Technological forecasting and regulatory assessmentan application to assisted reproductive technologies

Resumen

1. INTRODUCTION 1.1. Motivation The understanding of technological diffusion is necessary both in order to induce innovation and to direct its trajectories to the public benefit. Diffusion of innovation is “the process by which an innovation is communicated through certain channels over time” (Rogers, 1983, p. 12). It is a multi-cycle, two-way process of communication between different agents in society. The study of this process requires observing the factors influencing it, such as innovation’s relative advantage, compatibility with social values, levels of trialability, visibility, and complexity; in addition to the social structures, such as institutions, norms, and imaginaries (Rogers, 1983). The diffusion of medical innovation is particularly complex, as such innovations implement solutions to emerging problems; solutions which are rarely presented as a final product or service, but are instead developed by trial and error, progressively improved, refined and extended in their scope of application (Barberá-Tomás & Consoli, 2012). Therefore, the design and implementation of new medical solutions depend also on the creation of a generally accepted scientific approach, based on an agreement between different professional groups (Teece, 1986; Barberá-Tomás & Consoli, 2012). These agreements are often communicated through regulations and public procurement, which are set to deal with new technologies by providing responsible frames and institutions (Boon et al., 2015). Regulations are applied to correct inefficiencies or inequalities, information failures, and inadequate provision, as well as to reduce negative externalities and induce positive ones (Paraskevopoulou, 2012). The relationship between regulation and innovation is neither static nor single-directional; instead, it is reciprocal since regulation affects innovation and in turn, the outcomes of an innovation create new conditions to be regulated (Paraskevopoulou, 2012), and also alter the social values on which regulation is often based upon (Beck-Gernsheim, 2000). Different supply and demand factors influence the diffusion of innovation since technological trajectories are always shaped not only by scientific advances but also by economic, social, and institutional factors (Dosi, 1982). The technology-push approach highlights the role of science and technology, stressing that advances in scientific knowledge determine the trajectories of innovation. However, the demand-pull perspective underscores market features and changes in customers’ needs as the factors directing innovation toward the desired outcome. Therefore, the role of demand increases through the evolution of the technology’s life cycle. Indeed, the literature on technological change emphasizes that the process of innovation is not linear but interactive, as the technology and its users affect each other along the way (Walsh, 1983; Nemet, 2009; Peters et al., 2012; Di Stefano et al., 2012). In this thesis, we approach the diffusion of Assisted Reproductive Technologies (ART) from the supply, demand, and regulatory perspectives, and analyze the interaction between these three components. ART includes various methods involving the manipulation of both oocytes and sperm to assist human reproduction (CDC, 2018). Most commonly, it refers to In-Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI). In recent decades, the use of ART has proliferated, and it already accounts for over 5% of births in some leading countries (SEF, 2016; ESHRE, 2018; Ishihara, 2019). Since ART involves the fertilization of human embryos in-vitro, it allows conducting Preimplantation Genetic Diagnosis or Screening (PGD/PGS) by removing a biopsy from each embryo to detect genetic mutations (PGD) or chromosomal abnormalities (PGS). These techniques allow avoiding transferring an embryo with a severe genetic disorder (PGD) or serve to increase treatment prospects by choosing euploid embryos (PGS), i.e., those who carry a correct number and structure of chromosomes. The use of reproductive genetics is becoming common; in 2016, it took part in 22% of all IVF cycles in the U.S. (CDC, 2018). Additionally, in recent years, genetic engineering of human embryos by CRISPR/CAS has developed substantially, and it seems to be a matter of time until it will be regularly introduced for clinical use. Most recently, the use of CRISPR/CAS has caught the world’s attention with the announcement of the first birth of genetically edited babies in China in December 2018 (Krimsky, 2019). ART is a growing industry, currently mainly due to infertility, which according to different studies, amounts to 10-15% of the general population (Evers, 2002; Spar, 2006; Agarwal et al., 2015; ASRM, 2015). Some evidence shows that this share is increasing, due to the rising age of parenthood, environmental factors and lifestyle (Boivin et al., 2007; Mascarenhas et al., 2012; Johnson, 2014; Inhorn & Patrizio, 2015; Sobotka, 2016). It is also becoming more common among single women, lesbians, and gay male couples. At the same time, reproductive genetics is becoming a growth factor too, and not less important, it is more frequently being added to IVF cycles. Medical technology is marked by many as one of the most promising S&T areas in the 21st century, where increasing innovative efforts promise to extend human life and improve human well-being (Amir-Aslani & Mangematin, 2010; Harari, 2016; Godinho, 2016). In the previous century, medicine defined normal levels of health and medical policy and, in most countries, aimed at providing the majority of the public with health leveled according to these norms. However, in the 21st century, many medical innovations are aiming at surpassing these norms to produce an enhanced human (Silver, 1997; Fukuyama, 2003; Harari, 2011, 2016). In this context, ART is raising high expectations by enabling the extension of reproductive age, and through the introduction of reproductive genetics, which allows preventing diseases from the outset, and could even lead to enhancing the human race. The idea that human reproduction might increasingly shift into the lab where genetic manipulations of many sorts can be conducted has produced many hopes but also preoccupations. Many works in the fields of humanities and social sciences, as well as non-academic literature, have dealt with the implications of ART over individuals and society. ART may change the way human reproduce and, as a result, in a more distant perspective, might even change the human race itself (Lewis, 1943; Ramsey, 1972; Silver, 1997; Shulman & Bostrom, 2014; Greely, 2016), which raises questions regarding accessibility, equity, social justice and inclusiveness (Rawls, 1993; Paunov, 2013). Notably, the quest for the perfect baby raises many more ethical inquiries regarding embryo status, personal autonomy, parental responsibility, eugenics and social risks (Buchanan et al., 2000; Beck-Gernsheim, 2000; Habermas, 2003; Sandel, 2004). Expectations, imaginaries, and fears occupy a pivotal role in the innovation process by shaping its potential, particularly during the early stages when technology is under large uncertainty (Brown & Michael, 2003; Borup et al., 2006). Since ART, and particularly reproductive genetics, develop and diffuse slowly, expectations and concerns continuously accompany the social debate and the regulatory process and may differ between communities based on different values and knowledge (Borup et al., 2006). Interpretative flexibility of expectations often arises from asymmetries in access to information, as uncertainties of laboratory science are usually invisible to the broader public (Brown & Michael, 2003). There is, therefore, a knowledge gap between the science of ART and its philosophy concerning the IVF procedure, deriving from the complexity of the techno-scientific knowledge and the speed of technological progress (Marchant, 2011), which is influenced by numerous innovations in techniques, devices, and medicines. Also, there is a wide gap concerning genomics, an even more complex field of many uncertainties. Another disparity in understanding the potential trajectories of ART stems from the large differences in regulations between different jurisdictions. In some countries, ART is strongly regulated through legislation and public funding while in others a laxer regulation is being conducted based on voluntary guidelines (Johnson & Petersen, 2008; Chambers et al., 2009; Brigham et al. 2013). Analyzing expectations is a critical element in understanding scientific and technological change (Borup et al., 2006). This thesis aims to reduce the above-mentioned knowledge gaps by conducting technology forecasting and regulatory assessments based on Delphi surveys. It also aspires to provide some light to enable making strategic decisions regarding the future (Brown & Michael, 2003; Borup et al., 2006). 1.2. Objectives and research questions Our general objective is to assess the trajectories of ART and its pace of diffusion by identifying the factors that influence this process. This general objective can be split into the following specific objectives: Our first goal was to conduct a technology forecasting in order to better understand the potential developments in IVF, PGD, and genetic engineering. This initial research question was influenced by the extensive literature describing a future in which reproduction would mainly be practiced by IVF accompanied with embryo selection or genetic engineering, to produce healthier and enhanced offspring (Silver, 1997; Savulescu, 2001; Harris, 2007; Murphy, 2014; Greely, 2016). Much of this referred literature is based on expectations concerning the remarkable or dangerous implications of such a trend. However, those opportunities and risks can be considered purely speculative if they are not grounded in a likely future. Therefore, we began by questioning the viability of these assumptions and the technical requirements for their materialization. The second objective was to identify the factors affecting regulation and priority setting regarding ART and to review the responses to technological and market developments in the field, through a regulatory assessment and a comparative analysis between Israel and Spain (Ho et al., 2016; Hofer et al., 2015). Here we mainly focused on IVF and its present implications on society. We approached the diffusion of ART as a long process, influenced by today’s choices in ART clinics and by public policies. It was a central objective of this thesis to analyze the strengths and flaws of regulation and provision, and its impact over individuals and society. This comparative analysis was inspired by previous works from the U.S., Canada, the U.K., and other European countries (Nelson, 2006; Brigham et al., 2013; Pennings et al., 2014; Präg & Mills, 2017; Jasanoff & Metzler, 2018). Our final objective was to assess the regulatory trends that may (or not) lead to the “geneticization” of reproduction (Lippman, 1991), i.e., the shift of reproduction into the lab due to the ability to select or design genetic traits of embryos. This goal mainly focused on reproductive genetics and the regulatory response to potential futuristic developments. Moreover, it supplements the first goal since, in the field of ART, regulation plays a key role by interacting with both supply and demand. The combination of the two objectives, technology forecast and assessment of regulatory trends, allows us to get a better observation on the potential ART trajectories. These three sub-objectives define the structure of this thesis around three chapters, which have been drafted as independent papers to be published in scientific journals (see also section 1.4 below). Despite the focus on ART, this thesis also contributes to the broader field of diffusion of innovation and technology, predominantly in the field of medicine, by using qualitative methods through Delphi studies and in-depth interviews to evaluate technological developments and market trends, and by jointly analyzing supply, demand, regulation and the interactions between them (Nemet, 2009; Adner, 2015; Hammarberg et al., 2016). It represents a novel empirical approach, which might inspire future studies dealing with the diffusion of medical technologies. 1.3. Methods We began by elaborating a theoretical framework based on an extensive literature of an inter-disciplinary character. Summaries of the literature form the second section of each paper presented in chapters 2-4 and provide rich contents which may contribute to future studies. Chapter 2 begins with a background section which serves as an introduction to the field of ART, including the technical settings and the bioethical context, which leads to our first research question. Moreover, the analytical framework presented in chapter 3 classifies the critical dimensions of national ART regulations and identifies the factors which may explain different regulatory choices. It provides a useful set of categories for further analysis in different countries. In chapter 4, the hypothesis that reproduction is going through a process of geneticization was examined, by dismantling the factors required for its realization and classifying them in three categories: supply, demand, and regulation. Our empirical analysis was mainly based on the Delphi method, a widely used qualitative method for forecasting, assessment, and decision making regarding complex problems. It is developed through a quantitative survey in an anonymous and interactive process. A Delphi is built on a panel of experts who contribute with their knowledge, experience, and judgment to replace traditional statistical models and provide adequate sets of data when those are not available (Landeta et al., 2008; Salazar-Elena et al., 2016). The survey must be conducted in at least two rounds, to produce iteration following controlled feedback, allowing the experts to change their replies or add comments after learning the general views (Landeta & Barrutia, 2011; Von der Gracht, 2012; Mayor et al., 2016). The Delphi process allows experts to reach consensus or to build divergent scenarios (Landeta, 2002; Okoli & Pawlowski, 2004; Melander, 2018). We applied the Delphi method through two different surveys to extract knowledge from physicians, public officials, researchers and other service providers, whose careers are dedicated or closely related to ART. Confronting these experts experience with the expectations raised in academic philosophical debates serves to engage with the future as an analytical object, introduce realism into the discussion, and reduce the confusion produced by inflated hopes and dystopian scenarios (Brown & Michael, 2003). We focused on Israel and Spain, which are among the largest users of ART worldwide and can be characterized as “early adopters” (Rogers, 1983) of ART services. In the last decade, the total number of IVF cycles per year in Spain has increased remarkably, and according to most recent reports, it is the largest ART industry in Europe and third in the world (SEF, 2016; CDC, 2018; ESHRE, 2018, Ishihara, 2019). Israel is the largest ART industry in relative terms, partly due to its very comprehensive public coverage. Additionally, both countries have very supportive attitudes towards reproductive genetics, and PGD is practiced more commonly and with a larger portfolio than in most States (Pavone & Arias, 2012; Zlotogora, 2014; Zuckerman et al., 2017). Overall, Israel and Spain are currently among the most advanced countries with respect to ART, which makes them adequate targets for our empirical study. As an important component of empirical data collection, 44 in-depth interviews preceded the two Delphi surveys. Meetings of one hour on average with the experts assisted in updating and validating the knowledge obtained through the literature review. These professional experts are well informed of the latest literature in their fields, and many of them also contribute to scientific publications. The interviews were semi-structured and open to allow the experts directing the research to some points of interests which they identified as important. As a result, the questionnaires were also designed based on the interest and focus shown by the interviewees, and the comments registered from interviews enriched the analysis with qualitative insights to better explain the quantitative results of each survey. Subsequently, two Delphi exercises were conducted, each involving a different panel of experts which were consulted in two rounds. The first was undertaken between September 2016 and June 2018 and addressed 25 gynecologists and geneticists from elite clinics, 13 from Spain and 12 from Israel. The experts were questioned regarding developments in various technologies used for IVF, success rates and treatment possibilities, genomics, and genetic engineering and, finally, regarding demand forecast and attitudes towards regulation in a twenty years’ horizon. The second Delphi was conducted between October 2017 and January 2019 and addressed two groups of 18 experts each, formed to simulate typical bioethics committees from Israel and Spain. The survey had two sections, one assessing the regulation of ART and its current framework, and the other focused on the regulation of different applications of reproductive genetics. The two Delphi surveys partially approached similar issues with similar questions, although they addressed different types of experts. It allowed us to stand on the differences between suppliers (in our case, physicians) and regulators. While our methodological approach to ART can be directly practiced in other countries and different groups of experts, it could also be adapted to other fields of medical innovations, where the interactions between supply and demand are strongly influenced by regulation and public financing. The two questionnaires are annexed at the end of the thesis. This methodological approach, however, is not exempt from limitations. The use of the Delphi method based on experts always has a level of subjectivity, concerning the definition of an expert and the factors biasing his/her opinion (Devaney & Henchion, 2018). Therefore, different experts may express different attitudes, which could also direct the study to different focuses. It would also be interesting to contrast our results against other collectives, including various kinds of stakeholders (e.g., patient associations, hospital managers and non-practitioner scientists). Moreover, our selection of two countries in an advanced stage of diffusion, with very pro-ART attitudes and which tend to nourish a comprehensive public healthcare system, may produce some biases. Therefore, the forecast and the regulatory assessment provided for Israel and Spain might not represent the global scenario. A selection of different countries in earlier stages of ART, with a strong attachment to individualized and free-market economic theories (such as the USA) (Johnson & Petersen, 2008), or where the use of reproductive genetics is contested (i.e., Austria or Germany) (Hashiloni-Dolev & Raz, 2010; Griessler & Hager, 2017), could lead to different results. Finally, the reliability of forecasting is always limited due to the field’s complexity. Many developments in genomics, prenatal testing and medicine could affect the trajectory of ART. Moreover, the technology course is influenced by a broader range of related aspects, such as regulations, institutional and economic factors, consumer choices and pressures from different interest groups, which might be hard to capture (Brigham et al., 2013; Martin, 2014). Nevertheless, the experts who participated in the first Delphi are leading gynecologists and geneticists in Israel and Spain who have practiced IVF and PGD for many years, and their countries are at the forefront of the world’s ART industry. Indeed, many of the predictions introduced by the panels are compatible with recent literature (Lu et al., 2016; Casper et al., 2017; Nuffield Council on Bioethics, 2018), which substantiates the robustness of our methodological approach. 5. CONCLUSIONS AND POLICY IMPLICATIONS This thesis aimed to provide a more accurate understanding of the diffusion process of Assisted Reproductive Technologies (ART), including their trajectories, opportunities, limitations, and policy implications. First, through a technology and demand forecast for the following 20 years, as presented in chapter 2 and further developed in chapter 4, we assist in reducing the gap derived from asymmetries in technoscientific knowledge between ART and the socio-ethical literature. Our forecasting provides a more realistic insight towards the potentials and limitations of ART in general, and in Israel and Spain in particular. Second, a regulatory assessment of the current state of affairs in Israel and Spain, presented in chapter 3, provides both a general analytical framework for cross-country analysis and a case-study comparison between two leading ART industries. It assists in understanding better the factors affecting regulation and priority setting, and thus in interpreting the differences between countries. Moreover, it allows analyzing strengths and flaws of ART regulations, as well as identifying risks which may arise or extend from the expected growth of the ART industry. Third, building on our analysis in chapter 2, and combining it with experts’ attitudes towards the regulation of reproductive genetics extracted from the second Delphi, we assess the market and regulatory trends that may (or not) lead to the geneticization of reproduction. This analysis, presented in chapter 4, is the most far-reaching and speculative element of this thesis, in which we present possible scenarios for a geneticization or medicalization process in human reproduction. Chapter 4 introduces an approach to the diffusion of medical innovations based on supply, demand, and regulations, which may serve for future studies in other medical fields. Technology forecast: We may expect a significant increase in IVF birth rates for the next 20 years towards 50%, mainly resulted from improvements in the stages of egg fertilization and embryo implantation. However, we noted some doubts about the possibility of significantly increasing the number of extracted eggs, which could remain the scarcest resource in IVF treatment. It seems that the most expected improvements are related to equipment and clinic quality control, as average-budget clinics would close the gap with today’s premium ones, suggesting that IVF is evolving from a “pre-paradigmatic stage” to a “paradigmatic stage”, where a generally accepted scientific approach is gaining ground (Teece, 1986). The selection of embryos by genetic screening (PGS) is projected to improve and become more useful. The experts also raised high expectations for improvement in genomics, allowing better identification of the relationship between genes and various multifactorial diseases. Therefore, following an increase in the practice of PGS, PGD will also become more common, although a larger potential, particularly in the long run, was attributed to genetic engineering by CRISPR/CAS. Attitudes towards the regulation of reproductive genetics: The experts from both Delphi surveys approved any use of ART, given that it is safe and provide significant health benefits. The physicians have drawn a clear line between allowing the use of PGD for multifactorial diseases and banning it for non-medical reasons. Conversely, the “bioethics panels” from the second Delphi did not draw a clear line, but marked a grey-zone of regulation, concerning treatments of which health benefits are not yet clear, including the use of CRISPR/CAS, PGS for chromosome abnormalities or whole-exome screening, and the use of PGD for multifactorial diseases. It seems that the central dilemma on the regulatory agenda is whether or not these technologies may medically benefit the patient. It was neither the slippery slope argument nor any moral or ethical concern regarding the social consequences of reproductive genetics, although the experts were careful and attentive to those issues. The first stage of diffusion: The panel of physicians anticipated that, within 20 years, the share of IVF births in Israel and Spain would be around 14% and 19%, respectively. This forecast is not surprising, considering that many studies estimated that infertility affects up to 15% of the population (Evers, 2002; Spar, 2006; Agarwal et al., 2015; ASRM, 2015), and that this share may be growing due to the rising age of parenthood, environmental factors, lifestyle and social reasons (Boivin et al, 2007; Mascarenhas et al., 2012; Johnson, 2014; Inhorn & Patrizio, 2015; Sobotka, 2016). The panel also forecasted that PGD would growingly be a factor which increases demand for IVF and, more importantly, that it will become an add-on to IVF in about 40% of the cycles, in contrast to a much smaller share today (less than 5%). Also, at this stage of diffusion, CRISPR/CAS will be introduced as a more practical, efficient, and potent technology. Nevertheless, it may be a long and gradual process and, even after its first applications, preoccupations with safety and adverse effects will take time to dissolve. Hence, the use of CRISPR/CAS could, for an extended period, be limited to single-gene disorders and a few more conditions of limited complexity (Evitt et al., 2015; Nuffield Council on Bioethics, 2018). The implementation of the first stage: Israel and Spain are among the heaviest consumers of IVF due to various factors of which the most central is age-related infertility. In Spain, this trajectory has been described as “structural infertility” (Marre, 2009; Marre et al., 2018). It relates to socio-financial conditions that are leading many women and men to postpone parenthood to an age in which ART is often needed, and most likely requires donor-eggs. In Israel, cultural, political, and social environments are shaping public views on infertility, ART, and genetic relatedness. Thus, Israelis are repeating many IVF cycles, which are publicly funded until the age 44, attempting to fulfill their desire to form large families by giving birth to genetically related children (Birenbaum-Carmeli & Dirnfeld, 2008; Birenbaum-Carmeli, 2010). The prevalence of donor-eggs as a solution to infertility is a significant and growing matter in Spain, which is already among the largest producer of such donations in the world. Albeit, it is also a growing phenomenon in Israel, although most donations are coming from abroad. The market for eggs raises many ethical controversies, concerning the physical and emotional burden on female donors and the limitation on reimbursement for donations in comparison with the multiplied profit generated by intermediaries. Moreover, within a few decades, hundreds of thousands of people (also due to sperm donation) will have no access to one or both of their biological parents’ genetic information, medical history, and identity. It may provoke great disadvantage, both psychological and medical, considering the growing weight of genomics and precision medicine. Another controversial issue in both countries is the practice of PGS, a relatively new technology. Its efficiency is not yet proven; it is not publicly funded and is being offered as an add-on, providing large profits to clinics. Nevertheless, the use of PGS involves taking a biopsy from an embryo, which may as well pave the way to a significant increase in the use of PGD, by turning the screening for chromosomal abnormalities into a screening of large parts (or the whole) of the exome to detect mutations. The second stage of diffusion: At this stage, the only growth channel left for the ART industry is reproductive genetics, i.e., IVF dedicated for PGD or CRISPR/CAS. According to our findings from chapter 4, both panels strongly opposed the use of reproductive genetics for detecting desired physical and cognitive traits. The moral bases for this opposition could slowly be altered, affected by a spiral-shaped process in which technological development and values drive one another (Beck-Gernsheim, 2000). However, as long as this attitude holds, the only way for the industry to attract a larger share of the public would be by delivering (or, otherwise, promising) significant health benefits to people born by ART. Nevertheless, most babies born today are healthy, and most adult people live healthy lives, at least until oldness. Could reproductive genetics deliver babies who would suffer less multifactorial aging-associated diseases? Could such a promise appeal to the majority of the human population? In the long run, a full medicalization of reproduction based on geneticization could be realized, but the true potential of genomics is still foreign to us. We may very soon be able to cut and paste DNA segments of the human embryo in a swipe of a hand. Conversely, it will take much longer to fully understand genomics and the epigenetic implications of CRISPR/CAS. Reproductive genetics could also end up being a matter of choice between various alternatives concerning the genetic composition of an embryo, due to gene pleiotropy (Nuffield Council on Bioethics, 2018). Most importantly, the human lifecycle is long, and proofing the benefits of reproductive genetics aiming at multifactorial late-onset diseases will require the conduction of follow-up throughout the adult lives of ART babies. Of course, with the lack of full evidence, the market forces may induce scientific speculations, beliefs, and expectations, with socio-technical imaginaries generating perceived benefits of geneticization. Policy implications: This study has concluded that the medicalization of reproduction is a long and observable process and that the geneticization thesis will most likely not be realized due to a moment of breakthrough (Brown & Michael, 2003) in a particular research project of some institution or an enterprise. Alternatively, it will take the form of a spiral shaped-process, driven by the gears of market forces, private interests, trends nourished by socio-technical imaginaries and shifts in regulation. Such a process is not necessarily good or bad, but it is recommended to observe it and follow it, and also to attempt to influence and direct it to the benefits of society by means of both national and international regulation. Our “bioethics panels” were preoccupied with the large influence of commercial interests on regulations in contrast to a weak influence of ethical interests and health considerations. Regardless of the difference in the shares of private/public funding between the countries, in both markets, demand is, to some extent, induced by private interests. Our analysis raises that, despite the large economic benefits of the ART industry, governments should aspire to slow down the medicalization process. First, by distributing accurate information regarding both ART and infertility through available means (such as the media, education and health systems). We also advise regulators to carefully supervise the information delivered to the public by private clinics. The field is complex and involves large profits, meaning that the accuracy of the information should not be taken for granted, particularly when it comes to reproductive genetics for multifactorial diseases. Second, ART is not necessarily the optimal or only solution; other alternatives should be considered. Epidemiological research about infertility resulting in prevention should be a priority and should receive more resources. A further focus should be given to transparency, which could be done by improving national registries and increasing their scope, providing more details regarding clinical diagnosis, separating between PGD and PGS as two techniques with different aims, and adding economic dimensions, such as average costs, or private and public distribution analysis. Third, it is also important to realize that the medicalization process of reproduction is largely due to social trends since the modern lifestyle is driving the postponement of parenthood. An inclusive societal debate should deal with the adequacy (or inadequacy) of ART to solve such problem, in light of other social solutions based on welfare policies. As fertility preservation is already becoming a trend, we should cautiously test some other non-medical alternatives. Fourth, our analysis questions the institutional setting and recommends to observe the alternative of non-governmental statutory central regulatory agencies to regulate ART. Noticing the insufficient regulatory response to the first stage of diffusion concerning aspects of financial interest, disinformation and the pace of medicalization, we may greatly doubt whether Israel, Spain or any other country are ready to welcome the second stage. It leads us to the importance of international debate, which should result in regulatory collaboration, particularly regarding the use of advanced reproductive genetics. When CRISPR/CAS design artists offer their services, state borders and national regulations will play a very limited role (see also Martin, 2014). In sum, regulators should avoid “sleepwalking” into this process by allowing uncontrolled technological momentum (Nuffield Council on Bioethics, 2018), though our moral dimensions should also not be based on outdated or misleading contexts, which would lead to inflated hopes or dystopian theories. Alongside with the medicalization of reproduction, an open debate must regularly address questions of freedom of choice and personal autonomy in decision making, while being regularly updated according to the most realistic and accurate scientific context. Future research agenda A recommendation for further studies includes the approach to other countries in search of other evidence for the emerging medicalization process and regulatory deficiencies. Particularly, we identify potential interest in the largest and most fast-developing markets in the world, such as Japan, the U.S., China, India, France, Australia, the U.K., and Denmark. Regarding some of these countries, there might be considerable interest in identifying inequalities in access to services and their implications. It would also be interesting to study other institutional settings, based on non-governmental statutory central regulatory agency, in order to search for a more adequate solution to ART regulation, providing useful insights regarding regulatory frameworks and their true potential. Finally, it would be interesting to approach the demand-side through patients by other methods which may require further research resources but could provide some very important perspectives. For example, by interviewees and surveys, focusing on the factors that create inequality in access, and the possible reasons that may drive patients to approach reproductive genetics, as well as the moral limits they place for such approach, and how these limits may shift along time.