Stem cells clinical trials for cardiac repair: regulation as practical accomplishment
Address for correspondence: Dana M. Wilson-Kovacs, ESRC Centre for Genomics in Society (Egenis), University of Exeter, Byrne House, St German’s Road, Exeter EX1 4PJ
Macro-analyses on the regulation of new biomedical objects tend to focus on discursive structures and legislative categories in science policy debates at national and cross-national levels, but overlook how actors engage in regulatory practices on an everyday basis. Based on data from ethnographic fieldwork in British and German clinics, and 32 interviews with medical staff, this article provides an insight into the regulation of adult stem cell research and its clinical implementation. The argument illustrates the enactment of regulation at different stages and highlights the accompanying interpretative strategies employed by the medical personnel involved in the management of clinical trials using patients’ own (autologous) stem cells to regenerate damaged cardiac tissue. We argue that the implementation of regulation is a practical accomplishment in both national contexts. The complexities present in this process are instanced by the gradual crystallisation of practices within the organisation of clinical trials. This crystallisation is dependent on exchanges between members of medical teams and external agencies, and is set within a strategic ordering of regulatory measures that are mobilised to legitimise clinical research and reinforce professional interests.
Over the past 10 years stem cell research has become a distinct field of scientific inquiry that is seen to carry great potential for the treatment of cardiovascular disease, diabetes and various degenerative conditions (Bender et al. 2005, Webster 2007). In Europe, stem cell research has generated considerable scholarly discussions concerning its political governance and the salience of regulatory policies (Jasanoff 2005, Nowotny et al. 2007, Salter 2004). Such debates usually focus on the macro-dynamics of science development and the role of legislative bodies (Capps 2008, Kent et al. 2006) and rely largely on documentary resources (Wainwright et al. 2006). They tend to centre on the governance of ethically contested stem cells (i.e. human embryonic) and ignore the development of regulatory practices in adult stem cell research, which has moved into clinical application. Although commentators have acknowledged the contribution of scientists to the shaping and implementing of regulatory frameworks (e.g.Wainwright et al. 2006), little attention has been paid to the clinical aspects of this implementation and the ways in which medical practitioners make sense of emerging regulatory frameworks for stem cell therapies.
This paper provides an insight into the regulation of adult stem cell research and its clinical implementation. Based on data from 32 ethnographic interviews and fieldwork in laboratories and clinics, it presents a comparison of British and German stem cell research teams. It focuses on the practitioners’ understanding and use of regulation in the organisation of double-blind, randomised control trials (RCTs) using the patients’ own (autologous) bone marrow stem cells for cardiac repair. We discuss the enactment of regulation at different stages and explore the accompanying interpretative strategies employed by the medical personnel involved in the management of these trials. We show that the implementation of regulation is not as straightforward and unproblematic as the literature on regulation suggests, and argue that we need to examine the processes through which regulation influences research options and strategies in order to assess its effects. Our analysis reveals the interactions and exchanges that occur in these processes and illuminates the ensuing dynamic between professional interests and clinical research practices. Consequently, we propose a grounded perspective for the investigation of emerging regulatory and clinical practices, where regulation is examined in the context of its application and understood as a practical accomplishment.
The paper presents its argument in three parts: the first introduces the research context both theoretically, with reference to existing literature on regulation, and empirically, in terms of regulatory frameworks for RCTs using autologous stem cells in cardiac medicine, in the EU, Britain and Germany. Research in this area proceeds according to a similar logic of medical knowledge-gain where RCTs represent a crucial stage in the development of new treatments (May 2006, Timmermans and Berg 2003). This necessary step is structured by an intersecting set of regulations. Citing our empirical data, the second part introduces our participants’ understandings of regulation in British and German clinical stem cell research and highlights different aspects of its implementation. The final section outlines the development of regulatory practices as part of, and their embeddedness within, the ethical approval process. We show how during this process the collective interests of the professional groups involved in the trials are legitimised and reinforced.
Regulation and contextual social reproduction
While writing on regulation has been dominated by a black box approach to its subject, commentators from different fields have argued for an understanding of regulation that accounts for its social reproduction. Julia Black’s critique of formalist legal studies (2002), for instance, calls for a greater attention to ‘regulatory conversations’, i.e. communicative processes through which interpretative communities establish meaning. Such exchanges between actors tease out the contexts in which regulation is applied, and highlight its ‘surprisingly deliberative’ capacity. Likewise, Leigh Hancher’s and Michael Moran’s (1989) critical appraisal of economic regulation uses the concept of ‘regulatory space’ to explain power relations and the historical timing and temporal structure of regulatory change. Through its focus on structures of organisation, administrative hierarchies and operating procedures that influence decision-making processes, ‘regulatory space’ helps examine regulation in specific settings and distinguish between different interpretative practices (Scott 2001).
In a similar vein, social science and technology commentators have called for both a detailed examination of what policy makers recognise as expertise (Webster 2007) and a mapping of the sites and networks through which science policy is articulated (Nowotny, Scott, and Gibbons 2007). Sheila Jasanoff’s (2005) notion of the ‘co-production’ of science, for instance, incorporates the interpretative practices of large-scale units. Likewise discussions of ‘regulatory ordering’, provide an analysis of boundary setting and practices in the ‘tissue zone’ (Kent et al. 2006, Faulkner et al. 2006). Yet, in terms of the interaction between science and regulation in clinical settings, as Catherine Will (2005) shows in her analysis of risk assessment tools for chronic heart disease, regulations remain largely understood as given procedural frames.
An exception to this latter perspective is offered by Peter Keating and Alberto Cambrosio’s discussion of ‘biomedical platforms’ (2000). Addressing the central place of regulation in clinical practices, the authors propose an encompassing view that attempts to capture its multiple facets, complexly negotiated character and role in providing the infrastructure necessary to the pursuit of biomedical innovation. The biomedical platform brings together different scientific and clinical procedures through provisional ‘ways of arranging things in both a material and a discursive sense’ (Keating and Cambrosio 2000: 346). This intricate assemblage of practices and technologies involved in the construction of biomedical knowledge attains scientific recognition through the ‘collective production of evidence,’ where routines are established and conventions defined (Cambrosio et al. 2006). In this process, scientific and legal ways of elaborating rules inform each other: no longer hampering innovation, regulation becomes the condition ‘for the production, circulation, and interchangeability of novel entities’ (Keating and Cambrosio 2000: 386) and the basis on which ‘objectivity’ is constructed in biomedicine. Regulation incorporates formal and informal aspects of governance including ‘the circulation of standards (be they standardised reagents, procedures, or nomenclature) as well as the production of guidelines and the ongoing generation of consensus concerning acceptable, state-of-the-art clinical practices’ (2000: 378). It is this latter aspect of the continual production of medical knowledge via regulatory frameworks that we examine below.
The specificity of our case, namely clinical trials using patients’ own stem cells, predefines the ways in which we discuss regulation here. First, we understand regulation to include laws, governance frameworks and scientific and medical self-regulation (Schmidt-Assmann 2005). Secondly, there are at least two elements that supposedly influence the regulation-medical science interface. On one hand, stem cell research has a high public profile. Although ethical debates concern only embryonic stem cell research and adult stem cell research is usually framed as ‘good stem cell science’, especially in Germany, the nominally united field is subject to increased public attention. On the other hand, the regulation of medicine has to keep a balance between securing the wellbeing of patients and allowing for flexibility and negotiation in a fast changing clinical environment.
Using two distinct national examples, we propose a view of regulation as an on-going practical accomplishment of researchers, clinicians and regulators. We argue that the everyday governance of novel medical research emerges through the interactions and social exchanges between the various actors involved, and often crystallises to semi-routine procedures. In this process professional interests are reinforced as the new research achieves wider recognition. Our discussion adds a comparative dimension to the biomedical platform, highlights national similarities and differences in the implementation of European regulations and in the organisation of stem cell clinical trials, and examines how actors engage with regulatory measures in everyday practice. It thus provides important missing links in the literature on the regulation of biomedical innovations.
Cardiovascular disease and stem cell research for heart repair: background
Given the long-term disability and high mortality rates from chronic heart disease in Europe (Allender et al. 2008), improvements in heart repair are an important clinical priority. The use of stem cells in novel medical applications presents one potential solution to boost the regeneration of damaged tissue and to repair heart function. This regenerative model of intervention is seen in the media and areas of cardiovascular medicine as a new hope for a growing number of patients (Lipinski et al. 2007).
Heart repair constitutes one of the few areas where RCTs with adult stem cells have been undertaken in Europe, Brazil, the Far East and the US, since 2001.1 Both Britain and Germany have carried out such trials over the past few years. Based on trial outcomes, the Task Force of the European Society of Cardiology concluded that the practice is safe and that the clinical investigation into autologous stem cells repair of the heart should proceed with double-blind, large RCTs (Bartunek et al. 2006).
In the present paradigm of evidence-based medicine (EBM), such trials are regarded as the ‘gold standard’ of scientific medicine: the ultimate way to establish medical procedures and assess them in relation to the efficacy of the treatment (Timmermans and Berg 2003).2 The ‘protocol’, the experimental structure around which the trial is organised, seeks to measure the direct effect of a particular medical intervention. It is framed around controlling for and excluding potential ‘intervening’ factors and based on statistical methods of evaluation.3 For this, different sizes of patient collectives are needed: the progression from small to large numbers of patients helps establish the legitimacy of a particular medical intervention on the basis of a statistically significant final outcome measure.4
To date, the results of stem cell RCTs for heart repair remain equivocal. Improvements in the condition of patients have been small (Abdel-Latif et al. 2007) and the putative mechanisms that might be at work in heart tissue repair are not yet understood (Rosenweig 2006). We observed British clinical scientists working in this field discussing the benefit of RCTs with what are considered ‘safe cells’, in our case, adult autologous bone marrow-derived stem cell injections. These practitioners have sought to defend their position to members of the UK scientific and regulatory community who argue that failure of such trials may jeopardise the future of stem cell research as a whole and drain existing financial support (Cox 2007). In this context, as we show in this paper, regulation is interpreted and used strategically to organise stem cell RCTs according to EBM principles. Here, the undertaking of experimental protocols in clinical settings illustrates the ways in which the regulation of RCTs and the underlying logic of control in the elaboration of clinical knowledge become mutually articulated.
Regulating RCTs using autologous stem cells
The ways in which RCTs have taken shape and place in the UK and Germany are the result of a combination of specific institutional and socio-cultural settings, and regulatory frameworks (Hauskeller 2004).5 Both countries have invested in stem cell research and recognise in policy documents that stem cell research is important, especially in its potential clinical applications. However, as our data show, the German commitment to autologous stem cell therapy has been more consistent than in the UK.6 Regulatory, financial and socio-political support and institutional differences in the provision of health care have all contributed to the differences in the progress of stem cell RCTs in the two countries.
On a broad level, the regulation of clinical research using autologous bone marrow stem cells is part of an intersecting system of regulatory measures developed at international and EU levels and integrated differently into national frameworks in the last decade. These measures negotiate between the ethical issue of medical interventions with unknown and possible harmful effects and the facilitation of such interventions for the development of novel therapies. In clinical environments quality and safety are assured in relation to the conduct of clinical practice (routinely referred to as good clinical practice, or GCP), and the controlled processing and use of the object of medical intervention (known as good manufacturing practice, or GMP).7
GCP and GMP consist of a cross-referenced set of standards first developed in soft regulation at the intersection of the medical profession, industry associations, and national and cross-national institutions. GCP standardises research conduct along ethical and scientific guidelines, which involve the elaboration of experimental protocols based on prior evidence, the precise definition of every step in the protocol, the detailed documentation of each research step, and the clear choice of participation of individuals by means of informed consent. The protocol, documentation and consent procedures must be approved by an Ethics Committee acting as a body of collective oversight before the study can begin. In GMP terms, quality and safety are related to the detailed documentation and monitoring of technical practices and environment conditions for continual risk assessment, from the procurement to the re-insertion of the cells.
European provisions for clinical trial conduct and cell processing are specified in two overlapping regulatory frameworks: one referring to medicinal products (specified in a number of Directives and Regulations)8 and another to the use of cells and tissues in human application (the EU Tissue Framework).9
At a national level, the integration of EU legislative measures has taken different forms. In the UK, the regulation of medicinal products and human tissues has been elaborated in two frameworks that fall within the remit of two distinctive authorities. With regard to medicinal products, EU measures have been implemented within the original framework of the Medicines Act (1968). The Medicine and Healthcare Products Regulatory Agency (MHRA) set up in 2003, functions as a body of oversight.10 The legal framework for the use of human cells and tissues was set up in the Human Tissue Act 2004, on the basis of which the Human Tissue Authority (HTA) was established as a new regulatory authority in 2005. The Act was extended through the Human Tissue (Quality and Safety for Human Application) Regulations in 2007, which transpose EU tissue regulations into national law.11
In defining who is responsible for RCTs using autologous stem cells the question becomes whether the designated cells and tissues are regarded as either a medicinal product or a medical procedure. This issue has been open to interpretation and subject to uncertainty across Europe. Our analysis shows that in the UK the integration of medicinal product and tissue regulation in different legislative instruments permits questioning the regulatory status of autologous stem cells.
In Germany, both medicinal product and tissue regulations come under one main legislative framework: the German Medicines Act (1976). Relevant legislative changes as part of the EU implementation of medicinal product and tissue regulation include the Act’s 12th (2004) and 14th revisions (2005) and its amendment as part of the German Tissue Law (2007).12 The provisions of the Medicines Act transposing EU regulations have additionally been implemented through specific regulations.13 The Paul-Ehrlich Institute represents the central regulatory authority, which by contrast to the recently formed HTA and MHRA has extended continually its biological products remit since 1972. As a result, German trials using autologous stem cells are regulated as part of a more streamlined procedure that ranges across traditional pharmaceutics to novel categories of cell therapy.
The national implementation of the EU Directives illustrates the contextual elaboration of the regulation of novel medical treatments. Our participants identify this implementation as part of a process of interactive, practical accomplishment, where regulation is constitutive of and subject to negotiation in the articulation of clinical research in both the UK and Germany. Our analysis highlights this process at different stages: from a phase of adjustment in the UK, to a seemingly more formalised setting in Germany. We aim to show that the organisation of RCTs is dependent on exchanges between members of the medical teams involved and set within a strategic ordering of regulatory measures which are mobilised to legitimise clinical research and reinforce professional interests.
Our data are part of a larger dataset on the regulation of embryonic and autologous stem cell research and its impact on scientific and clinical practices. We have investigated the interrelationship between national governance frameworks and developments in stem cell science, and explored the ways in which scientists and clinicians relate to regulatory practices through an analysis of similarities and differences in the conduct of stem cell research in specific scientific, national and socio-political contexts.
The present findings are based on ethnographic observations at scientific meetings and in UK and German clinics conducting double-blind randomised trials with adult stem cells, and 32 in-depth interviews with clinical staff at different levels of seniority and from different medical backgrounds involved in the organisation and everyday running of such trials. The ethnographic fieldwork provided data on the organisation of the trials and helped fine-tune our interview questions. The methodological approach was based on understanding research as an on-going process centred on data production, where the rapport between researcher and participant is instrumental to the final outcome (Atkinson 1990). Participants were regarded as both experts and ‘conversational partners’ (Rubin and Rubin 1995: 11), and encouraged to use the interview to explore issues that they considered relevant. The interviews were taped, transcribed, when applicable translated from German, and analysed using a grounded theory approach, where emerging themes were developed in relation to participants’ stories (Glaser and Strauss 1967). The transcriptions were interpreted using open coding and a constant comparative perspective among different respondents and between the two countries.
Each national case study involves clinical teams working in university hospitals and having similar hierarchical structures. At scientific, clinical and procedural levels the teams employ comparable protocols, isolation techniques and methods of delivery in the extraction, processing and re-injection of the cells. The clinical division of labour in both countries consists of study nurses that deal with administration, recruitment and patient care. Doctors are involved in the screening and treatment of patients and the extraction of bone marrow. The principal investigators are responsible for the design of the studies and the overall approval procedures. The organisational logistics of the trials follow a similar path in both countries where proposals are compiled according to national and European guidelines and submitted for ethical and peer approval.
Our findings illustrate that the implementation of regulation is not independent of the individual beliefs and collective views that already exist in the given context. Two themes in particular are shared across national teams and professional ranks, and sustain the practices through which implementation is accomplished. The first relates regulation to the ‘hassle’ and ‘immense effort’ generated by the organisation of the trials and the time taken to fulfil regulatory requirements and compile necessary documentation. All our interviewees detailed the increasingly bureaucratic character of the work involved in setting up the trials, an aspect we will shortly return to. The second theme highlights regulation as a corrective tool through which ‘solid’ science is produced. This is good ‘in preventing wild outgrowth’ and stopping ‘cowboys from letting loose without considering the losses’ (M14, German consultant). Likewise, British participants talk about how ‘sufferers’ and ‘vulnerable people’ are exposed through the unregulated medium of the internet to ‘potential damaging therapies’ (M09, British consultant). Regulation is portrayed here as a necessary step in the routine undertaking of credible medical procedures and seen to order clinical practice, to help draw boundaries between acceptable and non-acceptable conduct and to legitimise professional positions within clinical autologous stem cell research. Below, we examine further our participants’ views on regulation, the ethical approval process and the organisation of trials in each national case.
Clinical teams wishing to carry out stem cell RCTs in the UK have to submit an application to the local NHS Research Ethics Committee where the proposed research will take place. The ethics submission contains a description of the study (its hypothesis, details of experimental design, intervention/s and proposed outcome measures) accompanied by protocols for each stage of the trial and every step of dealing with patients. Additional to compiling the submission, the principal investigator has to obtain the support of the other medical personnel involved in the trial.
British team members talk about the implementation of regulation as a multi-faceted, flexible enterprise, open to interpretation and diverse influences. Across the hierarchical structure, from nurses to clinicians, project leaders and the regulators themselves, regulation is seen as negotiated, rather than top-down. This is apparent from the early stages of study design development, when, before approval is sought from the Ethics Committee, resources need to be secured, as a research nurse manager explains:
There were a lot of difficulties […] knowing how to set it up in the first place. […] With stem cells, it was such a big thing, because it’s so new, it involves people who I’ve never had to talk to before, like the stem cell lab. […] [T]hen […] trying to get a bed for your patients, ’cause it’s a research bed and you have to pay for it, so you have to go and see the matron and make sure it’s alright and the bed manager and the ward sister. [E]very little thing takes time. Even going to the cardiac technicians and saying, ‘we need this certain type of echo’. They then have to learn to do it and you’ve got to have the staff to do it and […] make sure the same people are doing it, so there’s not too much variation. So before we could actually start the study, you’ve got to think what you’re going to do to the patient, to actually get all the equipment sorted out. And make sure you know who to go to […] and who’s going to pay, how much it costs and recruit the nurse and the doctor to do the study, so there was a lot going on at the same time to get this study started (F05).
While principal investigators and consultants are responsible for securing collaboration with their colleagues, the nurses sort out practicalities prior to submitting an application. We can see in the extract above how a necessary network of exchanges and dependencies is set in motion. In this ‘headache inducing problem-solving’ process, our participant uses local tacit knowledge and negotiates with different NHS actors to secure the relevant human and material resources. Standardised procedures help fulfil regulatory requirements, align the trials to EBM strictures, and strengthen their ethical robustness. Here it is further apparent how regulation in its standardisation imperative –‘not too much variation’– shapes what is done before the ethics approval procedure.
Moreover, in the alignment of material resources and clinical expertise for the study protocol, the exchange between haematologists and cardiologists plays a central role. While cardiologists have long-honed technical skills in heart treatment, they possess little practical knowledge of dealing with bone marrow. As the extraction of bone marrow and the processing of cells has been a standard procedure in haematology, haematologists become key collaborators in assisting with and training cardiologists in the collection of bone marrow. Rather than being limited to a simple borrowing and/or reframing of skills, this partnership centres on the integration of the cell-processing knowledge and experience held by haematologists into cardiologic practice. In order to use cells for human application, cardiologists need to isolate them in a laboratory procedure. Following the experimental principles of controlled intervention, the isolation procedure is standardised and needs to be undertaken according to defined conditions that monitor the risk of contamination. While cardiologists do not have these facilities, haematologists do. What aligns the two sub-disciplines are thus both a particular set of skills and institutional resources: clean rooms licensed as GMP facilities according to regulatory provisions and equipped with cell-processing technologies. The collaboration brings the institutional structures of haematology within the purview of cardiologic practice, and keeps the trial costs down by avoiding further expenses on building and staffing new hospital units, and purchasing expensive equipment. Furthermore, in forging the collaboration with haematologists, their regulated activity of bone marrow processing in an established facility is framed and interpreted as the basis for the safe and controlled cell-processing for the novel use of stem cells in cardiac repair. The joint venture allows for the elaboration of a study protocol, which articulates both the experimental logic of controlled intervention and clinical research as regulated activity, and is in turn dependent upon negotiations with the Ethics Committee and regulators.
Once the organisational logistics are secured, the documentation for the ethics stage is compiled. Alongside the re-framing of established practices and the integration of institutional structures present in the collaboration between haematologists and cardiologists, further negotiations are needed to keep abreast with the latest requirements in trial documentation, as one of the research nurses observes: ‘every time you open up a form, they’ve added something else and you’ve got to find out how to answer it’ (F04).
The ethics stage itself is the key point in obtaining approval for the trials: ‘the only law we’ve got […] that I can tell that governs the stem cells’, as another nurse states. Here the evidence in support of carrying out the trial is scrutinised by a panel of medical peers, hospital managers, lay representatives and sometimes ethical experts. This is a lengthy process, as the panel can request modifications of protocols and further justifications of medical procedures. Yet, there is open-endedness to the solving, as one research nurse manager explains:
I went to a meeting with the chairman of the Ethics Committee […] and he said, ‘you know, sometimes, if we’ve said, ‘we don’t like this, it’s not right;’ you can say ‘well, you’re wrong.’ He said, ‘because we are wrong sometimes’. And I’ve never thought of that […] never thought, ‘oh, I can’t answer this, because actually they’ve got it wrong.’ You just think you’ve got to try and justify it to them (F03).
Not only can the panel’s questions and the committee’s decisions be challenged by the clinical teams involved, but also the place of clinical stem cell research overall is subject to constant re-interpretation:
Everything that’s been through the regulators has been a product for sale, from a pharmaceutical company. They had no way of dealing with it. And they said ‘so, this is medical practice then? It’s like a blood transfusion, which is not regulated, because it is medical practice?’ I said, ‘no, it’s not medical practice. This is a new treatment. We want to know if you’re going to start making regulations on it, because we’ve got to adhere to those, we don’t want them half-way through the study’. They said, ‘but how can we regulate if you’re not keen to sell it and it’s not medical practice?’ So the regulators themselves are confused and they said ‘would you please keep talking to us?’ (M9)
The uncertainty in defining the status of the cells according to the given categories of ‘medicinal product’ or ‘medical procedure’ in the UK and EU contexts thus opens spaces for exchange, influence and persuasion at all regulatory stages. This brings actors together in an attempt to clarify the status of clinical stem cell research and negotiate its regulation. The recent institutionalisation of UK regulatory authorities and their remits14, contribute to the mutual articulation of clinical research and regulatory activities in this new area of biomedical application. By comparison, while equally subject to ongoing changes in regulation, in Germany more established regulatory practices regarding trials using stem cells for heart repair have crystallised. While some trial design challenges remain the same (e.g. submissions for the Ethics Committees and paperwork upkeep), others, as we observe next, are different.
Unlike the UK where the status of autologous stem cells is currently open to negotiation, the discursive ambiguity surrounding the classification of cell therapy has been dealt with in Germany by integrating EU tissue regulation into the German Medicines Act. Although the implementation of EU regulations in Germany has equally entailed negotiation and uncertainty in the interpretation of regulatory categories, these have been addressed in the context of longer established institutional structures. Furthermore, in comparison with the British, German researchers have carried out more studies in recent years. At present, they seek to upscale on that basis in an attempt to drive cell therapy towards a recognised treatment.
Like their British counterparts, German principal investigators are responsible for compiling the application material for their study’s ethical approval. As before, the application, which contains protocols detailing the experimental procedure, patient interventions, and outcome measures, has become increasingly elaborate as a result of the transposition of EU regulations into the national law. Undertaken by a federal authority in concordance with the Paul Ehrlich Institute, a second approval procedure for the preparation of cells needs to be included in the material for the Ethics Committee. This requires details of the context and conditions of cell-processing in order to minimise the risk of contamination. Finally, in addition to the Ethics Committee approval, the Paul Ehrlich Institute has to issue an overall authorisation for the trial before it can go ahead.
German cardiologists have also collaborated with haematologists in the extraction and processing of cells, and have drawn on haematological practice and regulatory expertise to reframe the established infrastructure. Accounts of negotiations for cell-processing with centres that operate in accordance with the rules set by the German Medicines Act, show that while German cardiologists could in principle work outside this framework by having the treatment undertaken in one medical procedure involving a low-tech set-up, they ‘prefer doing it officially, bigger style, with all the procedures and authorisations from the side of the authorities, via that route’ (M12).
Within this ‘bigger style’ framing of clinical research, the application for new trial approval becomes part of a formalised and routinised division of labour. The drawing up of the application for each trial’s cell preparation approval is now carried out by the cell-processing centre. This ‘is a very, very big part, which we are relieved of here, with the authorisation procedures, which are connected to the Regierungspräsidium [federal authority]’ (F08).
This division of labour with the cell-processing centre is strategic in terms of using an existing infrastructure and the delegation of regulatory tasks. Additionally, it mediates the implementation of the wider structuring of medical work that capitalises on the standardisation of practices as set out in GCP and GMP guidelines. In turn, this brings the possibility of catering for larger numbers of patients using multi-centre RCTs, a central model of EBM:
The patients are all over Germany, and a part of them can come here, and if you want to conduct really big analysable studies, well, if that’s, say, 100, 200 patients, then you can’t do that by yourself, you require partners. (F02)
Thus, the cell-processing unit has become the hub of a ‘satellite’ structure, where it works as a key point for the standardised processing of cells, while patients are treated in different study centres:
This satellite-shaped construct with one preparation location and several patient centres, is certainly the best construct, in order to simply get ahead faster, to gain insights, in order to get data more quickly... We have also already advanced one step further: the pilot study was only safety and feasibility. That has been shown and now we must put it onto solid legs big style, right? (M10)
The framing of practices in terms of streamlined medical procedures in identical settings accompanied by standardised data collection and analysis allows for the specific legitimisation of stem cell therapies according to EBM principles. Moreover, the coming together of various resources and agencies is seen to enable individual development and advance professional interests in ways that a low-tech set-up research arrangement would not readily facilitate:
It is [difficult] for smaller projects or in the beginning when one comes from an unknown group […] When one is not known that well, has a new idea and then to find a sponsor, who [pays for] laboratory material, equipment? Simply to fight for the space in the first place […] is very, very expensive. (M15)
In these accounts regulation is seen as a practical accomplishment. The ‘bigger style’ logic illustrates both the facilitation of research and the ways in which the collaboration between the cell-processing centre and cardiologists permits the standardised collection of data, and allows for the up-scaling of trials and the move towards larger patient numbers. These data are needed for statistical assessments of the final outcome measures required in order to have the research recognised as a viable treatment. The process is mediated by a further formalisation in the division of labour whereby hospitals become sub-contractors of the cell-processing centre. In securing and maintaining an approval for cell preparations, the cell-processing centre must ensure that all study centres adhere to particular rules of sterility in the extraction of bone marrow. As similar standards must be kept across all centres, local conditions and personnel are monitored. This additional formalisation of quality monitoring is acknowledged as a result of a mutual articulation of practices. Negotiations in each individual context concern the classification of ‘identical’ practices with regard to cleanliness, and are subject to elaboration between the cell-processing unit, the study centres, and the federal authorities granting cell preparation approval. Here, the alignment of material practices becomes part of an interpretative process, where particular aspects of such practices are central to the elaboration of cleanliness, while others become excluded from it. Thus, what is seen as standardisation on a formal and organisational level is in itself the result of a practical accomplishment. While this arrangement implies a lengthy period of time in obtaining the permission to begin a study, the investment in setting up complex approval procedures and negotiations between different actors is compensated for by the opportunity to develop a clinical trial satellite model that is constructed according to the demands of science and regulation, and draws legitimation from both. In the outcome, professional interests are protected and reinforced through the securing of material and human resources that help towards establishing stem cell therapies as recognised routine treatments.
Our focus on the clinical implementation of regulation, showed that stem cell trials are unambiguously perceived by those involved in running them as a necessary passage point (Epstein 1996). When we entered the UK field scientific discussion about trial designs was on-going and led to different stem cell RCTs for defined applications. The actual practice of setting up the UK trials pronounced the novel character of stem cell treatment, which required their regulatory articulation and made the implementation of regulations a matter of discussion. By comparison, German cardiologists had established stem cell RCTs and were concerned with mass standardisation and large-scale co-operation. Rather than the initial orchestration of clinical practices, this required a different level of negotiation to adjust the trials further to the demands of evidence-based practice (Bartunek et al. 2006). We found that the implementation of regulation is a practical accomplishment in both national contexts, which develops in negotiations among specialists, experts and institutions. In this process, the mechanics and rhetoric of regulation are applied and adapted to suit available resources and collective goals.
There are different ways of understanding regulation and interlinked, yet distinct levels at which sense-making processes take place. In the British context, regulation as an on-going achievement at different levels of the medical hierarchy is visible, for instance, in the stories of the research nurse who is invited to challenge the decision of the Ethics Committee and in that of the clinician who uses the classificatory uncertainty given by the terms of ‘medicinal products’ and ‘medical procedure’ to engage in the re-framing of regulatory categories. Here, regulation can be challenged and steered into desired directions where regulative structures are more flexible. In moving from the British to the German case, our data indicate that the implementation of regulation continues to be accomplished in everyday interactions for clinical practices that are increasingly embedded within formalised approval procedures. Even within the tighter legal framework (Burau 2005) German regulation is shown to be re-interpreted and used strategically to organise RCTs according to EBM strictures. Here it is not so much its openness to interpretation that gives it its practical accomplishment character, but the carefully planned modalities in which it is used collectively, across distinct clinical specialisms, to support the interests of specific groups. The German accounts illustrate how setting-up a satellite model to organise trials with much larger patient collectives requires negotiation, co-ordination, and an extensive network of collaborations. The implementation of regulation in ‘bigger style’ multi-centre RCTs is worked with to develop team work and advance professional interests, as large trials allow the medical community to progress towards having the treatment recognised by the rest of its members and by external agencies, such as health insurers, which are still to include the procedure as standard. It is also seen to serve a practical and political purpose, i.e. to reinforce the position of the autologous stem cell research community, and strengthen it in the global field of biomedical research.
Furthermore, in relation to the organisation of study protocols and the ensuing alignment of material resources and medical expertise, both British and German accounts show that the negotiation of protocols around haematological practices permits the concrete integration of material infrastructures and clinical knowledge that cardiologists require to advance novel cellular therapies. On the one hand, this can be seen as a strategic ordering of practices that allows clinicians in both countries to draw on existing resources and expertise that meet regulatory cell-processing requirements. On the other hand, this entails an interpretative framing of regulation where the recognised structures of haematological cell-processing become relevant to the safe processing of bone marrow stem cells in heart repair. Regulated in this manner, cell-processing becomes a standardised activity conducted in compliance with an evidence-based practice approach to the experimental logic of controlled intervention. The German case shows that this routine continues to be operational in a longer established clinical setting. The division of labour between the cell-processing centre and the study centre(s) illustrates that although this is formalised in the complex contractual set-up between the former and the latter, it is not a top-down imposition of regulatory requirements in the standardisation of clinical research. Instead, the participants’ descriptions of the process behind cell preparation approval show that ‘bigger style’ regulatory practices are the result of the negotiation of what is to count as identical, standardised practices. As such, regulatory practices can be seen to continually emerge as part of complex assemblages of social relationships and material resources in the production of medical novelty.
The streamlining of medical procedures into similar settings accompanied by standardised data collection and analysis allows for the legitimisation of stem cell therapies according to EBM principles. It constitutes the infrastructure for the ‘collective production of evidence’ following the rules of ‘regulatory objectivity’ (Cambrosio et al. 2006) and facilitates the circulation of results within the global field of biomedical research, potentially becoming the basis for leading the stem cell field and attaining international recognition. Our data indicate that in both national cases regulation is regarded as more than crisis intervention and standards setting (Keating and Cambrosio 2000). Not only does it lend legitimacy to routine engagements and ways of operating in the clinic, but it is also used as a tool to dispute arrangements and reinforce professional interests.
Finally, the articulation of regulatory practices within clinical research in both countries serves to recognise stem cell research as an innovative scientifically-based medical endeavour. Regulation is seen as both intrinsically embedded into the clinical research culture, its directions and outcomes, and constitutive of it. The ways in which regulation is elaborated in clinical research not only guides, channels and directs, but also excludes, creates hierarchies of expertise, forces alliances and forges collaborations in the production of new medical therapies.
The recognition of stem cell science depends on its assumed potential to provide new therapies. Double-blind RCTs are necessary to recognise and establish the use of autologous stem cells as effective treatments for heart repair following EBM principles. The success of such trials will consolidate the status and professional standing of the clinical teams involved and their communities of practice and contribute to the further legitimisation of stem cell research as a whole. Our analysis highlights the place of regulation in this process and the negotiations it entails for the 32 members of medical teams working with these treatments in the UK and Germany. As such, we make no claims for our participants’ narratives being ‘representative’ of the wider stem cell clinical research field, or for our bi-national comparison providing a comprehensive overview of the required steps in the implementation of regulation. Our findings contribute to the literature on regulation with an empirical analysis of the enactment of regulation in relation to the collective interests of key actors, in this instance, clinical teams working with adult stem cells in cardiac repair. Our argument shows how the exploration of the slippage between regulation and the ways in which it ‘happens’ in practice opens to investigation a new way of understanding the role of regulation in a clinical science context.
Moreover, our findings illustrate that the implementation of regulation is more than following and applying the text of a law. Evidence elsewhere suggests there is no straightforward connection between regulatory frameworks and social practices of regulation; rather, one has to look at how frameworks are interpreted and integrated in particular social situations (Lange 1999). As such, a focus on regulatory conversations (Black 2002), spaces and contexts where regulation is implemented (Hancher and Moran 1989) is essential to capture its practical accomplishment.
In the present case, regulation appears as more than a power exercise (be it the power to challenge the decision of the Ethics Committee, that of steering regulation in a desired direction, or that of granting licences). Instead, it encapsulates skilled negotiations that draw on distinct bodies of expertise at clinical and regulatory levels, and entail material practices through which the production of knowledge takes place. This process is instrumental to the legitimisation of new medical research and must be observed at a micro-level of interaction in order to understand the impact of regulation on clinical and scientific cultures.
Thus, the present findings confirm conclusions from a nascent field of studies of medical innovations, especially regarding the entwinement of distinct clinical practices and regulatory activities in the legitimisation of novel medical interventions (Bourret 2005, Keating and Cambrosio 2004, Metcalfe et al. 2005, Tournay 2008) and the consolidation of professional interests (Berg et al. 2000). Furthermore, our observation of regulation in action captures in detail this entwinement in the production of one such innovation, within different national contexts. Macro-analyses on the regulation of new biomedical objects tend to focus on discursive structures and the generation of legislative categories in science policy debates at national and cross-national levels (e.g.Jasanoff 2005, Nowotny et al. 2007, Waldby and Salter 2008), but overlook how actors engage in regulatory practices on an everyday basis. We argue that discussions of downstream implementation are problematic for their lack of insight into the tensions intrinsic to this process and for failing to take into account the interpretative practices that take place therein. Our findings not only suggest that professional interests are addressed in the ‘making-sense’ of regulation but also that regulation may be simultaneously interpreted and re-produced by different actors, at various stages of clinical and scientific legitimisation, in specific temporal frames and within distinct social, cultural and political parameters. Not only has our national comparison outlined the differences between two European countries in the implementation of legislation regarding the organisation of clinical trials using stem cells for cardiac repair, but it has also raised questions about any model that assumes similarities within Europe without a comprehensive analysis of specific regulatory and institutional settings. A greater understanding of the multiple intersections of these factors and their dynamics is thus required to provide the basis for developing a context-sensitive tool-kit for the evaluation of regulatory outcomes.
The procedure involves medical and laboratory expertise and is undertaken by teams of specialists whose practices are under regulatory control.
Despite controversies surrounding their use (cf. Nowak, R. (1994) Problems in clinical trials go far beyond misconduct, Science, 264, 1538–41).
There are different models of controlling the conditions and intervening variables of a treatment. Double-blind, placebo-controlled RCTs are seen as best standard in clinical research.
Here the ultimate measure is the lengthening of the life-span of patients after the bone marrow stem cell treatment.
While the UK has implemented a liberal framework allowing for the derivation of and research on human embryonic stem cell lines, Germany has outlawed research on human embryos and allowed only in special circumstances that on human embryonic stem cell lines. Consequently, the German focus has been on adult stem cell research (including autologous).
Although no comprehensive national funding reviews exist, the following figures illustrate the tendency for stronger socio-political support for adult stem cell research in Germany. Between 2000 and 2007 the German Ministry for Education and Research (BMBF), one of two main state-funding institutions, invested a total of 48.8m Euros in stem cell research. Of this 66.8 per cent (32.6m) was spent on adult and 33.2 per cent (16.2m) on embryonic stem cell research (with nine per cent of the latter into human embryonic stem cells) (cf.http://www.bmbf.de/pub/faq_stammzellen.pdf). The second major funding institution, the German Research Foundation (DFG) noted a focus on adult stem cell research in its overall spend of 70m Euros on stem cell research in the same period. By contrast between 2004 and 2006, the MRC invested a total of £31.3m to stem cell research. Of this 47 per cent (£14.7m) was allocated to adult and 53 per cent (£16.6m) to embryonic stem cell research. Between 2005 and 2007 the BBSRC estimated a spending of £19.7m on stem cell research. Of this 46 per cent (£3.7m) in 2005/6 and 44% (£5.1m) in 2006/7 was spent on adult stem cell research.
This understanding of GCP and GMP as regulatory concepts for organising practices does not overlap with their specific European definition, where GMP figures in medicinal product regulation but is not included in EU tissue regulation (which outlines similar principles in terms of the standardised processing of cells, without identifying it as GMP). Our participants use the term ‘GMP’ to describe standardisation, and for this reason we employ the term here in this broader sense.
The Medicinal Products Directive 2001/83/EC OJ L311/67, Amendment Directive 2003/63/EC OJ L159/46, Regulations (EC) No 726/2004 OJ L136/1, (EC) No 1394/2007 OJ L324/121 (Advanced Therapies Regulation). GCP and GMP provisions within medicinal products regulation: Good Clinical Practice Directives 2001/20/EC OJ L121/34, 2005/28/EC OJ L91/13, and GMP Directive 2003/94/EC OJ 262/22.
The EU Tissue Framework: Directive 2004/23/EC OJ L102/48 and Technical Directives 2006/17/EC OJ L38/40 and 2006/86/EC OJ L294/32.
Regarding the transposition of relevant EU medicinal products legislation since 2001 the following apply: The Medicines for Human Use Clinical Trials Regulations 2004 (SI 2004 No 1031) and 2006 Amendments (SI 2006 No 1928 and SI 2006 No 2984). Other non-statutory regulatory instruments which specifically relate to clinical research include the NHS Research Governance Framework updated in 2005.
This excludes the use of gametes and embryos in research and reproductive treatments which is regulated by the Human Fertilisation and Embryology Authority. The HTA has issued three sets of Directions since April 2006 setting out compliance requirements with respect to the EU directives.
12th and 14th revisions of the Medicines Act in BGBl I p. 2031, 5.8.2004 and BGBl I p. 2570, 5.9.2005; Tissue Law in BGBl. I p. 1574,27.7.2007.
These include GCP regulations (GCP-V in BGBl I, p. 2081, 12.8.2004) and GMP regulations on the production of medicinal products and on good practice in the manufacturing of products of human origin (AMWHV in BGBl I, p. 2523, 9.11.2006 and BGBl I, p. 521, 4.4.2008).
The MHRA resulted from the merger of two regulatory authorities: the Medical Devices Agency and the Medicines Control Agency.
This research was funded by an ESRC Social Science Initiative grant (RES-349-25-0002) and was made possible with the support of the ESRC Centre for Genomics and Society (Egenis) at the University of Exeter. We wish to thank Barry Barnes, Tia DeNora, Jean Harrington and the editors and anonymous reviewers of Sociology of Health and Illness for their comments.