Alter-Standardizing Clinical Trials: The Gold Standard in the Crossfire

ABSTRACT

The international landscape of medical research is in the midst of a process of diversification and change. The randomized controlled trial (RCT), long considered the global gold standard for clinical research, has become increasingly contested and is partly replaced by alternative methodologies, standards and forms of evidence. The contours of mainstream medical research are changing as a result. Regulatory paradigms and standards are, literally, being rewritten, at a global level. The evidence-based medicine (EBM) hierarchy of evidence is redefined. This special issue explores these developments through the concept of ‘alter-standardization’. The term refers to the processes, controversies and negotiations through which multiphase RCTs and the EBM system are challenged and gradually superseded by alternative methodological and regulatory forms and standards. This special issue examines the conceptual, practical and theoretical implications of these changes, and the ways in which these transformations influence the situation and possibilities of patients, knowledge producers, physicians, large pharmaceutical corporations, smaller biotech companies, as well as regulatory bodies, civil societal organizations and national health care systems. The articles in this special issue make use of comparative and historical perspectives that focus on scientific, social, economic and regulatory developments in the European Union, China, India, Japan, Argentina, the UK and the USA. They show that the alter-standardizing of clinical trials arises in a pluralistic way, that is driven by a variety of often conflicting factors, developments and expectations. These changes reflect a broad transformation in the culture and politics of biomedicine today, with implications for the ways in which new medicinal products, devices, procedures and technologies are developed, approved for clinical use, sold to consumers, and licensed by health care systems.

KEYWORDS:

• Clinical trials
• evidence-based medicine
• evidence hierarchy
• regulation of medical research
• alter-standardization

Background: The Global Distribution of Clinical Trials

Demands that the practice of medicine is founded on trustworthy, scientific evidence date back more than three centuries into the early Scientific Revolution and the Enlightenment (Djulbegovic and Guyatt, 2017). Calls for reliable treatments have also been raised in many other medical traditions throughout history (Selin and Shapiro, 2006). However, what counts as dependable evidence has been a site of ongoing contestation. As Science and Technology Studies (STS) have shown, the emergence of new forms of evidence, clinical methodologies and regulations is not only a function of developments in the medical sciences, but also the result of the changing sociocultural, economic and political relationships under which medical research and its regulation takes place (Unschuld, 2003; Abraham et al., 2003; Keating and Cambrosio, 2011).

In the second half of the twentieth century the multi-site, double-blinded, randomized controlled trial (RCT) emerged as the methodological ‘gold standard’ for the development and approval of new medicines, medical devices and medical technologies (Timmermans and Berg, 2003). Driven by the growth of the pharmaceutical industry and the global expansion of drug research (Cooper and Waldby, 2014; Rajan, 2017), the use of multi-phase RCTs has become a mandatory requirement for clinical validation, which is enforced by drug regulatory authorities across the world (Petryna, 2009). In the late 1990s, with the rise of the evidence-based medicine (EBM) movement, the RCT was placed at the top of an evidence-hierarchy, purportedly generating a higher quality of evidence than any other type of clinical study (Djulbegovic and Guyatt, 2017).

The growing significance of EBM principles and the adoption of RCT methodology in international pharmaceutical drug trials, have given rise to a massive standardization project in medicine research, with global dimensions (Mykhalovskiy and Weir, 2004; Petryna, 2009; Timmermans and Epstein, 2010). This is exemplified by the forging of international best practice standards and the creation of an internationally harmonized regulatory environment (Van Zwanenberg et al., 2011). The use of RCTs as a global gold standard has reshaped clinical research practices worldwide and influenced the progression of medical specialties such as oncology and immunology (Keating and Cambrosio, 2003, 2011). Regulatory harmonization has also led to increased cross-border trade in pharmaceuticals and has enabled the commercialization of new drugs to a wider global market (Van Zwanenberg et al., 2011).

RCTs and Global Inequalities

The operation of the international clinical trial industry is in important respects based on the strategic use of differences in wealth, health care and labor expenses (Petryna, 2009; Sleeboom-Faulkner and Patra, 2011; Cooper and Waldby, 2014). Rajan (2017) has in this respect argued that regulatory harmonization and the global distribution of RCTs has especially facilitated First World corporate interests. The multinational pharmaceutical industry has initiated forms of global governance that enable profit maximization and the provision of medicines in high-income countries, but often disregard the needs and interests of people in low and middle income countries (Rajan, 2017). For example, many of the drugs tested in these countries will only be sold in wealthy societies or will be available at prices that only few patients can afford (Yang et al., 2018).

Others have stressed that regulatory harmonization and the global dispersion of RCT methodology has also created advantages for countries with emerging and developing economies, such as active participation in international research partnerships, including academic projects, the building of new medical infrastructures and the strengthening of domestic innovation processes (Van Zwanenberg et al., 2011; Wahlberg et al., 2013; Andersen et al., 2019; Sariola and Simpson, 2019).

The gold-standard of biomedical research, RCTs, has been changed or replaced in plural ways. Doctor analysing digital image (Anouchka/iStock/Getty Images), Man walking down hospital corridor (sudok1iStock/Getty Images), Multicolored tablets and capsules (Canonmark/iStock/Getty Images), and People holding posters and banners (Credit: Anouchka/iStock/Getty Images).

Kuo, for example, commenting on the adoption of international clinical trial standards in Taiwan and other East Asian countries states that it is important to be careful when applying notions of hegemonic control and exploitation to the adoption of internationally harmonized research standards in East Asia (Kuo, 2009, 2012). Taiwan, China, South Korea and other societies in this region, as Kuo's research illustrates, have neither become just another market for the global pharmaceutical industry, nor have these countries passively accepted universal standards and industry demands (Kuo, 2009, p. 69). Regulators in China, for example, have for many years prevented the conduct of early phase trials by multinational drug companies (Cooper, 2011; Taylor, 2019). Moreover, in China, Taiwan, Japan, Singapore and South Korea diverging national visions on how clinical trial regulations should be crafted have influenced the ways in which international standards have been interpreted, adopted and re-defined (Kuo, 2012; Sleeboom-Faulkner et al., 2016).

A recently published study by Sariola and Simpson (2019) also counters ideas that local stakeholders in resource poor settings are merely passive or disadvantaged recipients of new techno-scientific rationalities. Based on an ethnography of two international trials in Sri Lanka, these authors show that ‘local researchers were not just reactive in the face of external interests’, but ‘highly active in creating and managing the conditions’ to initiate and enable participation in international clinical research projects (Sariola and Simpson, 2019, p. 55).

These contrasting perspectives are complementary, not contradictory. Each of these studies refers to different aspects of the internationalization of RCTs, and to the ways in which international trials are mapped onto global inequalities of wealth, healthcare and power. Rajan, for instance, discusses Big Pharma sponsored trials in India that involve human subjects often from deprived neighborhoods and social backgrounds. These trials generate international flows of capital and knowledge, but they seem to provide only marginal benefits to the local communities in which these studies take place (Rajan, 2017). Kuo, in turn, explores the views and actions of state administrators who actively (co-)develop regulatory rules, and who see international trials as a chance to attract investments and develop the domestic research sector. This analysis is important, because it challenges accounts of a dichotomous, hierarchical world order, in which regulatory standards are merely imposed top-down from Euro-American contexts to other parts of the world (Kuo, 2012). However, it also ignores the potential for patient exploitation and unequal benefits that international trials can create at the level of local communities. This is illustrated, for example, in a study of Cooper (2011) on medical accidents in the clinical trial industry in China (see also Cooper and Waldby, 2014).

The Alter-Standardization of Clinical Trials: A Missing Perspective

Existing literature in the social sciences on EBM and the adoption of RCT as global gold standard has been concerned in particular with the conceptual basis of EBM (Timmermans and Kolker, 2004; Greenhalgh et al., 2014), its historical origins (Pope, 2003; Gelijns et al., 2005; Bothwell et al., 2016), corresponding changes for clinical research and health care practice (Mykhalovskiy and Weir, 2004; Timmermans and Mauck, 2005; Keating and Cambrosio, 2011), the implications of EBM and RCTs for the organization and governance of medical research (Timmermans and Berg, 2003; Cambrosio et al., 2006; Knaapen, 2014), and their effects on global health (Buekens et al., 2004; Fan and Uretsky, 2017).

RCTs and the harmonized regulatory standards that the global use of RCTs have produced, have been criticized as representing primarily the interests of the pharmaceutical industry (Davis and Abraham, 2013; Stevens, 2018), skyrocketing the costs of medicine research (Pope, 2003; Angell, 2004; Yang et al., 2018), overriding locally evolved clinical practices (Lambert, 2006; Lock and Nguyen, 2018), as undermining the autonomy of medical practitioners and individual medical judgment (Armstrong, 2007; Knaapen, 2014; Stevens, 2018), and as being insensitive to the diversity of cultural values and conceptions that underlie forms of health care practice in divergent parts of the world (Greer et al., 2002; Lock and Nguyen, 2018). Criticism has been expressed too with regard to the methodological underpinnings of RCTs and the credibility of study results (Cartwright, 2007; Bothwell et al., 2016; Deaton and Cartwright, 2018).

A systematic exploration of the alter-standardizing of clinical trials, and the ways in which alter-standardization is manifest in different global sites, networks and newly emerging clinical practices and methodologies, has so far remained absent. With the term ‘alter-standardization’ we refer to the processes, controversies and negotiations through which the role of multiphase RCTs as the global gold standard in medicine research is being challenged and gradually replaced by the development of new types of standards, methodologies and forms of evidence. These transformations, as this special issue shows, produce substantial changes in the culture and politics of biomedical research today, with consequences that are only just coming into existence. In the light of the rise of new scientific and economic center regions in Asia and other world parts, the emergence of novel scenarios of global competition, and the formation of new transnational infrastructures through which alternative standards and forms of research governance are developed and promoted, such an exploration is urgently needed.

The Gold Standard in the Cross-Fire: An Evolving Process

The papers in this special issue show that the adoption of EBM standards and multi-phase RCTs methodology is increasingly contested as a universal standard. Alternative methodologies, standards and forms of evidence are emerging and increasingly accepted as part of mainstream medicine. The EBM hierarchy of evidence is redefined. Opposition and alternate forms have evolved not only in emerging fields of medicine research, where state regulations are still evolving and internationally harmonized regulatory frameworks are not yet in place, but also in established areas of medicine and in pharmaceutical research. Here is an overview of some of the changes that have emerged in recent years:

The Emerging of Big Data Analytics in Medical Research

Big data techniques, which include machine learning and the use of complex, heterogeneous data have evolved as an alternative to the more time-consuming and more expensive RCT (Zhang, 2014; Singh et al., 2018). Data sources comprise biomedical and life style information from electronic health records, routine population statistics and disease surveillance data, research data, genetic and multiomic information, real time data tracking of physiological functions through mobile medical devices, as well as information reported by patients, including narrative data posted on social media or other online platforms (Hogle, 2016; Ristevski and Chen, 2018; Zhang et al., 2018). Big data analytics in medical research uses integrated electronic databases, which include digital health records, data from medical insurance systems, registries for chronic and infectious diseases, biobanks in combination with data from clinical research studies (Zhang, 2014; Wang et al., 2018).

The use of big health data in medical research has steadily increased in recent years. Reports on the opportunities of big health data have been published since the early 2000s. However, since 2015 a growing number of publications present actual empirical findings from the use of big data analytics in medicine (Singh et al., 2018). It is expected that the quantity, sophistication and scale of this research field will grow continuously and progressively replace the use of RCT methodology (Ristevski and Chen, 2018; Singh et al., 2018; Zhang et al., 2018).

The Use of Adaptive Clinical Trial Designs

Adaptive trial designs have started to play an increasingly important role in drug development (Bretz et al., 2009). In contrast to traditional RCTs, that work with fixed study protocols, adaptive trial methodologies involve continual reassessment and allow for the modification of parameters such as dosage, sample size, selection criteria of patients and other factors, as a study progresses (Brennan, 2013; Pallmann et al., 2018). The conventional phase 1, 2 and 3 model of the RCT system is collapsed in favor of ‘a single study that adapts flexibly in real time as knowledge is gained’ (Lang, in Montgomery, 2017, p. 233)¹. As Catherine Montgomery (2017, part of this special issue) shows, adaptive trial designs have become part of mainstream drug development in recent years. This shift is driven by the promise of adaptive trial techniques ‘to fix experiments before they fail’ and to evaluate the clinical potential of candidate treatments faster, which is seen as an opportunity to save costs, time and to recruit fewer patients (Montgomery, 2017, p. 248). For these reasons, the pharmaceutical industry has increasingly adopted adaptive trials (Bothwell et al., 2018). The US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) have recently released guidance documents on adaptive trial designs (FDA, 2016, 2018a, 2018b; EMA, 2017). These documents have enabled drug application sponsors to use adaptive trials for licensing procedures (Bothwell et al., 2018).

The Emergence of Non-Standard Pathways for Market Approval

This is reflected in the introduction of a growing number of regulatory exceptions and exemptions (Faulkner, 2017, this issue). These non-standard pathways for market approval have been designed and implemented by drug regulatory agencies, and serve a variety of purposes. Regulatory exceptions such as the FDA's expanded access program and the EMA's compassionate use program, aim to enable access to drugs that are being tested but that have not yet been approved for market approval. Other non-standard pathways aim to speed up the transition from preclinical research to first-in-human trials, to accelerate the authorization from phase I to II, or from phase II to III trials. Still others, such as the European ‘conditional market approval’ scheme, allow the licensing of a candidate treatment during a later stage of phase III trials, when the collection of data for efficacy and safety has almost been completed.

Regulatory exceptions that aim to speed-up the clinical innovation process have also been issues by drug regulators in India, China, Argentina and other countries (Rosemann et al., 2018, this issue). An example of a regulatory exemption is the EMA's ‘hospital exemption scheme’, which permits the provision of cellular and tissue engineered medicinal products to patients in individual hospitals, under the professional responsibility of a doctor (Ivaskiene et al., 2016). (For a more complete overview of non-standard regulatory pathways in the EU see Faulkner, 2017, this issue; for similar developments in the USA, China, India and Argentina see: Rosemann et al., 2018, this issue). These non-standard pathways allow to speed-up the clinical research and licensing process of new medical interventions, which reduces clinical development costs and provides faster access to potentially helpful treatments.

The Adoption of Alternative, Less Rigorous Forms of Evidence

This is exemplified by the 21st Century Cures Act that was approved in the USA in December 2016. The Cures Act permits the use of a wide range of evidence that was once considered ‘junk science’ (Pitts et al., 2018). This includes observational data, self-reporting of patient experience, and the use of biomarkers (for example, a reduction of blood pressure is used as an indicator of a final, desired result) (Hogle and Das, 2017; Kesselheim and Avorn, 2017; Kassirer, 2018). As Jerome Kassirer, the former editor of the New England Journal of Medicine has pointed out:

Biomarkers are not the only loosening of standards. Instead of controlled trials, observational studies, summaries of the literature, and even case reports can be used as evidence of approval; all of these forms of evidence have been shunned, until now, as insufficiently reliable. (Kassirer, 2018, p. 159)

A new source of evidence is also the use of so-called ‘real-world data’, which can be patient-generated data (for example generated in home-use settings or through mobile devices) as well as information from electronic health records, disease registries and other sources (Kesselheim and Avorn, 2017; FDA, 2018c). With the Cures Act the FDA is authorized to use these forms of evidence ‘to support regulatory decision making, including approval of new indications for approved drugs’ (FDA, 2018c).

The development of the Cures Act was heavily supported by the pharmaceutical and device industry, and there have been widespread concerns that the passing of the Act reinforces financial conflicts of interests, increases risks and weakens the integrity of the medical profession (Hogle and Das, 2017; Kassirer, 2018). Others have pointed out, that the evidentiary flexibility that the Cures Act offers is important for the development of medical interventions that do not easily fit into established regulatory categories (Riley, 2018). However, the deregulation of market approval procedure can backfire, for instance by leading to the permission of ineffective or dangerous drugs on the market. This can undermine public trust, but also requires a higher level of vigilance and post-approval surveillance (Kassirer, 2018).

The Introduction of Early-Stage Conditional Approval

In 2013 and 2014 the Japanese government passed two Laws that radically altered Japan's regulatory procedures. The Regenerative Medicine Promotion Act (Government of Japan, 2013) and the Amended Pharmaceutical Affairs Law (Government of Japan, 2014), allow the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) to license new medical interventions for conditional, limited term market approval. While these rules are currently restricted to regenerative medicine products, conditional approval can reportedly be initiated after positive clinical results from as few as ten patients (Cyranoski, 2013), at least if these first-in-human applications demonstrate that the intervention is safe and likely to predict efficacy (Sipp, 2015). Once approved, the PMDA can provide conditional market approval for up to seven years. During this time, clinical efficacy and safety is tested more systematically in post-marketing procedures (Miyata, 2013). Japan's regulatory reform is the most radical break with the EBM and multi-phase trial system so far and is likely to influence regulatory approaches in other countries (Rosemann et al., 2018, this issue). However, the evolving regulatory model in Japan has relaxed the need to demonstrate the clinical utility of candidate products prior to marketing and raises critical methodological and ethical questions with regard to the testing of efficacy and safety (Sipp, 2015).

The Flexible Enforcement of Regulatory Requirements

A development that can especially be observed in low-and-middle income countries, is the flexible implementation of regulatory standards, which allows clinics, medical entrepreneurs and companies to circumvent regulatory rules. This has happened especially in emerging areas of medicine, such as stem cell, immune cell, gene therapy, and other forms of regenerative medicine research (Sleeboom-Faulkner et al., 2016; Rosemann et al., 2018, this issue). In China, India, Mexico and since more recently also in the USA, the provision of experimental for-profit interventions has for many years been tolerated by regulatory agencies, despite the fact that national regulations formally prohibit these applications (McMahon, 2014; Knoepfler and Turner, 2018).

Salter (2008), reflecting on medical innovation processes in China and India, has interpreted the flexible enforcement of regulatory standards as a deliberate strategy to situate these countries in a competitive global market space. From this perspective, the lack of regulation or lenient regulatory enforcement serves as a possible strategy of value extraction and a means to create new, at least temporary, markets (Birch, 2019). Sleeboom-Faulkner et al. (2016) has argued in this regard that for many researchers and companies in emerging economies the adoption of EBM and first world clinical research standards is unaffordable. In this view, the toleration of clinical and business practices that diverge from formal regulatory protocols, creates a space for domestic clinical innovation and profit generation that would be prevented if international clinical research standards would be implemented stringently (Sleeboom-Faulkner et al., 2016; Sleeboom-Faulkner, 2016).

Articles in this Special Issue: Four Analytical Angles

These examples show that the core foundations of clinical research and pre-market approval procedures are undergoing an extensive process of alter-standardization. They also illustrate that the alter-standardizing of clinical trials does not follow a singular or unified pattern.

Changes in research standards, methodologies and regulatory paradigms at a global level evolve in diverse and often contradictory ways. These developments raise important questions. Which actors drive and influence these changes, and on the basis of which interests, values and arguments? Who will benefit and who will suffer potential disadvantages from these choices? How will these changes transform the global landscape of clinical trials? What are the implications of the above transformations for patients, researchers, physicians, hospitals, companies, regulatory authorities, health care systems, funding bodies and society at a wider level? Which unintended consequences are likely to emerge? And how do answers to these questions differ between countries and global regions? The contributors to this special issue address aspects of these questions from comparative and historical perspectives and through case studies and examples from the European Union, the USA, China, India, Japan and Argentina. The articles are discussed in relation to four analytical themes: (i) the emergence of new forms and spaces of alter-standardization; (ii) the conditions under which alternatives to EBM and RCTs emerge; (iii) the implications of alter-standardization and (iv) the geographic dimensions of alter-standardization.

The Emergence of New Forms and Spaces of Alter-Standardization

A first area explores emerging alternatives to the EBM / RCT trial system. This involves a concern with the development and use of new clinical methodologies, forms of evidence as well as processes of regulatory intervention, and the ways in which these developments transform – and are increasingly accepted as part of – mainstream medicine. The special issue looks in particular at the ways in which these changing forms of clinical practice give rise to new types of standards, standardization policies and regulatory arrangements, through which existing hierarchies of evidence are redefined and reclassified. It explores these processes by focusing on the stakeholders, institutions and organizations through which these newly evolving standards and experimental practices are developed and applied. The special issue also examines the formation of new transnational networks through which new standards and regulatory practices are shaped, promoted and distributed across multiple global settings. As other studies have shown, this can either occur through international clinical trial networks, corporate networks or transnational regulatory networks (Davis and Abraham, 2013; Rosemann and Chaisinthop, 2016; Sleeboom-Faulkner et al., 2016; Hauskeller, 2017; Andersen et al., 2019).

The articles in this collection help build a critical understanding of these processes. Catherine Montgomery's paper explores the increasing popularity of adaptive trial designs, and the ways in which these have started to replace multi-phase RCTs in both industry-sponsored research and the public research sector (Montgomery, 2017; this special issue). She asks, how has change at the top of the evidence-based medicine hierarchy become possible, and how has adaptation come to gradually replace standardization in the RCT? Based on a genealogical analysis that traces arguments for and about adaptation in the scientific literature from the 1950s to the present, Montgomery shows that support for adaptive designs was initially based on claims about patient well-being and greater good in the 1960s and 70s, but shifted in the early 2000s to a discourse of efficiency, in which adaptive trials were framed as a way to save the pharmaceutical industry. In the last ten years, with the rise of ever more sophisticated modeling and simulation techniques, the focus has shifted to a discourse of virtualism, through which adaptive trials are portrayed as saving time, costs and future patients. These arguments, Montgomery suggests, have facilitated a move away from standardization as the central logic of clinical trials, towards an acceptance of adaptation, which promises ‘predictable uncertainty’ and the possibility of ‘fixing the future’ as it unfolds.

Alex Faulkner's paper explores the extent to which and forms in which regulatory agencies in the European Union (EU) have started to introduce flexibilities to the standard regulatory pathway for market approval of medicinal products, which involves the mandatory use of multi-phase RCTs (Faulkner 2017; this special issue). Based on a case study of EU regulations for advanced cells and tissue products, he discusses a range of regulatory exceptions and exemptions that allow investigators and research sponsors either to shorten and accelerate the multi-phase RCT process, or – as with the EU ‘hospital exemption scheme’ – to provide access to innovative (but unproven) medical interventions without preceding trials. Faulkner analyses these non-standard pathways through the concepts of ‘gatekeeping’, ‘gatekeeping regimes’ and ‘gateways’ which point to the ways in which regulatory institutions, health technology assessment organizations and the health authorities that purchase new medical services define and control entry – not only to the medical product marketplace, but also to the use of these products in public health care systems. According to Faulkner, the introduction of new regulatory flexibilities is a central means to steer innovation processes in ways that allow to maintain a connection between gatekeeping regimes and effective innovation.

The article of Achim Rosemann, Federico Vasen and Gabriela Bortz is also concerned with processes of regulatory diversification, but at a more global level (Rosemann et al., 2018; this special issue). Their article compares regulatory developments in the field of regenerative medicine in six jurisdictions: Argentina, China, the European Union, India, Japan, and the USA. They are interested in the ways in which regulatory changes in these regions diverge from the conventional model of EBM and the use of RCTs, and which tensions and consequences arise as a result of these transformations at a national and transnational level. In order to shed light on these questions they introduce a heuristic framework that is structured around four pairs of conflicting regulatory choices that underlie the formation of medicine regulation.

Their analysis indicates that, although the EBM model is still influential in regenerative medicine research, it is increasingly contested and partly replaced. Across the six regulatory jurisdictions, the case studies illustrate four dynamics of regulatory diversification: pharmaceutical-oriented models of cellular therapy development, non-standard pathways of market approval, flexible enforcement of regulatory standard and the complete abandonment of the multi-phase trial system. As a result of these changes, key regulatory concepts such as risk, safety, efficacy, evidence, responsibility and accountability acquire new meanings, and medical innovation processes are reshaped in far-reaching and often conflicting ways. Many of the regulatory developments that Faulkner as well as Rosemann, Vasen and Bortz describe in this special issue are not specific to regenerative medicine or cell therapy. As both papers indicate, these changes form part of a wider transformation process that is also reflected in other fields of medical research.

The contribution of Salla Sariola, Roger Jeffery, Amar Jesani and Gerard Porter (Sariola et al., 2018; this special issue) examines the ethical deliberation and action taken by civil societal organisations (CSOs) in India, in response to the increase of transnational clinical trials since the country's adoption of ICH Good Clinical Practice standards and international patent law in 2005. They ask, how academic medical researchers, public health experts and health activists expressed their opposition to how clinical trials were being conducted, and why they intervened and lobbied for a revised regulation in 2013, after the implications of the 2005 changes became gradually visible. A key finding of their research is that Indian CSOs did not challenge the methodology or conduct of multi-phase RCTs itself, but instead criticized the wider social justice implications of these trials. While these organizations strived for a change in national research regulation that would guarantee fairer access to tested medical treatments, better ethical review and more consistent informed consent, they did not contest RCTs as a hegemonic form of knowledge production. According to the authors, many activists and researchers welcomed the conduct of international trials and they shared the central notions regarding RCT methodologies with industry stakeholders.

However, this does not mean that processes of alter-standardization and opposition to the use of multiphase RCTs do not exist in India. For example, India's Central Drugs Standards Organization, which is the country's central drug authority, introduced in 2018 a regulatory exemption for the conduct of ‘academic clinical trials’ (i.e. research studies that do not seek permission of a new drug for marketing). Such trials only require local ethics committee approval and do not need to adopt RCT methodology (George, 2018). Moreover, Indian regulators have announced fast-track procedures for domestic trials, not for multi-national pharma trials, a measure that aims to boost indigenous drug research (Porecha, 2019).

The article by Christine Hauskeller, Nicole Baur and Jean Harrington examines the effects of the transnational harmonization of regulatory standards in the European Union (EU), by focusing on an academia-sponsored multi-country phase III trial that has tested an autologous stem cell intervention for the treatment of acute myocardial infarction (Hauskeller et al., 2017; this special issue). Their findings demonstrate the problems of harmonization, when new clinical standards must be brokered against historically evolved, locally situated institutional conditions and cultural expectations. Many of these challenges are outside of the trial protocol, but they affect clinical routines, increase expenses and create time-consuming organizational and practical problems.

Hauskeller, Baur and Harrington also reveal that EU harmonization of medicine regulation currently disadvantages low-cost clinician-lead trials, compared to industry-sponsored trials. This situation has created obstacles for investigator-initiated clinical trials, and prioritized the clinical development of particular forms of stem cell research over others, without valid medical or scientific justification. This imbalance and the practical challenge of achieving harmonization of academic, low-budget trials, have given rise to demands for alter-standardization and the reconfiguration of regulations to enable a fairer and more effective regulatory regime in EU contexts (Hauskeller et al., 2017; see also Hauskeller, 2018).

The Conditions under Which Alternatives to EBM and RCTs Emerge

A second area of interest concerns the circumstances and conditions under which alternatives to EBM and RCTs (and related laws, guidelines, best practice standards, and professional norms) arise. The special issue explores the clashes in values, interests, expertise, institutional arrangements and historical experiences that underlie these processes. It examines, furthermore, the ways in which these conflicts are informed by competition between different types of practitioners and professional groups, as well as differentiated access to financial, technological and infrastructural resources.

The article of Montgomery explains the move away from standard multi-phase RCTs towards adaptation in two central ways. On the one hand, the growing popularity of adaptive trial design is a story of technological change. The emergence of big data and transformative technologies in ICT have created new systems of analysis and prediction that allow for rapid adjustments of trial protocols, the growing use of virtual simulation and the enrollment of fewer number of patients. On the other hand, due to the possibility to save time and expenses, the usage of adaptive methodologies is widely seen to fix what Montgomery refers to as the ‘broken system’ of drug development, which is characterized by spiraling clinical development costs, too much red tape and a high failure rate of clinical trials. Hence, the pharmaceutical industry has been a key driver behind the shift towards adaptive trial designs. Changes in regulatory frameworks that permit and encourage adaptive methodologies have emerged in line with industry needs and the wish to benefit from a faster and more efficient drug development system.

Faulkner's study of emerging flexibilities in the EU regenerative medicine regulation shows however that industry is not always a decisive factor in influencing regulatory change. In the regenerative medicine sector, involvement of multi-national pharmaceutical and large-scale biotech companies is almost absent, and most of the activities and economic incentives in this area are in hospitals and small companies. The introduction of non-standard regulatory pathways, such as the above-mentioned EU ‘hospital exemption scheme’ serve the interests of these stakeholders, rather than large corporations. Conversely, patient organizations have also played a role in directing recent regulatory developments. As Faulkner points out, regulatory exceptions that provide earlier access to investigative treatments, such as compassionate use or conditional approval programs, can be traced back to the influence of patients, either directly or through advocacy groups.

Sariola and colleagues’ contribution shows that civil society organizations’ activism to change India's regulatory framework for RCTs emerged from a context of structural inequalities, whereby the Indian government was seeking to facilitate an increase in international clinical trials, while ignoring critical ethical and legal safeguards as well as social justice questions about the prevention of patient exploitation and fair access to new drugs in India. The authors emphasize that the CSOs’ actions reflect wider ethical concerns that specifically affect low-income countries. For example, India's adoption of international patent law in 2005 undermined a flourishing generics industry that previously made affordable drugs available to most patients. Advocacy and pressure on the government to change research regulation, from this perspective, is part of a broader struggle against neo-liberal pharmaceutical regimes and the inequalities they produce.

The paper of Hauskeller, Baur and Harrington indicates how the pressure and implications of EU-wide regulatory harmonization in the stem cell field create unintended consequences, additional expenses and organizational challenges that, in turn, trigger opposition and calls for regulatory alternatives. But disagreement with harmonized EU standards, as the article illustrates, has also emerged because EU regulation advantages industry-driven therapeutic solutions that preclude other, more affordable therapeutic options with potentially equal health value.

The essay of Rosemann, Vasen and Bortz reveals insights into the causes that underlie processes of alter-standardization in clinical research by exploring the tensions between different regulatory demands, in particular, the achievement of rapid access to new medical interventions vs. the systematic testing of efficacy and safety, the development of affordable medicines vs. the facilitation of corporate profits, the realization of international integration and access to global markets vs. the advancement of domestic innovation opportunities, as well as demands for state led forms of regulatory controls vs. de-regulation and scientific self-regulation. The development of new regulatory options requires strategic compromises between these conflicting demands, which result from complex negotiation processes between stakeholders that promote different visions of the future and bioeconomy-based development pathways.

The Implications of Alter-Standardization

A third area of interest concerns the implications of the changes in clinical and regulatory standards and practices that this volume describes. The special issue investigates the consequences and tensions that emerge from these transformations, and their effects on patients, corporations, clinical researchers, regulatory bodies and national governments. It examines who benefits from these changes, who suffers potential disadvantages, and also what unintended consequences are likely to emerge.

Montgomery argues that the shift to adaptive trials represents an evolution in medicine from a holistic conception of patients, towards a more disembodied, virtual patient, whose physiological and biochemical responses can be understood and managed computationally. While this development lessens the number of trial participants, it reduces patients to a set of data points where the index of value is information, and not in the first instance care. Patients, Montgomery claims, are thought of increasingly in terms of their probabilistic potential, and not in terms of their actual needs, desires and feelings. But the adoption of adaptive trial methodology also generates new regulatory challenges. While adaptation – with its potential to save costs and time – revitalizes the pharmaceutical industry, the conventional separation of trials into phases left space for regulators to reassess knowledge, risks, and whether a trial should be continued. The abandoning of this gap by the use of a seamless, adaptive design, Montgomery suggests, means that time for reflection is replaced by the constant updating of a trial's success narrative.

Faulkner, in his analysis of non-standard regulatory pathways in the EU, states that the proliferation of regulatory flexibilities should not lead to an over-estimation of their significance. While he acknowledges that regulatory relaxations such as the EU's compassionate use program or the hospital exemption scheme have widened access to experimental health interventions among patients, their overall effects on market access (i.e. the process that companies have to go through to ensure that their products can be sold and reimbursed by health care systems) is limited. The scope of these non-standard pathways, relative to the dominant regime, remains restricted. Regulatory exceptions and exemptions, at least in the context of the EU, have not favored innovative producers (such as clinical investigators, medical entrepreneurs and small companies) and their products on a large scale. Accordingly, the public health impact of these regulatory developments remains small.

Sariola et al.'s analysis of the ways in which civil society activism changed clinical trial regulation in India in 2013 shows that these changes resulted in a significant drop of trials in the country. The increased costs of improved ethical standards and the critical attention that activists directed towards international trials, reportedly disincentivized multi-national companies to conduct trials in India. Faced with economic losses and the threats of pharmaceutical companies to withdraw completely, the Drug Controller General of India quickly suggested the shortening of approval times and easing of further proposed changes.

These forms of pressure demonstrate that the achievements of India's civil society organizations are both, fragile and limited. While CSO activism resulted in heightened standards of rights protection for trial participants, demands for post-trial access of medicines in the Indian market remained unsuccessful. As Sariola et al. note, regulators feared that the expected costs of ‘mandatory’ access of international drugs tested in India, would make the country too expensive and a less attractive site for international trials. As a result, post-trial access remains a regulatory recommendation, not an obligatory requirement. Moreover, with the introduction of regulatory exemptions for academic clinical trials in 2018 (George, 2018) and plans for fast-track procedures for domestic trials (Porecha, 2019), the situation for trial participants may once again decrease.

A key finding of Hauskeller, Baur and Harrington's study is that the streamlining of stem cell therapies under a harmonized EU-wide regulatory framework poses various practical problems that make it difficult to conduct international research projects. The implementation of new standards does not only increase costs and organizational complexity, but it also confronts practitioners with the challenge to overcome micro-level differences of established clinical practices, values and culturally shaped perceptions of patient rights, autonomy, consent and other ethical aspects of the medical research process. While industry possesses sufficient resources to address these challenges, for academic researchers the conduct of multinational trials under the unified EU regulation is difficult to achieve. Academic research, that does not provide economic incentives for industry sponsors, is as a result marginalized.

The paper of Rosemann, Vasen and Bortz, finally, suggests that the increasing diversification of regulatory standards indicates a broader shift towards deregulation and increased medical self-governance. Regulatory developments such as the 21st Century Cures Act in the USA, the early-stage conditional approval system in Japan and the creation of a legal market of stem cell therapies under the EU hospital exemption scheme (see also: Salter et al., 2014), suggest that – outside of the regulation for pharmaceutical drugs – state intervention is downsized and partly replaced by self-regulation by medical institutions and associations (see also Cooper and Waldby, 2014; Rosemann and Chaisinthop, 2016; Kassirer, 2018; Haddad, 2019). A consequence of this is, however, that the oversight of experimental medical interventions is increasingly shaped and enacted by institutions and professional networks with vested interests. This can undermine scientific credibility and public trust. For patients, moreover, the relaxation of regulatory requirements and the acceptance of less rigorous clinical standards, creates a tension between earlier and more widespread access to medical interventions, and higher risks of adverse effects, financial and psychological exploitation as well as exposure to ineffective medicines.

The Geographical Dimensions of Alter-Standardization

The changes described in this special issue have important geographic connotations. As Rosemann, Vasen and Bortz show, many of the methodological and regulatory alternatives that this volume describes emerged outside of the USA and the European Union, where the majority of ‘international’ standards were created (or at least initiated). In China and India, for example, the long-standing toleration of clinical research and commercial practices that diverge from national regulatory rules (that mostly reflect international standards), is by many seen as a competitive advantage that stimulates domestic innovation and enables the realization of more rapid economic opportunities (Salter, 2008; Salter et al., 2014; Sleeboom-Faulkner et al., 2016). The adoption of more lenient regulatory standards for market approval in South Korea and Japan's shift away from the multi-phase trial system for regenerative medicine products has also been interpreted as an effort to increase international competitiveness (Sipp, 2015; Sleeboom-Faulkner et al., 2016; Lysaght, 2017).

But as the articles in this special issue show, processes of deregulation and the emergence of more flexible regulatory regimes have in recent years also surfaced in Western Europe and the USA. As Montgomery shows with the example of the growing popularity of adaptive trial designs, some of these changes have been fueled by industry demands and the objective to reduce health care costs. Several of the provisions of the 21st Century Cures Act in the USA were also pushed by industry lobbyists. Jerome Kassirer, the former editor-in-chief of the New England Journal of Medicine, has described the Act as ‘a major weakening of drug and device regulation’, which are ‘expected to speed up approvals and probably save the industry billions’ (Kassirer, 2018, p. 158).

However, as the papers of Faulkner and also Rosemann, Vasen and Bortz show, other changes such as the hospital exemption program in the EU and the growing number of right-to-try laws in the USA, are driven by pressure from patient organizations as well as medical practitioners who want to (re-)increase their role in the clinical innovation process. As Timmermans and Epstein (2010) have pointed out, international harmonization of regulatory standards stratifies social systems, and leads to new forms of inclusion and exclusion. The global distribution of the EBM and multiphase RCT system has threatened the autonomy of individual practitioners, and reduced and in many respects delegitimized physician-based forms of experimental medical practice (Knaapen, 2014). This has resulted in a power struggle between different professional groups, which has driven processes of alter-standardization and regulatory change at both national and international levels.

Hauskeller, Baur and Harrington's article provides an example of such a conflict at the intra-European level. The EU-wide harmonization of stem cell regulation, they demonstrate, has favored industry-sponsored research, but has created obstacles for academic researchers and trials that will not generate big profits. At a global level, interest conflicts exist between companies and medical researchers in high-income and emerging or developing countries. International clinical research standards, such as GCP have primarily been designed by and for corporations and researchers in rich countries (Davis and Abraham, 2013; Sleeboom-Faulkner 2016).

The global dissemination of these standards and their enforcement in low-to-middle income countries where only few stakeholders have the means to comply with international rules, reduces domestic innovation opportunities and delegitimizes locally-evolved practices and standards. This explains why especially in emerging fields of medical research, such as regenerative stem cell medicine, that are not dominated by the interests of large-scale pharmaceutical companies, opposition to the international EBM/multi-phase trial system has been particularly pronounced in developing and so-called ‘emerging’ countries.

Sariola et al.'s article illustrates that civil societal organizations can play an important role in counterbalancing the interests of multi-national corporations and national governments. The article also shows that the adoption of international standards is not necessarily a zero-sum game. Participation in multi-country pharmaceutical research projects, these authors argue, is by many stakeholders in resource poor settings seen as a form of positive development, which helps to strengthen domestic research infrastructures (see also Sariola and Simpson, 2019). This may explain why the Indian civil societal organizations that this article describes generally endorsed the conduct and methodology of multinational RCTs in India and criticized especially the social justice implications of the trials.

Conclusions

As the papers in this special issue make clear, the current landscape of international medicine research is in a process of far-reaching change. The contours of what counts as acceptable clinical methodologies, evidence and regulatory practice are redefined. Regulatory paradigms and standards are literally being rewritten. The EBM model and the use of multi-phase RCTs, while still influential, is in many respects contested as a universal standard, and partly replaced by methodological alternatives. These changes reflect a broad transformation in the culture and politics of biomedicine today, with implications for the ways in which new medicinal products, devices, procedures and technologies are approved for clinical use, sold to consumers, and licensed by health care systems. As a result, the boundaries between medical research and health care provision, as well as commerce and humanitarian service are re-articulated.

Many of the methodological and regulatory changes that this special issue describes indicate a wider shift toward deregulation, in which the supervisory role of state agencies is reduced and in part replaced by medical self-governance. These developments have repercussions for patients. Less regulatory oversight can potentially result in ineffective or dangerous products reaching the market, exposing patients to greater risks, harm the integrity of the medical profession and decrease public trust. As Jerome Kassirer has pointed out, deregulatory reforms such as the 21st Century Cures Act in the USA, requires a higher level of vigilance and post-approval surveillance (Kassirer, 2018). Between 2001 and 2010, almost one third of newly approved drugs by the FDA were affected by post market safety issues, which were not known at the time of approval (Pitts et al., 2018). This number is likely to increase; not only in the USA but also in other countries where medicine regulation is relaxed.

The essays in this volume show that the alter-standardizing of clinical trials does not follow a singular or unified pattern. The described regulatory changes have been driven by a wide variety of stakeholders, values and interests. As a result, alternative methodologies, forms of evidence and regulatory standards have evolved in diverse and often conflicting ways. The shift towards adaptive trials, for instance, has been strongly pushed by the pharmaceutical industry (Montgomery, 2017; Kassirer, 2018). Other changes, however, reflect the agency and interests of different stakeholders. The introduction of early-stage conditional approval for regenerative medicine products in Japan, for instance, has been initiated by the Japanese government to support small-to-mid size biotech companies and to facilitate the clinical translation of new treatment approaches in this field faster than other countries.

The flexible enforcement of regulatory standards in emerging fields of medicine research in China and India has also been interpreted as an attempt by national governments to stimulate domestic innovation, by facilitating clinical research that is affordable to local researchers and companies (Salter, 2008; Sleeboom-Faulkner et al., 2016; Sleeboom-Faulkner, 2016). Other developments, such as the surfacing of new types of regulatory exceptions and exemptions in the EU, and increasing access to experimental products in the USA, are partly the outcome of pressure from patient and consumer organizations, and partly a result of criticism from professional organizations that seek to enable more localized, physician-based forms of innovation (Cooper and Waldby, 2014; Faulkner, 2017; Rosemann et al., 2018).

This special issue, in short, shows that the international landscape of medicine regulation is in the midst of a process of diversification and change. Regulatory standards pluralize. The multi-phase RCT, long considered the global gold standard has come increasingly under pressure. These developments continue into the future. They are likely to create new inequalities and forms of inclusion and exclusion, that change the ways in which new medicines are developed, produced, marketized and consumed. They will also change who will have access to new medical treatments. Further research will be required to investigate how these transformations influence the situation and possibilities of patients, knowledge producers, physicians, large pharmaceutical corporations, smaller biotech firms, as well as regulatory bodies, civil societal organizations and national health care system.

Acknowledgements

I would like to thank the authors of this special issue for their contributions and Les Levidow and Kean Birch for their editorial support. I would also like to thank Margaret Sleeboom-Faulkner and my former colleagues at the International Science and Bioethics Collaborations Project and the Bionetworking in Asia Projects for their support and collegiality.

Disclosure Statement

No potential conflict of interest was reported by the author.

Notes on contributor

Achim Rosemann is currently a research fellow at the Department of Sociology, Philosophy and Anthropology of the University of Exeter. He has an interdisciplinary background in science and technology studies, medical anthropology as well as China and East Asian studies. Achim is also an associate researcher at the University of Sussex’s Centre for Bionetworking (which is part of the Anthropology Department). His work has examined the socio-cultural, economic and regulatory dimensions of technology developments in regenerative medicine, genetics, gene editing and synthetic biology.

Additional information

Funding

This article has benefited from research support provided by the ESRC (ES/I018107/1) (UK), ERC (283219) (EU).

Notes

1. This article was accidentally published in an earlier issue of Science as Culture. However, the article was written as part of this special issue. For this reason the article is listed and discussed as part of this issue, and a link has been included that provides access to the article. The article can also be accessed here: URL: https://www.tandfonline.com/doi/abs/10.1080/09505431.2016.1255721