The Large Grey Area between ‘bona fide’ and ‘rogue’ stem cell interventions Ethical acceptability and the need to include local variability

This article aims to put into perspective the binary opposition between ‘scientific’ clinical research trials and ‘rogue’ experimental stem cell therapies, and to show why the ethics criteria used by the dominant science community are not suitable for distinguishing between adequate and inadequate treatment. By focusing on the grey area between clinical stem cell trials and stem cell experimentation, the experimental space where patients, medical professionals and life scientists negotiate for diverging reasons and aims, I show why idealised notions of ethics are not feasible for many stem cell scientists in low- and middle-income countries. Drawing on fieldwork in China from 2012-2013, the article asks why ‘the unethical’ according to some is acceptable to Chinese life scientists. The case study of stem cell service provider Beike Biotech illustrates how stem cell interventions take place in a large grey area, where narrow notions of ethics are blurred with and supplanted by broader notions of ethics, co-determined by estimations of socioeconomic, political and cultural understandings of risk, opportunity and benefit. I borrow the term ‘bionetworking’, understood as the entrepreneurial aspects of scientific networks that engage in creating biomedical products, to analyse various forms of medical experimentation. I speak of the ‘externalisation’ and ‘internalisation’ of local factors, to elucidate how features of patient populations and their environments are subsumed in clinical research applications. Compared to polarized views of stem cell therapy, this approach increases the transparency of clinical interventions and broadens our understanding of why ‘stem cell tourism’ to some is ‘stem cell therapy’ to others.


Introduction
In the context of 'stem cell tourism', scientists and observers of ethics have made sharp distinctions between randomised controlled trials (RCTs) and 'experimental' stem cell therapy provision. Various forms and practices of stem cell research and therapy have been criticised, reported and analysed by social scientists and the press (e.g., McMahon & Thorsteinsdottir 2010;The Economist 2002;Sipp 2011b;Main et al 2014;Ogbogu et al 2014;Cyranoski 2012). Governments in the US, Hungary, the Netherlands, Germany, Ireland, Belize and elsewhere have closed down clinics that provide 'unauthorised' stem cell therapies, while others fail to stop stem cell providers from charging high fees to administer 'unproven therapies' (Sipp 2009).
The distinctions between 'legitimate ' and 'illegitimate', 'evidence-based' and 'traditional', and 'science-based' and 'experimental stem cell therapies' are subject to heated discussion among established scientists and critics. These distinctions presume that clinical stem cell interventions that are 'unproven' are applied only by quacks (Bharadwaj 2013): not with the aim to cure disease, but to exploit innocent victims Some works on the clinical application of stem cells in LMICs have emphasised the importance of analysing regenerative medicine in the context of globalisation, global politics and global governance (Webster, 2013;Zhang, 2012;Bharadwaj 2013;Chen & Gottweis 2013;Sleeboom-Faulkner & Patra 2011;Sleeboom-Faulkner 2014). These and others (Salter, Zhou & Datta 2015) have especially focused on the central role of bioethics in the global hegemony of 'Western' stem cell science, whereby bioethics and stem cell governance have become a pawn in a global race. Rather than making another claim about the global fees, medical ethics and scientific research fraud central to thinking about 'rogue' experimental stem cell provision (Sipp 2009;MacMahon & Thorsteinsdottir 2010;Sipp 2011b;Main et al 2014;Ogbogu et al 2014;Cauldfield 2015). But generalising and preconceived notions of global inequality, exploitation, and human experimentation on the poor and desperate fail to take into account the variability of their institutional embedding: they are unable to capture the significance of the active roles of patients, scientists and governments that facilitate innovative clinical stem cell applications in low-and middle-income countries (LMICs). The ethics of stem cell interventions, then, need to be understood in the socio-economic context in which its gains meaning, significance and is implemented. Rather than doing away with ethics, or understanding the ethics of stem cell applications in terms of 'rogue' and bona fide', this approach leads to a more realistic estimation of the meaning of 'international ethics' and the reasons for its lack of implementation.
Accounts of local factors underlying such applications are needed to nuance the binary that has been created between 'good' RCTs and 'rogue' stem cell experimentation (SCE) (see Table 1). In practice, most forms of clinical stem cell research feature a combination of these ideal-typical features, enabled by the various experimental spaces available in countries globally . By putting this binary into perspective this article tries to move beyond the view that good clinical practice is a matter of money, ethics and evidence-based science. Instead, it emphasises the importance of local factors that structure the exchanges between patients and research enterprises in shaping the clinical stem cell interventions that take place. This shift of focus from a narrow approach to ethics to value realisation through exchange networks in the life sciences increases the number of factors relevant to the ethics underlying the development and practice of clinical stem cell applications.

Bionetworking
In clinical stem cell research and its applications the value of scientific knowledge, medical skills, management and materials (including laboratories, assays, serums and biologics) are realised through many kinds of knowledge and material exchanges.
They are expressed in a range of commercial and trading assets, including iPR, product licensing, accreditations and scientific collaborations, and materialised in the trade of equipment and biomaterials, and clinical services. Value realisation here (Birch and Tyfield 2012) requires the strategic deployment of a range of socioeconomic relationships, entailing entrepreneurial skills, planning and management (Jones et al 2011). While the wellbeing of the patient may be central to scientists' concerns, it is clear that there are many other factors that condition their ability to sustain their work successfully, be it in an academic department, a company or a clinic. Central to value realisation in the life sciences is the way in which exchanges are positioned in strategic networks shaped through socio-economic, political-legal and cultural factors, or, 'bionetworking' (Sleeboom-Faulkner & Patra 2011), also involving a myriad of non-scientific activities, including networking, lobbying, managing, trading, and collaborating to produce science. These activities encompass interactions with a wide variety of stakeholders and institutions, ranging from political agencies, corporate sponsors and subsidiary companies to patient groups, local hospitals, universities, and the media. Such 'bionetworking' activities, according to Sleeboom-Faulkner and Patra, can be used to justify, prepare, and realise life science research and its applications in marked localities, incentivised not just by the promise of scientific results, but also by the demand of clients, collaborative partners, funding providers and by the development of new knowledge assets (Sleeboom-Faulkner & Patra 2011). The value realisation in bionetworks differs from the notion of biovalue, which pertains to the yield of vitality produced by the biotechnical reformulation of living processes (Waldby 2002 Table 2), and enable us to understand why 'unethical' stem cell applications are 'acceptable' to some. conditions of universal applicability. Such clinical trials tailor-made to the circumstances of patients are also referred to as 'pragmatic clinical trials' (Patsopoulos 2011). The struggle to make RCTs more 'relevant' to real world problems and populations requires researchers to take into account institutional settings and to accommodate variation among the circumstances of patients   When told that in the eyes of foreigners Beike Biotech engages in unethical practices, the 18 interviewees that had not lived abroad showed surprise. Only those that work in both China and the US or had been abroad for over a year found Beike 'unethical', for reasons of charging high fees, for using unproven and unauthorised therapies, and for not having open patient records.
There is great variety in quality among stem cell research centres and therapy providers in China, and it is not easy to gauge whether therapies are evidence-based, whether patient fees cover costs or constitute profit, and whether a lack of research oversight means that unacceptable research is taking place. Nevertheless, reports exist about clinics that provide injections of cells of unclear provenance for steep fees and without scientific records for diseases widely believed to be incurable. These so-

Distinguishing between forms of stem cell experimentation
Awareness of clinical stem cell applications as bionetworks focuses our attention on the entrepreneurial aspects of research finance (e.g., research funding, science investment, treatment fees), research policies (e.g., regarding standards, expertise, regulation, research data) and life values (e.g., values pertaining to health, bioethics, distributive justice) involved in life science innovation.
Experimental research that strictly follows scientific protocol, such as the four-phased, double-blind, randomised control trial with control groups, is designed to meet the standards of the world's leading peer-reviewed international scientific journals. The general validity of the RCT would make these trials universally repeatable and applicable. These kinds of trials are extremely expensive, not in the least because they need to meet the highest standards of GMP, GLP and IRBs, to be conducted by trained personnel, and have supervisory mechanisms in place to work according to authorised scientific protocol. Such RCTs are thought to be 'scientific evidence-based' and, ultimately, most beneficial to patients. However, wherever the intervention takes place, in practice many of the formal rules for clinical application and the 'patients' derive from high-income countries (Hunt & Khosla 2010;Nwobike 2006).
The research ethics of translational stem cell research and stem cell therapies are difficult to delineate in a consistent manner. I started out to explore this question using a 'research ethics continuum' ranging from 'rogue' to 'bona fide' stem cell applications, with RCTs as one extreme and 'snake oil' applications as the other: Although helpful in the European context, such a continuum can also be misleading.
For, what we call 'rogue' practices can become acceptable depending on the context in which they occur. In the case of patients with severe, intractable diseases, 'patientdriven experimentation' is performed in hospitals around the world. In cases where innovative cell products involve the testing of new procedures or drugs, regulatory provisions can be made. For example, doctors in Europe can now make use of the 'hospital exemption' (EMA 2010), while doctors in the US can test new treatments using the 'compassionate use programmes' (Moynihan 2012). But all of these clinical stem cell interventions are required to follow scientific protocol, independent review by an Institutional Review Board (IRB), and ethics procedures. In the case of the hospital exemption in Europe, experimental treatment forms part of the research framework in the form of a 'pilot-study'. Although these studies aim to systematically collect data, they are required to prioritise the welfare of the patient. In some countries, such as Spain, the number of patients involved can amount to hundreds of Second, patients want cures, independent of whether they are achieved through scientific knowledge, fluke, placebo or alternative treatments. To patients that cannot afford or find alternative healthcare in their country, commercial or experimental stem cell therapies may be their only option -especially if they see this as a chance for a higher quality or extension of life. A growing group of patients argues that any positive effect, even if the result of a placebo, and even if short-term, is preferable to no intervention (Chen & Gottweis 2013).
Third, many patients do not think that paid-for treatment is automatically unethical. Although making profit using experimental medicine is unethical according to some, many patients understand that those providing commercial stem cell To appreciate the workings of the bionetworks in which stem cell experimentation operates, rather than judging it by a narrow approach to bioethics, commercial aims, and research oversight alone, it is important to understand the healthcare needs of patients and the infrastructural resources available to populations.
Ethics oversight, fee-payment and scientific evidence are only some of the aspects relevant to the exchanges between patients, doctors and life scientists, which are better understood in the light of the globalisation of the healthcare industry in interaction with the ways in which localities aim to meet local needs.

The internalisation and externalisation of local factors
The binary of RCTs and SCE blinds us to the bionetworks that combine elements of  The evidence-based science orientation of RCTs was also criticised for creating medical products that are unaffordable due to intellectual property rights (iPR). However, medical products generated outside of RCTs can also carry iPR. For instance, Beike Biotech, who does not organise classical RCTs, promotes its 20 patents and AABB certificate (Beike Biotech 2014) in advertisements and in its negotiations with provincial biobanks and hospitals. And, Beike's stem cell products can be just as unaffordable, as will be illustrated below.

Internalisation
The scientific basis of the research may be affected by the social and physical circumstances in which it takes place, for it is not always possible to externalise the 'undesirable' conditions that are part and parcel of the field site (Montgomery 2012 calling it "the world's largest stem cell storage and processing facility" (Beike 2009).

Beike set itself an international mission:
Beike is the world's largest stem cell provider focusing on the research, (3) As for the placebo effect, interviewees 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 or not any signs of improvement are attributable to any placebo effect (interview H, J, K 1, July 2012).
(4) Although patient records have not been maintained in the past, Interviewee L said that they are being kept now, but cannot be opened for inspection by competitors and audit for reasons of iPR and patient confidentiality (interview M, July 2012). Those who want to know more were referred to Beike's website, which has patient case studies for the world to admire (Beike 2012a). This case-study of Beike Biotech shows why it is important to know how and why local factors are in/externalised into the clinical research. It allows us to discern the logic of 'acceptability' in its local context, such as • Whether patients pay fees to maintain the work of doctors and researchers and exorbitant profits that disappear into the pockets of individuals; • Whether patients are told fairy-tales or whether they are given realistic data on the therapeutic prospects; • Whether interventions are uncontrolled try-outs or whether they are part of larger-scale research; • The source of certifications and the quality of publications (e.g., whether a company has its own journal or publishes in widely-known journals; whether life scientists are main authors or free-riders on articles; whether certifications are bestowed by suppliers or well-known institutions with authority).
The relation between local context and the bionetwork changes over time: First, the internalisation of patient characteristics such as environment, diet, genetic make-up, age, gender and weight can take place for various reasons. For example, the logic of a clinical trial may require information on body weight, ethnicity or gender to determine the most appropriate drug dosage. But clinical trials might also include criteria for age and body-weight with the aim of extending a patent, even though the additional knowledge gained from the trial is of no scientific significance or relevance to the patients (Angell 2004   Rather than leading to a form of ethical relativism in the field of regenerative medicine, such improved understanding should alert initiators of the creation of global research and ethical guidelines that they will affect the clinical research activities of those who are excluded from their formulation. 'Snake-oil' providers can be detected globally, and are broadly condemned -there is no need for a formal ethical framework against these, just a legal one. However, if ethics and research guidelines are intended for global implementation, efforts are needed to include in the regulatory process scientists from parts of the world, whose practices may be frowned upon. This will require a more realistic understanding of the 'large grey area' of clinical stem cell research, and a reconsideration of the terms of global competition in regenerative medicine, a field widely perceived as fraught with ethically sensitive issues.