Section IIC - Towards Responsive Regulation

This section of the volume offers a contemporary selection of examples of where existing models of law and regulation are pushed to their limits. Novel challenges are arising that require reflection on appropriate and adaptive regulatory responses, especially where ethical concerns raise questions about the acceptability of the research itself. The focus in this section is on how these examples create disturbances within regulatory approaches and paradigms, and how these remain a stubborn problem if extant approaches are left untouched. The reference to ‘responsive’ here highlights the temporally limited nature of law and regulation, and the reflexivity and adaptability that is required by these novel challenges to health research regulation. The choice of examples is illustrative of existing and novel research contexts where the concepts, tools, and mechanisms discussed in Part I come into play.

The first part of this section speaks to nascent challenges in the field of reproductive technologies, an area of health research often characterised by its disruptiveness to particular legal and social norms. The first two contributions to this theme focus on human gene editing, a field of research that erupted in global public ethical and policy debates when the live birth of twin girls, Lulu and Nana, whose genes had been edited in vitro, was announced by biophysician He Jiankui in 2018. For Isasi (Chapter 34), recent crises such as this provide opportunity to transform not only global policy on human germline gene editing, but collective behaviours in this field. In this chapter, she analyses the commonalities and divergences in international normative systems that regulate gene editing. For Isasi, a policy system that meaningfully engages global stakeholders can only be completely effective if we achieve both societal consensus and governance at local and global levels. For Chan (Chapter 35), the existence of multiple parallel discourses highlighted by Isasi can be used to facilitate broader representation of views within any policy solution. Chan considers the wider lessons that the regulatory challenges of human germline gene editing pose for the future of health research regulations. She posits that human germline gene editing is a ‘contemporary global regulatory experiment-in progress’, which we can use to revisit current regulatory frameworks governing contentious science and innovation.

For the authors of the next two chapters, the order upon which existing regulatory approaches were built is being upended by new, dynamic sociotechnical developments that call into question the boundaries that law and regulation has traditionally relied upon. First, Hinterberger and Bea (Chapter 36) challenge us to consider how we might reconsider normative regulatory boundaries in their chapter on human animal chimeras – an area of biomedical research where our normative distinctions between human and animal are becoming more blurred as research advances. Here, the authors highlight the potential of interspecies research to perturb lasting, traditional regulatory models in the field of biomedical research.  Next, McMillan (Chapter 37) examines the fourteen-day limit on embryo research as a current example of an existing regulatory tool – here a legal ‘line in the sand’ – that is being pushed to its scientific limits. She argues that recent advancements in in vitro embryo research challenge us to disrupt our existing legal framework governing the processual entity that is the embryo in vitro. For McMillan, disrupting our existing regulatory paradigms in embryo research enables essential policy discussion surrounding how we can, and whether we should, implement enduring regulatory frameworks in such a rapidly changing field.

For the second part of this section, the final two chapters examine the downstream effects of health research regulation in two distinct contexts. For these authors, it is clear that innovation in research practice and its applications requires us not only to disrupt our normative regulatory frameworks and systems, but to do so in a way that meaningfully engages stakeholders (see Laurie, Introduction). Jackson (Chapter 38) challenges the sufficiency of giving patients information about the limited evidence-base behind ‘add-on’ treatments that are available in fertility clinics, as a mechanism for safely controlling their use. For Jackson, regulation of these add-ons needs to go further; she argues that these treatments should be deemed by the Human Fertilisation and Embryology Authority – the regulator of fertility clinics and research centres in the UK – as ‘unsuitable practices’. She highlights the combination of a poor evidence base for the success of these ‘add-on’ treatments and patients’ understandable enthusiasm that these might improve fertility treatment outcomes. Her contribution confronts this ‘perfect storm’ of the uncertain yet potentially harmful nature of these add-ons, which are routinely ‘oversold’ in these clinics, yet under-researched. Jackson’s offering gives us an example of an ongoing and increasing practice and process that requires us to disrupt prevailing regulatory norms. In the final chapter of this section, Harmon (Chapter 39) offers human enhancement as an example of how a regulatory regime, catalysed by disruptive research and innovation, has failed to capture key concepts. For Harmon, greater integration of humans and technology requires our regulatory frameworks to engage with ‘identity’ and ‘integrity’ more deeply, yet the current regulatory regime’s failure to do so provides a lack of support and protection for human wellbeing.

Together, these chapters provide detailed analyses of carefully chosen examples and/or contexts that instantiate the necessity for reflexivity in a field where paradigms are (and should be) disturbed by health research and innovation. It is clear that particular regulatory feedback loops within and across particular regulatory spaces need to be closed in order to deliver authentic learning back to the system and to its users (see Laurie, Introduction and Afterword). A key theme in this section is the call to approach health research regulation as a dynamic endeavour, continually constituted by scientific processes and engaged with stakeholders and beneficiaries. In doing so, this section provides grounded assessments of HRR, showing the positive potential of responsive regulation as new approaches to health research attempt to meet the demands of an ever-changing world.

34 Human Gene Editing Traversing Normative Systems

Rosario Isasi

34.1 Introduction

Gene editing technologies consist of a set of engineering tools, such as CRISPR/Cas9, that seek to deliberately target and modify specific DNA sequences of living cells.¹ They can enable both ex vivo and in vivo deletions and additions to DNA sequences at both somatic and germline cell levels. While technical and safety challenges prevail, particularly regarding germline applications, these technologies are touted as transformational for the promotion and improvement of health and well-being. Furthermore, their enhanced simplicity, efficiency, precision, and affordability had spurred their development. This in turn, has brought to the fore scientific and socio-political debates concerning their wide range of actual and potential applications together with their inexorable ethical implications.

The term ‘inevitable’ refers to the certainty or the unavoidability of an occurrence. Such was the worldwide response after the 2018 announcement – and later confirmation²– of the live birth of twin girls whose genomes were edited during in vitro fertilisation procedures. While foreseeable, shock followed and ignited intense national and international debates. China was placed at the epicentre of controversy, as the ubiquitous example of inadequate governance and moral failure. Yet, as the facts of the case unfolded, it became clear that the global community shared a critical level of responsibility.³ Crisis can provoke substantial changes in governance and fundamentally alter the direction of a given policy system. While the impact of the shock is still being felt, the subsequent phase of readjustment has yet to take place. A ‘window of opportunity’ is thereby present for collective assessment of its impact, for ascertaining accountability, and for enacting resulting responses. Reactionary approaches can be predicted, as demonstrated by the wave of policies in the 1990s and 2000s following the derivation of the first human embryonic stem cell line or the birth of ‘Dolly’ the cloned mammal. Indeed, the ‘embryo-centric’ approach that characterised these past debates is still present.⁴ Additionally, the globalisation phenomenon has permeated the genomics field, reshuffling the domain of debate and action from the national to the international. A case in point are the past International Gene Editing Summits aimed at fostering global dialogue.⁵

So far, human gene editing (HGE) has stimulated a new wave of policy by an extensive range of national and international actors (e.g. governments, professional organisations, funding agencies, etc.). This chapter outlines some of the socio-ethical issues raised by HGE technologies, with focus on human germline interventions (HGI), and addresses a variety of policy frameworks. It further analyses commonalities as well as divergences in approaches traversing a continuum of normative models.

34.2 Navigating Normative Systems for HGE

Across jurisdictions, the regulation of genomics research has generally followed a linear path combining ‘soft’ and ‘hard’ approaches that widely consider governance as a ‘domestic matter’.⁶ Driven by scientific advances and changes in societal attitudes that resulted in greater technological uptake, genomics has increasingly become streamlined. This is reflected in the departure from the exceptionalist regulation of somatic gene therapy, now ruled by the general biomedical research framework, or in the increasing acceptance of reproductive technologies, where pre-implantation genetic diagnosis is no longer considered as an experimental treatment.

Normative systems cluster a broad range of rules or principles governing and evaluating human behaviour, thereby establishing boundaries between what should be considered acceptable or indefensible actions. They are influenced by local historical, socio-cultural, political and economic factors. Yet, international factors are not without effect. These systems are enacted by a recognised legitimate authority and unified by their purpose, such as the protection of a common good. Often, they encompass set criteria for imposing punitive consequences in the form of civil and criminal sanctions, or by moral ones, in the form of social condemnation for deviations. The boundaries normative systems impose are sometimes set arbitrarily, while in others, these divisions are systematically designed. Thus, they either create invisible or discernible ethical thresholds by making explicit the principles and values underpinning them.

At the same time, normative systems are often classified by their coercive or binding nature, as exemplified in the binary distinction between ‘soft’ and ‘hard’ law. While this categorisation is somewhat useful, it is important to note that ‘hard’ and ‘soft’ laws are not necessarily binary; rather, they often act as mutually reinforcing or complementary instruments. The term ‘soft law’ refers to policies that are not legally binding or are of voluntary compliance, such as those emanating from self-regulatory bodies (e.g. professional guidelines, codes of conduct) or by international agencies (e.g. declarations) without formal empowered mechanisms to enforce compliance, including sanctions. In turn, ‘hard law’ denotes policies that encompass legally enforceable obligations, such regulations. They are of binding nature to the parties involved and can be coercively enforced by an appropriate authority (e.g. courts).

In the context of HGI, normative systems have opted for either a public ordering model consisting of state-led, top-down legislative approaches, or a private ordering one, which adopts a bottom-up, self-regulatory approach. In between them, there is also a mix of complex public–private models. Normative systems are present in a continuum from permissive, to intermediate, and to restrictive, reflecting attitudes towards scientific innovation, risk tolerance and considerations for proportional protections to cherished societal values (e.g. dignity, identity, integrity, equality and other fundamental freedoms). The application of HGE technologies in general, and HGI in particular, are regulated in over forty countries by a complex set of legislation, professional guidelines, international declarations, funding policies and other instruments.⁷ Given their diverse nature, these norms vary in their binding capacity (e.g. legislation vs self-regulation), their breadth and their scope (e.g. biomedical research vs clinical applications vs medical innovation). Notwithstanding all the previously stated heterogeneity in normative models, harmonised core elements are still present between them.

Resistance towards applying HGE in the early stages of development commonly rest on beliefs regarding the moral – and fortiori legal – status of the embryo, social justice and welfare concerns. Their inheritable capacity, in turn, brings to the fora issues such as intergenerational responsibility and the best interests of the future child, together with concerns regarding their population (e.g. genetic diversity), societal (e.g. discrimination, disability) and political impacts (e.g. public engagement, democracy).⁸ Remaining safety and efficacy challenges are also of chief importance and often cited to invoke the application of the ‘precautionary principle’. Lastly, fears over ‘slippery slopes’ leading to problematic (e.g. non-medical or enhancements) uses and eugenic applications are at the centre of calls for restrictive normative responses.⁹ However, across these systems the foundational principles underpinning a given norm and reflecting a society’s or an institution’s common vision and moral values are not always sufficiently substantiated, if at all articulated. As such, calls for caution to protect life, dignity and integrity, or against eugenic scenarios, appear as mere blanket or rhetorically arguments used for political expediency. As a consequence, the thresholds separating what is deemed as an acceptable or indefensible practice remain obscure and leave an ambiguous pathway to resolve the grey areas, mostly present in the transition towards clinical applications.

An unprecedented level of policy activity followed the rapid development of HGE. National and international scientific organisations, funding and regulatory agencies, as well advocacy groups have responded to these advances by enacting ‘soft laws’ appealing for caution, while others have opted for assessing the effectiveness of extant ‘hard’ and ‘soft’ policies.

34.2.1 National Policy Frameworks

Normative systems are often conceptualised using a hierarchy that differentiates between restrictive, intermediate and permissive approaches. Under this model, restrictive policies set up ethical and political boundaries by employing upstream limits – blank bans or moratoria – to interventions irrespective of their purpose. Pertaining to the application of HGI, restrictive approaches essentially outlaw or tightly regulate most embryo and gamete research. Supported by concerns over degrading dignity and fostering commodification of potential life, these approaches are based on attributing a moral – personhood or special – status to embryos, and thus advocating for robust governmental controls. Stipulations forbidding ‘genetic engineering on human germ cells, human zygotes or human embryos’¹⁰ or stating that no ‘gene therapy shall be applied to an embryo, ovum or fetus’¹¹ exemplify this model.

While apparently wide-ranging, restrictive policies contain several potential loopholes. Among their major shortcomings are their reliance on research exceptions for therapeutic interventions that are deemed beneficial or life preserving to the embryo, or which are necessary in order to achieve a pregnancy. Terminological imprecisions will render as inapplicable a norm once a particular intervention could be considered as medical innovation or standard medical practice. Similar gaps are present in norms referencing specific technologies and in legal definitions of what constitute a embryo or a gamete, as all of these could later be outpaced by scientific advances, such as those brought by developments in the understanding of embryogenesis, organoids, and pluripotent stem cells. Indeed, the growth of HGE technologies has brought back to centre stage reflections over what is a reproductive cell. Evocative of the debates that took place during the peak of the stem cell era, the scientific, legal, and moral status of these entities continue to be tested, while at the same time remaining as the most prevalent policy benchmark. Whether silent or overtly present in distinct conceptualisations (e.g. developmental capacity or precise time period), criteria defining these early stages of human development are at the core of policies directing the permissibility of certain interventions.

The most favoured policy position is, however, an intermediate one, in which restrictions are applied downstream by banning research with reproductive purposes. Yet, this position considers permissible the practices that are directed at fundamental scientific research activities, such as investigating basic biology or aspects of the methodology itself. Policies adopted in countries such the Netherlands,¹² reflect this moderate perspective by outlawing any intervention directed at initiating – including attempts to initiate – a pregnancy with an embryo – or a reproductive cell – that has been subject to research or whose germline has been intentionally altered. Balancing social and scientific concerns, this approach calls for modest governance structures, yet close oversight. Nevertheless, it is at the risk of internal inconsistencies and ambiguities, given that norms are often the result of political compromises, which seem necessary in order to achieve policy adoption. A case in point are those research policies that confer moral and legal status to the human embryo while – at the same time – mandating their destruction after a certain period of time, or in ambiguous norms regarding the permissibility of clinical translation.

Largely misinterpreted, liberal models do not necessarily postulate a laissez-faire or a blanket unregulated approach. Rather, they provide significant scientific freedom predicated on the strength of their governance frameworks. They seek to promote scientific advances as a tool for social progress. In the context of HGI, liberal policies¹³ allow for basic and reproductive research while banning clinical implementation. Given that these approaches depend on the effectiveness of their governance structures (e.g. licensing, oversight) with decisions often on a case-by-case or a de-facto basis, they are at the risk of arbitrary applications and system failure. Moreover, when the model rests on self-regulatory approaches devoid of effective enforcement mechanisms, they risk being – or being perceived to be – self-serving and following a market consumer model.

Throughout policy models, the progression from research to clinical purposes is at times blurred in the peculiarities of such approaches. In fact, uncertainty regarding the scope of requirements is particularly present when there are permissible exceptions to norms forbidding HGE in reproductive cells. This is the case of Israel, which outlaws ‘using reproductive cells that have undergone a permanent intentional genetic modification (germline gene therapy) in order to cause the creation of a person’,¹⁴ yet permits to apply to a research licence ‘for certain types of genetic intervention’ provided that ‘human dignity will not be prejudiced’.¹⁵ Similarly in France where ‘eugenic practice aimed at organizing the selection of persons’ and alteration(s) ‘made to genetic characteristics in order to modify the offspring of a person’ are banned,¹⁶ yet at the same time the law exempts interventions aiming ‘for the prevention and treatment of genetic diseases’¹⁷ without providing further guidance.

Notwithstanding heterogeneous normative approaches, these models share a common objective: fostering scientific innovation and freedoms while protecting their vision of a common good, mostly expressed in safeguarding human dignity. In order to do so, sanctions and other coercive mechanisms are often adopted as deterrents. Indeed, the global HGE policy landscape is frequently accompanied by some form of sanctions, ranging from criminal to pecuniary and other social penalties. In particular, when such systems are based on legislative models, criminal penalties – substantial imprisonment and fines – are the standard. Upholding criminal law in biomedical research is an exceptional approach, and societies around the world use this tool to send the strongest condemnatory message. Here, as in other fields, criminal law serves as a tool for moral education and for achieving retribution, denunciation, and/or deterrence. But other type of penalties, such as moral sanctions, could be equally powerful. A radical example of the latter is China’s ‘social credit system’¹⁸ where research misconduct is sanctioned by a wide umbrella of actors, which can impose an equally wide set of penalties and can even reach far beyond the traditional academic setting – from employment to funding, insurance, and banking eligibility. However, employing criminal law can be problematic because it often requires intentionality (mens rea). In the context of HGI, criminal law could create loopholes for downstream interventions when restrictions are limited to certain applications. For instance, German law bans the ‘artificial’ alteration of ‘the genetic information of a human germ line cell’¹⁹ and the use of such cell for fertilisation. Yet, such prohibition would not be applicable ‘if any use of it for fertilisation has not been ruled out.’²⁰ While under Canadian legislation, it is an offense to ‘knowingly’ ‘alter the genome of a cell of a human being or in vitro embryo such that the alteration is capable of being transmitted to descendants.’²¹

Comparably, an issue of shared concern across normative systems are references to the eugenic potential of HGI. Fears over the ability to alter the germline infringing dignity and integrity have been widely articulated in policies. These concerns are best illustrated in France, where a new crime against the integrity of the human species has been typified and which forbids ‘carrying out a eugenic practice aimed at organizing the selection of persons.’²² Similarly, Indian guidelines restrict ‘eugenic genetic engineering for selection against personality, character, formation of body organs, fertility, intelligence and physical, mental and emotional characteristics.’²³ In the same vein, Belgium outlaws carrying out ‘research or treatments of eugenic nature that is to say, focused on the selection or amplification of non-pathological genetic characteristics of the human species.’²⁴ However, these policies provide little guidance for interpretation: when should interventions seeking to repair deleterious gene mutations or confer disease immunity – at the individual or population level – be considered eugenic interventions? Or a non-medical or enhancement practice? Selecting or de-selecting traits, while not an ethically neutral intervention, is not per se eugenics. Therefore, contextualising thresholds and defining the paraments for scientific and ethical acceptability of such interventions are required not only to provide much needed legal clarity, but also to avoid being perceived as simply rhetorical calls for political expediency.

34.2.2 International Policy Frameworks

Significant policy activity followed the refinement of HGE. A wide range of professional organisations, funding and regulatory agencies, quickly reacted to these developments with statements reflecting an equally varied range of positions.²⁵A common theme among them is a circumspect attitude with appeals for the protection of dignity and integrity. While these positions endorse different normative approaches, they all pay particular attention to intergenerational responsibilities in their calls for principled restrictions to reproductive HGI.

Among the earliest international instruments addressing HGI are several non-binding Declarations adopted under the United Nations’ framework. First, are the UNESCO’s Universal Declaration on the Human Genome and Human Rights and the ensuing report on HGE by their International Bioethics Committee, which conceptualise the genome as the ‘heritage of humanity’ and in that vein, they plea for a moratorium on HGI that is based on prevailing ‘concerns about the safety of the procedure and its ethical implications.’²⁶ Succeeding UNESCO’s efforts, and after a failed attempt to adopt legally binding policy, the United Nations passed the UN Declaration on Human Cloning, calling on states ‘to adopt the measures necessary to prohibit the application of genetic engineering techniques that may become contrary to human dignity.’²⁷ The pleas raised by these UN bodies remain a contemporary mandate, appealing for concrete measures to implement moral commitments into national legislation with the necessary enforcement measures.

Following the human rights approach enshrined in the abovementioned instruments, two important regional policies were enacted: the Council of Europe’s Oviedo Convention²⁸ and the European Union Clinical Trials Regulation.²⁹ These remain to date as the only international legally binding instruments governing HGI. The Oviedo Convention – as a general rule – explicitly forbids research and clinical interventions seeking to modify the genome. Yet, it exempts interventions that are ‘undertaken for preventive, diagnostic or therapeutic purposes’ when the aim is ‘not to introduce any modification in the genome of any descendants’.³⁰ In turn, the cited EU Regulation focuses on gene therapy, banning clinical trials resulting ‘in modifications to the subject’s germ line genetic identity’.³¹ Yet, no guidance has been provided to define or interpret the notion of ‘genetic identity’ in order to fully grasp the scope and breadth of such provisions.

Actors from different fields and parts of the world³² have been quite prolific in articulating their positions with regards to HGE and in conveying how they envisage – or not – a path forward to reproductive HGE.³³ Even in China after the birth of the HGE twins, funding and professional organisations have swiftly publicised their positions,³⁴ aligning to mainstream ones. Indeed, all of these statements share several common threads. First, they all endorse a guarded approach to HGI, calling for temporary halts or moratoria, rather than advocating for permanent bans. The scope and breadth of such restrictions vary, from positions that seek to prevent clinical applications but allow reproductive research, to those that condemn any use. Second, a prospective approach also characterises them. While recent developments might render prevention a futile goal, precautionary measures fostering scientific integrity are still relevant. Third, they are by far based on scientific concerns, given the current inability to fully assess HGE’s safety and efficacy. Notably, societal considerations focusing on protecting human rights are also prevalent. Lastly, appeals for public engagement are widespread, including calls for participatory, inclusive and transparent dialogue in order to empower stakeholders, inform policy-making efforts, and foster trustworthiness.³⁵

34.3 The Road to Harmonisation

Reactionary responses often follow the advent of scientific developments deemed to be disruptive to notions of integrity and dignity, such as with HGI. A concomitant result of the debates over genetic engineering techniques that started decades ago, is an overall fraught policy landscape that generally seeks to condemn such interventions but is void of global governance. However, they steered a level of policy convergence.

The plethora of social debates and policies emanating in the context of HGE demonstrate that across the globe, policy harmonisation remains a laudable objective. These efforts seek convergence in fundamental ethical safeguards for research participants – and future patients – coupled with criteria for regulating the application of these technologies. Throughout the world, and with diverse levels of success, governance mechanisms have been established empowering authorities with granting licences, conducting ethical oversight and enforcing compliance. However, for these requirements to be effective, consistent implementation is needed in a manner that respects scientific integrity and freedoms.

Harmonisation is therefore apparent in convergent criteria that bar or condemn HGI. Yet, in some cases, these positions are only transitory by virtue of established moratoria or other precautionary temporary measures. Thus, they remain effective only while extant safety and other technical concerns remain. In fact, some responses seemed to be solely based on our current state of knowledge, as exemplified below:

Although our report identifies circumstances in which genome interventions of this sort should not be permitted, we do not believe that there are absolute ethical objections that would rule them out in all circumstances, for all time. If this is the case, there are moral reasons to continue with the present lines of research and to secure the conditions under which heritable genome editing interventions would be permissible.³⁶

Additional examples of the latter are found in Singapore policy forbidding HGI due to ‘insufficient knowledge of potential long-term consequences’³⁷ and pending ‘scientific evidence that techniques to prevent or eliminate serious genetic disorders have been proven effective’.³⁸ The same rationale underpins Indian policy restricting ‘gene therapy for enhancement of genetic characteristics (so called designer babies)’ based on ‘insufficient information at present to understand the effects of attempts to alter/enhance the genetic machinery of humans’.³⁹

Despite diverse normative systems and societal contexts, the world seems to be disposed towards harmonisation.⁴⁰ Which factors help explain this phenomenon? Policy transfer and emulation⁴¹ might be factors supporting policy growth and the emergence of global convergence. However, such consensus is still quite precarious as best exemplified by the level of international involvement and the strength of the response to recent developments.⁴² Scepticism over the stability of an emerging or actual consensus is based on the fact that policy responses thus far are grounded in distinct rationale. While they all call for ‘action’ and ‘caution’, they legitimately differ in their significance and understanding of such terms. As we have seen, in some instances a cautious approach has been translated in voluntary moratoria. This is the temporarily halting of certain types of clinical interventions or in promoting public engagement⁴³ so as to allow for policy to reflect changes in scientific knowledge or societal values. In other instances, precautionary responses – under vigilant oversight – purposely do not deter or outlaw research given the need for evidence in quantifying risks and benefits. Finally, in other circumstances, caution has signified enacting blank legal prohibitions.⁴⁴

Conceptual misunderstandings between the notion of harmonisation⁴⁵and standardisation are often present.⁴⁶ As such, appeals for standardisation frequently do not realise that they entail the creation of uniform legal and ethical standards, which are not only highly unachievable, but also undesirable particularly with respect to HGE. In the latter, sovereignty and moral diversity must be respected. Harmonisation⁴⁷ processes do not seek uniformity as the end result, they rather entail substantial correspondence between fundamental ethical principles present across the continuum of normative responses. They aim to foster cross-jurisdictional collaboration and thus governance. Still, harmonisation is not without challenges, particularly in regards to criteria for evaluating policy convergence and assessing variations in the regulation of fundamental ethical requirements, where thresholds for determining the significance of a given policy can vary. The latter is of great importance as variations could potentially undermine the integrity of ethical safeguards or societal values.

34.4 Conclusion

For the sceptics, attempts to meaningfully engage a global community of stakeholders to adopt binding policy and governance will inevitably end in ‘pyrrhic’ victories⁴⁸ – as in the past. History seems to be full of examples to support this position.⁴⁹ Indeed, thus far the inability to form a representative community to reconcile conflicting interests – economic and otherwise – and to prevent egregious actions, has taught us that sole condemnation of a particular intervention is futile for preventing abuses absent morally binding obligations and ‘actionable’ regulatory frameworks. For the optimists, the level of societal engagement, emergent policy convergence and swift condemnatory responses following the most contemporaneous and appalling gross violations of human rights and scientific standards⁵⁰ are grounds to believe that a level of policy harmonisation remain a realistic endeavour. Crisis provides the opportunity to significant alter the direction and strength of a given policy system, including reshaping governance mechanisms and reconfiguring the power of stakeholders. It therefore has the ability to transform more than policy; it can stir real change in collective behaviour. In the aftermath of this crisis, the central lesson must be that without defining and achieving societal consensus and governance at both the local and global level, no policy system would ever be completely effective.

35 Towards a Global Germline Ethics? Human Heritable Genetic Modification and the Future of Health Research Regulation

Sarah Chan

35.1 Introduction

Human germline genetic modification (HGGM) has been the subject of bioethical attention for over four decades. Recently, however, two areas of biomedical technology have revived debates over HGGM. First, the development of ‘mitochondrial replacement therapy’ (MRT) represents, some have argued, a form of HGGM, since it affects the genetic makeup of the resulting children in a way that may be passed on to future generations. Second, the advent of genome editing¹ technologies has made heritable genetic modification of humans for the first time a genuinely practicable possibility: one that was dramatically and prematurely realised when, in November 2019, it was announced that two genome-edited babies had already been born.²Amid renewed scrutiny of human genome editing, emerging clinical uses of MRTs, and the increasing globalisation of science and of health technology markets, the question of how HGGM can and should be regulated has gained new salience. Moreover, having been so long contested and in relation to such fundamental concepts as ‘human dignity’ and ‘human nature’, the issue of germline modification has assumed a significance beyond its likely direct consequences for human health.

The current ‘regulatory moment’ with respect to HGGM thus perhaps represents something of a watershed for the global governance of science more generally. Further, both the potential impacts of the technology, and the moral and political power of the human genome as a metaphor through which to negotiate competing visions of human nature and society, require us to consider these issues at a global scale. This also creates an opportunity for critical exploration of novel approaches to regulation.

Following on from the previous chapter’s analysis, this chapter considers broader lessons we might learn from examining the challenges of HGGM for the future of health research regulation. HGGM, I suggest, is a contemporary global regulatory experiment-in-progress through which we can re-imagine the regulation of (in particular, ethically contentious) science and innovation: what it should address, what its purposes might be, and how, therefore, we should go about shaping global scientific regulation. Through examining this, I argue that such regulation should focus on processes and practices, rather than objects; and that its utility lies more in mediating these processes than in establishing absolute prohibitions or bright lines. Especially in the case of emerging and controversial technologies, regulation plays an important role in negotiating ideas of responsibility within the science–society discourse. In so doing, it also affects, and should be shaped by attention to, the global dynamics of science and the consequences for global scientific justice.

35.2 Germline Technologies: A Brief Overview

Earlier techniques used for genetic modification were inefficient and simply impractical to allow the creation of genetically engineered humans.³ The ‘game-changing’ aspect of genome editing technologies⁴ is their ability to achieve more precise gene targeting, with much higher efficiency, in a wide range of cell types including human embryos. The best-known genome editing technology is the CRISPR/Cas9 system, the use of which was described in 2012.⁵ Following the publication of the CRISPR/Cas9 method, it rapidly became clear that HGGM needed urgently to be reconsidered as a real possibility. In 2015, reports of the first genome editing of human embryos⁶ spurred scientists to call for restrictions on the technology,⁷ and prompted further investigations of the associated ethical and policy issues by various national and international groups.⁸

Notably, many reports, including those of the US National Academies⁹ and the UK’s Nuffield Council on Bioethics,¹⁰ concluded that heritable human genome editing could be acceptable, providing certain conditions were met. These conditions included further research to ensure safety before proceeding to clinical application, and sufficient time for broad and inclusive engagement on governance. Neither of these conditions were fulfilled, however, when He Jiankui announced to the supposedly unsuspecting world¹¹ that he had already attempted the procedure.

Somewhat before genome editing technologies came onto the scene, MRTs were already being developed as a treatment for certain forms of mitochondrial disease.¹² According to the possibility foreseen in the 2008 amendments to the Human Fertilisation and Authority Act, and following an extensive consultation process, in 2015 it became legal for MRT to be licensed in the UK.¹³ In the USA, the Institute of Medicine likewise concluded that MRT could be acceptable,¹⁴ though it is not currently legal in the USA. Pre-empting the regulatory process, however, in September 2016 John Zhang, an American scientist, announced that he had already performed the first successful use of MRT in the clinic,¹⁵ using embryos created in the USA and shipped to Mexico for intra-uterine transfer.

While reams have been written on the ethics of HGGM, the most pressing questions with respect to HGGM no longer concern whether we ought to do it at all, but how; where; by and for whom; and with (or without) what authority it will be done. This is not a claim about the inadequacy of regulation in the face of technological inevitability but a statement of where things currently stand ethically and legally, as well as scientifically. MRT is legal and being carried out in a number of countries; heritable genome editing, while not yet legalised, has been deemed ethically acceptable in principle. One way or another, HGGM is becoming a reality; regulation can guide this process. To do so effectively will require careful consideration of what is regulated and how, with what justifications, and with whose participation.

35.3 What Are We Regulating? What Should We Regulate?

As pointed out in the previous chapter (see Isasi, Chapter 34 in this volume) regulation can serve to articulate normative concerns but does not always do so coherently or consistently. In setting out to regulate ‘germline modification’ or ‘the human genome’, what concerns might be entangled?

The term ‘germline modification’ is itself subject to interpretation. Technically speaking, ‘the germline’ can encompass any cell that is part of the germ lineage, including gametes and embryos; thus a prohibition on modifying the germline might be taken to preclude any use of genome editing in human embryos, including for basic research. Early calls for a moratorium favoured this highly restrictive approach: some argued that because ‘genome editing in human embryos … could have unpredictable effects on future generations … scientists should agree not to modify the DNA of human reproductive cells’.¹⁶ This, however, ignores that genome editing of human embryos is only likely to have direct effects on future generations if those embryos become people! Context, in other words, is key.

Moreover, novel technologies may potentially render ‘the germline’ an impossibly broad category. It is now possible to reprogramme somatic cells to pluripotent cells,¹⁷ and to turn pluripotent cells into gametes.¹⁸ Any cell could therefore in theory become part of the germline, meaning any genetic modification of a somatic cell could potentially be a ‘germline’ modification. It is not, however, ‘the germline’ in the abstract, but the continuity or otherwise of particular, modified or unmodified germlines, that should be our concern.

The ‘human genome’ is likewise a nebulous concept: does it refer to an individual’s genome, or the combined gene pool of humanity? References to the human genome as the basis of ‘the fundamental unity of all members of the human family’ and ‘the heritage of humanity’¹⁹ seem to suggest a collective account, but it is hard to see how the ‘collective genome’ could be regulated. Indeed, one might argue that the human genome, in the sense of the collective gene pool of humanity, would not be altered were genome editing to be used to introduce a sequence variant into an individual human genome that already exists within the gene pool.²⁰

Even the term ‘modification’ raises questions. MRT involves no change to DNA sequence, only a new combination of nuclear and mitochondrial DNA; the Institute of Medicine report, however, recommended that its use be limited to having male children only, to avoid this ‘modification’ being transmitted. Yet this combination of nuclear and mitochondrial DNA might also have arisen by chance rather than design, naturally rather than via MRT. The same can be said about genome editing to introduce existing genetic sequence variants. In regulating technology, we should consider whether the focus should be on outcomes, or the actions (or inactions) leading to them – and why.

The difficulty of regulating the ‘germline’ or the ‘human genome’ highlights the problem of regulating static objects rather than the dynamic relations and practices through which these objects move. In regulating a ‘thing’ in itself, the law tends to fix and define it, thereby rendering it inflexible and unable to evolve to match developments in technology (see McMillan, Chapter 37 in this volume). Especially in the area of biomedicine, both the pace of research and the propensity of science to discover new and often unexpected means to its ends can result in overly specific legislative provisions becoming rapidly obsolete or inapplicable.

Examples of this can be seen in previous legislative attempts to define ‘the human embryo’ and ‘cloning’. The original Human Fertilisation and Embryology Act (1990) s1(1)(a) defined an embryo as ‘a live human embryo where fertilisation is complete’. The development of somatic cell nuclear transfer technology, the process by which Dolly the sheep was cloned, immediately rendered this definition problematic, since embryos produced via this technique do not undergo fertilisation at all. Addressing this legal lacuna necessitated the hurried passage of the Human Reproductive Cloning Act 2001,²¹ before the eventual decision of the House of Lords brought ‘Dolly’-style embryos back within the Act’s purview.

A similar situation occurred in Australia, before the passage of uniform federal laws: in the state of Victoria, the embryo was defined as ‘any stage of human embryonic development at and from syngamy’,²² leaving unclear the status of embryos produced via nuclear transfer, in which syngamy never takes place. In South Australia, meanwhile, the law prohibited cloning, but defined ‘cloning’ specifically as referring to embryo splitting, again leaving nuclear transfer embryos unregulated.

These examples illustrate the pitfalls of over-determining the objects of regulation. Attempts to regulate HGGM, though, may suffer not only from being too specific in defining their objects, but also from being too vague. For example, references to ‘eugenic practices’ in national and international legal and policy instruments leave open the question of what actually constitutes a eugenic practice (see Isasi, Chapter 34 in this volume). Without any processes in place to determine how such terms should be interpreted, their inclusion tends to obfuscate rather than clarify the scope of regulation.

Similar examples abound: the EU Clinical Trials Directive declared: ‘No gene therapy trials may be carried out which result in modifications to the subject’s germ line genetic identity’,²³ a position further affirmed by the replacement Clinical Trials Regulation.²⁴ But what exactly is ‘germ line genetic identity’? UNESCO’s Declaration opposes ‘practices that could be contrary to human dignity, such as germ-line interventions’,²⁵ but does not indicate how or why germline interventions ‘could be contrary to dignity’ – making it difficult to distinguish whether they actually are.

The requirements of being neither too specific nor too vague may seem a Goldilocks-style demand with respect to defining the appropriate targets of regulation. What this illustrates, however, is that regulation is important for the processes and practices it establishes, as much as the definitions of objects to which these pertain.

35.4 Research or Reproduction? The Importance of Context

In regulating HGGM, our concern should be, not whether a modification is in principle heritable but whether it is in fact inherited. The context, both social and scientific, in which the modification procedure is carried out therefore matters a great deal. Attempting to regulate this solely in terms of permitting or prohibiting particular technologies would be extremely limiting.

Instead, we should consider how our concerns can be addressed by regulating practices with respect to assisted reproduction; and relations between healthcare practitioners, healthcare systems, patients, research participants and the market. Such practices and relations are key to the processes by which future generations, and our relationships with them, are created. Regulation of this sort can be effective at transnational as well as intra-national level: cross-border surrogacy is another situation where particular practices and relations, not just the technology itself, create ethical concerns – India’s regulatory response represents an example of correlative attempts to address them.

Focusing our regulatory attention on processes and relations also allows us better to distinguish desirable versus undesirable contexts for the application of technology. Basic research on embryos never destined for implantation is very different to the creation of genetically modified human beings; regulation ought accordingly to enable us clearly to separate these possibilities. This might be done in various ways, as can be seen by considering UK and USA examples.

The UK’s Human Fertilisation and Embryology Act to some extent regulates embryos relationally and in terms of practices: what may be done to or with an embryo depends on the relationships among actors connected to the embryo, their relationships with the embryo itself, and the embryo’s own relational context, in terms of its origin, ontology, and history. By creating the category of ‘permitted embryos’ as the only embryos that may be implanted, the Act effectively separates reproductive use from other applications.²⁶

In comparison, US federal regulation affecting HGGM incorporates aspects of both object-focused and contextual regulation. Laws prohibiting federal funding of human embryo research apply to research with any and all embryos, regardless of origin, context, or intended destination.²⁷ When it comes to genetically modifying those embryos, however, context matters: via the FDA’s jurisdiction, current laws effectively prevent any clinical applications involving modified embryos,²⁸ while basic research falls outside this domain.

Looking ahead to the possible futures of HGGM, what sorts of purposes and processes might we be concerned to regulate? Many of the worries that have been expressed over HGGM can be addressed via regulation (in the broad sense) of processes across different contexts. For example, the dystopian vision of a society in which parents visit a ‘baby supermarket’ to choose their perfect designer child is quite different to one in which the healthcare system permits parents to access reproductive interventions that have been accepted as safe (enough) for particular purposes within defined contexts. This being the case, it is far from evident that our response to these possible futures should be to forgo exploring the potential benefits of gene therapy for fear of ‘designer babies’: the two possibilities may be mediated via the same technologies but involve very different contexts, relationships, roles and practices. These can be differently regulated; and regulation in turn can shape which practices emerge and how they evolve.

One possible regulatory position, often motivated by a ‘slippery slope’ argument, is that we should prohibit all embryo genome editing research, in order to avoid the extreme dystopian futures it might one day enable. As argued above, however, context is key and focusing on technology alone fails to take account of this. Restricting research today in order to prevent one of the distant possible futures it might enable also forecloses any beneficial outcomes it might produce. To prohibit something that is prima facie acceptable merely because it may make possible the unacceptable is drawing the line in the wrong place.

Although concerns over technological development often invoke the ‘slippery slope’, this metaphor ignores the fact that science is not a single, uni-directional process with a defined endpoint. Instead, research and the applications it might enable are more like a ‘garden of forking paths’,²⁹ a labyrinth of infinite possibilities. Regulatory slippery-slopeism, for fear of one of those possibilities, would foreclose the remainder.

That said, it might be true that what seems unacceptable from our present perspective will, from halfway down the slope, be less so. Studies of public opinions show greater acceptance of novel genetic technologies among younger demographics who have grown up in the age of IVF and genetic screening; and it was suggested with respect to MRT that this might be a slippery slope to other forms of HGGM such as genome editing³⁰ – though this would be difficult to prove with certainty.

The response to slippery-slope fears is often to try to draw a ‘bright line’. Any lines we might draw, however, are liable to suffer from the above-mentioned problem of either over-determination or vagueness. Some distinctions themselves may be less clear. For example, a commonly held position in relation to genome editing is that it should be used only for therapy, not for enhancement; but as much bioethical scholarship has revealed, the line between therapy and enhancement is not so easily defined. In a similar way, however, the definition of ‘serious’ disability, illness, or medical condition, for which the HFEA permits pre-implantation embryo testing, is subject to interpretation; yet its provisions have, nonetheless, been effective because there is a regulatory process for legitimate decision-making in the case of ambiguity.

Moreover, as the scientific and ethical landscape shifts, bright lines may eventually become grey areas: for example, the fourteen-day rule on embryo research was a regulatory (if not ethical) bright line for decades yet is now once again the subject of discussion(see McMillan, Chapter 37 in this volume). We should not assume that we are currently at the pinnacle of ethical understanding such that the only way is down: what we now perceive as ‘slipping’ might in future generations be understood as moral progress. Regulation on the slippery slope might sometimes involve drawing lines, but these should be seen as pragmatic necessities, not moral absolutes.

One supposed ‘bright line’ in HGGM that may not prove so clear is the somatic / germline distinction: is this really as legible or significant as it has been made out to be? Publics might not think so: recent engagement initiatives have shown widespread acceptance for therapeutically oriented genome editing, including heritable HGGM,³¹ while in the wake of He’s attempt at creating genetically modified babies, crossing this supposed ethical Rubicon, the projected public backlash does not seem to have manifested. Moreover, in considering the possible consequences and balance of risks involved in somatic versus germline modification, we might argue that the two are not as dissimilar as might be assumed.³² Neither then in regulation should the germline be assumed to be a bright line in perpetuity: as for the fourteen-day rule, its importance as a line lies in the processes invoked when considering whether to cross it.³³

35.5 Regulation, Responsibility and Cooperative Practice

Given the above, what is the justification for regulating HGGM? Clearly, it is not absolute protection of the germline or genome itself: nothing stops someone visiting a plutonium refinery and exposing their germ cells to ionising radiation, or wearing too-tight underwear, and then subsequently engaging in reproduction via natural means, even though both of these processes are likely to result in heritable genetic changes. Nor would we consider it appropriate to attempt to regulate such activities.³⁴ What, then, is regulation doing here?

It may seem peculiar to allow reckless random genetic modification by individuals while the much more controlled deliberate use of directed technology should be prohibited. But the aim of regulation is not simply, or not only, to prevent certain factual outcomes. A shift in the language points us to what is at stake here: before the era of genome editing, HGGM was considered ‘too risky’; now, instead, ‘it would be irresponsible’.

The question then becomes what ‘responsibility’ requires and how should it be enacted. This highlights an important role of regulation in relation to risk, specifically in determining how we understand risk and responsibility when something goes wrong. Regulatory responsibility is not about assigning blame to individual actors, be they scientists or clinicians, but instead deciding as a society how much and what kind of risk we are collectively willing to take responsibility for. That is, in regulating to permit something, we are implicitly accepting a certain degree of accountability for the practice and for its consequences. Even as scientific responsibility has been theorised in ways that go beyond the individual scientist to the collective community,³⁵ wider social responsibility for science requires a consideration of the interplay between social norms, regulation, and scientific practice.

Regulation therefore can also, and should, facilitate cooperative practices among different actors. At the Second International Summit on Human Genome Editing, David Baltimore described He Jiankui’s attempts to create genome-edited children despite all scientific and ethical advice to the contrary as representing ‘a failure of self-regulation’.³⁶ But this is only necessarily true if we understand the primary purpose of regulation as being the absolute prevention of particular outcomes. Moreover, for ‘the scientific community’ to assume all of the blame for failing adequately to police its members ignores the function of states and the existence of state regulation, while arrogating what is arguably a disproportionate level of self-governance to scientists.

In fact, as Chinese bioethicists and legal scholars were quick to assert,³⁷ there were various existing regulatory instruments that were breached by He’s work. Genome-edited babies may have been created, but the real test of regulation is what happens next: how regulators and policy-makers (broadly categorised) respond, to this case specifically and in terms of regulating HGGM more generally, will determine whether regulation can be judged to have succeeded or failed. Notably, the imposition of a prison sentence for He³⁸ signals that, although scientific convention and existing oversight mechanisms may not have been sufficient deterrent beforehand, the criminal law was, nonetheless, capable of administering appropriate post hoc judgment. While the criminal law in regulating science may serve a partly symbolic function in assuring social licence for morally contentious research,³⁹ its value in this role must be backed by a willingness to invoke its ‘teeth’ when needed: He’s punishment aptly demonstrates this.

As this case illustrates, regulation is not just about absolute prevention, but involves mediating a complex set of relationships. Rather than viewing scientific self-regulation as a law unto itself and a separate domain, we should consider how scientists can effectively contribute to the broad project of regulation, understood as a combination of law and policy, process and practice, at multiple levels from individual to community, local to global.

35.6 Global Regulation and Scientific Justice

A common theme in discussions of the regulation of HGGM is that decisions about these technologies need to involve global participation. In order to determine what ‘global participation’ ought to consist of, it is worth considering why a global approach is appropriate.

Some have suggested a global approach is required because in affecting the human genome, HGGM affects all of us. George Annas and colleagues, for example, write that ‘a decision to alter a fundamental characteristic in the definition of human should not be made … without wide discussion among all members of the affected population … Altering the human species is an issue that directly concerns all of us’.⁴⁰ Yet the sum of the reproductive choices being made by millions of individual humans in relation to ‘natural reproduction’ is vastly greater than the potential effect of what will be, in the short term at least, a tiny proportion of parents seeking to use genome editing or MRTs.

In fact, many areas of science and policy will have far-reaching consequences for humanity, some probably much more so and more immediately than HGGM. Environmental policy, for example, and the development of renewable energy sources are likely to have far greater impact on the survival and future of our species, and affect far more people now and in the future, than HGGM at the scale it is likely initially to be introduced.

Doom-laden predictions overstating the possible consequences of HGGM for ‘the human race’ or ‘our species as a whole’ tend to demand precaution, in the sense of a presumption against action, as a global approach. Such calls to action have rhetorical force and appeal to emotion, but rest on shaky premises. Overblown claims that in altering the genome we are somehow interfering with the fundamental nature of humanity are a form of genetic essentialism in themselves, implying that what makes us worthy of respect as persons and what should unite us as a moral community is nothing but base (literally!) biology.

Nevertheless, the political history of genetics has reified the moral and metaphorical power of the ‘germline’ concept, as something quintessential and common to all humans. This history has seen heredity, ‘the germline’, and ‘the genome’ used as a tool both for division and for unification, from eugenics to the Human Genome Project,⁴¹ imbuing genetics with a significance well beyond the mere scientific. While the biological genome as the ‘heritage of humanity’ and the basis of human dignity⁴² does not stand up well to analysis, the political genome, as object of multiple successive sociotechnical imaginaries, has acquired tremendous power as a regulatory fulcrum.

It is therefore genome alteration as a social and political practice, not its direct biological consequences, that we should be concerned to regulate. Beyond just requiring a global approach, this creates an opportunity to develop one. HGGM represents a socio-techno-regulatory ‘event horizon’, the significance of which has been contributed to by the long historical association of genetics with politics, and which aligns with a broader trend towards engaging publics in discourse over science with the aim of democratising its governance. The immediate consequences of HGGM for human reproduction are likely to be fairly small-scale, and while opening up the possibility of clinical applications of genome editing will no doubt influence the direction of the field, as MRTs are already doing for related technologies, human genome editing is just one area of the vast landscape of scientific endeavour. Yet, in providing both opportunity and momentum to produce new approaches to global regulation, HGGM may have much wider implications for the broader enterprise of science as a whole.

An important feature of any attempt to develop a global approach to regulation is that it should account for and be responsive to transnational dynamics. This requires attention to equity in terms of scientific and regulatory capacity, as well as the ability to participate in and develop ethical and social discourses over science. When it comes to emerging and contested technologies such as embryo research, cell and gene therapies, and now genome editing, countries with more advanced scientific capacity have tended also to lead in developing regulation, and to dominate ethical discussion. The resulting global regulatory ‘patchwork’ creates the possibility of scientific tourism, which in turn combines with uneven power over regulatory and ethical discourse to reproduce and increase global scientific inequities. This can be seen, for example, in the consequences of Zhang’s Mexican MRT tourism and its effects on global scientific justice.⁴³

Another feature of the variegated regulatory landscape for controversial technologies is concern, among countries with high scientific capacity but restrictive regulation, about remaining internationally competitive, when researchers in other countries may take advantage of lower regulatory thresholds to forge ahead. This was a prominent factor in the embryo research debates of the early 2000s. Examining the expressions of concern with respect to human embryo genome editing research in China, about ‘the science … going forward before there’s been the general consensus after deliberation that such an approach is medically warranted’,⁴⁴ versus in the UK being described ‘an important first … a strong precedent for allowing this type of research’,⁴⁵ it seems that international dynamics and ‘keeping pace’ may also be a consideration here. Dominant actors may seek to control this pace to their advantage by re-asserting ethical and regulatory superiority, in the process reinforcing existing hegemonies.

The significance of the present ‘regulatory moment’ with respect to HGGM is that it offers opportunities to disrupt and re-evaluate these hegemonies, across geographic, cultural, disciplinary, political, and epistemic boundaries. This should include critical attention to the internalised narratives of science: in particular, the problem of characterising science as a competitive activity. The race to be first, the scientific ‘cult of personality’ and narratives of scientific heroism (or in the case of He Jiankui, anti-heroism) may serve to valorise and promote scientific achievement, but also drive secrecy and create incentives for ‘rogue science’. What alternative narratives might we develop, to chart a better course?

35.7 Conclusion: Where Next for Global Germline Regulation?

Seeking a new paradigm for global health research regulation will require a conscious effort to be more inclusive. We need to examine what constitutes effective engagement in a global context and how to achieve this, across a plurality of cultural and political backgrounds, varying levels of scientific capacity and science capital, and different existing regulations.

Consider, for example, the contrasts that might emerge between the UK and China, where expectations over discourse, governance and participation differ from those in which UK public engagement has been theorised and developed.⁴⁶ Distinct challenges will arise for engagement in Latin America, where the politics of gender and reproduction overtly drive regulation, and where embryo research and reproductive technologies are heavily contested. The discourse is not necessarily uniform among all countries: discussing embryo genome editing is more challenging where IVF itself is still controversial. In approaching these issues, we need also to be aware of potential negative impacts the discussion may have, for example on women’s access to reproductive health services.

Furthermore, we need to engage not just with publics and not just ‘the scientific community’ but with scientific communities. As we recognise in the field of engagement that there is not just a single unitary Public but a wide range of publics with different perspectives, values and beliefs, we need also to acknowledge pluralism of values, practices and motivations among scientists. In thinking about the governance of science, we must consider what factors might influence these and how, as an indirect form of regulating research. Some attention has already been given to the potential of actors such as journal publishers and funders to shape scientific culture and influence behaviour; further research might more clearly delineate these evolving regulatory roles, their limitations and how they work in tandem with ‘harder’ forms of regulation such as criminal law.

At the time of writing, the various proposed approaches to global governance of human genome editing have yet to coalesce into a single solution. The He incident triggered renewed calls for a moratorium.⁴⁷ While the scientific academies behind the International Summits were already considering aspects of regulation, the process was probably likewise hastened by these events, resulting in the formation of an International Commission; the WHO have launched their own inquiry;⁴⁸; and numerous statements have been published over the past five years,⁴⁹ with many initiatives ongoing and proposals issued.

It seems clear that a moratorium is unlikely to emerge as the answer, despite reactions to He’s transgression. In the first place, it is far from clear that a moratorium would have prevented He’s experiment: the consensus of scientific communities publicly expressed was already that it should not be done. A moratorium without enforcement mechanisms would have been no more effective than the existing guidelines; and any symbolic value a moratorium would have would be rapidly eroded if it were not respected. Other proposals include, as per the WHO, a registry to promote greater information and transparency and facilitate the involvement of wider scientific players including funders and publishers; a global observatory⁵⁰ is another proposed mechanism to enable governance. With any of these, we will still need to attend to the dynamics of discourse, which interests are represented and how.

With that in mind, perhaps a single solution is not what we should be seeking. The proliferation of initiatives aimed at determining principles and frameworks for acceptable governance of HGGM may lead some to wonder whether we really need so many cooks for this broth, and to raise objections regarding potential inconsistencies when multiple bodies are charged with a similar task. Yet, even among the number of bodies that currently exist, the full range of diverse views has not been represented. The existence of multiple parallel discourses is not necessarily a bad thing: more can be better if it allows for broader representation. The meta-solution of integrating these is the challenge; approaching regulation as dynamic, constituted by practices and concerned with processes and relations, may be a way to meet it.

36 Cells, Animals and Human Subjects Regulating Interspecies Biomedical Research

Amy Hinterberger and Sara Bea

36.1 Introduction

The availability of new cellular technologies, such as human induced pluripotent stem cells (iPSCs), has opened possibilities to significantly ‘humanise’ the biology of experimental and model organisms in laboratory settings. With greater quantities of genetic sequences being manipulated and advances in embryo and stem cell technologies, it is increasingly possible to replace animal tissues and cells with human tissues and cells. The resulting chimeric embryos and organisms are used to support basic research into human biology. According to some researchers, such chimeras might be used to grow functional human organs for transplant inside an animal like a pig. These types of interspecies biomedical research confound long-established regulatory and legal orders that have traditionally structured biomedicine. In contexts where human cells are inserted into animal embryos, or in the very early stages of animal development, regulators face a conundrum: they need to continue to uphold the differences in treatment and protections between humans and animals, but they also want to support research that is producing ever-more intimate entanglements between human and animal species.

In research terms, human beings fall into the regulatory order of human subjects protection, a field of law and regulation that combines elements of professional care with efforts to preserve individual autonomy.¹ Animals, however, belong to a much different regulatory order and set of provisions relating to animal welfare.² To this end, animals have been used, and continue to be used, for understanding and researching human physiology and disease where such experiments would be unethical in humans. Researchers can do things to animals, and use animal cells, tissues and embryos in ways that are very different from human cells, tissues and embryos. Traditionally, ethical concerns and political protection have focused on the human subject in biomedical research, with ensuing allowances to address animal welfare and human embryos. However, such divisions are now under immense strain and are undergoing substantial revision. This chapter investigates these transformations in the area of interspecies mammalian chimera. We ask: what forms of regulation and law are drawn on to maintain boundaries between human research subjects and experimental animals in interspecies research? What kinds of reasoning are explicitly and implicitly used? What kinds of expertise are invoked and legitimised?

We will begin with a brief overview of the chimeric organisms in the context of new cellular technologies. We will then explore significant national moments and debates in the UK and USA that highlight the tacit presumptions of regulatory institutions to explore where disagreement and contestation have arisen and how resolutions were reached to accommodate interspecies chimeras within the existing regulatory landscape. Through these national snapshots, the chapter will explore how human–animal chimeras become objects of regulatory controversy and agreement depending on the concepts, tools and materials used to make them. The final sections of the chapter provide some reflections on the future of chimera-based research for human health that, as we argue, calls forth a reassessment of regulatory boundaries between human subjects and experimental animals. We argue that interspecies research poses pressing questions for the regulatory structures of biomedicine, especially health research regulation systems’ capacity to simultaneously care for and realign the human and animal vulnerabilities at stake within interspecies chimera research and therapeutic applications.

36.2 From Dish to Animal Host

Chimeric organisms, containing both human and non-human animal cells, sit at the interface between different regulatory orders. The ‘ethical choreography’ that characterises health research regulation on interspecies mixtures is densely populated with human and animal embryos, pluripotent stem cells, human subjects and experimental animals.³ Much depends on the types of human cells being used, the species of the host animal that will receive the cells, along with age of the animal and the region where human cells are being delivered. Regulation thus includes institutional review board approval for using human cells from living human subjects. There also needs to be approval from animal care and use committees that assess animal welfare issues. Depending on the country, there might also be review from a stem cell oversight committee, which must deliberate on whether the insertion of human cells into an animal may give it ‘human contributions’.⁴ There are significant national differences in regulatory regimes, making for diverse legal and regulatory environments at both national and international levels because countries regulate human and animal embryos, stem cells and animal welfare very differently.⁵

In the biological sciences, the term chimera is a technical term, but it does not necessarily refer to one specific entity or process. Generally speaking, chimeras are formed by mixing together whole cells originating from different organisms.⁶ It is a polyvalent term and can refer to entities resulting from both natural and engineered processes.⁷ Historians of science have explored how species divides, especially between humans and other animals, are culturally produced and historically situated both inside and outside the laboratory.⁸ The regulatory practices we explore in this chapter are not separate, but rather embedded in these larger structures of cultural norms about differences – and similarities – between humans and animals. As the life sciences continue to create new types of organisms, there are currently many groups and regulatory actors in different countries involved in producing definitions and forms of regulation for new human-animal mixtures. As we will see below, it is precisely the debates over the naming and classification of these new entities where the regulatory boundary work between the human and animal categories is illuminated.

36.3 Animals Containing Human Material

In the following two sections, we will explore national snapshots from advisory and regulatory bodies in the UK and USA. We will examine how they are confronting issues of responsibility and jurisdiction for boundary crossing entities that cannot easily be siphoned into the traditional legal and regulatory orders of either human or animal. We will show that while each country’s response via report or guidelines focuses on the human and animal division as primary to maintain in research practices, they each provide different solutions to the problems raised by interspecies mammalian chimera. These two sections of the chapter thus illuminate how interspecies chimera confound long-standing regulatory divisions in health research that challenge the law’s capacity to simply encompass new entities.

In 2011, the UK’s Academy of Medical Sciences released what is regarded as the first comprehensive recommendations to regulate the creation and use of chimeric organisms, called Animals Containing Human Material. The central conclusion of the Academy’s report is that research that uses animals containing human material is likely to advance basic biology and medicine without compromising ethical boundaries. The report itself was part of a much longer history of deliberation around the status of the human embryo in the UK where specific forms of human–animal mixtures have been proposed, debated and, in the end, legislated. The UK regulatory landscape is significant in this respect as no other nation has written into law human–animal mixtures – which in UK law are called ‘human admixed embryos’. The term human admixed embryo was introduced in 2008 amendments to the Human Fertilisation and Embryology Act 1990 (HFE Act). While it was the ‘cybrid embryo’ debate that became the most controversial and well-known related to these new legal entities, the legislation outlines a number of different kinds of human and animal mixtures that fall under its remit, including chimeric embryos. According to the Act, a human admixed embryo is any embryo that ‘contains both nuclear or mitochondrial DNA of a human and nuclear or mitochondrial DNA of an animal but in which the animal DNA does not predominate’.⁹

A 2008 debate in the House of Lords over the revised HFE Act and the term ‘human admixed’ highlights the classification conundrums of how boundaries between human and animal are drawn. The Parliamentary Under-Secretary of State for the Department of Health explained, regarding the term ‘human admixed embryo’: ‘It was felt that the word “human” should be used to indicate that these entities are at the human end of the spectrum of this research’.¹⁰ Responding to this notion of the spectrum, the Archbishop of Canterbury responded that:

‘the human end of the spectrum’ seems to introduce a very unhelpful element of uncertainty. Given that some of the major moral reservations around this Bill … pivot upon the concern that this legislation is gradually but inexorably moving towards a more instrumental view of how we may treat human organisms, any lack of clarity in this area seems fatally compromising and ambiguous.¹¹

This lack of clarity referred to by the Archbishop, which may ‘be fatally compromising’, sought to be addressed by the Animals Containing Human Material report.¹² Clarity, in this case, is provided by carefully considered boundaries and robust regulation, to remove elements of uncertainty. In the UK, the Human Fertilisation and Embryology Authority (HFEA) is the central body responsible for addressing proposals for embryo research in the UK. It is the body that licenses human embryonic stem cell research, oversees IVF treatment and the use of human embryos.

Violations of the licensing requirements of the HFEA are punishable under criminal law, which is both a literal and symbolic marker of respect for the conflicting and contested views on embryo research in the UK.¹³ However, the HFEA only has jurisdiction over human embryos (not animal embryos). Research on animal embryos is governed and regulated by an entirely different body, The Home Office, which regulates the use of animals in scientific procedures through the Animals (Scientific Procedures) Act 1986 (ASPA).

Assessing whether the human or animal DNA is most predominant may be harder with chimeric research embryos since their cellular make-up may change over time. Thus, it can become unclear whether their regulation should fall within the remit of the HFEA or the Home Office. Any mixed embryo judged to be ‘predominantly human’ is regulated by HFEA and cannot be kept beyond the 14-day stage, whereas currently in the UK an animal embryo, or one judged to be predominantly animal, is unregulated until the mid-point of gestation and can in principle be kept indefinitely. Whether or not an admixed embryo is predominantly ‘human’ is, according to the Academy’s report, an expert judgement. However, it recommended that the Home Office and HFEA, two government bodies that had not previously been connected, needed to work together to create an operational interface at the boundaries of their new areas of responsibility.

The Academy report purifies, both through language and regulatory approach, ambiguities raised by chimeric organisms by trying, as best as possible, to compartmentalise research into human or animal regulatory orders. The term ‘animals containing human material’ itself highlights this goal. According to the report, animals containing human material are animals first and foremost. In this respect, the report places the regulatory responsibility for these new chimeric entities squarely in the already regulated domain of animal research. To this end, the UK remains a highly regulated but permissive research environment for different types of chimera-based research, and is the only country to formerly write into law the protection of biological chimeras containing human and animal cells.

36.4 Assessing ‘Human Contributions’ to Experimental Animals

Unlike the UK, in the USA there is no formal legal regulation of interspecies chimera research. The 2005 National Academy of Science (NAS) Guidelines continue to be the cornerstone of scientific research involving embryos, stem cell biology and mammalian development. The Academy is not a governmental agency, nor does it have enforcement power but the guidelines are viewed to be binding by governmental and institutional authorities. The NAS guidance acts as the principal reference on the recommendations applicable to research using interspecies chimera involving human embryonic stem cells and other stem cell types.

Stem Cell Research Oversight (SCRO) committees are the localised bodies that put into action the NAS Guidelines. During the stem cell controversies that characterised the USA, the Academy recommended that all research involving the combination of human stem cells with non-human embryos, fetuses, or adult vertebrate animals must be submitted to not only the local Institutional Animal Care and Use Committee (IACUC) for review of animal welfare issues, but also to a Stem Cell Research Oversight (SCRO) Committee for consideration of the consequences of the ‘human contributions’ to any non-human animal.¹⁴ Thus, SCRO committees need to meet to discuss any experiment where there is a possibility that human cells could contribute in a major organised way to the brain or reproductive capacities particularly.

In late September 2015, the National Institutes of Health (NIH) in the USA declared a moratorium on funding chimeric research where human stem cells are inserted into very early embryos from other animals. However, like other instances where federal research monies were removed from controversial research – e.g. human embryonic stem cell lines – such research continued, but with private monies. The moratorium was met with scepticism and criticism of researchers working in this domain who, in a letter to Science, argued that such a moratorium impeded the progress of regenerative medicine.¹⁵ Following a consultation period in 2016, the NIH announced that it would replace the moratorium with a new kind of review for specific types of chimera research, including experiments where human stem cells are mixed with nonhuman vertebrate embryos and for studies that introduce human cells into the brains of mammals – except rodents, which will be exempt from extra review.

As the UK’s predominant predicament demonstrated, currently it is difficult to predict how and where human cells will populate in another species – when cells are added at the embryonic or very early fetal stages of life. This predicament was recently characterised as the problem of ‘off-target’ humanised tissues in non-human animals.¹⁶ Currently, animal embryos with human cells are only allowed to develop for a period of twenty-eight days – four weeks – in the USA. As we explained above, animal embryos fall under a separate legal and regulatory structure from human embryos, which traditionally have been allowed to develop for fourteen days, though this number is subject to increasing debate (see McMillan, Chapter 37 in this volume).¹⁷ In practice, this means that assessments of human contributions to an animal embryo are restricted to counting human cells in an animal embryo. Current published research puts the human contribution to the host animal embryo at 0.01–.1.¹⁸ This is primarily because a chimeric embryo is only allowed to gestate for twenty-eight days.

In 2017, privately funded researchers in the US published findings from the first human–pig embryos. While labs have previously created human–animal chimeras, such as mice transplanted with human cancer cells or immune systems or even brain cells, this new experiment was unique because the researchers placed human stem cells — which can grow to become any of the different types of cells in the human body — into animal embryos at their earliest stages of life. Broadly, the making of these human–pig chimeras included collecting pig zygotes (eggs), that were then fertilised in vitro to become blastocysts – a progressive phase in embryonic development. Human induced pluripotent stem cells were then pipetted into the developing pig embryo that had been genetically modified. That embryo was then put into a female pig and left to develop for twenty-eight days. After twenty-eight days the animal was sacrificed, and the entire reproductive tract of the animal removed and studied to see where the human cells developed and grew in the embryo.

This study, and others like it, raised ethical concerns relating to ‘off-target’ humanised tissue with concern for an animal’s central nervous system (brain) and reproductive capacities. In the below excerpt, the study leader explains how these concerns of ‘off-target’ humanisation can be handled in the development of human-pig chimeric embryos:

… we must pay special attention to three types – nerves, sperm and eggs – because humanizing these tissues in animals could give rise to creatures that no one wants to create … We can forestall that problem by deleting the genetic program for neural development from all human iPSCs before we inject them. Then, even if human stem cells managed to migrate to the embryonic niche responsible for growing the brain, they would be unable to develop further. The only neurons that could grow would be 100 percent pig.¹⁹

Scientists are developing a variety of techniques to ensure ‘on target’ organ complementation so that a fully human organ can be grown inside an animal, and to avoid any ‘off-target’ problems that could potentially confer human qualities to the non-human experimental animal.

Possible ethical breaches relating to human research subjects and chimeras have been intensely discussed by scholars; however, until recently, concerns over animal welfare have largely taken a back seat in the regulatory and ethical debates over interspecies chimera. When we turn from the regulation of stem cells to the regulation of the organism – or animal – a new set of concerns open. The overwhelming emphasis on avoiding risky humanisation by measuring and counting the number of human cells in a non-human animal can obfuscate the crucial discussion about how animal welfare staff members might monitor changes in behaviour and attributes of experimental chimeric animals. For example, bioethicist Insoo Hyun²⁰ has argued that people tend to assume the presence of human cells in an animal’s brain might enhance it above its typical species functioning. This ‘anthropocentric arrogance’ is, he points out, completely unfounded.²¹ Why, he asks ‘should we assume that the presence of human neural matter in an otherwise nonhuman brain will end up improving the animal’s moral and cognitive status?’²² The much more likely outcome, he suggests, of neurological chimerism is not a cognitive humanisation of the animal but ‘rather an increased chance of animal suffering and acute biological dysfunction and disequilibrium, if our experience with transgenic animals can be a guide’.²³

Animal care and use committees are less interested in cell counts and more interested in whether potential ‘human contributions’ may cause unnecessary pain and distress in an animal. Further, the question of how ‘human contributions’ might be measured in the behaviour of non-human animals is difficult and requires expert knowledge related to the species in question. If highly integrated chimeras are allowed to develop, the role of animal husbandry staff will be crucial in assessing and monitoring the behaviours and states of experimental animals – thus, animal behaviour and animal welfare knowledge may be a significant emerging component of measuring ‘humanisation’ in health research regulation.

36.5 Shifting Regulatory Boundaries between Cells, Human Subjects and Experimental Animals

As a domain of science that is continually reinventing and reconceiving the human body and its potentials, the futures of stem cell science and its regulation is not easy to predict or assess. However, it is in this context of ambiguity and change that we situate our discussion. First, theoretically and conceptually, chimera-based research has given rise to new living entities, from ‘animals containing human material’ to ‘human contributions to other animals’ that challenge assumed regulatory boundaries, rights, and protections provided for human subjects in contemporary societies. By tracing out how the categories human and animal are enacted in health research regulation we have shown that interspecies chimera requires a double-move on the part of regulators and researchers: animals must be kept animals, and humans must be kept humans. From this vantage point, we can see that interspecies chimera are not so marginal to health research regulation. The regulatory deliberations they elicit require re-examining the most basic and foundational structures of contemporary biomedical research – both human subjects research regulation, and animal care and welfare.

In health research regulation, animals are often defined in law; however, what constitutes or defines a human subject is generally not written down in law or legislation. What constitutes the human is, almost always, taken for granted or tacit regulatory knowledge. The national snapshots we examined here encompass Euro-American political and cultural contexts where regulatory containers, such as the human research subject, are shown to be potentially variable – or at least, drawn into question. For example, deliberations in the USA over what constitutes a ‘human contribution’ to another animal brings to light how the human subject is not a universal given, but a legal and regulatory designation that has the potential to be made and remade. Scientists, policy-makers and regulators approach the category human and animal differently across cellular and organismal levels, showing that these categories do not precede health research regulation but are actively co-produced within it.

Second, on the technical front, our review of current scientific practice shows how life scientists increasingly work according to the consensus that life is a continuum where species differences do not travel all the way down to the level of cells and tissues, thus destabilising assumed species differences and raising new questions about cell integration and containment across species. Third, politically, we are witnessing increasing agitation around both human and animal rights, in a context where bioscience is taking a significant role in the public sphere by not only informing debates about what life is, but also what life should be for.²⁴

The stem cell techniques we have discussed above were first developed not with human materials but with animal. While dilemmas over the humanisation of other animals may appear to be new, these technical possibilities only exist because of previous animal research, such as the creation of mice–rat chimeras. For example, rat embryonic stem cells were injected into a mouse blastocyst carrying a mutation that blocked the pancreas development of a mouse, resulting in mice with a pancreas entirely composed of rat cells. These rat–mouse chimeras developed into adult animals with a normal functional pancreas, demonstrating that xenogeneic organ complementation is achievable.²⁵ Recent media coverage of the first human-–pig interspecies chimera can conceal from view these longer and less discussed histories of biological research. To come to grips with the regulatory dilemmas elicited by interspecies chimera then, we must be attentive to biomedical research itself and the many kinds of living organisms used to advance scientific knowledge and to develop therapeutic applications for human health problems.

As we have shown, the USA established new private committees where members must assess whether an experiment might give ‘human contributions’ to experimental animals. Whereas governance in the UK clearly defines and names new legal and regulatory categories such as ‘human admixed embryo’ or ‘animals containing human material’. In contrast, the phrasing ‘human contributions’ in the USA is suggestive of more of a spectrum rather than new legal and regulatory containers for boundary-crossing biological objects, such as in the UK. Chimeric organisms embody new articulations about the plasticity of biology and the recognition that assumed species differences do not travel all the way down to the molecular level. Consequently, explicit deliberations for regulation and governing procedures are also pushed and pulled in new directions. This remodelling of boundaries in biological practice and state governance has consequences for humans and animals alike.

36.6 Conclusion: Realigning Human and Animal Vulnerabilities

With the advent of new and sophisticated forms of human and animal integration for the study of disease, drug development and generation of human organs for transplants, keeping the human separate from the animal, in regulation, becomes increasingly difficult. The disruptions posed by interspecies chimeras give rise to growing conundrums as disparate regulatory actors try to accommodate chimeric entities within existing health research regulation structures that enact a clear division between the human/animal opposition.

In Europe and North America, the regulation of therapeutically oriented biomedicine has historically been split into two vast and abstracted categories: human and animal. Numerous legal and regulatory processes work to disentangle human material, bodies and donors from organisms and parts categorised as animal. Regulators and policymakers thus find themselves in a tricky situation needing to sustain the regulatory and legal estrangement between humans and other animals, while facilitating basic and applied research on human health – such as the kind described above – that relies on the incorporation of human and animal material in new biological entities.

Our explorations above suggest that health research regulation will need to be sufficiently reflexive on the limits of boundaries that reify the foundational human/animal division and be flexible enough to allow a re-consideration of classificatory tools and instruments to measure the extent and consequences of prospective interspecies chimera research. If human/animal chimeras provide to be an efficient route to engineering human organs, as opposed to genetically modified pigs or organoids,²⁶ then the humanisation of experimental animals will likely develop further. An ethical and effective health research regulation system will need to be simultaneously reactive and protective of both human and animal vulnerabilities at stake.

In practice, this implies that regulatory efforts could be directed at fostering and maintaining dynamic collaborative relationships between regulatory actors that often work separately, such as stem cell research oversight, human subjects and animal care and use committees. Establishing efficient communicative pathways across disparate regulatory authorities and institutional bodies will demand a mutual disposition to consider and incorporate divergent and emerging concerns. The collaborative relationships should also be invested in the development of novel regulatory tools capable of addressing the present and coming challenges raised both at the level of the cell and at the level of the organism by interspecies research. This means going beyond the existing instruments to measure ‘human contributions’ at the cellular level to monitor ‘on target’ human organ generation as well as ‘off-target’ proliferation of human tissue in experimental animals. Collaboration between regulatory actors that have traditionally operated separately would also need to integrate the knowledge and expertise from animal behaviour and welfare professionals, such as animal husbandry staff.

A learning health research regulation system that operationalises the multi-level collaborative relationships across regulatory actors complemented by the introduction of animal care experts would be better prepared to engage in the disruptions that interspecies chimera research poses to existing regulatory mechanisms, actors, relations and tools. The direction and increased traction of stem cell biotechnologies clearly signposts that the development and growth of human health applications of interspecies chimera research requires a gradual intensification of entanglements between animals and humans. Health research regulation will thus need to reflect on the ethical and practical consequences for experimental animals’ and human research subjects’ vulnerabilities and address the shifting boundary between experimental animals and human subjects in biomedicine to make room for the new life forms in the making.

37 When Is Human? Rethinking the Fourteen-Day Rule

Catriona McMillan

37.1 Introduction

The processual, rapidly changing nature of the early stages of human life has provided recurring challenges for the way in which we legally justify the use of embryos in vitro for reproduction and research. When the latter was regulated under the Human Fertilisation and Embryology Act 1990 (as amended) (‘the HFE Act’), not only did regulators attempt to navigate what we should or should not do at the margins of human life, but they also tried to navigate the various thresholds that occur in embryonic and research processes. In doing so, the response of law-makers was to provide clear-cut boundaries, the most well-known of these being the fourteen-day rule.¹

This chapter offers an examination of this rule as a contemporary example of an existing mechanism in health research that is being pushed to its scientific limits. This steadfast legal boundary, faced by a relatively novel challenge,² requires reflection on appropriate regulatory responses to embryo research, including the revisitation of ethical concerns, and an examination of the acceptability of carrying out research on embryos for longer than fourteen days. The discussion below does not challenge the fourteen-day rule, or research and reproductive practices in vitro more generally per se, but rather explores the ways in which law could engage with embryonic (and legal) processes through attention to thresholds (as a key facet of these processes). This framing has the potential to justify extension, but not without proper public deliberation, and sound scientific and ethical basis. The deliberation and revisitation – not necessarily the revision – of the law is the key part to this liminal analysis.

To begin, this chapter gives an overview of how the fourteen-day rule came into fruition, before going on to summarise the research, published in early 2017, that has given rise to new discussions about the appropriateness of the rule, twenty-seven years after it first came into force. Thereafter, the rest of the chapter builds on the theme of ‘processes’ from Part I of this volume, and asks, briefly: what might we gain from thinking beyond boundaries in this context? Moreover, what might doing so add to contemporary ethical, legal and scientific discourse about research on human embryos? I argue that recognising the inherent link between processes and the regulation of the margins of human life, enables us to ask more nuanced questions about what we want for future frameworks, for example, ‘when is human?’,³ one that legal discussion often shies away from. Instead I will argue that viewing regulation of embryo research as an instance of both processual regulation and regulating for process has the potential to disrupt existing regulatory paradigms in embryo research, and enable us to think about how we can, or perhaps whether we should, implement lasting frameworks in this field.

37.2 Behind the Fourteen-Day Rule: The Warnock Report, and a ‘Special Status’

The fourteen-day time limit on embryo research is of global significance. It is one of the most internationally agreed rules in reproductive science thus far,⁴ with countries such as the UK, the USA, Australia, Japan, Canada, the Netherlands and India all upholding the rule in their own frameworks for embryo research⁵ The catalysts for the implementation of the rule into many of these public policies are often accredited to two key reports:⁶ the US Report on embryo research of the Ethics Advisory Board to the Department of Health, Education and Welfare,⁷ and the UK report of the Warnock Committee of Inquiry into Human Fertilisation and Embryology.⁸ This chapter will focus on the latter.

In 1984, the Warnock Committee published the Report of the Committee of Inquiry into Human Fertilisation and Embryology, also known as ‘the Warnock Report’. This deliberative, interdisciplinary process was a keystone to law-making in this area in the UK. As a direct result of these deliberations, the use and production of embryos in vitro is governed by the HFE Act. This Act, which stands fast over thirty years later, brought legal and scientific practice out of uncertainty – due to the lack of a statutory framework for IVF and research pre-1990 – to a new state of being where embryos can be used, legally, for reproductive and research purposes under certain specified circumstances.

The Warnock Report was quite explicit that it was not going to tackle questions of the meaning of human ‘life’ or of ‘personhood’. Instead, it articulated its remit as ‘how it is right to treat the human embryo’.⁹ The Report examined the arguments for and against the use of human embryos for research. Here, the Committee noted the plethora of views on the embryo’s status, evidenced by the submissions received prior to the Report. They discussed each position in turn, before concluding that while the embryo deserves some protection in law, this protection should not be absolute. Notably, the source of this protection is not entirely clear from the Report. It cited the state of law at the time, which afforded some protection to the embryo, but not absolute protection.¹⁰ Nonetheless, one can glean from their recommendations that this protection is sourced – at least in part – by virtue of embryos membership of the human species.

It is important to note that the Warnock Report did not explicitly answer the question of ‘when does life begin to matter morally?’, but rather considered the viewpoints submitted and ‘provide[d] the human embryo with a special status without actually defining that moral status’.¹¹ Thus, in the HFE Act’s first iteration,¹² not only did regulators attempt to navigate what we should or should not do at the margins of human life, but also the rapidly changing nature of those margins. The regulatory response to this has been to provide clear-cut boundaries surrounding what researchers can and cannot do, in reference to embryos in vitro, the most well known of these being the subject of this chapter, the fourteen-day rule, as contained in s3(4) of the HFE Act. The rule reads as follows:

1. 3. Prohibitions in connection with embryos.

   1. (1) No person shall bring about the creation of an embryo except in pursuance of a licence.

      …

   2. (3) A licence cannot authorise—

      1. (a) keeping or using an embryo after the appearance of the primitive streak,

      2. (b) placing an embryo in any animal

      3. (c) keeping or using an embryo in any circumstances in which regulations prohibit its keeping or use,

   3. (4) For the purposes of subsection (3)(a) above, the primitive streak is to be taken to have appeared in an embryo not later than the end of the period of 14 days beginning with the day on which the process of creating the embryo began, not counting any time during which the embryo is stored. [emphasis added]

This section of the HFE Act also introduced the subsection that famously embodies the Warnock Report’s abovementioned ‘compromise position’, which affords human embryos some ‘respect’. It placed a clear boundary to the process of research: it is illegal to carry out research on an embryo beyond fourteen days, or after the primitive streak has formed, whichever occurs sooner. After that, the embryo cannot be used for any other purpose, and must be disposed of. In other words, as discussed further below, if decidedly an embryo created and/or used for research purposes, it may only ever be destroyed at the end of the research process.

Why fourteen days? The rule is based upon the evidence given to the Warnock Committee that it is around this stage that the ‘primitive streak’ tends to develop. It is also the approximate stage at which the embryonic cells can no longer split and thus produce twins or triplets, etc.¹³ It was thus felt that this stage was morally significant, reinforced by the belief that this was the earliest known moment when the central nervous system was likely to have formed. This stage also marks the beginning of gastrulation, the process by which cell differentiation occurs. At the time, it was seen as a way to avoid, with absolute certainty, anyone carrying out research on those in the early stages of human life with any level of sentience or ability to experience pain.^{14, 15} In this way, as a reflection of the Committee’s recommendations, embryos in vitro are often described as having a ‘special status’ in law; not that of one with personhood – attained at birth – but still protected in some sense. This in and of itself may be described as recognising the processual; it is implicit in the Committee’s efforts to replicate a somewhat gradualist approach that recognises embryonic development – and any ‘significant’ markers within it.

While many would agree that a ‘special status’ in law results from this rule, the word ‘status’ – or any other of similar meaning – does not appear at all in the HFE Act (as amended) in reference to the embryo. It is clear, however, that the recommendations of the Warnock Report, made in light of its proposal for a ‘special status’, are reflected in this steadfast piece of legislation to this day, operationalised through provisions such as the fourteen-day rule.

Despite their contentions (see above), the Committee can arguably be understood as implicitly having answered the question of ‘when life begins to matter’, by allowing research up to a certain stage in development.¹⁶ In other words, they prescribed that ‘as the embryo develops, it should receive greater legal protection due to its increasing moral value and potential’.¹⁷ This policy, known as the gradualist approach, is somewhat in line with the Abortion Act 1967, which affords more protection to the fetus as it reaches later stages in development¹⁸ (although in other ways these laws do not align at all). In doing so, while not explicit, the Act captures the processual aspect of embryonic/fetal development.

It seems that the human embryo hovers between several normative legal categories, i.e. ‘subject’ and ‘object’.¹⁹ While it clearly does not have a legally articulated ‘status’ under the HFE Act, it occupies a legal – and for some people, moral – threshold between all of these aforementioned categories, which we can see by the special status it has been given in law. Thus, while there is no explicit legal status of the embryo, what we have, legally, is still something. By virtue of giving the embryo in vitro legal recognition, with attached allowances and limits, it arguably has a status of sorts. Bearing in mind that the law adopted most of the Warnock Report’s recommendations, its status may indeed be described as ‘special’, as the Report prescribed. It is ‘not nothing’,²⁰ yet not a ‘person’: it is the quintessential liminal entity, betwixt and between. From what we have seen, its status remains ‘special’, the meaning of which is unclear except that it is afforded ‘respect’ of sorts. Beyond that, we can glean little regarding what the extent or nature of this from domestic law is. It does not have an explicit legal status, but, as some argue, it may have one implicitly.²¹ This begs the question: what does it mean to have ‘legal status’? Is it enough to be protected by law? Recognised by law? Entitled to something through law? These are the types of questions we may want to consider for any amendments, or new frameworks, going forward.

37.3 Beyond fourteen days?

As we have seen, the fourteen-day rule is the key legal embodiment of the embryo’s decidedly ‘special status’ and the application of a legal and moral boundary at the earliest stages of human life. Yet throughout the incremental amendments to the HFE Act (e.g. the HFE Act 2008), there has been little enthusiasm among policy-makers for revisiting, let alone revising, the rule. For some, the latter did not necessarily matter, as, for twenty-seven years, this limit was ‘largely theoretical’;²² up until very recently, no researcher had been able to culture an embryo up to this limit.

In early 2016, for the first time, research published in Nature²³ and Nature Cell Biology²⁴ reported the successful culturing of embryos in vitro for thirteen days. With the possibility of finding out more about the early stages of human life beyond this two-week stage, calls have been made to revisit the fourteen-day rule.²⁵ Why? It appears that some valuable scientific knowledge may lie beyond this bright legal line in the sand, within this relatively unknown ‘black box of development’. For example, it would enable the study of gastrulation, which begins when the primitive streak forms (around fourteen days).²⁶

Yet what might all of this mean for compromise, respect, and the resulting ‘special’ legal status of the embryo? If this rule were to change, would the embryo still be ‘special’? Moreover, do we believe this matters? These questions should be addressed if we revisit the rule; it seems that discussions surrounding the fourteen-day rule are part of a broader issue that needs to be addressed. There is a very strong case for public and legal discourse on the meaning and ‘special’ moral status of the embryo in UK law. One question that we may want to revisit is: if we value the recommendations of the Warnock Committee (‘special’, ‘respect’, etc.), does it still have resonance with us today? For example, one might ask: even if the ‘special’ status has a justifiable source, how can we ‘value’ it in practice except by avoiding harm? It is arguable that the ‘special respect’ apparently afforded in law seems meaningless in practical terms.²⁷

It is difficult to enable a ‘middle position’ between protection and destruction in practice; we either allow embryos to be destroyed, or we do not. For some, the embryo’s ‘special status’ is thus, arguably, purely rhetorical; it does not oblige us to ‘act or refrain in any way’.²⁸ However, compromise is arguably more nuanced than allowing or disallowing destruction of embryos. Time is an essential component of legal boundaries within the 1990 Act (as amended). Either one can research the embryo for less than fourteen days, or one cannot. This means that we cannot research the embryo for any longer period of time, for example thirty days or sixty days. Rhetoric aside, the concept of the ‘special status’ is still very powerful and has acted as a tool to ‘stop us in our tracks’ with regards to research on embryos. It is arguably a precautionary position, which reflects that we as a society afford a degree of moral and legal value to embryos, and thus the special status caveat requires us to proceed cautiously, to reflect, to justify fully, to revisit, to revise and to continue to monitor as we progress scientifically. If we did not value the embryo at all, then we would have carte blanche to treat it however we wished. If that were the case, research at 30 or 60 or 180 days would not present a problem. Therefore, the embryo’s special status need not be an all-or-nothing brake on research, nor a green light position. It thus means something in that sense, however (admittedly) meaningless. The ‘special status’, then, is – in a way – not a ‘compromise’, but what I would term a legal and ethical comfort blanket.²⁹

This is not to criticise the language used by the Committee, however. The Warnock Committee’s emphasis on ‘compromise’ was made in the name of moral pluralism. In other words, it emerged as the Warnock Committee’s way of navigating the uncertainty/ambivalence surrounding how to treat embryos in vitro, legally. This is not to say that poles of opinion between which this compromise was set have changed. The rule, a reflection of this ‘compromise’ was, in many ways, a new boundary and threshold akin to its historical counterparts (such as quickening). Yet if we decide that it is worth considering this boundary and whether we want to change it, how can – or should – we rethink it? If we believe that the process embryonic and scientific development is a relevant factor in determining an appropriate regulatory response, what might further focus on these key points in transition bring to contemporary debates?

The rest of this chapter argues that if we want to think beyond the boundary of the fourteen-day rule, one way of framing discussion is by recognising the inherent link between processes and regulating of the margins of human life. When considering frameworks, the latter enables us to ask questions surrounding not only ‘what is human?’, but ‘when is human’? Asking ‘when?’ – used here as an example – allows us to re-focus on not only embryonic development as process, but questions surrounding we need to place different boundaries within that process.

37.4 Revisiting the Rule

Throughout the regulation of the early stages of human life, law has changed to reflect the changing boundaries of what is ‘certain’ and ‘uncertain’.³⁰ Where new uncertainties arise,³¹ some old ones will always remain.³² We have thus moved, in some ways, from one type of uncertainty to another when it comes to embryo regulation, and this is because what we are dealing with is an inherently processual entity, that in and of itself has not changed. In other words, the complex and relatively uncertain nature of embryos, the stage of human life at which development occurs at its fastest pace, continues to cause widespread ambivalence³³ on how it is right to treat it.

When considering whether to alter the rule, multiple thresholds – such as the threshold for humanity – within embryonic and research processes come into consideration.³⁴ As we have seen, there was a strong nod to the gradualist approach in the thought behind the fourteen-day rule – an approach that recognises that human development is a process. The Report did not set out to answer ‘when is human?’, but pointed to an important stage in the process of becoming human, when limiting research to fourteen days. As we have seen, the Warnock Committee used ethical deliberation and evidence available at the time to suggest this boundary beyond which research could not pass. A key part of this deliberation, although not referred to in terms of ‘thresholds’ per se, were particular (perceived) biological thresholds, such as the threshold for experiencing pain – which they associated with the start of the primitive streak – and thresholds for being able to cause harm therein. One might say that if the fourteen-day rule is a limit or a boundary, then something that we may want to consider – if we deem it appropriate to revisit this rule – is the presence of thresholds therein, and the importance that we want to attribute to those thresholds.³⁵ While being in a liminal state or space connotes occupying a threshold, a key part of the liminal process is moving out of the liminal state, i.e. over or beyond that threshold. Thinking about liminal beings such as embryos in such terms highlights the presence of these boundaries and their potential for impermanence, especially in a legal context. For example, if we decide it is appropriate to consider extending the rule, these types of moral boundaries (i.e. harm, or sentience, etc.) may very well come into play again, for example if a ‘twenty-eight-day rule’ is proposed. Further, talks around extending it have already given rise to discussion surrounding another kind of boundary: would extending the rule be of adequate benefit to science? Some argue that there is much more that we can learn from extending the limit.³⁶ Yet, what amount of benefit is enough benefit to justify extension? Therein lies the threshold, a threshold of the reasonable prospect of sufficient scientific ‘benefit’.

If the crossing of thresholds within biological and research processes have been implicitly important for us thus far, what might we learn from this? With regards to the legal processes that we already have, attention to process – and therefore thresholds – highlight the following:³⁷

• Once an embryo created in vitro passes the threshold of being determinedly a ‘research’ embryo, it cannot (legally) be led back past the said threshold, and it can only come out this process as something to be disposed of after being utilised.

• In contrast, there are lots of thresholds that embryos are led through for a ‘reproductive’ path, for example: (non)selection after PGD, implantation, freezing and unfreezing, implantation, gestation etc. – indeed, this includes the possibility of crossing the threshold from ‘reproduction’ to ‘research’ if, say, PGD tests suggest non-suitability for reproduction.

• When the progenitors of embryos are making decisions regarding what to do with their surplus embryos, they may cross various thresholds themselves, e.g to donate or not, either for research or to others seeking to reproduce.

Regarding the last point, persons/actors are, of course, an essential part of these processes and this should not be lost in any renewed discussions surrounding the rule. Considerations for the actors around embryos can be different for each threshold, i.e. we may consider different sets of factors depending on which threshold any particular embryo is at. For example, at the third threshold above, many factors come into consideration for donors, including their attitudes towards research and their feelings about and towards their surplus embryos and their future (non)uses.³⁸ Moreover, each threshold is coupled with clear boundaries, be it the fourteen-day rule for ‘research’ embryos, or rules around what may/may not be implanted for ‘reproductive’ embryos.

Thresholds – or indeed boundaries – are not necessarily ‘bad’ here, per this work’s analysis. Indeed, both moral and legal thresholds are of crucial importance. Rather, I suggest that we should be alive to their presence and their place among the broader network – of actors, or silos, etc. – in order to ask questions about the conditions we want in order to cross those thresholds.³⁹ As I have argued elsewhere: ‘Considering the multiplicity, variability, and in many ways, subjectivity of these thresholds might enable us to regulate in a more flexible and context-specific way that allows us to recognise the multiplicity of processes occurring within the framework of the [HFE Act].’⁴⁰ Attention to process cannot necessarily say how any revisitation might turn out.

It is important to revisit the intellectual basis for any law, but especially so in a field where technology and science advance so rapidly. If we do not, we cannot ask important questions in light of new information, for example: what or when is the threshold for ‘humanity’? Or if indeed we want ‘when is human’ to factor into how we regulate embryos, as it has done in the past. Discussing questions such as these would be a great disturbance to the policy norm of the past twenty-seven years or so, which have stayed away from these types of questions. But I argue that within disturbance, we can find resolution through proper legal and ethical deliberation, and public dialogue. In other words, it would not be beneficial of us to shy away from disruptions for fear of practice being shut down, as these disturbances present us with a chance to feed experiences and lessons of those involved in – and benefit from – research back into regulatory, research, and – eventually – treatment practice.

37.5 Conclusion

While the time limit on embryo research has undoubtedly been a success on many fronts, if it is to remain ‘effective and relevant’,⁴¹ we must be open to revisiting it, with proper deliberation and public involvement, with openness and transparency.⁴² Not only that, but when doing so, we must not shy away from asking difficult questions if law is to adapt to contemporary research.

The latter part of this chapter has argued that a focus on process has the potential to disrupt existing regulatory paradigms in embryo research and enable us to think about how we can, or perhaps whether we should, implement lasting frameworks in this field. The above did not challenge the pros and cons of the fourteen-day rule, or research and reproductive practices in vitro more generally per se, but rather briefly explored one of the ways which law could engage with embryonic (and legal) processes through attention to thresholds (as a key facet of these processes).

Overall, while the framing offered here has the potential to justify an extension of the fourteen-day rule, it cannot be done without proper public deliberation. This deliberation would need to be subject to sound scientific objections, and perhaps most importantly, subject to scrutiny regarding prevalent moral concern over pain and sentience.⁴³ This analysis challenges us to deliberate, and revisit – not necessarily the revise – the law surrounding this longstanding rule. Responsive regulation, per the title of this section of the volume, need not respond to every ‘shiny new thing’ (e.g. advances in research, such as those discussed in this chapter), but be reflexive (and reflective) so that HRR does not become stagnant.

38 A Perfect Storm Non-evidence-Based Medicine in the Fertility Clinic

Emily Jackson

38.1 Introduction

In vitro fertilisation (IVF) did not start with the birth of Louise Brown on 25 July 1978. Nine years earlier, Robert Edwards and others had reported the first in vitro fertilisation of human eggs,¹ and before Joy Brown’s treatment worked, 282 other women had undergone 457 unsuccessful IVF cycles.² None of these cycles was part of a randomised controlled trial (RCT), however. After decades of clinical use, it is now widely accepted that IVF is a safe and effective fertility treatment, but it is worth noting that there have been studies that have suggested that the live birth rate among couples who use IVF after a year of failing to conceive naturally is not, in fact, any higher than the live birth rate among those who simply carry on having unprotected sexual intercourse for another year.³

Reproductive medicine is not limited to the relatively simple practice of fertilising an egg in vitro, and then transferring one or two embryos to the woman’s uterus. Rather, there are now multiple additional interventions that are intended to improve the success rates of IVF. Culturing embryos to the blastocyst stage before transfer, for example, appears to have increased success rates because by the five-day stage, it is easier to tell whether the embryo is developing normally.⁴

Whenever a new practice or technique is introduced in the fertility clinic, in an ideal world, it would have been preceded by a sufficiently statistically powered RCT that demonstrated its safety and efficacy. In practice, large-scale RCTs are the exception rather than the norm in reproductive medicine.⁵ There have been some large trials, and meta-analyses of smaller trials, but it would not be unreasonable to describe treatment for infertility as one of the least evidence-based branches of medicine.⁶

In addition to an absence of evidence, another important feature of reproductive medicine is patients’ willingness to ‘try anything’. Inadequate NHS funding means that most fertility treatment is provided in the private sector, with patients paying ‘out of pocket’ for every aspect of their IVF cycle, from the initial consultation to scans, drugs and an ever-increasing list of ‘add-on’ services, such as assisted hatching; preimplantation genetic screening; endometrial scratch; time-lapse imaging; embryo glue and reproductive immunology. The combination of a poor evidence base, commercialisation and patients’ enthusiasm for anything that might improve their chance of success, results in a ‘perfect storm’ in which dubious and sometimes positively harmful treatments are routinely both under-researched and oversold.

Added to this, although clinics must have a licence from the Human Fertilisation and Embryology Authority (HFEA) before they can offer IVF, the HFEA does not have the power to license, or refuse to license the use of add-on treatments. Its powers are limited to ensuring that, before a patient receives treatment in a licensed centre, patients are provided with ‘such relevant information as is proper’, and that ‘the individual under whose supervision the activities authorised by a licence are carried on’ (referred to as the Person Responsible), ensures that ‘suitable practices’ are used in the clinic.⁷ In this chapter, I will argue that, although giving patients information about the inadequacy of the evidence-base behind add-on treatments is important and necessary, this should not be regarded as a mechanism through which their inappropriate use can be controlled. Instead, it may be necessary for the HFEA to categorise non-evidence-based and potentially harmful treatments as ‘unsuitable’ practices, which should not be provided at all, rather than as treatments that simply need to be accompanied by a health warning.

38.2 A Perfect Storm?

In order to be appropriately statistically powered, it has been estimated that a trial of a new fertility intervention should recruit at least 2610 women.⁸ Trials of this size are exceptional, however, and it is much more common for smaller statistically underpowered trials to be carried out. Nor does meta-analysis of these smaller trials necessarily offer a solution, in part because their outcomes are not always reported consistently, and the meta-analyses themselves may not be sufficiently large to overcome the limitations of the smaller studies.⁹

Fertility patients are often keen to ‘try something new’, even if it has not been proven to be safe and effective in a large-scale RCT.¹⁰ IVF patients are often in a hurry. Most people take their fertility for granted, and after years of trying to prevent conception, they assume that conception will happen soon after they stop using contraception. By the time a woman realises that she may need medical assistance in order to conceive, her plan to start a family will already have been delayed for a year or more. At the same time, women’s age-related fertility decline means that they are often acutely aware of their need to start treatment as soon as possible.

Although, in theory, fertility treatment is available within the NHS, it is certainly not available to everyone who needs it. The National Institute for Health and Care Excellence’s (NICE) 2013 clinical guideline recommended that the NHS should fund three full cycles of IVF (i.e. a fresh cycle followed by further cycles using the frozen embryos) for women under 40 years old, and one full cycle for women aged 40–42, who must additionally not have received IVF treatment before and not have low ovarian reserve.¹¹ Implementation of this NICE guideline is not mandatory, however, and in 2018 it was reported that only 13 per cent of Clinical Commissioning Groups (CCGs) provide three full cycles of IVF to eligible women; 60 per cent offer one NHS-funded cycle – most of which fund only one fresh cycle – and 4 per cent provide no cycles at all.¹²

The majority of IVF cycles in the UK are self-funded,¹³ and although the average cycle costs around £3350,¹⁴ costs of more than £5000 per cycle are not uncommon. As well as simply wanting to have a baby, IVF patients are therefore commonly also under considerable financial pressure to ensure that each IVF cycle has the best possible chance of success. In these circumstances, it is not surprising that patients are keen to do whatever they can to increase the odds that a single cycle of IVF will lead to a pregnancy and birth.

One of the principal obstacles to making single embryo transfer the norm was that, for many patients, the birth of twins was regarded as an ideal outcome.¹⁵ Most patients want to have more than one child, so if one cycle of treatment could create a two-child family, this appeared to be a ‘buy one, get one free’ bargain. In order to persuade women of the merits of the ‘one at a time’ approach, it was not enough to tell them about the risks of multiple pregnancy and multiple birth, both for them and their offspring. Many women are prepared to undergo considerable risks in pursuit of a much-wanted family. Instead, the ‘one at a time’ campaign emphasised the fact that a properly implemented ‘elective single embryo transfer’ policy did not reduce birth rates, and tried to persuade NHS funders that a full cycle of IVF was not just one embryo transfer, but that it should include the subsequent frozen embryo transfers.¹⁶

Not only are patients understandably keen to try anything that might improve their chance of success, they are also paying for these extra services out of pocket. As consumers, we are used to paying more to upgrade to a better service, so this additional expense can appear to be a ‘sign of quality’.¹⁷ Rather than putting patients off, charging them several hundred pounds for endometrial scratch and assisted hatching may make these additional services appear even more desirable. New techniques often generate extensive media coverage, leading patients actively to seek out clinics that offer the new treatment.¹⁸ Clinics that offer the non-evidence-based new intervention are therefore able to say that they are simply responding to patient demand.

As well as the appeal of expensive high-tech interventions, patients are also attracted to simple and apparently plausible explanations for IVF failure. If an IVF cycle does not lead to a pregnancy because the embryo fails to attach to the lining of the woman’s uterus, it is easy to understand why patients might be persuaded of the benefits of ‘embryo glue’, in order to increase adhesion rates. Alternative therapists have also flourished in this market: acupuncturists are said to be able to ‘remove blocks to conception’; and hypnotherapists treat women ‘with a subconscious fear of pregnancy’.¹⁹ In practice, however, the evidence indicates not only that complementary and alternative medicine (CAM) does not work, but that live birth rates are lower for patients who use CAM services.²⁰

Perhaps the most egregious example of an apparently simple and plausible explanation for IVF failure being used to market a non-evidence-based and potentially harmful intervention is reproductive immunology. The existence of the unfortunately named ‘natural killer cells’ in the uterus has helped to persuade patients that these cells might – unless identified by expensive tests and suppressed by expensive medications – ‘attack’ the embryo and prevent it from implanting. News stories with headlines like ‘The Killer Cells That Robbed Me of Four Babies’²¹ and ‘My Body Tried to Kill My Baby’²² suggest a very direct link between NK cells and IVF failure. The idea that the embryo is a genetically ‘foreign’ body that the woman’s uterine cells will attack, unless their immune response is suppressed, sounds plausible,²³ and as Datta et al. point out, ‘couples seeking a reason for IVF failure find the rationale of immune rejection very appealing’. It has no basis in fact, however.²⁴

There is no evidence that natural killer cells have any role in causing miscarriage; rather despite their name, they may simply help to regulate the formation of the placenta. As Moffett and Shreeve explain, regardless of this lack of evidence, ‘a large industry has grown up to treat women deemed to have excessively potent uterine “killers”’.²⁵ In addition to the absence of RCTs establishing that reproductive immunology increases success rates, the medicines used – which include intravenous immunoglobulins, TNF-α inhibitors, granulocyte-colony stimulating factor, lymphocyte immune therapy, leukaemia inhibitory factor, peripheral blood mononuclear cells, intralipids, glucocorticoids, vitamin D supplementation and steroids – may pose a risk of significant harm to women.²⁶

The lack of evidence for reproductive immunology, and the existence of significant risks, has been known for some time. In 2005, Rai and others described reproductive immunology as ‘pseudo-science’, pointing out that ‘Not only is there no evidence base for these interventions, which are potentially associated with significant morbidity, the rationale for their use may be false’.²⁷ The HFEA’s most recent advice to patients is also clear and unequivocal:

There is no convincing evidence that a woman’s immune system will fail to accept an embryo due to differences in their genetic codes. In fact, scientists now know that during pregnancy the mother’s immune system works with the embryo to support its development. Not only will reproductive immunology treatments not improve your chances of getting pregnant, there are risks attached to these treatments, some of which are very serious.²⁸

Despite this, patients continue to be persuaded by a simple, albeit false, explanation for IVF failure, and by ‘evidence’ from fertility clinics that is better described as anecdote. The Zita West fertility clinic blog, for example, contains accounts from satisfied ex-patients with headlines like ‘I Was Born to Be a Mum and Couldn’t Have Done It Without Reproductive Immunology’.²⁹ It is not uncommon for clinics’ websites to ‘speak of “dreams” and “miracles”, rather than RCTs³⁰ Spencer and others analysed 74 fertility centre websites, and found 276 claims of benefit relating to 41 different fertility interventions, but with only 16 published references to support these, of which only five were high level systematic reviews.³¹

From the point of view of a for-profit company selling fertility services, why bother to do expensive large-scale RCTs, when it is possible to sell a new therapy to patients in the absence of such trials? If patients do not care about the lack of evidence, and are happy to rely upon a clinician’s anecdotal report that X therapy has had some success in their clinic, the clinic has no incentive to carry out trials, which may indicate that X therapy does not increase live birth rates.

A free market in goods and services relies upon consumers choosing not to buy useless products. If a mobile phone company were to produce a high-tech new phone that does not work, then after an initial flurry of interest in a shiny new product, its failings would become apparent and the market for it would disappear. Because there can be no guarantee that any cycle of IVF will lead to the birth of a baby, and almost every cycle is more likely to fail than it is to work, it is much harder for consumers of fertility services to tell whether an add-on service is worth purchasing. Rather than relying on individual patients ‘voting with their feet’ in order to crowd out useless interventions, it may be important instead for an expert regulator to choose for them.

38.3 Regulating Add-On Services

There are three mechanisms through which the provision of add-on services in the fertility clinic is regulated. First, if it involves the use of a medicinal product, that product must have a product licence from the European Medicines Agency or the Medicines and Healthcare products Regulatory Agency. The Human Medicines Regulations 2012 specify that, before a new medicine can receive a product licence, the licensing authority must be satisfied that ‘the applicant has established the therapeutic efficacy of the product to which the application relates’, and ‘the positive therapeutic effects of the product outweigh the risks to the health of patients or of the public associated with the product’.³² In short, it must be established that the product works for the indication for which the product licence is sought, and that its benefits outweigh its risks.

In practice, however, the use of medicines as add-ons to fertility treatment generally involves their ‘off-label’ use. Reproductive immunology, for example, may involve the use of steroids, anticoagulants and monoclonal antibodies. Although efficacy and a positive risk–benefit profile may exist for these medicines’ licensed use, this is not the same as establishing that they work or are safe for their off-label use in the fertility clinic. There are comparatively few controls over doctors’ freedom to prescribe drugs off-label, even though, when there has not been any assessment of the safety or efficacy of a drug’s off-label use, it may pose an unknown and unjustifiable risk of harm to patients.

The General Medical Council (GMC) has issued guidance to doctors on the off-label prescription of medicines which states that:

You should usually prescribe licensed medicines in accordance with the terms of their licence. However, you may prescribe unlicensed medicines where, on the basis of an assessment of the individual patient, you conclude, for medical reasons, that it is necessary to do so to meet the specific needs of the patient (my emphasis).³³

The guidance goes on to set out when prescribing unlicensed medicines could be said to be ‘necessary’:

1. a. There is no suitably licensed medicine that will meet the patient’s need …

2. b. Or where a suitably licensed medicine that would meet the patient’s need is not available. This may arise where, for example, there is a temporary shortage in supply; or

3. c. The prescribing forms part of a properly approved research project.³⁴

Doctors must also be satisfied that be ‘there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy’, and patients must be given sufficient information to allow them to make an informed decision.³⁵ It is possible that a doctor who prescribed medications off-label could have his fitness to practise called into account, although, in practice, it seems likely that clinicians will simply maintain that these medicines ‘meet the patient’s need’, and that they have sufficient experience within their own clinic to ‘demonstrate safety and efficacy’.

Second, before receiving treatment services in a licensed centre, section 13(6) of the Human Fertilisation and Embryology Act 1990 specifies that patients must be provided with ‘such relevant information as is proper’, and that they must give consent in writing.³⁶ Although add-ons are not licensable treatments, it could be said that the clinician’s statutory duty to give patients clear and accurate information extends to the whole course of treatment they receive in the clinic, not just to the treatment for which an HFEA licence is necessary. Indeed, the HFEA’s Code of Practice specifies that:

Before treatment is offered, the centre should give the woman seeking treatment and her partner, if applicable, information about … fertility treatments available, including any treatment add ons which may be offered and the evidence supporting their use; any information should explain that treatment add ons refers to the technologies and treatments listed on the treatment add ons page of the HFEA website.³⁷

The Code of Practice also requires centres to give patients ‘a personalised costed treatment plan’, which should ‘detail the main elements of the treatment proposed – including investigations and tests – the cost of that treatment and any possible changes to the plan, including their cost implications’.³⁸ Before offering patient an add-on treatment, clinics should therefore be open and honest with patients about the risks, benefits and costs of the intervention.

In practice, however, patients will not necessarily be put off by underpowered trial data, especially when more optimistic anecdotal accounts of success are readily available online. In order to try to counter the circulation of misinformation about treatment add-ons, the HFEA has recently instituted a ‘traffic light’ system that is intended to provide clear and unambiguous advice to patients. At the time of writing, no add-on is green. Most are either amber (that is, ‘there is a small or conflicting body of evidence, which means further research is still required and the technique cannot be recommended for routine use’), or red (that is, ‘there is no evidence to show that it is effective and safe’). The HFEA further recommends that patients who want more detailed information ‘may want to contact a clinic to discuss this further with a specialist’.³⁹

It is, however, unsatisfactory to rely upon informed patient choice as a mechanism to control the over-selling of unproven add-on treatments. The fertility industry has ‘a pronounced predilection for over-diagnosis, over-use and over-treatment’, and the widespread adoption of a ‘right to try’ philosophy in practice translates into clinics profiting from the sale of unproven treatments.⁴⁰ For example, the HFEA gives intrauterine culture – in which newly fertilised eggs are placed in a device inside the woman’s womb – an amber rating, and informs prospective patients:

There’s currently no evidence to show that intrauterine culture improves birth rates and is safe. This is something you may wish to consider if you are offered intrauterine culture at an additional cost.

It could instead be argued that the fact that a treatment is expensive and is not known to be either safe or effective is not merely something that patient should ‘consider’ when deciding whether to purchase it, but rather is a reason not to make that treatment available outside of a clinical trial.

Third, while the HFEA does not license add-on services, Persons Responsible are under a duty to ensure that only ‘suitable practices are used in the course of the activities’.⁴¹ If the HFEA were to decide that those add-on services that it ranks as red are not suitable practices, then clinicians should not use them in the clinic. It has not (yet) done this.

38.4 Won’t Patients Go Elsewhere?

Given patients’ interest in add-on services, many of the 70 per cent of UK clinics that offer at least one of these treatments claim to be responding to patient choice.⁴² Reputable clinicians maintain that if they cease to offer add-on services, patients are likely to go instead to clinics that do provide these treatments, either within the UK – where a clinic does not need a licence from the HFEA if it is only providing add-on services – or overseas.⁴³ If patients are going to pay for these treatments elsewhere anyway, then, so the argument goes, it is better to provide them in safe, hygienic, regulated clinics, rather than abandoning patients to the wild west of unregulated fertility services.

The easiest way to see why this argument should be dismissed is to imagine that it is being made about a different sort of non-evidence based treatment, such as stem cell therapies for the treatment of spinal injury. Although stem cell therapies hold very great promise for the treatment of a wide range of conditions, most are still at the experimental stage. That does not stop unregulated clinics overseas from marketing stem cell therapies for the treatment of a wide range of conditions, and as a miraculous cure for ageing.⁴⁴

If a UK doctor was to justify injecting stem cells into a patient’s spinal column, on the grounds that, if he did not do so, the patient would be likely to travel to China for unproven stem cell treatment, it could be predicted that the GMC might be likely to investigate his fitness to practise. The argument that, if he did not offer unproven and unsafe treatment in the UK, patients might choose to undergo the same unsafe treatment in a foreign clinic, would be likely to be given short shrift.

38.5 Conclusion

It is important to remember that add-on treatments are not simply a waste of patients’ money, though they are often that as well. Many add-on treatments are also risky. Despite this, patients are enthusiastic purchasers of additional services for which there is little or no good evidence. In such circumstances, where the lack of robust clinical trial data does not appear to dent patients’ willingness to buy add-on treatments, there is little ‘bottom-up’ incentive to carry out large-scale RCTs.

The HFEA’s information for patients is clear and authoritative, but it is not the only information that patients will see before deciding whether to pay for additional treatment services. Patients embarking upon fertility treatment also seek out information from other patients and from a wide variety of online sources. It is increasingly common for ill-informed ‘discourses of hope’ about unproven treatments to circulate in blogs and in Facebook groups, coexisting and competing with evidence-based information from scientists and regulators.⁴⁵ Fertility patients often report doing their own ‘research’ before embarking on treatment, and this generally means gathering material online, from sources where the quality and accuracy of information may be distinctly variable.⁴⁶

In this perfect storm, it is unreasonable to expect patients to be able to protect themselves from exploitation through the application of the principle of caveat emptor.⁴⁷ On the contrary, what is needed instead is a clear message from the regulator that the routine selling of unproven treatments should not just prompt patients to ask additional questions, but that these treatments should not be sold in the first place. Of course, it is important that reproductive medicine does not stand still, and that new interventions to improve the chance of success are developed. But these should first be tried in the clinic as part of an adequately powered clinical trial. Trial participants must be properly informed that the treatment is still at the experimental stage, and they should not be charged to participate. The GMC also has a role to play in investigating the fitness to practise of doctors who routinely sell, for profit, treatments that are known to be risky and ineffective. As Moffett and Sheeve put it: ‘it is surely no longer acceptable for licensed medical practitioners to continue to administer and profit from potentially unsafe and unproven treatments, based on belief and not scientific rationale’.⁴⁸

39 Medical Devices Regulation New Concepts and Perspectives Needed

Shawn H. E. Harmon

39.1 Introduction

This section of the Handbook explores how technological innovations and/or social changes create disturbances within regulatory approaches. This chapter considers how innovations represent disturbances with which regulatory frameworks must cope, focusing on innovations that can be characterised as ‘enhancing’. Human enhancement can no longer be dismissed as something with which serious regulatory frameworks need not engage. Enhancing pursuits increasingly occupy the very centre of human experience and ‘being’; one can observe widespread student use of cognitively enhancing stimulants, the increasing prevalence of implanted technologies, and great swathes of people absently navigating the physical while engrossed in the digital.

Given the diversity of activities and technologies implicated, the rise and mores of the ‘maker movement’,¹ and the capacity of traditional – commercial – health research entities to locate innovation activities to jurisdictions with desirable regulation, it is impossible to point to a single regulatory framework implicated by enhancement research and innovation. Candidates include those governing human tissue use and pharmaceuticals, but could also include those governing intellectual property, data use, or consumer product liability. The medical devices framework, one might think, should offer a good example of a regime that engages directly and usefully with the concepts implicated by enhancement and the socio-technical changes wrought by enhancing technologies. As such, this chapter focuses on the recently reformed European medical devices regime.

After identifying some enhancements that are available and highlighting what they mean for the person, the chapter introduces two concepts that are deeply implicated by enhancing technologies: ‘identity’ and ‘integrity’. If regulation fails to engage with them, it will remain blind to matters that are profoundly important to those people who are using or relying on these technologies. Their observance in EU Regulation 2017/745 on Medical Devices (MDR),² and EU Regulation 2017/746 on In Vitro Diagnostic Medical Devices (IVDR),³ is examined. It is concluded that they are, unfortunately, too narrowly framed and too innovator driven, and are therefore largely indifferent to these concepts.

39.2 Enhancing Innovations

Since the first use of walking canes, false teeth and spectacles, we have been ‘enhancing’ ourselves for both medical and social purposes, but the so-called technological ‘revolutions’ of late modernity – which have relied on and facilitated innovations in computing, biosciences, materials sciences and more – have prompted changes in the nature and prevalence of the enhancements that we adopt. We now redesign and extend our physical scaffolding, we alter its physiological functioning, we extend the will, and we push the potential capacities of the mind and body by linking the biological with the technological or by embedding the latter into the former.

In the 1960s, Foucault anticipated the erasure of the human being.⁴ We might now understand this erasure to be the rise of the enhanced human, which includes the techno-human hybrid (cyborg).⁵ This ‘posthuman’ thinks of the body as the original prosthesis, so extending or replacing it with other prostheses becomes a continuation of a process that began pre-natally.⁶ Even if one does not subscribe to the posthuman perspective, ‘enhancing’ technologies are commonly applied,⁷ and are becoming more complex and more intrusive, nestling within the body, and performing not only for us, but also on and within us.⁸ Examples include a wide range of smart physiological sensors, cochlear implants, implanted cardiac defibrillators, deep brain stimulators, complex prostheses like retinal and myoelectric prosthetics, mind stimulating/expanding interventions like nootropic drugs, neuro-prosthetics, and consciousness-insinuating constructs like digital avatars, which allow us to build and explore wholly new cyber-environments.

These technologies have many labels, but they all become a part of the person through processes of bodily ‘incorporation’, ‘extension’ or ‘integration’.⁹ Depending on the technology, they allow the individual to generate, store, access and transmit data about the physiological self, or the physical or digital realms they occupy/access, making the individual an integral element of the ‘internet of things’.¹⁰ The resultant ‘enhanced human’ not only has new material characteristics, but also new sentient and sapient capacities (i.e. to experience sensation or to reason and cultivate insight). In all cases, the results are new forms of co-dependent human-technology embodiment. Even more radical high-conscious beings can be envisioned. Examples include genetically designed humans, synthetically constructed biological beings, and artificially intelligent constructs with consciousness and self-awareness.¹¹ The possibility of more radical high-conscious beings raises questions about status that are beyond the scope of this chapter.¹²

39.3 Core Concepts Implicated by the New Human Assemblage

This increasingly complex and commonplace integration of bodies and technologies has given rise to theories of posthumanism and new materialism to which the law remains largely ignorant.¹³ For example, there is a growing understanding of the person as an ‘assemblage’, a variably integrated collection of physiological, technological and virtual elements that are in fluid relation to one another, with some elements becoming prominent in some contexts and others in other contexts, with no one element being definitive of the ‘person’.¹⁴ The person has become protean, with personhood-defining/shaping characteristics that are always shifting, often at the instigation of enhancing technologies. This conditional state – or variable assemblage – with its integration and embodiment of the technological, makes concepts such as autonomy, privacy, integrity, and identity more socially and legally significant than ever before. For reasons of space, I consider just integrity and identity.

Integrity often refers to wholeness or completeness, which has both physical and emotional elements, both of them health-influencing. Having physical integrity is often equated with conformity to the ‘normal’ body. The normativity of this concept has resulted in prosthetic users being viewed as lacking physical integrity.¹⁵ However, there is a growing body of literature suggesting that physical integrity need not impose compliance with the ‘normal’ body.¹⁶ Tied to the state of physical integrity – however we might define it – is the imperative to preserve physical integrity (i.e. to respect the individual and avoid impinging on bodily boundaries), and this implicates emotional/mental integrity. One study uncovered twelve conceptions of integrity, concluding that integrity is supported or undermined by one’s view of oneself, by others with whom one interacts, and by relationships.¹⁷ Ultimately, integrity is a state of physical and emotional/existential wellness, both of which are influenced by internalities and externalities, including one’s relationship with oneself and others. Critical elements of integrity – feelings of wholeness, of being ‘onself’, or of physical security,¹⁸ notions of optimal functioning, interactions with others,¹⁹ and so on – are agitated when technologies are introduced into the body, and there is scope for the law to modulate this agitation, and encourage wellness.

Identity has been described as a mix of ipse and idem²⁰ (see also Postan, Chapter 23 of this volume). Ipse refers to ‘self-identity’, the sense of self of the human person, which is reflexive and influenced by internalities such as values and self-perceptions. It is the point from which the individual sees the world and herself; there is nothing behind or above it, it is just there at the source of one’s will and energy, and it is persistent, continuous through time and space but by no means stable.²¹ Idem refers to ‘sameness identity’, or the objectification of the individual that stems from categorisation. One might hold several idem identities depending on the social, cultural, religious or administrative groups to which one belongs (i.e. the range of public statuses that may be assigned at birth or throughout life, or imposed by others). It expresses the belonging of one to a category, facilitating social integration. Ultimately, identity is both internal and fluid, and external and equally fluid, but also potentially static.²² It can be constructed, chosen or imposed. It can be fragmented and aggregated, and it can be commodified. Both ipse and idem elements will be shaped by enhancing technologies, both mechanical and biological, which have been described as ‘undoing the conventional limits of selfhood and identity’.²³ Empirical research has found that both elements of identity in prosthetic users, for example, are deeply entangled with their devices.²⁴

Of course, neither integrity nor identity are unknown to the law. Criminal law seeks to protect our physical integrity, and it punishes incursions against it. Human rights law erects rights to private and family life, which encompass moral and physical integrity and the preservation of liberty.²⁵ Health law erects rights to physical and mental integrity through mechanisms such as consent, best interests and least restrictive means.²⁶ Law is also a key external shaper of identity, creating groups based on factors such as developmental status (i.e. rights of fetuses to legal standing and protection),²⁷ sexual orientation (i.e. right to marriage or work benefits)²⁸ and gender (i.e. right to gender identity recognition).²⁹ It also defines ‘civil identity’, a common condition for access to basic services.³⁰ And notions of identity have been judicially noticed in relation to new technologies: in Rose v Secretary of State for Health,³¹ which concerned disclosure of information about artificial insemination, the court found that information about biological identity went to the heart of identity and the make-up of the person, and that identity included details of origins and opportunity to understand them, physical and social identity, and also psychological integrity.

Unfortunately, these two increasingly important concepts have not been well-handled by the law. They are subject to very different interpretations depending on one’s view of human rights as negative or positive.³² Severe limits have been placed on the law being used to enable or impose those conditions that facilitate individuals living lives of meaning and becoming who they are (or wish to be). Narrow views as to what counts as a life of worth have resulted in limitations being placed on what individuals can do to become who they wish to be, with decision-makers often blind to the choices actually available (e.g. consider discourses around a ‘good death’ and medical assistance in dying). Thus, at present, neither integrity nor identity are consistently articulated or enabled by law. This could be the result of their multifaceted nature, or of the negative approach adopted in protecting them,³³ or of the indirectness of the law’s interest in them.³⁴ The question of their treatment in health research regulation remains, and it is to this that we now turn.

39.4 Core Concepts and Medical Device Regulation

The market authorisation framework for medical devices is an example of health research regulation that shapes the nature, application and integrative characteristics of many enhancing technologies. Thus, it is profoundly linked to practices aimed at expanding and diversifying the human assemblage, and so it might be expected to appreciate, define and/or facilitate the concepts identified above as being critical to the person. In Europe, the development and market authorisation of medical devices is governed by the previously noted MDR and IVDR, both of which came into force in May 2017, but which will not be fully implemented until May 2020 and May 2022 respectively.³⁵

As will be clear from other chapters, the framing of regulatory frameworks is critical. Framing signals the regime’s subject and objective; it shapes how its instruments articulate problems, craft solutions and measure success. It has been observed that the identification, definition and control of ‘objects’ is a common aim of regulatory instruments; specific objects are chosen because they represent an opportunity for commerce, a hazard to human health, or a boon – or danger – to social architecture.³⁶ Certain fields focus on certain objects, with the result that silos of regulation emerge, each defined by its existence-justifying object, which might be data, devices, drugs, tissue and embryos, etc., and the activity in relation to that object around which we wish to create boundaries (i.e., production, storage, use).

The MDR and IVDR are shaped by EU imperatives to strengthen the common market and promote innovation and economic growth, and are thus framed as commercial instruments.³⁷ Their subject is objects (e.g. medical devices), not people, not health outcomes and not well-being. MDR Article 1 articulates this frame and subject, stating that it lays down rules concerning placing or making available on the market, or putting into service, medical devices for human use in the EU.³⁸ MDR Article 2(1) defines medical device as any instrument, apparatus, appliance, software, implant, reagent, material or other article intended to be used, alone or in combination, for human beings for a range of specified medical purposes (e.g. diagnosis, prevention, monitoring, prediction, prognosis, treatment, alleviation of disease, injury or disability, investigation, replacement or modification of the anatomy, providing information derived from the human body) that does not achieve its principal intended action by pharmacological, immunological, or metabolic means.

The MDR and IVDR construct their objects simultaneously as ‘risk objects’, ‘innovation objects’ and ‘market objects’, highlighting one status or another depending on the context and the authorisation stage reached. All three constructions can be seen in MDR Recital 2 (which is mirrored by IVDR Recitals 1 and 2):

This Regulation aims to ensure the smooth functioning of the internal market as regards medical devices, taking as a base a high level of protection of health for patients and users, and taking into account the … enterprises that are active in this sector. At the same time, this Regulation sets high standards of quality and safety for medical devices in order to meet common safety concerns as regards such products. Both objectives are being pursued simultaneously and are inseparably linked …

They then classify devices on a risk basis, and robust evidence and post-market surveillance is imposed to protect users from malfunction. For example, MDR Recital 59 acknowledges the insufficiency of the old regime, stating that it is necessary to introduce specific classification rules sensitive to the level of invasiveness and potential toxicity of devices that are composed of substances that are absorbed by, or locally dispersed in, the human body; where the device performs its action, where it is introduced or applied, and whether a systemic absorption is involved are all factors going to risk that must be assessed. MDR Recital 63 states that safety and performance requirements must be complied with, and that, for class III and implantable devices, clinical investigations are expected.³⁹ These directions are operationalised in MDR Chapters V (Classification and Conformity Assessments),⁴⁰ and VI (Clinical Evaluation and Clinical Investigations).⁴¹ IVDR Recitals 55 and 61, and Chapters V and VI are substantively similar.

The above framing imposes a substantial fetter on what these instruments are intended to do, or are capable of doing. It serves to largely erase the person and personal experience from their perspective and remit. The recipient of a device is constructed as little more than a consumer who must be protected from the harm of a malfunctioning device. An example of the impoverished position of the person is the Regulations’ treatment of risk. They rely on a narrow understanding of risk, framing it as commercial object safety at various stages of development and roll-out. Other types of risks and harms are marginalised or ignored.⁴² Thus, there is no acknowledgement that their objects – medical devices – will not always be – and will really only briefly be – ‘market objects’. Many devices will become ‘physiological objects’ that are profoundly personal to, and intimate with, the recipient. Indeed, many will cease to be ‘objects’ altogether, becoming instead components of the human assemblage, undermining or facilitating integrity, and exerting pressures on identity. As such, the nature of the risks they pose changes relatively quickly, and more so over time.

Had broader human well-being or flourishing been foregrounded, then greater attention to public interest beyond device safety might have been expected. Had legislators given any consideration to the consequences of these technologies once integrated with the person and becoming a part of that human assemblage, then further conditions for approval might have been expected. Developers might have been asked to present social evidence about the actual need for the device, or the potential social acceptance of the device, or how the device is expected to interact with other major – or common – health or social technologies, systems, or practices. In short, the patient, or the non-patient user, may have featured in the market access assessment.

The one exception to the Regulations’ ignorance of social experience is that relating to post-market surveillance. MDR Recital 74 requires manufacturers to play an active role in the post-market phase by systematically gathering information on experiences with their devices via a comprehensive post-market surveillance system. It is operationalised in Chapter VII.⁴³ However, while these provisions are useful, they fail to acknowledge the now embodied condition of the regulatory object, and the new personal, social, ethical and cultural significance that it holds. In other words, they evince an extremely ‘bounded’ perspective of their objects. Such has been criticised:

The attention of law and regulation on ‘bounded objects’ … should be questioned on at least two counts: first, for the fallacy of attempting to ‘fix’ such regulatory objects, and to divorce them from their source and the potential impact on identity for the subjects themselves; and, second, for the failure to see such objects as also experiencing liminality.⁴⁴

This is pertinent to situations where technologies are integrated into the body, situations which exemplify van Gennep’s pattern of experience: separation from existing order; liminality; re-integration into a new world.⁴⁵ The features of this new world are that the regulatory object (device) becomes embodied and incorporated in multiple ways – physical, functional, psychological and phenomenological.⁴⁶ Both the object (device) and subject (host) are transformed as a result of this incorporation such that the typical subject–object dichotomy entrenched in the law is not appropriate;⁴⁷ the Regulations’ object-characterisations are no longer apropos and their indifference to the subject is potentially unjust given the ‘new world’ that now exists.

This cursory assessment suggests that the Regulations are insufficient and misdirected from the perspective of ensuring that the full public interest is met through the regulated activity. As previously observed, new and emerging technologies can be conceptually, normatively and practically disruptive.⁴⁸ Technologies applied to humans for purposes of integration – treatment or enhancement – are disruptive on all three fronts, particularly once they enter society. Conceptually, they disrupt existing definitions and understandings of the regulatory objects, which are transformed once they form part of the human assemblage. Normatively, they disrupt existing regulatory concepts like risk, which are exposed as being too narrow in light of how these objects might interact with and harm individuals. Practically, they disrupt existing medical practice – blurring the lines between treatment and enhancement – and regulatory practices – troubling the oft-relied-on human/non-human and subject/object dichotomies.

This assessment also suggests that the historical boundaries between, or categories of, ‘devices’ and ‘medicines’, are increasingly untenable because of the types of devices being designed (e.g. implanted mechanical devices and mixed material devices that interact with the physiological, sometimes through the release of medicines). This area of human health research therefore highlights both fault-lines within instruments and empty spaces between them. It might be that the devices and medicines regimes need to be brought together, with a realignment of the regulatory objects and a better understanding of where these objects are destined to operate.

39.5 Conclusions

As the enhanced human becomes more ubiquitous, and the radical posthuman comes into being, narrow or negative views of integrity and identity become ever more attenuated from the technologically shaped lived experience. Moreover, the greater the human/technology integration, the greater the engagement of integrity and identity. Insufficient attention to these concepts in regulatory frames, norms and decisions raises the likelihood that such will undermine rather than support or protect human well-being. Only with clear recognition will the self-creation – the being and becoming – that they underwrite be facilitated through the positive shaping of social conditions.⁴⁹

The MDR and IVDR are directly implicated in encouraging, assessing and rolling out integrative technologies destined for social and clinical uses, but they do not match the technical innovation they manage with sufficient regulatory recognition of the integrity and identity that is engaged. Despite their recent reform, they do not evince a greater regulatory understanding of the common natures and consequences of tissue, organ and technological artifacts, and they therefore do not represent a significantly improved – more holistic and less silo-reliant – regulatory framework.

Had they adopted a broader perspective and value base, they would have taken notice of people as subjects, and crafted a framework that contributed to the development of innovations that are not only safe, but also supportive of – or at least not corrosive to – what people value, including integrity and identity. At base, they would have benefited from:

• a clearer and broader value base;

• an emphasis on decisional principles rather than narrow (technical) objects on which rules are imposed; and

• greater notice of what the devices become once they are through the market-access pipeline.

Ultimately, medical device regulation is an example of health research regulation that operates in an area where innovation has created disturbances, and those disturbances have not been resolved. Though some have been acknowledged – leading to the new regime – the real disturbances have hardly been appreciated.

Afterword What Could a Learning Health Research Regulation System Look Like?

Graeme Laurie

1 Introduction

This final chapter of the Cambridge Handbook of Health Research Regulation revisits the question posed in the Introduction to the volume: What could a Learning Health Research Regulation System look like? The discussion is set against the background of debates about the nature of an effective learning healthcare system,¹ building on the frequently expressed view that any distinction between systems of healthcare and health research should be collapsed or at the very least minimised as far as possible. The analysis draws on many of the contributions in this volume about how health research regulation can be improved, and makes an argument that a framework can be developed around a Learning Health Research Regulation System (LHRRS). Central to this argument is the view that successful implementation of an LHRRS requires full integration of insights from bioethics, law, social sciences and the humanities to complement and support the effective delivery of health and social value from advances in biomedicine, as well as full engagement with those who regulate, are regulated, and are affected by regulation.

2 Lessons from Learning Healthcare Systems and Regulatory Science

The US Institute of Medicine is widely credited for making seminal contributions to debates about the nature of learning healthcare systems, primarily through a series of expert workshops and reports examining the possible contours of such systems. A central feature of the normative frameworks proposed relies on the collapsing – or at least a blurring – of any distinction between objectives in the delivery of healthcare and the objectives of realising value from human health research. The normative ideal has been articulated as follows:

… a system in which advancing science and clinical research would be natural, seamless, and a real-time byproduct of each individual’s care experience; highlighted the need for a clinical data trust that fully, accurately, and seamlessly captures health experience and improves society’s knowledge resource; recognized the dynamic nature of clinical evidence; noted that standards should be tailored to the data sources and circumstances of the individual to whom they are applied; and articulated the need to develop a supporting research infrastructure.²

It is the challenge of developing and delivering a ‘supporting research infrastructure’ that is the core concern of all contributions to this volume. We have stated at the outset that our approach is determinedly normative in tackling what we believe to be the central features of any ecosystem of health research regulation. The structure and content of the sections of this volume reflect our collective belief that the design and delivery of any effective and justifiable system of human health research must place the human at the centre of its endeavours. Also, when seeking to design systems from the bottom-up, so to speak, we contend that this human-centred approach to systems must go beyond patient-centredness and exercises in citizen engagement. In no way is this to suggest that these objectives are unimportant; rather, it is to recognise that these endeavours are only part of the picture and that a commitment to delivering a whole system approach must integrate both these and other elements into any system design.

There is, of course, the fundamental question of where does one begin when attempting system design? Each discipline and field of enquiry will have its own answer. As an illustration, we can consider a further workshop held in 2011 under the auspices of the Institute of Medicine and other bodies; this was a Roundtable on value and science-driven healthcare that sought to ‘apply systems engineering principles in the design of a learning healthcare system, one that embeds real-time learning for continuous improvement in the quality, safety, and efficiency of care, while generating new knowledge and evidence about what works best’.³ Once again, these are manifestly essential elements of any well-designed system, but it is striking that this report makes virtually no mention of the ethical issues at stake. To the extent that ethics are mentioned, this is presented as part of the problem of current fragmentation of systems,⁴ rather than as any part of a systems solution: ‘[e]ach discipline has its own statement of its ethics, and this statement is nowhere unified with another. There is no common, shared description of the ethical center of healthcare that applies to everybody, from a physician to a radiology technician to a manager’.⁵

Furthermore, while the Roundtable was styled as being about value- and science-driven healthcare, it is crucial to ask what is meant by ‘value’ in this context of systems design. Indeed, the Roundtable participants did call for greater enquiry into the terms, but as it was characterised in various presentations and discussions, the term was used variously to refer to:

• - Value to consumers;

• - Value from ‘substantially expanded use of clinical data’;⁶

• - Value in accounting for costs in outcomes and innovation

• - Value in ‘health returned for dollars invested’;⁷

• - Value as something to be measured for inclusion in decision-making processes.⁸

As extensively demonstrated by the chapters in this volume, there is a crucial distinction between ‘value’ seen in these terms and the ‘values’ that underpin any structure or system designed to deliver individual and social benefit through improved health and well-being. This distinction is, accordingly, the focus of the next section of this chapter.

Before this, a further important distinction between healthcare systems and health research systems must be highlighted. As an earlier Institute of Medicine report noted, patient-centred care is of paramount importance in identifying and respecting the preferences, needs and values of patients receiving healthcare.⁹ This position has rightly been endorsed in subsequent learning systems reports.¹⁰ However, for LHRRS, and from a values perspectives, there is arguably a wider range of interests and values at stake in conducting health research and delivering benefits to society.¹¹ This is the principal reason why this volume begins with an account of key concepts in play in human health research (see Section IA), because this provides a solid platform on which to conduct multidisciplinary, multisector discussions about what is important, what is at risk, and what accommodations should be made to take into account the range of interests that are engaged in health research. This is a further reason why, in Section IIA, our contributors engage critically and at length with the private and public dimensions of health research regulation.

From this, two important top-level lessons arise from this volume:

• - There is considerable value in taking a multi- and inter-disciplinary approach to systems design that places bioethics, social sciences and humanities at the centre of discussions because these disciplinary perspectives are crucial to ensuring that the human remains at the focus of human health research; indeed, an aspiration to trans-disciplinary contributions would not be remiss here.

• - There is a need for further and fuller enquiry into ways in which the values underpinning healthcare and health research do, and do not, align, and how these can be mobilised to improve regulatory design.

On this last point, we can look to recent initiatives in Europe and the UK that have as their focus ‘regulatory science’ and we can ask further how the contributions in this volume can add to these debates.

A July 2020 report from the UK advocated for innovation in ‘regulatory science’ as it relates to healthcare in order to complement the nation’s industrial strategy, to enable accelerated routes to market; to increase benefits to public health; to assure greater levels of patient safety; to influence international practice; and to promote investment in the UK (Executive Summary).¹² ‘Regulatory science’ is defined therein as ‘[t]he application of the biological, medical and sociological sciences to enhance the development and regulation of medicines and devices in order to meet the appropriate standards of quality, safety and efficacy’.¹³ The authors prefer this definition among others as a good starting point for further deliberation and action, both for its breadth and inclusiveness as to what should be considered to be in play. The report offers a very full account of the present regulatory landscape in the UK and offers a strong set of recommendations for improvement in four areas: (i) strategic leadership and coordinated support, (ii) enabling innovation, (iii) implementation and evaluation, and (iv) workforce development. However, a striking omission from the report is any direct and explicit mention of how ‘sociological sciences’, let alone bioethical inquiry, can contribute to the delivery of these objectives.

Similarly, in March 2020, the European Medicines Agency (EMA) published its strategy, ‘Regulatory Science to 2025’. The stated aim is ‘to build a more adaptive regulatory system that will encourage innovation in human and veterinary medicine’. For the EMA, regulatory science refers to

the range of scientific disciplines that are applied to the quality, safety and efficacy assessment of medicinal products and that inform regulatory decision-making throughout the lifecycle of a medicine. It encompasses basic and applied biomedical and social sciences and contributes to the development of regulatory standards and tools.¹⁴

As with the UK report, however, there is no more than a cursory mention of the concrete ways in which social sciences and bioethics contribute to these objectives.¹⁵

This returns us to the key questions that frame this Afterword: where is the human in human health research? Also, what would a whole-system approach look like when we begin with the human values at stake and design systems accordingly?

3 From Value to Values

Currently, there is extensive discussion and funding of data-driven innovation, and undoubtedly, there is considerable value in the raw, aggregate, and Big Data themselves. However, given that in biomedicine the data in question predominantly come from citizens in the guise of their personal data emanating from a growing number of areas of their private lives, it is the contention of this Afterword, and indeed the tenor of this entire volume, that it is ethics and values that must drive the regulation that accompanies the data science, and not a science paradigm. As the conclusion to the Introduction of this volume makes clear, public trust is vital to the success of the biomedical endeavour, and any system of regulation of biomedical research must prove itself to be trustworthy. As further demonstrated by various contributions to this volume,¹⁶ a failure to address underlying public values and concerns in health research and wider uses of citizens’ data can result in a net failure to secure social licence and doom the initiatives themselves.¹⁷ This has been re-enforced most recently in February 2020 by an independent report commissioned by Understanding Patient Data and National Health Service (NHS) England that found, among other things, that NHS data sharing should be undertaken by partnerships that are transparent and accountable, and that are governed by a set of shared principles (principles being a main way in which values are captured and translated into starting points for further deliberation and action).¹⁸

Thus, we posit that any learning system for human health research must be values-driven. To reiterate, this explains and justifies the contributions in Section IA of the volume that seek to identify and examine the key values and core concepts that are at stake. Normatively, it would not be helpful or appropriate for this chapter to attempt to suggest or prescribe any particular configuration of values to deliver a justifiable learning system. This depends on myriad social, cultural, economic, institutional and ethical factors within a given country or jurisdiction seeking to implement an effective system for itself. Rather, we suggest that values engagement is required amongst all stakeholders implicated in, and affected by, such a system in its given context, and this is the work done by Section IB of the volume in identifying key actors, including publics, and demonstrating through examples how regulatory tools and concepts have been used to date to regulate human health research. Many of these remain valid and appropriate after years of experiences, albeit that the analysis herein also reveals limitations and caveats to existing approaches, for example with consent¹⁹ and proportionality,²⁰ while also demonstrating the means by which institutions can show trustworthiness²¹ and/or conduct meaningful engagement with publics and other stakeholders.²²

But to understand what it means for a system to be truly effective in self-reflection and learning, we can borrow once again from discussion in the learning healthcare context. As Foley and Fairmichael have pointed out: ‘Learning Healthcare Systems can take many forms, but each follows a similar cycle of assembling, analysing and interpreting data, followed by feeding it back into practice and creating a change’.²³ The same is true for a HRRLS. Thus, a learning system is one that consists not only of processes designed to deliver particular outcomes, but also one that has feedback loops²⁴ and processes of capturing evidence of what has worked less well.²⁵ Self-evidently from the above discussion, ‘data’ in this context will include data and information about values failure²⁶ or incidents or points in the regulatory processes where sight has been lost of the original values that underpin the entire enterprise.

From the perspective of regulatory theory and practice, this issue relates to the ever-present issue of sequencing: when, and at what point in a series of processes should certain actions or instruments be engaged to promote key regulatory objectives?²⁷ In regulatory theory, sequencing is often concerned with escalation of regulatory intervention, that is, invoking a particular regulatory response when (and only when) other regulatory responses fail. However, this need not be the case. Early and sequential feedback loops in the design and delivery of a system can help to prevent wider systemic failure at a later point in time. This is especially the case if ethical sensitivities to core values remain logically prior to techno-scientific considerations of risk management and are part of risk-benefit analysis.²⁸ Indeed, as pointed out by Swierstra and Rip, human agency can make a difference at an early stage of development/innovation, when issues and directions are still unclear, but much less so in later stages when ‘alignments have sedimented’.²⁹

Key among the ethical objectives of any health research system is the need to deliver social value (or at least that prospective research has a reasonable chance of doing so).³⁰ Some of us have argued elsewhere that there is at present an unmet need to appraise social value iteratively throughout the entire research lifecycle,³¹ and this builds on existing arguments to see social value as a dynamic concept. The implications of this for a LHRRS are that the research ecosystem would extend from the research design stage through publication and dissemination of research results, to data storage and sharing of findings and new data for future research. This means that social value is not merely something promissory and illusive that is dangled before a research ethics committee as it pores over a research protocol,³² but that it is potentially generated and transformed multiple times and by a range of actors throughout the entire process of research: from idea to impact. Seen in this way, social value itself becomes a potential metric of success (or failure) of a learning health research system, and opens the possibility that value might emerge at times and in spaces previously unforeseen. Indeed, Section IIB of this volume is replete with examples of the importance of time within good governance and regulation, whether this be about timely research interventions in the face of emergencies,³³ the appropriateness and timing of effective oversight of clinical innovation,³⁴ or the challenge of ‘evidence’ when attempting to regulate traditional and non-conventional medicines.³⁵

As a final crucial point about how an ethical ‘system’ might be constructed with legitimacy and with a view to justice for all, we cannot overlook what Kipnis has called infrastructural vulnerability:

At the structural level, essential political, legal, regulative, institutional, and economic resources may be missing, leaving the subject open to heightened risk. The question for the researcher is, ‘Does the political, organizational, economic, and social context of the research setting possess the integrity and resources needed to manage the study?’

… [c]learly the possibility of infrastructural vulnerability calls for attention to the contexts within which the research will be done.³⁶

Questions of the meanings and implication of vulnerability are addressed early in this volume as a crucial framing for the entire volume.³⁷ It is also clear that this concern is not one for researchers alone. This brings us to the important question of who is implicated in the design and delivery of a LHRSS ecosystem?

4 Who is Implicated in this Ecosystem, and With Which Consequences?

In 2019, Wellcome published its Blueprint for Dynamic Oversight of emerging science and technologies.³⁸ This is aimed determinedly at the UK government, and it is founded on four principles with which few could take exception.

Dynamic oversight can be delivered by reforms underpinned by the following principles:

Inclusive: Public groups need to be involved from an early stage to improve the quality of oversight while making it more relevant and trustworthy. The Government should support regulators to involve public groups from an early stage and to maintain engagement as innovation and its oversight is developed.

Anticipatory: Identifying risks and opportunities early makes it easier to develop a suitable approach to oversight. Emerging technology often develops quickly and oversight must develop with it. UK regulators must be equipped by government to anticipate and monitor emerging science and technologies to develop and iterate an appropriate, proportionate approach.

Innovative. Testing experimental oversight approaches provides government and regulators with evidence of real-world impacts to make oversight better. Achieving this needs good collaboration between regulators, industry, academia and public groups. The UK is beginning to support innovative approaches, but the Government needs to create new incentives for the testing of new oversight approaches.

Proportionate. Oversight should foster the potential benefits of emerging science and technologies at the same time as protecting against harms, by being proportionate to predicted risk. The UK should keep up its strong track record in delivering proportionate oversight. These changes will only be delivered effectively if there is clear leadership and accountability for oversight. This requires the Government to be flexible and decisive in responding to regulatory gaps.

Wellcome, A Blueprint for Dynamic Oversight, (2019)

We can contrast this top-down framework with a bottom-up study conducted by the members of the Liminal Spaces team as part of the project funding this volume. The team undertook a Delphi policy³⁹ study to generate empirical data and a cross-cutting analysis of health research regulation as experienced by stakeholders in the research environment in the United Kingdom. In short, the project found that:

[t]he evidence supports the normative claim that health research regulation should continue to move away from strict, prescriptive rules-based approaches, and towards flexible principle-based regimes⁴⁰ that allow researchers, regulators and publics to coproduce regulatory systems serving core principles.⁴¹

As a concrete illustration of why this is important, we can consider the last criterion listed as part of the Wellcome Dynamic Oversight framing: proportionality. The Delphi study revealed novel insights about how proportionality as a regulatory tool is seen and operationalised in practice. In contrast to the up-front risk management framing offered above, the Delphi findings suggest that proportionality is often treated as an ethical assessment of the values and risks at stake at multiple junctures in the research trajectory. That is, while it can be easy to reduce proportionality to a techno-bureaucratic risk/benefit assessment, this is to miss the point that the search for proportionality is a moral assessment of whether, when, and how to proceed in the face of uncertainty. Furthermore, the realisation that a role for proportionality can arise at multiple junctures in the research ecosystem, including into the phase about data access⁴² and potential feedback of results to research participants, highlights that the range of actors involved in these processes are diverse and often unconnected. For example, Delphi participants frequently stated that reporting of adverse events was a downstream disproportionate activity:

the definitions of adverse events result in vast numbers of daily events being classed as reportable with result that trials gets bogged down in documenting the utter unrelated trivia that are common in patients with some disorders and unrelated to the drug to the neglect of collecting complete and high quality baseline and outcome data on which the reliability of the results depend (25, researcher).⁴³

However, this should be contrasted with the possible identity interests of patients and citizens, which can be impacted by (non)access to biomedical information about them, as argued elsewhere in this volume.⁴⁴ The ethics of what is in play are by no means clear-cut. The implication, then, is that a regulatory tool such as proportionality might have far wider reach and significance than has been previously thought; as part of a LHHRS this not only has consequences for a wider range of actors, but the ethical dimensions and sensitivities that surround their (in)action must be duly accounted for.

Regarding possible means to navigate growing complexity within a research regulation ecosystem, some further valuable ideas emerged from the Delphi study. For example, one participant supported the notion of ‘regulators etc. becoming helpers and guiding processes to make approval more feasible. Whilst having a proportionate outlook’ (27, clinician). Other survey respondents called for ‘networked governance’ whereby, among other things, ‘regulatory agencies in health (broadly understood) would need to engage more with academics and charities, and to look to utilise a broader range of expertise in designing and implementing governance strategies and mechanisms’ (5, researcher).⁴⁵

Manifestly, all of this suggests that a robustly designed LHRRS is a complex beast. In the final part of this section, we offer regulatory stewardship as a means of better navigating this complexity for researchers, sponsors, funders and publics, and of closing feedback loops for all stakeholders.

Regulatory stewardship⁴⁶ has no unitary meaning, but our previous research has demonstrated that examples from the literature nevertheless point to a commonality of views that cast stewardship as being about ‘guiding others with prudence and care across one or more endeavours – without which there is risk of impairment or harm – and with a view to collective betterment’.⁴⁷ More work needs to be done on whether and when this role is already undertaken within research ecosystems by certain key actors who may not see themselves as performing such a task nor receiving credit for it. One of the Liminal Spaces team has argued that ethics review bodies take on this role to a certain extent – empirical evidence from NHS Research Ethics Committees (RECs) in the UK suggests a far more supportive and less combative relationship with researchers than is anecdotally reported.⁴⁸ However, by definition, ethics review bodies can only operate largely at the beginning of the research lifecycle – who is there to assess whether social value was ever actually realised, let alone maximised to the range of potential beneficiaries, including the redressing of social injustices relating to health and even health/wealth generation?

Further empirical research has shown that productive regulation is often only ‘instantiated’ through practice;⁴⁹ that is, it is generated as a by-product of genuine cooperation of regulators and a range of other actors, including researchers, attempting to give effect to regulatory rules or statutory diktats. We suggest, therefore, that there might be a role for regulatory stewardship as part of an LHRRS as a means of giving effect to the multiple dimensions that must interact to give such a system of operating in a genuinely responsive, self-reflexive, and institutionally⁵⁰ auto-didactic way.

5 What Could a Learning Health Research Regulation System Look Like?

In light of the above, we suggest that the following key features are examples of what we might expect to find in an LHRRS system:

• A system that is values-driven, wherein the foundational values of the system reflect those of the range of stakeholders involved;

• A demonstrable commitment to inclusivity and meaningful participation in regulatory design, assessment and reform, particularly from patients and publics;

• Robust mechanisms for evidence gathering for assessment and review of the workings regulatory processes and relevant laws;

• Systems-level interconnectivity to learn lessons across regulatory siloes, perhaps supported by a robust system of regulatory stewardship;

• Clear lines of responsibility and accountability of actors across the entire trajectory of the research enterprise;

• Coordinated efforts to ensure ethical and regulatory reflexivity, that is, processes of self-reference of examination and action, requiring institutions and actors to look back at their own regulatory practices, successes and failures;

• Existence of, and where appropriate closing of, regulatory feedback loops to deliver authentic learning back to the system and to its users;

• Appropriate incentives for actors to contribute to the whole-system approach, whether this be through recognition or reward or by other means, and eschewing a compliance culture that drives a fear of sanction supplanting it with a system that seeks out and celebrates best practice, while not eschewing errors and lessons from failure.⁵¹

• Transparency and demonstrated trustworthiness in the integrity of the regulatory system as a whole;

• Regulatory responsiveness to unanticipated events (particularly those that are high risk both as to probability and as to magnitude of impact). The COVID-19 pandemic is one such example – the clamour for a vaccines puts existing systems of regulation and protection under considerable strain, not least for the truncated timeframe for results that is now expected. Values failure in the system itself is something to be avoided at all cost when such events beset our regulatory systems.

6 Conclusion

As indicated at the outset of this volume, the golden thread that runs through the contributions is the challenge of examining the possible contours of a Learning Health Research Regulation System. This, admittedly ambitious, task cannot be done justice in a single Afterword, and all chapters in this volume must be read alone for their individual merit. Notwithstanding, an attempt has been made here to draw elements together that re-enforce – and at times challenge – other work in the field that is concerned with how systems learn and to suggest possible ways forward for human health research. And, even if the ambition of a fully-integrated learning system is too vaulting, we suggest nonetheless that adopting a Whole System Approach to health research regulation can promote more joined-up, reflective and responsive systems of regulation. By Whole System Approach we mean that regulatory attention should be paid to capturing and sharing evidence across the entire breadth and complexity of health research, not just of what works well and what does not, but principally of identifying where, when, and how human values are engaged across the entire research lifespan. This approach, we contend, holds the strongest prospect of delivering on the twin ambitions of protecting research participants as robustly as possible while promoting the social value from human health research as widely we possible.