Recent media reports highlight the need for public authorities at all levels to enforce their legal responsibilities to ensure that patients only have access to those treatments that comply with relevant quality standards and for which there is appropriate traceability of materials, treatment protocols and patient follow-up measures. The European Medicines Agency stresses that the protection of patients is at the core of those rules.
Introduction
Owing to its global dynamics, regulatory developments in regenerative medicine simultaneous repel and incorporate what is condemned as ‘unethical’. This chapter understands such regulatory boundary-work through the notions of regulatory immunity and regulatory tolerance (also see the introduction to Part II). Just as the notion of immunity emphasises the boundaries of the body or of the community, this approach to regulation emphasises the crucial role of the creation and ‘performance’ of regulatory boundaries in jurisdictions. After discussing the possibility of universal regulation of clinical stem cell provision, I will compare regulation for clinical applications of mesenchymal stem cells (MSCs) in the context of an LMIC (China) and in various HICs (US, Australia and the EU). Even though this comparison is very general, it will tell us something about the ways in which countries with different regulatory reputations and national income deal with scientific uncertainty and the ethics of ‘experimental’ interventions. It will become clear that countries, disregarding their regulatory reputation, find ways of circumventing the rules. My aim is to show that a country’s tolerance for regulatory flexibility depends on the international position and science policies in a global context. Finally, I will briefly discuss the call for regulatory harmonisation and global regulatory oversight through the World Health Organisation (WHO).
Regulatory boundaries in regenerative medicine came about when political authorities took over the responsibility from professional communities to regulate themselves. The various stakes scientists have in the political economy of their trade, characterised by fierce competition and strategic collaborations, make self-regulation a liability. The regulation of regenerative medicine facilitates and delimits what otherwise would be regarded as an experimental practice. Stipulating the conditions under which innovation takes place aims to optimally safeguard the rights and safety of patients and the quality of science. Without regulation, it is suspected, promising technological innovations would be imitated by profit-motivated copycats and traded in an uncontrollable manner. This fear leads regulators to stress the public importance of their legal responsibilities. For example, EU’s regulator EMA in the epigraph heading this chapter insists on the priority of patient protection in its 2007 Regulation (EC No 1394/2007).
Without regulation and standards, rivalry among providers of stem cell interventions could culminate in physical and mental harm to patients, financial loss, opportunity costs and anxiety about the reliability of such interventions. Its lack would also hamper the growth of scientific knowledge, as a difference in procedures would make a systematic comparison impossible. Though regulation has the potential to protect a stem cell community against violators, as we shall see, views on what are reliable stem cell interventions and scientific knowledge differ widely across regions. Moreover, what counts as the risk of physical and mental harm to patients, financial loss and opportunity costs also starkly differs. This means that countries require their regulation to do different jobs, and it is this that opens up structural spaces for competition.
I here use René Girard’s notion of ‘mimetic rivalry’, defined in the introduction to Part II as a form of competition based on self-identification with others, to characterise competition in the world of regenerative medicine, that is, imitating what are hyped as promising approaches in the field. New trends in life-science innovations are followed globally, some of which include the shift in clinical research focus from adult stem cell therapy, tissue-engineering, hESCR, gene-therapy and iPS to direct reprogramming, immunotherapy, stem/progenitor cell therapy and transplantation and a recent shift towards organ bioengineering utilising stem- and progenitor cells and genome-editing. These shifts are accompanied by new political decisions about project funding, research regulation and economic forecasts. As illustrated by a discussion from the House of Lords in the UK, such discussions are about global competition, regulation and national productivity:
The UK is facing increased competition for investment from Pharma relative to far-eastern markets, including India and China: disinvestment in the UK is a severe threat, given the GVA and rents accruing to the UK from the pharma industry. Growth in cell therapies offers a strategy to substitute and safeguard high value jobs in the UK. Comparative advantage: the UK is losing its comparative advantage in pharma manufacturing, R&D and clinical trials, despite the resilience of UK pharma manufacturing, the very positive changes brought about by NIHR and the recent Government initiative to reduce regulatory barriers. The UK retains a comparative advantage in cellular therapies and is for the moment pre-eminent in Europe. Action to support regenerative medicine nationally will ensure that this comparative advantage is enhanced. Indirect economic benefits: These benefits accrue to patients wherever treated, so therapies developed, manufactured in the UK and exported will benefit economies globally. Nonetheless, the NHS in being an early adopter of cell therapies will give the UK an advantage in labour factor productivity, relative to its global competitors, through reduced levels of sickness absences.
To gain insight into relations between national ‘Selves’ vis-à-vis regenerative medicine and healthcare provision at home, on the one hand, and vis-à-vis their global position in the world, on the other, this chapter asks how frictions between national Selves and Non-Selves – that is, other jurisdictions – can be explained in terms of regulatory immunity and regulatory tolerance.
Since the 1980s, the growing importance of the reputation of regenerative medicine has increasingly cast doubt on the regulatory and ethical integrity of science (Carpenter Reference Carpenter2010). The US halt in 2001 to federal funding of research using new hESC lines for ethical reasons, for instance, shows that research regulation involved much more than the safety of patients and the efficacy of research. Protection against reputational risk (Larkin Reference Larkin2003; Sleeboom-Faulkner Reference Sleeboom-Faulkner2010) demanded that recipients of state funding would not just have a scientifically safe and sound research plan; ideally, they would also fulfill moral expectations, have publications in international peer-reviewed journals, perhaps engage in prestigious international science collaborations and have a good ‘scientific’ reputation, both internationally and at home. The same is true in countries often critically and strategically associated with ‘rogue’ science, such as China and India (see Chapter 1). China’s Ministry of Health (MoH) published formal guidelines for hESR in 2003 (Sleeboom-Faulkner 2008). Scientists involved in hESR felt the urge to distance themselves from both ‘muddlers in the countryside’ and from scientists engaging in Traditional Chinese Medicine (TCM) (Sleeboom-Faulkner Reference Sleeboom-Faulkner2010). A leading stem cell scientist doubling as regulator in Beijing, for instance, accused a successful TCM scientist working on burn wounds of trading in snake-oil business, while the TCM scientist scolded established scientists for failing to see the body as a whole, as well as for wasting millions of government funding. In a global context, established Chinese scientists involved in hESR compared Chinese science favourably to its Western counterpart by pointing to China’s ‘scientific atheism’ being able to steer clear from anti-abortionists and to China’s highly capable leaders, who are engineers, rather than lawyers or actors (Sleeboom-Faulkner Reference Sleeboom-Faulkner2010).
Scientific boundary-work (Gieryn Reference Gieryn1983) can tarnish reputations with far-reaching consequences. Chinese regulators have felt the need to combat ideas about China’s science community as the ‘Wild East’ (Bionet 2007; Zhai et al. Reference Zhai, Ng and Lie2016). A negative international reputation can weaken the credibility of a nation’s science, make it harder for scientists to get through peer review of international journals, make China less attractive for science collaboration with renowned science institutions and make it harder for Chinese scientists to defend the value of homegrown research ideas in a global setting (Sleeboom-Faulkner Reference Sleeboom-Faulkner2010; Zhang Reference Zhang2012). Under these conditions, it became important for China’s government to stimulate Chinese science institutions while at the same time defend the reputation of China’s pioneers, including its main target of international criticism for ‘stem cell tourism’: Beike Biotechnology Company or ‘Beike’. Beike was established in 2005 in Shenzhen. With 25,000 unauthorised treatments in its first decade (BeikeBiotech 2016b), Beike became a thorn in the side of both foreign and national elite laboratories in the field of regenerative medicine.
A global loss of the reputation of a research field might be blamed on the ethical recklessness of countries that try to forge ahead with controversial clinical applications no matter what (Tam Reference Tam2011; Salter et al. Reference Salter, Zhou and Datta2015; Chen Reference Chen2017). Cultures of scapegoating obtain when the ‘universal’ rules of the powerful are mobilised against violators to protect the reputation of the field. A globalised world, in which scientific self-regulation cannot be trusted and where global institutions that can enforce regulation are absent, cultures of scapegoating are fostered through mimetic rivalry, whereby some set the standards and others are expected to follow. Countries use regulation to protect the quality of scientific research and patients subject to clinical research and practices. The ascribed reputation of regulation, I refer to as ‘regulatory immunity’. Paradoxically, within the same jurisdiction, such regulatory immunity can go hand in hand with regulatory tolerance for unauthorised stem cell activities. Other countries may be accused of failing to implement regulation for these very same activities. In other words, the frictions between Self and Non-Self as embodied in regulatory values are internalised, requiring regulatory tolerance for regulatory ‘sin’. An exploration of regulatory immunity aims to clarify why countries decide to destroy and/or internalise what they condemn.
From approximately 2008, clinical stem cell providers have been criticised, reported and analysed by social scientists and the press (Kiatpongsan and Sipp Reference Kiatpongsan and Sipp2009; McMahon and Thorsteinsdottir Reference McMahon and Thorsteinsdóttir2010; Cyranoski Reference Cyranoski2012a). Governments in the US, Hungary, the Netherlands, Germany, Ireland, Belize and elsewhere closed down clinics that provided ‘unauthorised’ SCIs, while others failed to stop stem cell providers from charging high fees to administer ‘unproven therapies’ (Sipp Reference Sipp2009). The distinctions between ‘legitimate’ and ‘illegitimate’, ‘evidence-based’ and ‘traditional’ and ‘science-based’ and ‘experimental’ stem cell research and therapy have been subject to heated discussion among established scientists and critics. Observers make these distinctions to imply the existence of forms of stem cell research, applied by quacks, not to cure disease, but to exploit innocent mugs. Anthropologist Aditya Bharadwaj was among the first to question these distinctions in the context of India (Bharadwaj Reference Bharadwaj2013), criticising the binary between ‘kosher’ randomised control trials (RCTs) and ‘rogue’ stem cell clinics. As a result of the sharp and highly publicised distinction made between ‘universal RCTs’ and local forms of ‘rogue experimentation’, discussions failed to take into account the historical, cultural and political of these global developments.
Criteria for Allowing Clinical Stem Cell Intervention
There are at least four political desirables entangled in discussions about regulatory harmonisation of clinical science applications. First, there are patient needs and demands that need to be addressed; second, the quality of scientific research needs to be protected; third, methods of testing need to be affordable; and fourth, investment of regenerative medicine needs to be economically lucrative. The first two desirables underpin regulatory ideals, while the last two are often viewed as a matter of political preference. We know there are patient demands, but where there is scientific uncertainty and disagreement, such as in the areas of ‘mesenchymal’ cells, it is questionable whether they can address the needs of patients. How countries deal with such issues very much depends on the third and fourth desirables of affordability and the political desire to turn science into income.
As pointed out in Chapter 2, the regulation of autologous stem cells has been subject to heated discussion, because when removed from the body, they may change in an undesired and risky way. A widely discussed legal dispute came about regarding an injunction against Regenerative Sciences in the US regarding Regenexx-C. It concerned the point at which isolated bone marrow stem cells from the patient become unsafe to administer as a therapy against joint pain. In 2010, the FDA called it illegal, referring to it as the ‘manufacturing, holding for sale, and distribution of an unapproved biological drug product’, a judgement that was upheld in 2012 (Cyranosky Reference Cyranoski2010, Reference Cyranoski2012b).
A closely related issue pertains to the safety and efficacy of ‘MSCs’. MSCs have gained great currency in the world of regenerative medicine. Currently there are hundreds of clinical trials using ‘MSCs’ for conditions ranging from immune disorders, diabetes and stroke to lung disorders, arthritis and heart disease. This trend is gratefully cited on the websites of unauthorised stem cell clinics, without mentioning its controversial nature (Magellan Stem Cells 2020). Stem cell scientist Paolo Bianco warned against what are traded globally as MSC-therapies. He pointed out that they do not contain stem cells and are risky (Bianco Reference Bianco2013). Although they may have some transient impact, even when used autologously, they are not safe: intravenously infused MSCs die rapidly and form bone (Bianco et al. Reference Bianco, Cao, Frenette, Mao and Robey2013a, Reference Bianco, Barker, Brüstle, Cattaneo and Clevers2013b). In fact, many scientists, including Arnold Caplan (who came up with the category of mesenchymal stem cell), now argue that MSCs are not stem cells but ‘mesenchymal stromal cells’ or ‘medicinal signaling cells’ (Sipp et al. 2018b). Chinese scientists in a well-equipped lab in Shanghai (Qi, 16/11/2012*) agreed that it is by no means clear by which method and how many cells should be administered, where the cells go and whether they home in, transform or disappear.
Scientists’ warnings about the lack of clarity of how MSCs work and the risk of, for instance, undesirable immune responses, tumour formation and the transmission of incidental agents (Bianco et al. Reference Bianco2013; Bianco Reference Bianco2014; Bianco and Sipp Reference Bianco and Sipp2014; Robinson et al. Reference Robinson, Murray and West2019; Saeedi et al. Reference Saeedi, Halabian and Fooladi2019), had little effect. Providers, however, sometimes make distinctions between careless and explorative applications. An example of the first are ‘MSC-therapies’ that fail to distinguish on their overview for clients listing treatable conditions between the treatment of disease conditions, such as Alzheimer Disease, diabetes, Parkinson’s Disease and Spinal Cord Injury (SCI) (e.g., BeikeBiotech 2021). A pilot study specialising in only one condition, say treating Parkinson’s disease with dopamine neurons (Yin et al. Reference Yin, Tian, Liu, Zhao, Wang and Shen2012) or spinal cord injury with umbilical cord blood derived mononuclear cells (ChinaSCInet 2020), would be more acceptable.
When speaking with scientists in Shanghai, Beijing and Guangzhou in 2013, there was also disagreement about why MSCs seem to have at least some desirable effects. The effect of MSCs was generally thought to be short lived (3–6 months at the most), but other applications, such as that to Graft versus Host Disease (GvHD) were subject to much controversy and was explained to me variously as fusion, transdifferentiation and paracrine effect. In short, the fact that the ‘the science’ was contested among or not understood by scientists (Knoepfler Reference Knoepfler2017), as is often the case in the context of innovation, allowed for much uncertainty among patients, investors, regulators and also scientists and therefore stimulated research and hope in this area.
This is where the desirables of the affordability of clinical trials and profitability of stem cell science are in friction with the wish to conduct clinical research and to treat patients. Although many scientists insist on testing regenerative medicine through RCTs to avert ‘experimentation’, they have been criticised for trying to develop standard cures for what are populations subject to variable disease and environmental conditions (e.g., Mirowski and Sent Reference Mirowski, Sent, Mirowski and Sent2002; Rajan Reference Sunder Rajan2006; Fisher Reference Fisher2009; Petryna Reference Petryna2009; Will and Moreira Reference Will and Moreira2010; Dumit Reference Dumit, Good, Fischer, Willen and DelVecchio Good2012). Although some RCTs have come to take into account the local needs and circumstances of diverse patient populations (Epstein Reference Epstein1996; Will Reference Will2007), most RCTs serve ‘first world’ healthcare needs conforming to ‘first world’ standards (Nwobike Reference Nwobike2006; Hunt and Khosla Reference Hunt and Khosla2010). Due to different standards of care and scientific research capacity, national governments in ‘developing countries’ face potentially exploitative conditions, where local patient populations serve ‘universal’ medicine. Further, the introduction of the standard ethics of idealised clinical trials might incapacitate the efforts of LMICs to develop their ‘own’ translational research. It also encourages life scientists to seek alternative regulation to conduct research and satisfy patient demands. Countries have ‘dealt’ with this by trying to ‘immunise’ the field by adopting ‘universal’ regulation while tolerating its selective or feeble implementation.
Research standards and ethics may be important for the safety of patients and the development of scientific knowledge, but the guidelines of bioethics are inadequate for universal application. Thus, widely criticised ‘unethical’ practices, such as financial payment for experimental medicine, using experimental treatment as regular therapy and reliance on local healthcare systems when commercial treatment fails (Gunter et al. Reference Gunter, Caplan, Mason, Salzman and Janssen2010; Lindvall and Hyun Reference Hyun2010) are common in large parts of the world. Nevertheless, there are reasons for them to continue:
First, financial contribution to medical treatment, both approved and unapproved, is a conventional practice in LMICs and is also used in some countries that provide first-class healthcare. Thus, pilot studies for experimental treatment usually do not charge fees, but can ask for a contribution to the direct cost of the therapy (e.g., hospital bed, medicine and nursing) and insurance. For instance, in Japan, patients pay for the basic costs of new drugs that have not yet past the PMDA, and in the US, the FDA Code of Federal Regulations (CFR) 312.8 allows charging for investigational drugs under IND (US-FDA 2012).
Second, in many countries clinical trials are regarded as a realistic healthcare opportunity, despite the lack of evidence of the efficacy of treatments. Thus, in countries with low standards of healthcare provision, patients may view foreign experimental medicine as their best option, even when risks are involved that are unacceptable elsewhere and even if medicines are not guaranteed after the trial.
Third, clinical trials may have adverse effects that require family care. Rather than taking responsibility, some RCTs address national insurance schemes in cases of adverse effect first or fall back onto the care of family members when no hospital care is available (personal communication, IRB member in a hospital in Suzhou, China in 2014).
Finally, some providers of stem cell interventions are more seriously interested in research results than in therapeutic outcomes, while others are not interested in either. Awareness of this tactical form of risk differentiation makes governments and scientists more tolerant of some unauthorised stem-cell therapy providers than others. Thus, setting up GLP/GMP clinical trials without government permission and at considerable risk to patients may be regarded as less harmful compared to driving patients into the arms of pop-up commercial stem cell therapy providers (Conversations He, 25/7/2012*; Gan, 21/6/2014*). Of course, regulatory agencies do not generally regulate patient (buyer) behavior or choice: they regulate what manufacturers of medical products are allowed to bring into the market. But the awareness of patient options for treatment plays a role in what regulatory priorities are set and which stem cell industries are tolerated.
These observations show that local circumstances and diverging healthcare contexts put into perspective the ethics criteria associated with idealised RCTs. There are also other, more general, reasons why the ethical appraisal of stem cell treatment provision cannot be defined in universal terms. First, and as discussed above, scientific appraisal can be problematic, due to dissent among experts and their competing interests (Bianco Reference Bianco2013). When investigating plans for clinical studies, most governments struggle to identify the ‘most scientific’ or reliable camps. As we saw in Chapter 3, among scientists in China there are those who support relaxed guidelines for translational medicine and others who insist on strict legislation. This situation is complicated by the systematic pressures exerted by public health experts that lobby for investment into epidemiology (Ba, 3/7/2012*). Second, many patients hope for effective treatment, independent of whether it is achieved through scientific knowledge, fluke, placebo or alternative treatments. Without alternatives, direct-to-consumer (DTCs) provision may be welcomed as a chance on a higher quality or extension of life. A growing group of patients argues that any positive effect, even if the result of placebo, and even if short-term, is preferable to not doing anything (Chen and Gottweis Reference Chen and Gottweis2013). Third, many patients do not think that paid-for stem cell interventions are automatically unethical, reckoning that not all commercially providing scientists regard patients as a mere source of profit. Rather, they need to maintain the viability of their enterprise to help patients.Footnote 1 And, finally, both patients and scientists acknowledge that experiments are needed for the advancement of science. Many researchers regard small-scale studies as expedient to yielding data of, for instance, SCIs for a complex and multi-systemic condition such as Parkinson’s Disease (Hyun Reference Hyun2010) as preparation for large-scale clinical trials (Deng, 25/4/2013*).
Regulatory Tolerance in an LMIC: The Evolution of Beike Biotech Company
Examining the case of the stem cell company Beike Biotech in the PRC can shed light on how, under the global dynamics or regulatory capitalism, a large LMIC with global ambitions in the life sciences had to adopt ‘international’ regulation that did not suit its circumstances, thereby disabling its elite stem cell laboratories for years. In 2009, the plans for the adoption and development of ‘international’ standards in China culminated in a regulatory halt on all unauthorised SCIs; it took nearly six years for the government to develop implementable regulation that aimed to accommodate the needs of elite laboratories, industry and others (Zhang Reference Zhang2017; Li et al. Reference Li, Verter, Wang and Ning2019). As explained in Chapter 2, a number of clandestine stem cell providers continued to operate, but most state institutions closed down their clinical research practices in hospitals. There were exceptions, however, one of whom was Beike Biotech. Although a number of its branches stopped advertising its wares, the company continued to operate both internationally and in China.
In 2010, after the prohibition on stem cell clinics in 2009, it was announced in its Information Guide that Beike protocols utilise UC-MSC stem cells and recommending all MS and SCI patients to receive this type of stem cell injection ‘as the cells not only produce important growth factors and differentiate into desired cell types but can also regulate the immune system, reducing inflammation, scarring, and cell apoptosis’ (BeikeBiotech 2021b [2010]).Footnote 2 Flying in the face of the 2009 regulations, it also claimed in its Information Guide that ‘China has been a pioneer in adult stem cell treatments for several years. The hospitals and medical staff working with and in Beike are experienced and confident in handling the stem cells and monitoring patients’ treatments’ (BeikeBiotech 2021b [2010]). As will become clear below, Beike’s activities were no secret to the government. So, what drives this kind of regulatory tolerance?
Around the same time, in Europe, Beike was well known for its ‘stem cell tourism’ and had a dubious scientific and ethical reputation as provider of SCIs for over a decade. One critic wrote:
Beike is one of the biggest and baddest of all the companies that have made their millions selling untested, unregulated and uncontrolled stem cell injections to patients suffering from a wide range of serious diseases.
But within China, Beike received sympathy, if not widespread support, including from investors, such as Beijing University, Hong Kong University of Science and Technology and Shenzhen’s Municipality (BeikeBiotech 2016). In 2012, when I visited Beike to find out why Chinese medical professionals, regulators and ethicists expressed confusion and surprise when I explained Beike’s image in Europe as ‘unethical’.
Beike attracts patients internationally through its therapy providing centre, through agencies for stem cell tourism and through websites. Most of its collaborative hospitals were private and endowed with various levels of luxury and treatment methods to cater to patients of different means and taste. Although Beike’s staff regarded therapy fees as ‘paltry compared to buying a car’ (Dong 22/4/2013*), for many patients the 30–100k RMB (c. 5–16k US$) paid for ‘treatment’ in 2013 was a fortune. Staff justified its prices in reference to the licensing fees levied by ‘American’ corporations, such as its AABB certificate (Dong 22/4/2013*). The fees of self-financing patients enabled Beike to continue its research. This contrasts starkly with similarly highly educated experts in state scientific institutes and hospitals, who usually do not have access to the funding. Although Beike did not have State Food & Drugs Administration (CFDA) permission, it had been conducting medical trials registered on the US NIH’s website (clinicaltrials.gov 2013) and received funding from the CFDA for its clinical trials through collaborations, such as its clinical trial for the treatment of systemic lupus erythematsus using UCMSCs (BeikeBiotech 2014). Other clinical trials were partly financed by provincial governments and cities, mostly conducted in private and in military hospitals (Deng, 25/4/2013*).
Although government regulation had prohibited unauthorised stem cell trials from 31 October 2009 through its new regulation on the risk management of medical technologies (Sui and Sleeboom-Faulkner Reference Sui and Sleeboom-Faulkner2015; Wu et al. Reference Wu, Chen, Wu, Pan, Xuan, Wei, Wang, Li and Song2016) and articles critical of stem cell tourism were appearing in the Chinese media (Lue 2013), Beike’s scientific image in China was not usually disputed. The majority of the discussions on ‘stem cell tourism’ in Chinese newspapers and on the Internet had been carefully censured. Conversations with scientists in 2012 and 2013 indicated that only the scientists that had part-time jobs abroad or had resided abroad for a prolonged period of time seemed to be aware of the poor scientific reputation Beike has outside China. These scientists mentioned the criticism that can also be found in the international media: not keeping medical records for outsiders to inspect, providing unproven therapies to patients, taking advantage of the placebo effect and not publishing its results in international science journals of reputation (e.g., Lim Reference Lim2008; McCullough Reference McCullough2008; Johnson Reference Johnson2010; Tam Reference Tam2011; Brown Reference Brown2012; Chen and Gottweis Reference Chen and Gottweis2013).
Such views were treated as false allegations by other scientists and policy-makers who had not lived abroad and who cite Beike Biotech’s website, articles and company events to counter them.
1. Beike has built up a varied experience of therapy provision, simultaneously engaging in collaborative research and clinical trial, which has led to the joint publication of articles in international journals, for example, the Journal of Translational Medicine, PlosOne and Stem Cells (also see BeikeBiotech 2016a).
2. In 2009, Beike was visited by Premier Wen Jiabao, who praised Beike’s scientific and therapeutic competence in comparison with the world’s most renowned life science hubs (Beikebiotech 2010).
3. As for the placebo effect, interlocutors argued that if it is true that the scientific basis of stem cell therapies is not clearly understood yet, then it is also unclear whether any signs of improvement are attributable to the placebo effect (Gong, 10/7/2012*; He, 25/7/2012*; Gan, 21/6/2014*).
4. Although patient records have not been maintained in the past, they are in 2012. But according to Dr Gong, they cannot be opened for inspection by competitors and audit for reasons of IPR and patient confidentiality (Gong, 10/7/2012*). Those who want to know more are referred to Beike’s website, which displays patient case studies (BeikeBiotech 2012a).
5. Any queries about the provenance of the stem cells used in therapy are referred to the cord blood banks it runs and its connection networks (BeikeBiotech 2016c). Especially its collaboration with provincial governments in the management of provincial UCB banks and the state support it receives through grants and collaborations (BeikeBiotech 2016b) are cited to indicate Beike as a bastion of reliability (Gong, 10/7/2012*).
6. Interlocutors refer to the world’s ‘highest certificate for blood banking’, referring to Beike’s AABB and other certifications and awards (Hao, 9/7/2012*; Lin, 9/7/2012*; BeikeBiotech 2016a).
High-profile interlocutors seemed to have no problem rebutting foreign criticism of Beike, many of whom referred to ‘China-bashing’ (Cai, 28/10/2012*).
The conditions under which patients had to pay for what are experimental therapies, interlocutors do not regard as unethical per se. After all, therapies falling outside China’s local healthcare provision lists are largely sold on a commercial basis, and total healthcare insurance coverage is rare. Patients are used to paying for private and authorised therapies. Furthermore, the practice of giving ‘red envelopes’ (bribes) to create goodwill is common (Yang Reference Yang2007), while patient choice of medical doctors/surgeons has become a right in China, for which many patients nevertheless also pay extra. The fact that Beike’s services attract ‘foreign’ patients, who for a long time paid twice the amount Chinese patients did (Dong, 22/4/2013*), was regarded as further proof in support of Beike’s reliability. Considering that there were no other affordable healthcare options for most patients, and that established life science centres did not receive permission to start phase I trials in stem cell applications (Chinese Academy of Science 2013), Beike’s provision of what has been criticised as experimental stem cell interventions were viewed by patients and scientists as a reasonable alternative and also for patients that do not suffer from life-threatening or intractable conditions (also see Salter et al. Reference Salter, Zhou and Datta2015).
It would be easy to condemn Beike Biotech as a jumbo snake-oil peddler for exorbitant pricing and preying on weak and desperate patients, and it would be easy to criticise China’s efforts at stem cell governance (Chen Reference Chen2017). Although one can be opposed to ‘unauthorised’ and ‘unproven’ SCIs for very good reasons, it is not very helpful to do so without taking into account Beike’s position in the global context of regulatory capitalism. China, as a large LMIC, in its efforts to ‘catch up’, just like other countries that do not want to ‘miss the boat’, mimic key innovators and try to adopt their regulations. Not having been involved in the creation of ‘international’ regulation in the first place, most of China’s state laboratories could not afford to adopt them. Working to adapt ‘international’ regulation and proclaiming a universal prohibition of unauthorised SCIs aimed to immunise the country against being labelled as rogue chancers. But the expenses and bureaucracy involved alienated the life-science industry, which, though engaging in the trade of biomaterials and equipment, largely refrained from involvement with clinical trials of stem cell interventions during the regulatory impasse from 2009 until 2015. Nevertheless, some regulatory violations were tolerated, if not celebrated.
Beike Biotech, run by biochemist (though better known as stem cell scientist) Xiang Hu, had good connections abroad and with scientific leaders of state laboratories and private hospitals. He was also a capable network-builder and scientist: he conducted research, gathered data, set up GMP-facilities, collaborated with universities and hospitals in clinical trials, engaged in umbilical cord banking (UCB) banking in various provinces and largely managed to collect its own funding. Beike’s role in China’s stem cell industry became increasingly important, and official support for Beike has not waned over time. In March 2014, Xiang Hu was invited to visit Germany with Chinese president Xi Jinping, and in the same year, 13 per cent of Beike was bought up by the other main industrialiser of regenerative medicine, Zhongyuan Union Stem Cell Bioengineering Corporation (Zhongyuan Union 2014). These two companies would champion the cause of industry during China’s regulatory struggles and exert substantial influence on the 2015 regulation (Rosemann and Sleeboom-Faulkner Reference Rosemann and Sleeboom-Faulkner2016; Zhang Reference Zhang2017; Li et al. Reference Li, Verter, Wang and Ning2019). Today, despite everything, scientific collaborations with Beike no longer seem to be taboo. The UK’s prestigious UKRI funds a project on ‘the role of pro-inflammatory mesenchymal stem cells in rheumatoid arthritis’ supported by its claim that it has ‘close collaborative links with industrial partners such as Beike Biotechnology, China’s leading biotechnology company on the development and commercialization of adult stem cell therapies’ (UKRI 2022). Although this might say more about the UKRI’s interests in ‘immunodeficiancy’, this certainly seems to lend credibility to formerly lambasted Beike Biotech.
In brief, China tried to immunise its clinical research into regenerative medicine by adopting what it saw as international regulation and adapting it. The impasse that followed created inactivity and uncertainty among its elite laboratories and frustrated the industrial sector. At the same time, however, China’s regulatory tolerance for Beike’s SCIs gave in to the development of what it saw as a promising industry, hoping for international recognition and to advance in stem cell science in the long run.
Regulatory Tolerance in HICs – Autologous Stem Cell Intervention
The notion of the West, if referring to modern, technologically advanced and well-regulated societies, is misleading. According to sociologist Bruno Latour ‘the West’ was never modern in the sense of society having emancipated itself from nature by means of science and technology (Latour Reference Latour1993); rather, any society should be seen as a construction of systems that mix politics, science, technology and nature. What is ‘technologically advanced’, then, is disputable, as advancement has to be measured against what people wish their society to be like. Nevertheless, if we can associate ‘state-of-the-art’ and ‘cutting-edge technologies’ with ‘advanced’ industrialised societies, we must also conclude that the world no longer has a single technologically advanced centre. The view that countries outside of the US and Europe are scientifically and technologically advanced has become increasingly accepted over the last century. But, whether they are ‘well regulated’ or not is very much contested, and there is no global agreement about what it means to be ‘well regulated’.
In Chapter 1, we have already seen that the notion of ‘deregulation’ can be confusing, if it denotes a liberation from bureaucratic obstacles to the scientific investigation of promising therapies. For what is usually referred to as ‘deregulation’ is directed at defining the conditions under which new scientific practices are enabled. In fact, the notions of ‘prohibitive’ and ‘permissive’ regulation, though not accurate, better reflect the dimension of enablement, which I believe is an important underlying motivation for regulating new clinical stem cell applications. Examining examples of regulatory immunisation and regulatory tolerance in ‘the West’ may give us insight into the politics of regulation. In this arena, we find that cliché concepts of patients, scientists and entrepreneurs are mobilised as pawns in the overhyped arena of regenerative medicine. After the discussion of regulatory boundary-work, I will reflect on whether global regulatory harmonisation can offer a way out.
The United States
Regulation does not just restrict, it can also enable exceptions through clauses, and in the US, research on a number of clinical procedures has been made possible through such regulatory flexibility. In the US, human cell and tissues products are designated as ‘361 products’ if they are minimally manipulated and intended for homologous use, that is, in the same way as the natural endogenous function it performed. If more than minimally manipulated (transforming the biological properties of the starting cell or tissue so that it becomes a distinct entity) – and when intended for non-homologous use (uses of cells/tissues, manipulated or not, in a physiological/anatomic context different from their origin) – they are subject to a much wider range of FDA requirements as ‘351 products’ (Sipp and Turner Reference Sipp and Turner2012; von Tigerstrom Reference Von Tigerstrom2015). Regulatory requirements include authorisation of investigational use in clinical trials, pre-market approval based on clinical trial data and controls in the form of pre-market authorisation (a biologics license) and quality standards, and they must comply with GMP-requirements (US-FDA 2007). Although it is intended to protect patients and science against damaging practices, the regulation also affords flexibility, for instance, through provisions for ‘expanded access’ to investigational drugs for patients with a serious or life-threatening conditions, through mechanisms to expedite approval of drugs and biological products for serious conditions and through the Breakthrough Therapy Designation, which has less stringent data requirements before market approval (von Tigerstrom Reference Von Tigerstrom2015; chapter 2).
The regulation is robust in its inoculatory efforts, but its protective effects vary with the use of provisions for regulatory accelerations and permissions, such as the Accelerated Approval Program (US-FDA 2014c). By offering immunising protection, US regulation may also be viewed as tolerant, because it is not implemented according to the spirit of the regulation itself, that is, its implementation does not chime with its own justification. Since the late noughties, unauthorised stem cell clinics in the US have been criticised for endangering and overcharging patients and are accused of deceit through false advertising, but the unauthorised stem cell provision has truly mushroomed since the mid-2010s. A battalion of social scientists, legal scholars, ethicists and journalists have formulated arguments against the practices of ‘rogue clinics’ in North America (for some recent examples: Sipp et al. Reference Sipp, Caulfield, Kaye, Barfoot, Blackburn and Chan2017; Sipp Reference Sipp and Okano2018; Caulfield and Murdoch Reference Caulfield and Murdoch2019; Murray et al. Reference Murray, Chahla, Frank, Piuzzi, Mandelbaum and Dragoo2020), addressing the challenges of regulators with regulatory, educational and political weapons to combat these rogues.
There are ‘regulatory loopholes’, such as the same surgical procedure exception: when treated as medical procedure, rather than as medical product, unauthorised businesses commonly market human cell–based products that are harvested and re-implanted in a single ‘medical procedure’ without being subject to FDA oversight (FDA 2017a; Sipp Reference Sipp and Okano2018: 26). But due to the risks of contamination and infection, in 2014, the US Court of Appeals reaffirmed that autologous HCT/Ps are not regarded as medical procedure and are subject to FDA oversight (Turner and Knoepfler Reference Turner and Knoepfler2016). Only now and then individual states manage to fine and halt unauthorised stem cell clinics, such as US Stemology, which offered Covid, asthma, lupus, Parkinson’s disease, congestive heart failure and multiple sclerosis treatments (Washington State 2022). Nevertheless, a sizable industry continues to sell ‘same surgical procedure’ interventions, including its champion, Regenexx (http://regenexxdesmoines.com), which has performed over tens of thousands of ‘Regenexx procedures’, and through the franchise Cell Surgical Network (CSN), operating in over twenty states (Sipp Reference Sipp and Okano2018).
Other allegations include the marketing of autologous cell interventions as ‘pay-to-participate’ medical experiments. For instance, instead of ‘conditions treated’, CSN advertises what it is ‘currently studying’ on its website (CSN 2018). While asking for substantial payment, it refrains from making medical claims and denies liability, justifying the interventions as investigational studies to advance regenerative medicine. Other companies offering ‘pay-to-participate’ medical experiments, such as Stemgenex and US Stem Cell, register open-label clinical studies in the NIH Clinicaltrials.gov database, suggesting a measure of clinical oversight (Turner Reference Turner2017). In addition, the FDA, in 2007, started to allow sponsors to charge for investigational drugs under an IND application for the purpose of either clinical trials or expanded access for treatment, but these are strictly limited and subject to pre-approval and supervision by the FDA (21 CFR 312.8) (US-FDA 2007).
On the one hand, scientists push for stricter regulatory oversight over stem cell clinics, but, on the other, they push for regulatory exemptions and accelerations for their own research and marketing of promising research and regenerative products. This seems to motivate patients, such as those represented by ‘Patient For Stem Cells’ (PFSC 2021), and hundreds of clinics to offer these promising treasures more cheaply and faster. The FDA didn’t clearly assert its authority over ‘rogue’ clinics until 2017 (FDA 2017b), when it announced its revised guidelines pertaining to cell-based therapies. Despite four years of FDA ‘enforcement discretion’, the number of clinics has increased and hardly any clinic applied for FDA approval (Perrone Reference Perrone2021).
This regulatory landscape closely resembles China’s offensive against unauthorised SCIs, especially in the early 2010s (MoH 2012; MoST 2013; Sui and Sleeboom-Faulkner Reference Sui and Sleeboom-Faulkner2015). Rather than mainly critiquing entrepreneurial scientists that are peddling unauthorised and unproven therapies, we need to admit the possibility that regulatory enforcement is not generally viewed as desirable in the US. It may make more sense to view FDA regulation as regulatorily ‘tolerant’, though some would say regulatorily powerless. I will return to the issue in the concluding section.
Australia
In Australia, in the 2010s, we find a similar situation in that regulatory classification, which determines the amount of oversight, affords practices that are widely regarded as experimental. However, whereas in the US regulation is not enforced, that is, ‘tolerant’, in Australia it has been permissive. Australia’s Regulatory Framework for Biologics, established in 2011, distinguishes between cell and tissue products according to whether they require close oversight: ‘Things that are not Biologics’ (TGA 2011, 2015) are not regulated as Biologics, but are viewed as ‘Therapeutic Goods’. Biologics are defined as ‘a thing made from, or that contains, human cells or human tissues, and that is used to: treat or prevent disease, ailment, defect or injury, diagnose a condition of a person, alter the physiological processes of a person, test the susceptibility of a person to disease, replace or modify a person’s body parts’ (TGA 2015). As Biologics, in contrast with EMA and FDA regulation, did not include autologous stem cell interventions, this afforded private companies to advertise and provide ‘therapies’ that are elsewhere unauthorised. Critics referred to them as ‘exempt’ and criticised these SCIs for displaying ‘loopholes’ and allowing unethical research (Munsie and Pera Reference Munsie and Pera2014; McGregor et al. 2015; von Tigerstrom Reference Von Tigerstrom2015). But stem cell interventions defined as Therapeutic Goods, unlike those regulated under the Hospital Exemption (HE) in the EU, were not exemptions; rather, they were reclassified as a different kind of product. Also, the notion of ‘loophole’ suggests that the practices involving Therapeutic Goods are part of a wider regulatory framework but have somehow fallen between the cracks. Here, we need to recognise the possibility that policies behind biologics regulation were not meant to disenfranchise commercial clinical research practices that, eventually, could lead to marketable products.
As in the US, many clinical researchers in Australia tend to view experimental studies as medical procedure, that is, as part of the medical profession. Commercial clinics providing stem cell interventions classified as Therapeutic Goods are not just vehicles for making profit; they are expedient in developing a proof-of-concept, honing skills and knowledge of the administration of stem cells, developing new techniques and conducting research. For instance, Australian regulation allowed Magellan Stem Cells to supply autologous stem cell treatments as Therapeutic Goods, but it was ‘currently conducting clinical trials based on the use of allogeneic stem cells (or ‘donor’ stem cells) with the aim of seeking regulatory approval to be able to offer “off the shelf” donor stem cell treatments’ (Magellan Stem Cells 2020). Its publication in the journal Regenerative Medicine shows that MSC therapy was performed within a private medical facility and funded by the patients/participants, confirming its acceptability (Freitag et al. Reference Freitag, Wickham, Shah, Li, Norsworthy and Tenen2020).
Stem cell companies usually start as grass-root clinics or laboratories with links to hospitals, and, like China’s Beike Biotech, they need fertile ground to grow on. Uninhibited by unauthorised practices, promising companies that were ready to face Biologics Regulation could expand and, if successful, look forward to support in place for cross-border expansion from, for instance, the AusBiotech Regenerative Medicine Advisory Group (RMAG), which deal with industrial organisations for regenerative medicine in Japan (FIRM) and Korea (CARM). Like in the US, a ‘grey’ experimental industry affords the opportunity to practice skills and to nurture talent and research, fertilising Australia’s soil to strengthen its ability to compete in the global arena of regenerative medicine. Australia’s regulator until the late 2010s could not be said to be regulatorily tolerant; rather it was ‘permissive’ compared to the US, leaving the fate of the ‘client’ in the (relatively) uncontrolled hands of entrepreneurial researchers and clinicians.
But in the late 2010s, public pressure led to the revision and clarification of rules for regenerative medicine in Australia in 2019 (TGA 2019), which expands TGA’s (Therapeutic Goods Association) oversight to stem cell regulation, now including a substantial proportion of autologous cell products that are more than minimally manipulated, non-homologous and manufactured and used outside an accredited hospital. The TGA prohibits the advertising of DTC and requires medical practitioners to report adverse medicinal events. According to Patrick Foong, the regulation aims to shrink the hidden domestic stem cell marketing industries and to enhance the reputation of the Australian stem cell industry (Foong Reference Foong2018). Nevertheless, forecasts of substantial growth of the stem cell market based on 2018–2021 trends in Australia for the period of 2022–2028 (Inkwood 2022) indicate that the stem cell market can create fierce competition between hospitals and stem cell clinics, as has been the case in the US. Competition incentivises stem cell clinics to partner with hospitals to qualify for regulatory exemption or tempts clinics to use the regulation for so-called Class I biologics to provide stem cell products that do not meet the exempt product requirements of minimal manipulation or homologous (Ghinea et al. Reference Ghinea, Munsie, Rudge and Stewart2020). Although, in the past, experimental research has been encouraged through government policies and government funding calls that finance innovative stem cell applications and regulatory acceleration (NHMRC 2023), it is also clear that public pressure has led to regulatory adjustments to prevent harm to patients.
The EU
The EU’s European Medicines Agency (EMA) regulates cells, tissues and other medical products through the EU Tissue and Cells Directive (EU-TDCD 2004/23/EC). Its 2007 regulation (EMA 2007) defines stem cell transplantation as a medicine, which means that they have to be shown safe and effective in rigorous clinical trials (Mahalatchimy et al. 2017). A distinction is made between somatic cell therapies, which includes established human stem cell applications in medicine, such as bone marrow transplantation for blood diseases, and cell therapies. Where there is more than minimal manipulation of cells destined for clinical application or where their use diverges from their normal function in the body, EMA refers to advanced therapy medicinal products (ATMPs) (European Parliament 2007; Faulkner Reference Faulkner2019; EMA 2021). While regulatory robustness aims to enable a flourishing community of regenerative medicine, its subsidiarity principle (Raffaelli Reference Raffaelli2018; European Parliament 2020) makes political space for different national interpretations. In fact, it allows accommodation of Europe’s diverse cultural and political orientations. Thus, in the case of hESC research, countries are free to determine stricter policies compared to those formulated by EMA.
Below, it will become clear that the EU’s gatekeeping ability is bolstered through mutual surveillance by both scientists and regulators, especially when it concerns a fast growing and competitive field of translational research such as regenerative medicine. Regulation immunises the EU against reputational damage to its research in regenerative medicine while it allows different interpretations of the regulation through the subsidiarity principle within national borders. This explains why controversial stem cell interventions, such as those of the much-cited-as-rogue company XCell, were banned in the Netherlands in 2007, whose regulation banned private stem cell interventions (Sheldon Reference Sheldon2007), and in Germany in 2011, whose 2009 regulation (based on EU regulation) allowed XCell to operate during the transition period (Pyre Reference Pyre2012). However, other cell applications, such as ‘fresh-cell therapy’ in Germany, which involves injecting cells or cell components of animals, usually sheep, into humans, still attract customers from Europe, Thailand and the Philippines and are still operating as ‘regenerative’ therapies (Chaisingthop 2013; Villa Medica 2020). Furthermore, is it is widely known that EMA’s Hospital Exemption (HE) is open to abuse (Hills et al. Reference Hills, Awigena-Cook, Genenz, Ostertag, Butler, Eggimann and Hubert2020). There was no apparent urge for regulators to facilitate the expansion of the field of fresh cell therapy.
EU marketing of ATMPs requires national and EMA permission, but EU countries subject to EMA can use the HE to apply new therapies for a limited number of patients (see Chapter 2). Apart from the Medicines Adaptive Pathways to Patients (MAPPs) programme (see Chapter 2), which aims to create an approval process that adapts quickly to a given patient’s response to therapies (Forda et al. Reference Forda, Bergström, Chlebus, Barker and Høngaard Andersen2013; EMA 2014), it has created regulatory provisions for Priority Medicine (PRIME) through accelerated assessment and scientific advice (EMA 2018). Although some find these provisions damaging with regard to surrogate endpoints and post-marketing oversight (Lee and Lysaght 2018), others plea for more generous regulatory measures. For example, clinical trials are fully regulated by EMA, making multi-national hospital-led clinical trials forbiddingly expensive (Hauskeller Reference Hauskeller2018). Those that do go ahead, such as ADIPOA1 and REMEDI – investigating stem cell interventions using adipose-derived mesenchymal stromal cells for knee arthritis – are subject to what they experience as regulation. The comments by REMEDI’s coordinator reflect this:
From our perspective rigorous, objective and definitive proof about stem cell therapies can only emerge from carefully conducted, well-controlled, multicentre clinical trials. We do not make any claims that are not based on strong evidence. We also work in a fully regulated environment and would only seek to provide these treatments to patients with approval from national and Europe-wide regulatory authorities. Every stem cell treatment should have the same conditions attached.
When, in May 2013, the Italian government decided to support the Stamina Foundation, which claims that its MSC-based therapy can treat a whole host of diseases, ranging from spinal cord injury to motor-neuron disease, widespread protest culminated in a campaign among stem cell biologists (Abbott Reference Abbott2013). They pulled up a clear scientific boundary between themselves and Stamina by appealing to EMA:
If Government supports even one single event of an uncertified therapy proposed by an uncertified entity in an official health structure this may be considered by people as an official recognition of the therapy, i.e. a strong support for its potential uncontrolled use … hospitals will become simply places in which anybody may administer unproven therapies.
The campaign emphasised that patients’ freedom to choose treatment did not mean that they could opt for snake oil, especially if not following regulatory stipulations. Professor Charles French-Constant, director of the University of Edinburgh’s MRC Centre for Regenerative Medicine, illustrates the importance of scapegoating in the regulatory immunisation of regenerative medicine in the EU:
These unproven and ill-prepared stem cell therapies, for which there is no scientific basis, will do nothing for patients and their families except make them poorer. For a European country that is home to some of world’s finest and most rigorous stem cell biologists to approve such an approach sends a confused and counterproductive message to the world community.
The Italian Medicine’s Agency, AIFA, put a halt to support for Stamina’s marketing of MSC-applications in October 2014. By separating in-house applications from licensed marketable products, EMA’s inoculation of the EU community of regenerative medicine seems to have taken effect.
EMA’s inoculation also works where governments stealthily abuse EMA’s HE regulation, as shown by Poland’s breach of EU law on ATMP. Dulak et al. (Reference Dulak and Pecyna2023) document how clinics affiliated with academic institutions exploit the HE, using ATMP status as an indicator of permission for the marketing of stem cell applications under the HE. Between 2011 and 2020, over 1,800 patients were treated with Wharton’s jelly cells, of which the majority received the cells as an ‘experimental therapy’ (Dulak et al. Reference Dulak and Pecyna2023: 1613). Not only are the practices in breach of ATMP-HE, Poland’s regulation also violates it by lacking stipulations for proving that the product is manufactured for a given patient (rather than for many, or for treating various conditions) and does not require the submission of pre-clinical or clinical data concerning the mechanism of action to justify the intended therapeutic use.
Like Australia and the US, EU countries have been housing hundreds of stem cell clinics that are ready to provide stem cell injections for conditions ranging from osteoporosis to neurodegenerative diseases (see, e.g., Turner and Knoepfler Reference Turner and Knoepfler2016; Curwen Reference Curwen2020; Turner 2020). As long as governments refrain from openly supporting them, this regulatory tolerance does not seem to severely taint the reputation of the EUs stem cell community.
Regulatory Tolerance – Should There Be Global Oversight?
In this chapter, I looked at how countries with different scientific institutional histories and income levels have dealt with scientific uncertainty and the ethics of ‘experimental’ interventions using so-called MSCs. Examining regulatory practices for clinical research and commercial interventions in the context of global competition, I took account of the complex intertwinement of the desirables of catering to patient needs and demands, the protection of high quality scientific research, the affordability of testing methods and the prospect of economic growth through investment into regenerative medicine in an LMIC and in HICs. The desirables of catering to patient needs and demands and the protection of high quality science underpin regulatory ideals, while affordability and economic returns on investment are often viewed as a matter of political preference.
HICs that traditionally have had the power to define standards and conditions set by regulation, even when that power is on the wane, still seem to enjoy considerable regulatory immunity. Nevertheless, we saw that HICs have been adept at creating regulatory clauses to soften their regulation and that they have shown substantial regulatory tolerance for violations. In HICs, a scientific boundary is commonly asserted between established stem cell scientists and clinical research providers that spoil the broth by not sticking to the official recipe. Scapegoating, here, is used as means to defend the reputation of the regulated collective against unauthorised stem cell clinics. Examples show that especially the US and the EU have used regulatory immunisation to protect the stem cell community’s reputation against violators. This immunisation effort included provisions for ‘regulated exemptions’ under which experimentation, condemned under other circumstances, can take place in a controlled manner. The mushrooming of stem cell clinics in the US for this reason has become a hotly disputed topic. In the EU, where countries seem to have various attitudes towards unauthorised stem cell clinics (EBE 2011; European Commission 2014), there is great sensitivity regarding official dissidence, as was illustrated by the case of Italy’s support for Stamina.
We also saw that regulatory immunised countries can afford to tolerate clinical research combined with therapy provision. Thus, the US and EMA immunised their established stem cell communities, making provisions for exemptions and accelerated pathways at the same time. Australia’s regulatory reputation, however, has been tarnished by minimally regulating autologous therapies as Therapeutic Goods. Hampered by its limited capacity to set up expensive clinical trials with its small-size population, the Therapeutic Good regulation afforded a way for research clinics to grow and compete outside its regulatory pathways for Biologics. This fed into Australia’s regenerative medicine capacity, especially when shielded by and integrated with international collaboration. In this way, the Therapeutic Goods regulation sidestepped the need for regulatory tolerance. The regulatory reforms of Australia’ Therapeutic Goods regulation (TGA 2019), however, includes a much larger proportion of autologous cell products. Though intended to decrease the hidden stem cell industry (Foong Reference Foong2018), the new competition is has created might encourage collaborations between stem cell clinics and hospitals with little oversight to provide unsafe clinical research applications (Ghinea et al. Reference Ghinea, Munsie, Rudge and Stewart2020).
Rising power China for decades has had similar ambitions to rival HICs in the field of regenerative medicine. To gain global recognition, it has attempted to strengthen its regulatory immunity by adopting and adapting ‘international’ regulation. When, partly due to expenses associated with the regulation and local incommensurable priorities, it failed to implement it convincingly, China’s efforts to develop the field were met by both constructive advice and, especially, global prejudice. An analytical distinction between failing to ‘clamp down’ on small for-profit clinics offering stem cell interventions and an indirect support for large companies that combine research with stem cell provision, such as Beike, is needed. The example of Beike shows why universal regulation is problematic to large LMICs that have the political ambition to become a global power in the field of regenerative medicine. Not being able to fulfill HIC regulatory requirements drove the PRC to tolerate Beike’s regulatory violations and led scientists from elite laboratories to blame Beike for tainting the reputation of both the field and China. It is not surprising, then, that there has been much regret among scientists outside the US and the EU that there has been relatively little ‘outsider’ say in the creation of regulation for stem cell science.
Ironically, a decade later, many of China’s dilemmas turn out to be endemic to the US: illegal stem cell clinics treating ‘no-option patients’ and patients without healthcare insurance. And, it is especially the exponential increase of mushrooming direct to consumer (DTC) clinics in the US that has prompted scholars to recognise the WHO as a global regulator of regenerative medicine. Master et al. (Reference Master, Matthews and Abou-El-Enein2021) argue that there is a diminishing trust in government institutions, such as the FDA and EMA, as a result of their inability to tackle harmful DTC of stem cell interventions. They maintain that the FDA, the US Federal Trade Commission (FTC) and state Attorneys General do not have enough clout to enforce regulation and to prevent the mushrooming of stem cell clinics. The main tasks of the WTO on regenerative medicine would be, first, ‘the harmonization of regulatory definitions and practices for cell-based therapies’; second, ‘using existing policies and regulations as a model’, it ‘could develop a regulatory framework or template regulations for countries to adopt’; and, third, it ‘would allow industry and clinics to understand more fully what techniques and products will be regulated and what is considered outside the scope of regulatory oversight’.
The proposal to have the WHO as main global regulatory authority assumes the use of a regulatory template based on US and EMA regulation and presumes that the rest of the world would follow. Again, we know that under regulatory capitalism, the designers of international regulation have a competitive advantage. If the WHO were to be in a position to take charge, it would do so, partly, because the US as major funder sets the agenda. But the WHO does not have the power to impose health policies on national governments: it is unlikely that the WHO would have more regulatory clout than the FDA in that country. Rather than trying to create a new but feeble global institutional ‘authority’, as I will argue in Chapter 9, we need to rethink the way in which science and science regulation are currently shaped through national competition and international collaborations.
In regulatory capitalism, regulation is part of the competitive arena, which requires a constant effort at regulatory delineation from (‘inferior’) others, that is, boundary-work. The binary between ethical and unethical research practices, then, is relevant not just as rhetorical medium but also as instrumental in steering the direction of innovation in regenerative medicine. For instance, prominent scientists in HICs still accuse the ‘Far East’ of spoiling the field of regenerative medicine, by dint of which they recommend regulatory enablement, before ‘They’ will start experimenting with immature clinical applications. Such boundary-work, as the next chapters shall confirm, is politically necessary both to maintain a competitive edge and to productively collaborate internationally. But without credible transcendental authority in a world dominated by regulatory capitalism, rather than protecting patient health, the regulation fails to safeguard the procedures and qualities of science that protect them.
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