A stem cell scientist in an LMIC explains international science collaboration: ‘Basically, you need something in your pocket, something that they don’t have, or they do not want to collaborate. You need a niche. Our niche is B-Thallasemia. That is what they don’t have …. We also have friendly regulation.’
Introduction
As shown in Chapter 1, HICs and LMICs tend to engage in different regulatory boundary-work. But even though elite laboratories in HICs scapegoat countries with ‘inferior’ regulation, some players in HICs, including the state, display a surprising measure of regulatory tolerance in their wish to engage in collaboration with the very same countries. Much of what we regard as ‘global’ collaboration is in fact ‘international’ collaboration, especially when it is the differences in national conditions that enable the collaboration. This chapter’s case study on international science collaboration between scientists in Chulalongkorn University (Chula) in Bangkok and scientists and managers of Kawasaki Heavy Industry (KHI) from Kobe and other cities shows how competitive desire incentivises international science collaboration. Although the collaboration is formed around a mutual interest in the development of a cell processing robot, important to industry and medical experts, it was largely enabled by differences in regulation, scientific expertise, available patient pools and material capacity. The collaboration did not just involve scientific interests, it also concerned the interests of the Thai and Japanese states.
The project around which the collaboration evolves received state support in both countries. This raises three questions pertinent to regulatory capitalism. First, how does regulation figure in negotiations between the two institutions/countries? To examine this question, I treat regulation as a form of capital that is negotiated. Second, how is science collaboration brokered in a context of regulatory capitalism, which is based on global competition? By examining how regulation figures as capital in international collaboration in a world propelled by regulated competition, I aim to show how the desire to collaborate and to compete form part of the same process. Third, how does international science collaboration based on regulatory discrepancy affect regulatory immunity? If countries collaborate based on the knowledge that they transgress the spirit of their own regulation, how does the immunitary politics around this collaboration impact the credibility of regulatory regimes?
A huge robotic machine was unveiled to the public on 30 September 2013 at a formal ceremony in Bangkok attended by scientists, company CEOs and officials from Japan and Thailand, including, the then Crown Princess Sirindhorn and the Japanese Ambassador to Thailand (Chulalongkorn University 2013). The robotic cell-processing machine, R-CPX, is core to a joint research collaboration between Chulalongkorn University and Kawasaki Heavy Industry (KHI) with the aim to conduct clinical trials for osteoarthritis treatment in Thailand. The clinical trials were expected to reveal that cells subjected to automated up-scaling using R-CPX could be a safe and efficacious basis for marketable therapeutic products. The robotic machine was installed at a research centre at Chulalongkorn University, which I name THAI [pseudonym]), by KHI, with financial support from the Thai government and Japan’s Department of New Energy and Industrial Technology Development Organization (NEDO).
But what brought Japan to collaborate with Thailand on this? Stem cell and ‘medical tourism’ in Thailand have long been criticised for profiteering at the expense of patients (Kiatpongsan and Sipp Reference Kiatpongsan and Sipp2008; Coghlan Reference Coghlan2010), an image it continues to struggle with. Despite adjustments to its regulation of business advertising (Wangkiat Reference Wangkiat2015), it has not been able to shake off its image of snake-oil provider (e.g., Thailand Medical News 2019) and continues to be scapegoated for damaging the reputation of regenerative medicine. In Thailand, however, ‘cell therapies’ on offer generally involve private clinics or hospitals, not elite research centres such as THAI. Speaking with the Japanese scientist who first worked on the robotic machine, I soon realised that a regulatory discrepancy between Japan and Thailand had been a major incentive for KHI to initiate the collaboration: the regulatory discrepancy became capital in the scientific collaboration.
When trying to understand the dynamics of global powers, there is a temptation to view the notions of competition and collaboration as opposites, while in fact, conflict and cooperation emerge together when forging of social relations. Conflict, according to philosopher Paul Demouchel, takes shape in the context of cooperation between those with conflicting interests. To occur in the first place, conflict requires some form of order or coordination of interests. I argue that, in a world characterised by competition, regulation is what binds different countries, especially when their regulations diverge. Collaboration thrives under regulatory discrepancy, as it affords exchanges to take place, not just related to regulation but also in relation to other ‘inequalities’, such as those pertaining to infrastructures and production resources, such as scientific and medical expertise, financial resources, healthcare provision and insurance systems. Such exchange involves acute awareness of the regulatory conditions and cultures and other difference involved.
Science collaboration, therefore, is not simply a question of pooling assets and bundling efforts to achieve a shared scientific goal. Rather, it involves a scrutinisation of how socio-economic, political and regulatory conditions enable available resources to be used to satisfy a range of goals, many of which may not be shared. Regulation from this angle is a form of capital negotiated, not just between institutions but also between the converging and diverging conditions in diverging regulatory jurisdictions. As we shall see, the mobilisation of regulatory capital also has consequences for our interpretation of the way collaborating countries are affected in the long run.
After introducing the notion of regulatory capital and the details of the collaboration around the robotic machine R-CPX, I will present four main themes of concern among Japanese and Thai scientists who were directly involved in the collaboration: science, medicine, economy and trust and regulation. The different takes by the collaborating partners on the four themes highlight points of competition within the collaborations and the way the collaboration serves a range of ends of which they only share some. The themes, as will become clear, either implicitly or explicitly, are contingent on the way in which regulatory capital has enabled this international collaboration. Finally, I will discuss the implications of this regulatory capital–based collaboration for the regulatory immunity of both countries.
Following the example of the memoranda of understanding (MOUs) between the collaborating partners, I refer to them as ‘Thai Team’ and ‘Japan Team’, which reverberates with the self-identification of Thai and Japanese interlocutors.
Regulatory Capital and the Japanese–Thai Collaboration around R-CPX
The term regulatory capital, referring to regulation as negotiable in collaboration across regulatory jurisdictions, allows us to view regulation as part of a collaboration, not just among institutions but also between countries. Much social-science work interprets scientific collaboration in positive terms of pooling assets to realise a common scientific plan (Shrum et al. Reference Shrum, Joel and Ivan2007; Shrum Reference Shrum, Parker, Vermeulen and Penders2010). But without an understanding of the potential drivers of collaboration, including regulatory and other discrepancies, such as available expertise, financial capital, health care provision and equipment, one fails to understand the dynamics of the collaboration and the conflicting interests that make the collaboration worthwhile.
The Japanese–Thai collaboration illustrates how regulatory discrepancy enables an international science project. Initially, a colleague drew my attention to the installment of the R-CPX in Bangkok. The regulatory discrepancy came to light when a Japanese scientist working on the R-CPX told me about their collaboration with Kawasaki Heavy Industry. KHI, in turn, explained that the collaboration was based on a win-win situation, enabling Thai scientists to conduct research using GLP equipment and allowing Japanese scientists to work toward clinical trials. To gain further understanding, I visited hospitals, companies and laboratories in Japan, the UK and Thailand between November 2013 and August 2014.
Thailand’s science policies in support of the development of regenerative medicine were designed to deal with widespread disease conditions, including thallasemia and heart disease. Investment into regenerative medicine was hoped to save public health spending in the long run. Although basic stem cell research is not unaffordable, for its results to gain international recognition, it needs considerable investment into the training of expertise, setting up GLP laboratories, high quality laboratory equipment and materials and administrative tools for governance and sophisticated regulation. Although Thailand announced its regulation for regenerative medicine in 2009, highly constrained financial budgets and a young life science community placed Thailand’s regenerative medicine on a weak footing. The intention of the science community was to strengthen Thailand’s international scientific reputation and to protect its budding international scientific collaborations, such as those with the EU.
For Thailand, then, its regulatory reputation was important. When KHI proposed the collaboration, reactions among scientists were mixed. The proposal seemed to confirm that Thailand’s community of regenerative medicine was viewed as robust enough to attract industrial scientists from Japan, a country then known for its prohibitive stem cell regulation. At the same time, however, KHI clearly indicated that its aim was to show that its robotic machine could process cells that were fit for clinical trials in Thailand, cells that, at the time, Japan’s regulators did not view as suitable for use in clinical trials. So, Thai regulation for regenerative medicine seemed strong enough for conducting international clinical trials, while at the same time it was weak enough for attracting collaborators from Japan.
This is how, lacking financial capital and scientific assets, Thai regulation became regulatory capital in negotiations that led to a collaboration between unequals. Although, within Thailand, various science institutes – in possession of similar regulatory capital – were approached for collaboration, in the end the prestigious THAI agreed to be main collaborator in the project around R-CPX. But agreements based on regulatory capital entail much uncertainty. As the ownership of regulatory capital is not openly exercised, and does not appear in contracts, the informal understandings of the agreement were not spelled out. And, as we shall see below, there is no guarantee that regulatory relations between countries will remain the same.
R-CPX: The Robotic Machine
R-CPX is a boxed-in space for the automation of cultivating cells and experimentation (See Figure 5.1). The robotic cell processor was central to the Japanese–Thai collaboration, but as a ‘science object’ it meant different things to them (Mol Reference Mol2002). To KHI it embodied the lucrative prospect of upscaling a slow and burdensome process of processing cells, which when shown to be safe and effective in therapy, would revolutionise the field of regenerative medicine; to THAI, its Good Laboratory Practice (GLP) status formed an immediate possibility to process cells and to conduct scientific experiments under internationally recognised conditions.
R-CPX.
The scientists working on R-CPX said that it promises a labour-extensive means of culturing cells on a large scale. At the time, the cultivation of cells used manual technologies at high cost and took weeks to months of highly skilled, dedicated labour. The quality of the hand-cultivated cells is uneven, and varies per institution, which influences the outcome of clinical trials. Automation is thought to improve precision and reproducibility, thereby enhancing the ability to comply to GLP standards, which are viewed as indispensable in the world of responsible and safe therapy provision (Williams et al. Reference Williams, Thomas, Hourd, Chandra and Ratcliffe2012; Soares et al. Reference Soares2014). Scientists compete in developing the robotics of automated and high-throughput cell culture systems. The Healthcare Engineering Group in Loughborough, UK, uses The Automation Partnership Biosystems (TAP Biosystems) for the cultivation of human embryonic stem cells and bone marrow-derived cells (Thomas et al. Reference Thomas, Chandra, Hourd and Williams2008), and KHI, Tokyo, has developed a robotic stem cell processing machine, R-CPX, using Auto-Culture®. Japanese scientists claimed TAP was less efficacious compared to Auto-Culture® (Kami et al. Reference Kami, Watakabe and Yamazaki-Inoue2013), which is advertised as uniquely capable of automatically replacing the culture medium, centrifuge cells, split cells and taking photographs for morphological assessment, as well as running according to Good Manufacturing Practice (GMP) standards.
As the cells are intended for clinical applications for a number of serious, intractable diseases and cosmetic applications, the quality of the cells is crucial. In regenerative medicine, where ‘the product is the process’ (Mason and Hoare Reference Mason and Hoare2007), just a slight difference in processing environment can lead to cell ossification. The question of upscaling is crucial to whether it is possible to manufacture consistently (Hargreaves Reference Hargreaves2019; Raymond and Williams Reference Rayment and Williams2010). And as the criteria for these mesenchymal stem cells (MSCs) are rather loose (see Chapter 4), it is difficult to check the influence of upscaling on the behavior of the cells (Michaels, 13/8/2014*). In short, although the adoption of the R-CPX machine promises an efficient environment for conducting clinical trials, scientific experimentation and the creation of medicinal products, there are wider concerns about the quality of the processed cells. These concerns are variously framed per regulatory system, and the views of scientists differ on the subject.
Regulatory Discrepancy
In 2011, discrepancies between regulatory regimes in Japan and Thailand led the Japanese company, KHI, to approach Thai scientists to discuss formal collaboration. In 2006, Japan had published guidelines on the ethical conduct in somatic stem cell clinical research, including guidelines on informed consent for donors and patients and privacy protection, the safety and determination of efficacy, quality assurance and transparency (MoHLW 2006). A two-tiered system for review was put into place, requiring principal investigators (PIs) to apply for permission from their local institutional review board (IRB) and from a governmental committee. By February 2010, only twenty-four out of thirty-six research applications had been approved (Kawakami et al. Reference Kawakami, Sipp and Kato2010), an indication of both the scrutiny and bureaucracy with which Japan’s bureaucracy treats regenerative medicine (e.g., Colman Reference Colman2008; Levine Reference Levine2008). Collaboration with clinics providing direct-to-consumer services was not an option, as it risked losing any state and public support (Sonoda, 5/11/2013*). All in all, Japanese scientists often mentioned the frequent delays in the regulatory bureaucracy as impeding Japan’s international competitiveness (Sawa, 11/11/2013*; Sonoda, 5/11/2013*).
In Thailand, the Medical Council of Thailand (MCT) in 2009 announced the development of regulation for clinical stem cell applications. In the same year, the Thai Food and Drug Administration (TFDA) announced that regenerative medicine would be treated on a par with drugs. The Drug Act’s amendment on the Control and Supervision of Drugs and Products from Stems Cells stated that all stem cell therapies, apart from hematopoietic stem cell transplantations, are to be considered experimental and were to be approved through a two-tiered system of review before being offered to patients. Researchers and medical practitioners were to submit protocols to both the ethics committee of their institutions (or the ethics panel of the Ministry of Public Health) and the scientific and ethic committee of the Medical Council of Thailand (MCT) for an independent review and approval (for English language details, see HISO 2010; Olson 2015). Violation of the regulation, which became effective on 11 May 2010, could result in medical licenses being revoked.
Following the law’s promulgation, private hospitals that had formerly advertised and admitted patients for experimental stem cell therapies claimed to have ceased provision. While there was some resistance to the regulation, with some scientists threatening to take research to neighbouring countries such as Cambodia (Sirisunthon and Sarnsamak 2009), and clandestine provision continuing under the heading of ‘cosmetic’ or other clinics (Nantakam, 26/6/2014*), the regulations appear to successfully combat clinical experimentation in state and private hospitals. At THAI, scientists hoped that the increased reliance on ‘international’ regulation in Thailand would protect patients and enable and guide clinical research on stem cells and iPSCs, supported by the allocation of material and knowledge resources; on an international political level, the publication of ‘international’ regulatory standards were hoped to lead to international recognition and opportunities for collaboration. But, at the same time, a reputation for slack regulatory enforcement of the new regulation and the absence of regulation for marketing also attracted potential collaborators.
The Japanese–Thai Collaboration
KHI’s proposal to collaborate came just before Thailand and Japan celebrated their ‘125th anniversary of friendship’ (Thanawin 2013). An MOU was signed on 27 November 2012 with the Department of Trade Negotiation (DTN), the Ministry of Commerce of Thailand and NEDO, Japan’s Ministry of International Trade and Industry (MITI), KHI, DSP Research Co., Ltd. and Mukogawa Women’s University and the Faculties of Medicine of Chulalongkorn and Srinakharintarawiroj Universities and AESKULAP Clinic (Asia) Co., Ltd, a subsidiary of Thanawin Holding, to agree on The Cell Cultivation Research by using the Robot Cultivate Cell Culture (R-CPX) developed by KHI. The opening ceremony took place on 30 September 2013 and further MOUs were signed among the ‘Thai’ and ‘Japanese’ Teams. According to the MOU, KHI would build and donate R-CPX to Thailand with financial support from NEDO (Thanawin 2013). It was expected that the promotion of the project would bolster Japan’s advanced regenerative and cell-related medical technologies and further vitalise the medical industries of both Japan and Thailand. A NEDO document illustrates how the R-CPX collaboration allows surveillance and control from Japan by means of instructions to and training of Thai scientists and through electronic CT data and X-ray images being sent to Japan (NEDO 2013). The document presents the project as part of Japan’s global expansion strategy, which forecasted an annual market of 3.8 billion Yen in 2050 [£25.8m]. While KHI uses the ‘donated’ R-CPX machine to diversify into medical devices that support the development of regenerative medicines, Japan’s long-term aim was to expand its Asian market and beyond (JSTA 2015).
The collaboration around R-CPX was based, on the one hand, on a similar interest in conducting scientific research into regenerative medicine, and, on the other hand, on diverging interests, whereby R-CPX and the regulation meant different things to the partners. For the Japanese partners, it was the marketing of the robotic machine, knowledge assets and expansion into Asia that counted most, while for the Thai partners, it was the opportunity to conduct scientific research, learn from Japan’s experts, and develop internationally recognised clinical trials. These different aims were reflected in the unequal work relations, whereby the Japan Team provided the machine and took the lead in the areas of design, training and supervision, while the Thai Team provided expertise for everyday maintenance, acquired knowledge and followed guidance from the Japanese Team. The notion of regulation, further discussed below, also meant different things to the Teams. Whereas to the Japanese Team, regulation in Japan is viewed as an obstacle, the regulation in Thailand was expected to be expedient to reach their aims. For the Thai Team, regulation was a crucial part of the reputation of scientists and essential to Thailand’s science community to thrive internationally.
The Competing Interests Underlying Collaboration: Concerns among the Thai and Japan Teams
Through conversations with the collaborating scientists, I came to understand how the convergence of interests of parties can reproduce diverging interests among collaborative partners, leading to clashing expectations and prompting diverging actions. I identified four themes of concern on the basis of what scientists from both sides of the collaboration referred to as main incentives for working together: scientific results, medicine, trust and regulation. The divergent interests show how, under regulatory capitalism, regulatory capital forges together collaboration with competition.
Scientific Results
For the Japanese scientists involved in the R-CPX project, scientific evidence is crucial to the success of Japanese–Thai collaboration. Japanese collaborators from the National Center for Child Health and Development (Tokyo) and the National Institute of Advanced Industrial Science and Technology (NAIST) have published materials that emphasise the safety and efficacy of R-CPX and its practical and economic advantage (Kami et al. Reference Kami, Watakabe and Yamazaki-Inoue2013). By identifying the connections between authors, regulators and KHI, I found that the authors of ‘Large-scale cell production of stem cells for clinical application using the automated cell-processing machine’ (Kami et al. Reference Kami, Watakabe and Yamazaki-Inoue2013) have a collaborative agreement with KHI, and that one of them was a deputy-director of Japan’s Pharmaceutical and Medical Drugs Agency (PMDA): there was a close link between authors, Japanese regulators and KHI. It was clear to all concerned that KHI needed independent recognition for R-CPX, which is why it was lobbying with world-renowned Kyoto University’s Centre for iPS Cell Research and Application (CiRA) to use the robot in clinical induced pluripotent stem cell (iPSC)-trials (Sawa, 11/11/2013*). CiRA, which has established an iPSC bank for allogeneic applications, was hoped to welcome the up-scaling of cell cultures through the use of KHI’s R-CPX. At the time, according to Sawa, Japan’s regulation would no time soon allow a clinical trial on one of the therapy targets, including osteoarthritis, using the cells processed by R-CPX (Sawa, 11/11/2013*). Both the Japanese scientists and managers from KHI were aware that the R-CPX was key to the Japanese–Thai collaboration. They thought that the use and marketing of cells processed by the GMP-graded R-CPX in Thailand would prove the machine’s worth and at the same time serve the Thai scientists as they conducted scientific experiments. Both teams saw it as a win-win deal.
THAI puts much effort into expanding its global scientific network, and prides itself on a good reputation. Scientists from elite laboratories explicitly subscribed to the regulation published by the International Society for Stem Cell Research (ISSCR) and the International Society for Cellular Therapy (ISCT), and they referred to their collaboration with the Association of Southeast Asian Nations (ASEAN) in developing robust regulation for medical devices and biologicals. At the same time, scientists found it challenging to deliver high quality scientific results with limited means. In this context, the collaboration with KHI, including the use of R-CPX, enabled Thai researchers to experiment with the culturing of various amounts and kinds of cells with little labour and in a fast and efficient manner. Dr Sombat explains:
The Kawasaki robot is very precise. It can handle many cells, over 10k, and it is very reliable. The machine can do many things. You can try to vary the protocol, add more of this chemical, or more of that chemical.
The collaboration allowed the Thai researchers to gain knowledge and receive advice, which puts them in a position to develop their own knowledge assets, including IPR, and to publish papers in high-standard international scientific journals. But a lack of resources hampered them in their efforts to achieve this:
It is very hard to publish a paper. You need to do a whole list of experiments before they accept. In genetics, you can do ten papers in a year, because it is an established field and does not cost much. But in iPS and stem cell research it costs a lot. You may have to do whole-genome sequencing or epigenetic scaling. Even if you have a brilliant idea and have experimented with it, you will still need to do more experiments. You need at least ten postdocs to do the work and then you still need five years. The alternative is publication in a small-shop [unimportant] journal. After Yamanaka published his iPS [discovery], Harvard soon was up to speed with many papers. They do not even have unique or original ideas. In many branches you also need bioinformatics, and for this you need a large database. This is how Singapore gets in.
A machine that can do large-scale culturing and experiments is a large step forward for the Thai Team. As the Thai Team lacked financial resources, R-CPX, a closed box that can function as a GMP lab in its own right, was regarded as a welcome asset:
There is no GMP yet in Chula, for products are still under development. The lab will be finished next year. Now we use a small cleanroom lab. It is very expensive to develop GMP. For the public, it is ridiculous to spend so much money. Here 1% more risk means therapy provision is 100 times cheaper. Treatment for spinal cord injury, for instance, needs to be affordable.
Although R-CPX allowed the hospital to have GMP equipment, various scientists found the planned clinical application for osteoarthritis immature. The MOU specified that the Thai were in charge of the implementation of the protocol, but according to the Thai orthopedist Dr Wilipana, the choice was made by the Japanese, who ‘went straight to the Department of Orthopedics’, which accords with Dr Sawa’s interest in osteoarthritis.
The application involves the cultivation of MSCs for osteoarthritis treatment. Dr Wilipana was pessimistic:
I think it is far too early. It will probably not be effective. They may need to optimise the extracellular matrix: it may not be cartilage that is formed, for you need a scaffold for this. You just get chondrocytes that disappear after a while. You need some mechanical force to keep the cells there.
Asked if they had discussed this with KHI, Dr Wilipana responds:
I discussed this so many times with them. I said, why not do a clinical trial in an area where they are already doing clinical trials? You only need to prove that the machine works. But they do not listen. They want to do OA [osteoarthritis]. But they need a therapy with a solid knowledge background, a scientific basis. If they fail, they lose all credibility …. If Kawasaki wants approval or further collaboration it is OK, but I can’t sell cells or machines and products for them. I will only write a report.
Though Dr Wilipana expressed worry about the choice of osteoarthritis, he did not think that the patients were taking a great risk, so he went along with the plans.
To acquire acknowledgement of the reliability of R-CPX in processing cells for conducting clinical trials in Thailand, the Japan Team wanted to conduct a clinical trial for OA, a condition important to Japan’s ageing population. Though hard to acquire in Japan, the Japan Team expected to get regulatory permission for conducting its planned clinical trial in Thailand as well as a license to market its products. In exchange for these regulatory assets, the Thai Team could use the R-CPX, which it valued as a means of conducting research and gaining experience, even though they had little control over specificities of the clinical trial. The Thai Team was motivated to conduct the research for what it saw as legitimate scientific reasons.
Medicine
KHI’s ‘donation’ of R-CPX was expected to support the expansion of regenerative medicine in Thailand and beyond. This view, however, was not shared by the Thai Team, which doubted Thailand’s ability to provide public care using regenerative medicine any time soon.
Regenerative medicine is thought to bring benefits to Japan’s rapidly ageing society and economy (Umemura Reference Umemura2015). Shinya Yamanaka’s Nobel Prize in 2012 for his work on iPSCs, the new law for the promotion of regenerative medicine, which promises that subsequent governments will support it and the growing economic activity in the field (Azuma Reference Azuma2015) all supported this belief. According to the Thai Team, KHI scientists and managers firmly believed that regenerative medicine would benefit Thailand’s healthcare. R-CPX would be instrumental: by offering affordable regenerative medicine to its aging population, and by becoming a destination for ‘medical tourism’, Thailand would be able to finance its own healthcare provision using R-CPX (Sawa, 11/11/2013*; Matsunami, 11/11/2013*).
The Thai scientists from THAI confirmed that R-CPX would be instrumental in the development of evidence-based therapy provision and a solution to the ever-increasing healthcare bill. They believed that regenerative medicine would eventually cure a range of conditions, and this justified investment into the field. In this context, Thailand’s prevalent blood condition, β thalassemia, was frequently mentioned as a target for stem cell therapy:
Bone marrow transplantation [for β thalassemia] is very expensive for Thais. Although there is universal health coverage available, it does not cover certain procedures, including bone marrow transplantation, which costs the patient £25k.
Other diseases for which stem cell therapy was mentioned as promising were graft-versus-host disease, Down syndrome, Parkinson disease, Alzheimer’s disease, heart disease and diabetes. As universal health coverage is insufficient, many Thai patients cannot afford treatment in other countries:
Only the rich can pay for some procedures. The government needs to find strategies: healthcare is important for all.
It is because of the high hopes placed on regenerative medicine, according to Dr Nantakam (26/6/2014*), that the government finds itself in a dilemma: to stimulate high-standard life-science research recognised by the dominant international community to produce expensive cell products or to allow less costly research that produces affordable cell products that may not work or, worse, be harmful. Dr Sombat similarly doubted the imminent use of regenerative medicine, even in Japan:
The ultimate goal for the Japanese, perhaps, is cell therapy: even though it is still far off, this is what has to be said to justify the research to the public.
The Japan Team, then, stressed that the value of affordable medicine is made possible by upscaling through automation, but the Thai Team doubted that these medical products would be affordable in Thailand any time soon (though exceptions would be made in cases of serious intractable conditions when experimental interventions was seen as justifiable). Only in the long run was there hope that conditions such as B Thallasemia would be cured. Nevertheless, both KHI and NEDO defined the collaborative arrangement as mutually beneficial: Japan would gain a strategic market for its medical products through Thai regulation, while Thailand would benefit from innovative, safe and affordable therapeutic products.
Trust
The long history of friendly relations between Japan and Thailand was mentioned repeatedly by both Teams and was said to be helpful in the collaboration’s efforts of trust-building. The signing of the MOU in June 2012 and the opening of the Robotic Stem Cell Incubation Laboratory on 30 September 2013 were accompanied by a wealth of ceremony. The opening ceremony of the Robotic Stem Cell Incubation Laboratory was presided over by the then Crown Princess Maha Chakri Sirindhorn, executive vice-president of the Thai Red Cross Society and patroness of the Red Cross Hospital. To the Japanese, the presence of the princess played an important role in building trust and goodwill. KHI scientists thought that the princess was there to receive the R-CPX as a ceremonial gift (gifuto) and a contribution (kifu) to the collaboration. The presence of the princess at the inauguration was not interpreted as just a matter of pride and honour, it was also read as a sign of probable permission for conducting a clinical trial using the machine and for the marketing of the cells it processed. In this context, senior KHI researcher said: ‘Not allowing it would be “warui” [bad form]’ (Nakasone, 11/11/2013*).
When asked why KHI had chosen Thailand as Asian partner, KHI scientists said that bad political relations challenged such efforts in case of China; South Korea was too much of a global competitor; Singapore was not considered as it is developing its own machine; and India’s regulation was thought to be too strict for the purposes of KHI. Thailand, however, was just right, said Dr Nakasone: ‘They are [our] friends’ (Nakasone, 11/11/2013*).
Initially, Thai scientists had little trust in the collaboration, reflected in their views on the status of R-CPX: it was not a ‘gift’. When explicitly asked, Wilipana said (25/6/2014*) that ‘the university has a document that says it was donated to them, but you never know’, while Sombat, who does not work directly with KHI but had been involved in the initial negotiations with KHI, said that ‘The original ownership of the robot lies with the Japanese, but they let us use the equipment under certain conditions’ (27/6/2014*). Both scientists, however, also expressed doubts about whether permission would be given for the planned clinical trials. In contrast with Japanese interpretations of the ceremony, Wilipana made it clear that
the fact that the Princess opened the ceremony for R-CPX had nothing to do with permission. But the permission will come, if the mesenchymal stem cells are shown to be safe and the machine produces the cells in the proper way.
It was the hope of key researchers that the project would force the Thai FDA to further develop the regulation for biologicals and set up an accreditation committee. This would benefit the work of all scientists in the field and help Thailand’s regenerative medicine to be treated on a par with advanced scientific powers (Wilipana, 25/6/2014*; Sombat, 27/6/2014*). This, it was argued, would establish a better foundation for collaboration.
Despite the initial mistrust of THAI scientists towards the Japanese, Sombat said that even though he knew that the robotic machine was not a free gift, the Japanese scientists were helpful and seemed sincere. But it was clear all the same that they wanted Thai FDA approval and a marketing license for the product (Sombat, 27/6/2014*). The scientist in charge of assisting the Japanese delegations, Dr Wilipana, expressed a similar view:
Kawasaki represents the state of the art, and the Japanese want to export their products to this part of the world. That is fine. The Japanese Minister from MITI came to Thailand, which shows that they are taking this seriously.
Dr. Wilipana characterised the collaboration as mutually beneficial. For instance:
The collaboration with KHI is based on mutual help: Chula can help them get approval for the trial and be a collaborator. This is something reasonable to do for the patients – and we can use their protocol. They say what media, protocol to use, and what patient selection to apply it to. We do it as they designed it.
Despite dissatisfaction with the amount of time dedicated to the collaboration, Dr Wilipana found Kawasaki representatives good to work with.
The Japan Team clearly chose Thailand as host for collaborative scientific research for strategic reasons, including political and historical ones, and considerations of competition. But the ability to conduct a clinical trial and market cell therapy using cells processed by R-CPX was crucial to them. The ceremonial inauguration of R-CPX confirmed the view of the Japan Team that they could trust that their ‘donation’ would eventually lead to regulatory leniency. The Thai Team, by contrast, regarded the honesty about the regulatory motivation from the side of the Japan Team as an important sign of trust. Even though friendly relations and assistance were highly appreciated, the patchy clarity over issues of ownership and scientific collaboration was not conducive to trust.
Regulation
Regulations form the basis for authorising clinical trials and the licensing of cell products, and they underpin stipulations for the use of scientific protocol, standards for the use of GLP, GMP, equipment and research governance. When KHI approached Bangkok regarding R-CPX, Japan’s regulation was seen as strict and bureaucratic, while Thailand’s was seen as lenient (Nakasone, 11/11/2013*; Matsunami, 11/11/2013*). But prominent Thai stem cell scientists, such as Manote, Wilipana, and Sombat, all insisted that Thailand needed specific and more extensive stem cell regulation urgently, as without it, Thailand would not be taken seriously as an international scientific player. The scientists maintained that unauthorised stem cell therapies using MSCs were still provided in clinics, not only for cosmetic purposes but also for many medical conditions ranging from autism to cardiovascular disease. Manote (24/6/2014*) and Nantakam (26/6/2014*) called these practices ‘unethical’, because ‘they do not have “ethical permission”’ from an Institutional Review Board (IRB), let alone from the MCT. In this respect, the Thai Team expressed doubt and anxiety when discussing Japanese expectations of lenient regulatory treatment. Mention of likely Japanese disappointment suggested that some Thai scientists regretted what were thought of as Japanese perceptions of Thai regulation as ‘easy’ and ‘corrupt’.
All Thai scientists I spoke with expressed hope that stem cell science under the new, military regime would be supported and that the regulation for regenerative medicine would improve soon. Dr Wilipana related how, over the previous five years, it had been impossible to develop new regulation:
It is not uncommon in Thailand to find that people in powerful positions have vested interests in the lucrative cell therapy business. For example, in the past, someone working in the government was involved in selling stem cell therapies in hospitals. The MCT and the Thai Physician Association (TPA) do not accept them – they maintain the stance that only hematopoietic stem cell therapies are safe and effective. So, this person asked the MCT and the TPA to revise their position and to issue statements and regulations accepting questionable therapies. I was outraged [by the request]. This was just one of the many examples.
The MCT and the TPA refused to revise their position, and, presently, Dr Wilipana related, the Stem Cell Research Society of Thailand is developing new guidelines for clinics that are not officially recognised as scientific institutions. This effort was supported by the ASEAN, which designed its own regulation (TFDA 2017). Furthermore, the MCT was working on a Roadmap for Regenerative Medicine and on new regulations for ‘Stem cell products as advanced-therapy medicinal products’. Professor Manote, a member of the MCT, said that despite earlier regulatory efforts Thailand’s regulation is relatively permissive (24/6/2014*). He believed that further regulation was needed for further controls on non-hematological clinical stem cell applications. Currently, he clarified, Thai hospitals are conducting unauthorised MSC-trials for cartilage and for retinal diseases.
Dr Wilipana explained (25/6/2014*) that in order to be taken seriously as a stem cell researcher in Thailand, you need to apply for local IRB and MCT permission for clinical applications. The MCT has a board for the application of stem cell products: ‘Normally it takes about 1–2 months – it is a checkpoint for ethics and informed consent, so that people don’t just go ahead with anything’ (25/6/2014*). Dr Wilipana, too, was in favour of streamlining the regulation:
The quality of IRBs in medical school varies considerably. The MCT has no action arm – they cannot do anything about malpractice – unless someone reports it. Only then they can intervene.
To improve control over stem cell applications, the government was creating regulatory space for stem cell research by specifying stem cell products used in a clinical setting. But this plan harbours a dilemma. As Dr Nantakam argues:
If you were to follow the rules of the American FDA or the ISSCR, then you would not do anything. The regulation [in Thailand] has to be flexible. There are many problems. If you want to publish, you need GLP and GMP for translational research: how?! You cannot use the same rules, because the context is different. Ordinary people cannot get access [to therapy] otherwise. They cannot pay a million baht for treatment in a GMP facility.
For the Japanese and the scientists at THAI, however, GLP and GMP were crucial:
KHI wanted R-CPX in Thailand because they wanted an outcome: a therapy for the patient, and they wanted a ‘product’ tested on it within three years.
Scientists at THAI found the availability of R-CPX very helpful, as it conformed to GLP and GMP standards. R-CPX was designed after the industrialisation of cell culturing was permitted in 2011 (Azuma Reference Azuma2015; Tobita et al. Reference Tobita, Konomi, Torashima, Kimura, Taoka and Kaminota2016), which led the successful application for a patent by KHI. Professor Sawa, the originator of the idea for this particular robotic cell processor (Sawa, 11/11/2013*), had worked on patients’ worn knees for many years. He wanted to conduct a clinical trial on osteoarthritis patients in Thailand, as it was not allowed in Japan. Professor Sawa explained:
In Japan, you first need to show that the ligament is being created through the mesenchymal stem cells [rather than through growth factors].
A consideration was that, if growth factors alone could create ligament, it would not be necessary to conduct clinical stem cells trials. Professor Sawa had not conducted clinical stem cell trials yet, but he had published many clinical studies in international journals, for which he had permission from the Ministry of Health, Welfare and Labor (MoHWL) in Japan. But even if KHI were to receive the go-ahead in Japan under the new regulation (Azuma Reference Azuma2015), it was the R-CPX ability to culture large numbers of cells according to protocol without human error and within the required time that was crucial to the Japan Team. An accelerated process for applying for permission for the clinical trial was believed to be more likely to happen in Thailand – in the context of a friendly subsidised collaboration – then in Japan. To make sure that all would go according to plan, Professor Sawa had an office wall–wide projection screen at his university in Japan, which enabled ‘close-up’ observation of the laboratory and holding meetings with the Thai Team in Bangkok.
When asked about the regulatory expectations of the Japan Team, Dr Sombat from the Thai Team explained that the two-tier approval system was very challenging as the committee overseeing clinical trials had the reputation of being strict:
You first submit the protocol, and you might need to re-apply …. You need to submit the protocol to MCT. Once you have been through the clinical trial, you still need to apply [to the MCT] to get permission for marketing the product. There is no law yet for stem cell products. So, it is not controlled – we do not have a [formal] definition for the product. Yesterday we had a meeting about it with the Ministry of Health, but we don’t know if it is acceptable to the TFDA.
In Thailand, then, stem cells were still regulated as drugs. And, even if a clinical application using R-CPX were to prove successful, without a definition of stem cells as a stem cell product, it was thought that marketing would be problematic. Although KHI may have wanted to gain approval for a stem cell product to show that R-CPX is an attractive processing option, but without a definition of its stem cell output as stem cell product, the TFDA would not be able to provide marketing permission.
Regulatory Contingencies
Although Japanese and Thai interests in the collaboration converged on prioritising scientific results, medicine, mutual trust and suitable regulation, the teams ascribed very different meanings to these terms. Where the Japan Team’s scientific interests prioritised regulatory permission and marketing licenses, the Thai team prioritised scientific expertise; where the Japan team believed in the immanent realisation of the promise of somatic stem cell therapy, the Thai team desired it but doubted its feasibility; where the Japan team saw trust in terms of regulatory lenience and mutual support for its scientific aims, the Thai team saw trust in terms of mutual support of scientific aims. The divergences of these perspectives all pointed to a clash between respective expectations about Thailand’s regulation of regenerative medicine.
Thailand’s regulation of regenerative medicine had been central to the initiative and negotiations of the Japanese–Thai collaboration. But as the value of Thai regulation as asset had not been made explicit, the terms of the collaboration were liable to change. For the Japan Team, Thai regulatory capital had been crucial to proving the worth of R-CPX. But as this expectation was a source of great reputational worry to the Thai Team, scientists were keen to emphasise that regulation in Thailand, although ‘strict’ already, needed to be improved and specified even further. While the Japan Team had planned to make strategic use of the regulatory discrepancy, the Thai expected a tightening of the regulation for regenerative medicine.
KHI obtained permission for the planned clinical trial for osteoarthritis, much later than expected. On 27 December 2016, KHI announced on its website ‘Cells Cultured by Automation Are Used for a World-first Clinical Study in Thailand’, for cell therapy of knee cartilage, using mesenchymal stem cells cultured by Auto-Culture® (Kawasaki 2016). But whether the resulting biological product will ever receive marketing permission remains unclear. An online R-CPX brochure indicates that KHI is still in the process of proving that the robotic machine is a superior tool: ‘For regenerative medicine and cell therapy using automatic cell processing system, the actual proof by clinical research is pursued’ (Kawasaki brochure, undated).
Since the start of the collaboration, both Thai and Japanese have been changing the direction of their regulatory boundary-work. Thailand revised its regulation in 2017 to build its regulatory capacity. The Thai Revised Drug Act, developed in concert with ASEAN, now requires a license for the manufacture and selling of drugs (including biologics) and pre-marketing electronic dossier registration. Advertising needs to be approved, and post-market requirements now include regular sampling, inspections and GMP clearance (Adcock Humhuan 2016; MOPH 2017; TFDA 2017). Further regulatory changes are still expected (Sombat, 27/6/2014). In the meantime, however, Japan’s regulation has become far more permissive and supportive since its regulatory overhaul of 2013 (Azuma Reference Azuma2015). There has been a flurry of offers from around the world to collaborate with Japanese enterprises, in the belief that Japan’s new regulation is permissive. It is Japan’s regulation that is now being used as regulatory capital, especially in relation to the clinical application of so-called MSCs (Sipp and Okano Reference Sipp and Okano2018). Regulatory change, then – more permissive in Japan, and stricter in Thailand – has reconfigured the lay of the regulatory land.
But what did this mean in terms of Thai–Japanese collaboration? In pursuit of the proof of the machine’s worth, the Japan Team continued to supervise clinical trials conducted by the Thai Team. And under the aegis of the Japan Team, the Thai Team continued to use R-CPX as a learning tool. But expectations were lowered as uncertainty around the marketing of therapy products created using R-CPX had decreased. The situation had made it more difficult for the Thai Team to address issues around the costs the Thai laboratory was facing. The R-CPX was useless without its software, and because the software updated regularly, the laboratory was presented with hefty bills. In addition, the import costs for assays and other instruments are extremely expensive for Thailand, as it trades under GATT rules (Sombat, 12/11/2014*).
The Thai Team, then, is facing the costs of its dependence on the Japan Team to continue using R-CPX. In addition, Thailand’s regulatory capital seems to have dwindled. In 2015, Japan’s government took it upon itself to invest into the harmonisation of Asian regulation for clinical trials in regenerative medicine and the marketing of therapies and medicinal devices (MoHWL 2015; PMDA 2017; FIRM 2018) such as R-CPX. No doubt the workshops and training seminars for multi-regional clinical trials Japan’s PMDA organises in Southeast Asia (PMDA 2018) will facilitate new forms of ‘collaboration’.
Regulatory Capital and Science Collaboration in Regulatory Capitalism
This chapter proposed the concept of ‘regulatory capital’ to shed light on the role of regulation in scientific international collaboration as illustrated by the case of the Japanese–Thai collaboration around R-CPX. The point of departure was the idea that regulatory discrepancies can stimulate particular forms of cross-border collaborations. Regulatory capital, as a relational concept, concerns the relations between potential collaborators. We saw how in the Thai–Japanese science collaborations regulatory capital was used to negotiate collaborative conditions. As the role of regulatory capital was not formally spelt out, there was uncertainty about the realisation of the core aims of the collaboration and ambiguity about the meanings of interactions and events, such as the opening ceremony of the collaboration. Thus, the Japan Team interpreted the installation of the robotic machine in THAI as a ‘donation’, while the Thai Team saw it as a lease and sometimes as an ‘expensive’ one at that.
An examination of the role of regulatory capital in the Japanese–Thai science collaboration shed light on the nature of regulation as an asset in negotiation. First, the relationality of the value of regulatory capital was realised not just in relation to the jurisdiction of the collaborative partners but also vis-à-vis the authority of significant others, such as the ISSCR, EMA and ASEAN. In the examined case, Thai regulatory capital increased after Thailand had announced ‘international’ regulation. At the same time, Thailand’s regulatory capital increased in negotiation with Japan, as its ‘international’ regulation was not viewed to be as problematic as Japan’s restrictive regulation. Second, the Japan Team did not read Thai regulation as forbidding but relied on its lack of detail and its flexible implementation. Flexible implementation of regulation, then, can increase the value of regulatory capital in international science collaboration but also its uncertainty. Third, the state may play an important role in cementing a collaboration. In Japan’s case, NEDO decided to circumvent the spirit of Japan’s own regulation, indirectly acknowledging the deficit of KHI’s regulatory capital; in the case of Thailand, the TFDA accepted the collaboration without guaranteeing the regulation authorisation needed to realise Japan’s ultimate aim of the collaborative project. Fourth, awareness of the value of regulatory capital can bring governments either to regulate (in case of Thailand) or to deregulate (in case of Japan) in order to enhance the country’s international position. Fifth, the relative nature of regulatory capital and its contingence on regulatory reform can increase uncertainty around a collaboration. Depending on how the collaboration is sustained and maintained, the expectations and the terms of the collaboration can be adjusted. Finally, the possession of other forms of capital (financial, scientific, medical, political) is crucial to whether a country can exercise its regulatory capital. In this case study, it was the awareness of both regulatory discrepancy and the capital inequality in other areas that made Japan approach Thailand for collaboration and for Thailand to accept.
This case study makes clear that, unlike idealistic views that define collaboration in terms of the pooling of efforts and resources to realise a common scientific goal, in the context of inequality, collaboration is often based on the fertile feeding ground of competing interests and aims. What the collaborative partners share is a broad direction of agreed research and other collaborative aims, some of which are shared by the collaborators more than others and some not at all. For instance, the transfer of expertise through the deposition of R-CPX was important to the Thai Team, while processing cells of a standard high enough to create therapeutic products tested by clinical trial was crucial to the Japan Team. As a consequence, the inauguration of the laboratory containing the robotic machine had diverging meanings for the Teams. Due to the competing aims of the partners, Thai regulation of regenerative medicine has also different significance. With their diverging scientific and material aims, the competing interest of the Teams in the regulation clashed. In this sense, we can speak of a fundamental interdependence of competition and collaboration. It is therefore not divergence but the convergence of interests that leads to conflicts about how to pursue them (Girard 1965; Demouchel Reference Demouchel2017).
As convergence in this case clearly connects unequal partners, partners had to tread carefully: trust and a positive atmosphere was crucial to the collaboration, expressed in the ritual inauguration of R-CPX. On the one hand, conflict avoidance was expressed in the preparedness to help and express friendship; on the other hand, the inexplicit role of regulatory capital and inequalities inherent to the collaboration encouraged a mutual understanding based on differences around control, surveillance, expertise, expenses, profit through these expressions of friendship and helpful attitudes. Conflict around finance, regulation and scientific aims was held at bay but continued to bubble under the surface. Thus, the Thai Team felt that they were paying too much for the use of R-CPX and were working on projects not entirely of their choice. On the other hand, the Japan Team, the dominant partner, saw its strategy backfire when instead of lenient, they were confronted by researchers bent on asserting their sense of what they considered acceptable scientific research by means of regulatory reform: by the time that KHI received the go-ahead for the clinical trial, Japan’s regulatory reform had already enable similar clinical trials at home (Cyranoski Reference Cyranoski2013; Azuma Reference Azuma2015; Sipp and Okano Reference Sipp and Okano2018).
In the R-CPX project, inequality proved to be both a source of conflict and of collaboration. But whether such inequality is aggravated, reproduced or diminished depends does not just on the circumstances of the collaborative partners; it is also contingent upon how interests are played out in the international dynamics of regulatory capitalism. Thus, in a situation in which the Thai Team was under pressure to help the Japan Team to lobby for regulatory permission, this would be in the interest of KHI but at the same time aggravate the global position of THAI scientists. In other words, by pleasing the Japan Team and maximising the benefits from the collaboration, this strategy could diminish the long-term regulatory fitness of the Thai elite science: its regulatory immunity would weaken. The notions of regulatory capital and regulatory tolerance can shed light on what it means to have a science collaboration under the global dynamics of regulatory capitalism. At the outset of Japanese–Thai collaboration, the Japan’s regulatory immune system was robust: it was known for its regulatory prohibition. In this situation, even research supported by NEDO, a Japanese ministry, could afford to be regulatorily tolerant: it financially supported a collaboration that violated the spirit of Japan’s regulation by seeking comfort abroad. For Thailand, however, as a developing nation, the acknowledgement of the role of regulatory capital in the collaboration would have been deeply damaging to its scientific ambitions, especially those of elite laboratories. For this reason, the Japan Team was wholeheartedly engaged in a struggle for a regulatory upgrade.
The use of regulatory capital in international science collaboration, then, is not just an indication of regulatory tolerance; it may also be an indication of ‘regulatory contagion’, that is, a collaboration that involves the local regulatory regime could be seen as infecting the reputation of the sciences in its jurisdiction. Elite laboratories need to avoid such infection at all costs, even when they are part of such collaboration. In terms of immunitary politics, the Thai Team felt that collaboration on ‘unethical’ science with its well-reputed Japanese partner was misrecognised symbolically in the ritual celebration of R-CPX. However, the collaboration with Japan in itself was hoped to make up for it and have a cathartic effect. This contrasts with the regulatory ‘pure’ country, Japan, which externalised its ‘unethical’ science with full support of the state. In Part III on ‘regulatory redemption’, I will elaborate on the link between immunitary politics and the ritualisation of regulation.
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