keeping these market figures in mind, Mr Kumar emphasised that, while the medical device market was projected to grow to $5.5 billion in 2014, with a CAGR of 15 per cent, indigenously developed technologies would address the temporary financial shortfall. Therefore, while the first product is the ultimate objective of Stempeutics, the latter two are meant to capture the currently emerging market. In other words, what is affordable, sellable and regulatorily manageable was the key to product functionality: how products work is important financially, scientifically and reputationally, but where the means did not reach, the efficacy of the product might have to be near-enough and first applied in less well-regulated areas. Biomedical platforms, then, can be disjointed.
Stempeutics’ New Regulatory Orientation as Model
By switching its focus from clinical stem cell applications to product development, Stempeutics had already been able to improve its image as a ‘responsible’ industry, but its role in changing India’s regulatory scenario turned it into a ‘model’ for others to follow.
India had reformed its stem cell regulation between 2008 and 2012. This was a time of expansion of clinical stem cell applications and of patients visiting India for stem cell treatment from abroad (Srinivasan Reference Srinivasan2006; Bharadwaj and Glasner 2009). In this period, the ICMR and DBT took steps to address gaps in the 2007 stem cell guidelines. This happened in the context of media reports about medical malpractice, false clinical claims and issues of patient safety, vilifying the practices of unlicensed therapy providers (Lau et al. Reference Lau, Ogbogu, Taylor, Stafinski, Menon and Caulfield2008; Pandya Reference Pandya2008; Kiatpongsan and Sipp Reference Kiatpongsan and Sipp2009; Patra and Sleeboom-Faulkner Reference Patra and Sleeboom-Faulkner2009; Bharadwaj Reference Bharadwaj2012; Tiwari and Raman Reference Tiwari and Raman2014).
Stempeutics played an active role in this crucial period in India’s regulatory revision by representing the stem cell industry in India in various committees. This provided Stempeutics with an opportunity to familiarise itself with the systemic, scientific and managerial requirements for regulatory approvals. Dr Vimal (pseudonym), who represented Stempeutics at several deliberations and drafting committees of guidelines, explained that the application for clinical trials was difficult on two counts. First, Stempeutics was new to the field, which itself was emerging, so there was a need to develop R&D protocols for pre-clinical and clinical studies and to write good project proposals. And second, as regulatory bodies and their external expert committee members had limited knowledge of stem cell science and technology, including the evaluation of project proposals and research outputs, it was a learning experience for most (Vimal, 8/5/2014*). As one former evaluation committee member for clinical trials on osteoporosis, Professor Srinivasan (pseudonym), remarked:
The Stempeutics case was more of a learning experience than an evaluation. We had to look at what happened in cases in the USA and other places. At times, we dealt with ‘firsts’, so we had to educate ourselves before assessment took place.
With hindsight, many at Stempeutics believe that the initial challenge turned into an advantage for Stempeutics. Dr Vimal explained that after the first approval in 2009, they learned how to negotiate and how to reach the expectation levels of the regulatory committee members. They then were invited to all deliberations on regulatory body meetings. Some of the staff became invited members to various committees.
Initially, Stempeutics hardly knew how protocols were to be prepared, how clinical-grade cells were made for products, how to address the needs of the regulators and how to plan clinical trials. In fact, members of its central regulatory body admitted that they had lacked expertise. In 2017, the Drugs Controller General actually granted conditional approval for manufacturing and marketing of Stempeucel products for the treatment of Critical Limb Ischemia. This was celebrated as a major triumph. Stempeutics, then, is satisfied that it has transformed its image from being engaged in unauthorised stem cell experimentation to a leader and benefactor of regulatory capacity building.
Stempeutics has emerged both as an experimental space of the state’s regulatory experiment and as an agent in addressing the regulatory challenges of cell-based product development. Nevertheless, the question remains how Stempeutics’ research outcomes will be received and also how they will be rated scientifically. First, the reputation of India’s regulation as un-implementable may still stain Stempeutics’ name, and, second, the fact that Stempeutics conducts clinical trials also in Kuala Lumpur, where regulation is viewed as more forgiving, may arouse doubts about the quality of the trials. Clearly, in order for a biomedical platform to work, it does not just need to be in functioning order and comply with international standards; it also needs to be recognised as such. Stempeutics’ biomedical platform developed stem cell products based only partly on India’s medical needs and mainly on what was regarded as internationally lucrative, risky and regulatory feasible. At the same time, its products catered to different categories of clients, followed different regulatory pathways and targeted different market logics.
The varying product requirements make for different political, economic and regulatory demands of the biomedical platform. The challenge for Stempeutics, then, was to prepare itself to steer the course of harmonisation as a ‘process of recognizing and reconciling regulatory differences’ (Issai 2009) in the evolving Indian stem cell field, rather than to explore the standards and infrastructure appropriate for a desired therapeutic product. In short, Stempeutics’ shift in its business plan was incentivised largely by the politics of standardisation and international competition and affected the operational basis of the biomedical platform. In other words, the biomedical platform was not so much about how to cater to particular biomedical conditions in an effective way but about which products and regulatory pathways could lead to permissions, recognition and the market.
Conclusion
Although we cannot generalise the implications of the case studies to the world, it is possible to discern a pattern of boundary-work based on the way regulation is created in LMICs under regulatory capitalism. The hegemonic currency of ‘international regulation’ has implications for rising powers and large LMICs, if not for other countries, too. Although, in theory, enabling innovative research and technologies in ambitious LMICs to compete internationally with elite laboratories elsewhere, innovators do not have the space to develop standards that are suitable to the financial capacity and availability of expertise relevant to particular biomedical platforms. In both China and India, this situation led to a split between elite scientific laboratories that aim to compete in the ‘international science community’ and those involved in the life-science industry and medical care. This split is one of several that result from regulatory capitalism, which polarises creators and followers of regulation on both an international level and on a national level, leading governments to engage in regulatory boundary-work and local players to develop particular regulatory orientations.
We saw that even model biomedical companies and institutes struggle to follow the high standards of regulation, which they themselves sometimes help to develop. This situation aggravates the conflict between elite research centres and other research institutions, including those in the biotech industry. Although the biotech industry invests in research equipment, materials and processes, it has often shied away from the prohibitive costs of clinical trials. We saw that in China this led local investors to collaborate with researchers and hospitals directly, developing their own guidelines, a shift of translational research to the military hospitals and to clandestine therapy provision; in the example of India’s Stempeutics, we saw that industry was invited to play a role in formulating the regulation, which raised the preparedness of industry to invest. Nevertheless, this did not prevent commercial providers from continuing to offer unauthorised stem cell interventions.
Regulatory capacity-building, then, does not just serve scientific and technological requirements for ‘catching up’ with advanced players in the race to clinical firsts in regenerative medicine; rather, it follows the strategic priorities of competing internationally in the future and being competitive to survive in the present. The chapter’s case studies show from different angles how the development of regulation in LMICs are closely linked to government policies that need to cater to economic growth targets and address public health issues, including thalassemia, GvHD, Diabetes Mellitis and liver cirrhosis. To remain competitive, companies strategically target products that are sought after, such as ‘cosmetic cell therapies’ and conditions with existing treatments, next to other long-term therapeutic product targets.
A widespread view, including STS debates on biomedical platforms, attribute the technological rationale of biomedical platforms as informing regulation. What is underexposed, however, is that the globalisation of regulation gives a temporal advantage to pioneering industries. Rising powers show that the future of regenerative medicine does not so much result from a linear process of scientific and technological capacity (Keating and Cambrosio Reference Keating and Cambrosio2000, Reference Keating and Cambrosio2003) but is actively created in the present through contested claims over technological potential and its economic viability. For this reason, ‘regulatory capacity building’ is not just a matter of mimicking industrially advanced countries. Global regulatory hegemony is partial and dynamic and therefore modulated by the reality of local needs and developments, especially in LMICs. This chapter, therefore, concludes that neither global hegemony approaches nor approaches that emphasise the scientific rationale of regulations are sufficient to explain the global dynamics of regulatory development in the field of regenerative medicine. Any such explanation would have to take into account the dialectic between the political desire to compete globally and the regulatory orientations that underpin the country’s regulatory boundary-work.
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