Herbert Gottweis , Christian Haddad : Life Science Governance Institute , Vienna Haidan Chen : STS Research Center

1. Governing Clincial Trials with Stem Cells in Europe, the United States, and China: Towards a Global Model? • REMEDiE meeting, June 2010 Herbert Gottweis, Christian Haddad: Life Science Governance Institute, Vienna Haidan Chen: STS Research Center, Zhejiang University

3. Risk Uncertainty Governing Regenerative Medicine low high hESC Gene Transfer Therapies (Adult) Stem Cell Therapies iPS siRNA low high

4. Clinical trials: are intended to develop drugs that are safe and efficient.   20-80 healthy volunteers Up to 200/300 patients Up to 3000 patients  Hospital Laboratory               Phase 1 Phase 2 Phase 3 (Clinical use) SOCIETY preclinical studies CLINICAL TRIALS  • Good quality • Safe in animals • Promising effects? • Safe for human trials     safety Proof of concept Does it work? Therapeutic proof  Pharmacy    Haddad, 2010 • Research subjects need to be protected from harm • Protocoll for clinical trials is build around these ideas. • Clinical trial protocols often vary greatly between settings, such as between Europe, the United States, and China.

5. Clinical trials as we know them today have a comparatively young history • emerged out of socio-scientific and political struggles over medical authority in context of the rise of Evidence Based Medicine, the growing dominance of laboratory over clinical medicine, a series of drug disasters in Europe and the US, as well as the growing relevance of risk discourse “histories of clinical research draw attention to the ways in which trials emerge out of conflict or collaboration between different disciplinary groups, as well as working as means of managing interactions between doctors, researchers and pharmaceutical companies, or demanding patients and governments” (Catherine Will 2007: 87)

6. Our Argument: • Clinical trials are arrangements with objective, neutral goals build around the idea of protecting patients in the context of clinical research and drug development, and of developing drugs that are safe and beneficial. • But: Clinical trails are also a socio-political phenomenon, inseparable from complex ethical, regulatory, historical, or economic constellations. • Steven Shaping/ Simon Schaffer: “Solutions to the problem of knowledge are solutions to the problem of social order” (1986, 332) • Constructing/building technoscientific/medical entities/phenomena or projects (like clinical trials) and bringing them into being and operation implies the simultaneous production and reproduction of scientific ideas, experiments and scientific-technological assemblages AND of other social practices – such as norms and standards of ethical research, credible systems of ordering economic and political realities (governance), and socio-political narratives.

7. Our argument: • protocols and standards for clinical trials do not only follow scientific considerations, but are also the result of and interact with a complex set of societal developments and factors. These factors are not only operating on the national level, but also operate globally. • Both Europe & US: competition in global biotech-industries combines with highly risk averse regulatory environments that co-produce societal models of dealing with issues of risks, danger, subject research and ethics in clinical trials. • China, by contrast, is not characterized by a predominance of these risk-averse bioethical and regulatory apparatuses, and its location in the globalized bio-economy favors both, tendencies towards FDA-style state regulation and towards understanding a situation of a regulatory vacuum in stem cell trials as a strategic advantage in the global bio-economy.

8. Regulation in the US: Normalizing Stem Cell Trials • Regulations dates back to the federal Biologics Control Act (“Virus, Serum and Toxin Act”) from 1902. Since then it progressively refined, but its principles still serve today for governing cell and gene therapy products. • Three central principles necessitate the manufacturer to secure control of the biological source; control of the production process, control of the bulk and final product. (cf. Kessler, Siegl, et al 1993). • GMO controversy: each of these three dimensions (the bio-object, the process, and the final product) were subjects of fierce discursive struggles and political negotiations, and these struggles have taken different forms in different political contexts (Gottweis 1998, Jasanoff 2005).

9. Regenerative medicine and stem cell therapy: it was not clear and a matter of political negotiation: how to regulate these products • Stem cell therapy far from being proved: many aspirations toward SC cures, but highly dependent on indication, product, etc. • Nevertheless: many patients with unmet medical needs hope for SC cures • Both: patient activism to promote research and create favorable research environments (M. Fox,…) • Patient “Self-organization” via narrative medical histories, using Web 2.0 • tools (blogs, etc.) leads to “Empty hope” and stem cell tourism In the US, all stem cell-based products fall under category “human cells, tissues, and cellular and tissue-based products”, defined in the Public Health Safety Act (PHSA) Section 361 as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion or transfer into a human recipient” (Halme and Kessler 2006: 1730).

10. Geron • First hESC-based investigational therapy, seeking IND approval to start trials for years. FDA very reluctant.

11. 21000 pages document under review • Regulatory stop/go for months  more data needed (confidentiality: public doesn’t know exactly why FDA puts Trial on hold) • Product: hESC-derived oligodendrocytes (nerve cells), intended indication: regeneration of damaged spinal cord nerves after spine injury. • Originally derived from research-grade cell lines  difficulties to engineer them as clinical grade cell line • Patient “recruitment”: very difficult (young, trauma patients, must give consent quicky after accident, … need to train many surgery departments to prepare them for difficult operation)

12. The Risk-based-approach in the US system provides that products that contain cells or tissues that “are highly processed, are used other than their normal function, are combined with non-tissue components, or are used for metabolic purposes” also need to be subjected to regulations governing the manufacturing and licensing of biologic products. • These additional requirements apply to vast majority of stem-cell based products. • Categorized as biologic, as defined in PHSA Section 351, manufacturers need to file an IND (new investigational drug) application, containing preclinical data that suggest evidence of likely safety and efficacy of the product, before they can be tested (or used) in clinical context. GMP requirements are key to this process: the manufacturer of a biologic product must demonstrate that it is “safe, pure, and potent”.

13. FDA’s risk assessment before a trial can start: determination of risks and benefits. Building on expertise and experience of FDA regulatory science: • “As the theoretical basis for somatic-cell and gene therapy has evolved, substantial concern has been voiced about its risks, both to individual patients and to the public at large, and its ethics. The public and the scientific community are well served, and the continuing development of new forms of technology is best ensured, by the independent, authoritative evaluation of risks that the FDA review process provides.” (Kessler et al 1993) • Conclusion Halme and Kessler (p. 1734f.):“As new stem cell based therapies are developed, the regulatory framework is likely to evolve. Meanwhile, existing regulations pertaining to biologic products and human cells, tissues, and cellular and tissue-based products provide an appropriate structure for ensuring the safety and efficacy of the next generation of stem-cell–based products.”

14. The US System MAA MAA Pre- clinical Pre- clinical Phase II Phase II Phase III Phase III Phase III Phase III Phase I Phase I Phase IV Phase IV Phase III Phase III Phase II Phase II <--------------------- Drug Development --------------------> <--------------------- Drug Development --------------------> The Developer‘s View The FDA View End of Phase II Pre-IND 14

15. The European System The Developer‘s View MAA Pre- clinical Phase II Phase III Phase III Phase I Phase IV Phase III Phase II <--------------------- Drug Development --------------------> The European Regulator‘s View MAA Phase III Phase II Phase III Pre- clinical Phase IV Phase I Phase II Phase III <--------------------- Drug Development -------------------->

16. Regulation in Europe: Focus on New Risks? • In 2007: new piece of Community regulation that, for the first time, brings a vast array of regenerative medicine products under the same framework. • “Advanced Therapies Regulation” (more precisely “advanced therapies medicinal products”, ATMP) • Our argument here: Harmonization and creation of “advanced therapies” as a regulatory, legal, and institutional category was simultaneously regulatory project and project to regenerate Europe’s stagnating biotech sector as well as to advance European integration. New European regulatory landscape reflected less new or different risk discourse than attempt to govern on European level

17. US a huge single market with on central competent authority, the US Food and Drug Administration (FDA). • Preclinical and clinical R&D, as well as marketing authorization is regulated under the authority of the FDA, and FDA “project managers” usually follow a manufacturer and its products from the very beginning through the entire process of development. • By contrast, in Europe industry is confronted with a highly diversified regulatory landscape. • Despite increased efforts to harmonize European drug laws and regulations within the last decade, regulatory idiosyncrasies persist and regulatory authority is divided between member states and the Community. • Most prominently, clinical trials remain under the authority of national agencies, whereas marketing authorization (at least for “biologics” and advanced therapies) need to go through the Community’s centralized procedure.

18. USA versus Europe FDA EMA Natl. CA Drug Development Clinical trials in Member States

19. At the supranational level in Europe, regulatory competences are divided between the European Medicines Agency (EMA) and the European Commission. The division of labor between the two institutions provides for the EMA to deal with the technical and scientific details of the regulatory process and to develop advice or recommendations for the Commission, who finally makes the decision [Rothstein et al 2006 have argued that there is an observable tendency to separate risk assessment (“impartial science”) from risk management (“politics”)]. • many significant structural differences between the EMA and the US FDA. First, the EMA is in comparison a very small scientific agency, best perceived as a huge secretariat where representatives of national regulatory officers and scientists from the Member States and the Community meet. • The FDA gathers, as many US independent regulatory agencies, legislative, executive, and juridical powers, whereas these powers are distributed in Europe between EMA and the Commission. • Another historical difference: whereas the EMA is a very young agency that has only incrementally expanded its competences, the FDA has a long tradition and was often publicly very visible (and were able to increase their reputation in the US public by averting public health crises, e.g. the Thalidomide disaster).

20. Regulation in Europe • In the European Union, cellular and gene therapy products have been legally defined in Annex I of the Human Medicines Directive (Directive 2001/83/EC) as medicinal products with additional requirements. • Interestingly, the 2007 Advanced Therapies Regulation (EC 1394/2007) has established a novel regulatory framework that regulates products based on genes, human cells, and tissues under the same umbrella. • Before the Regulation, a regulatory/legal gap analysis has shown that the European Community harmonization of medical laws provides no Community regulation for tissue engineered products. The Regulation lays down “specific rules concerning the authorization, supervision and pharmacovigilance of advanced therapy medicinal products” (ATMP).

21. Regulation draws on existing regulation of gene therapy and somatic cell therapy products, and merely introduces a new definition of tissue engineered products. For different requirements still persist for these three categories, there remains a hierarchy between these products: products that fall under the category of both somatic cell as well as tissue engineered product will be regulated as the latter. If any product can be classified as gene therapy product it will be regulated as such. • Risk-based hierarchy: somatic cells – tissue engineered products – gene therapy products. Another exception exists for combined products which consist of a ATMP and a medical device. • Most importantly, the European Union Regulation concentrates on marketing authorization of ATMPs. Community does not have any competence of regulating clinical trials which remain in the hands of national authorities (the Clinical Trials Directive 2001 sought to harmonize clinical trials standards and practices of the Member States, and to introduce obligatory GCP guidelines).

22. Second, there exists the so-called “hospital exemption” in the Advanced Therapies Regulation, limiting its scope to ATMPs that are “either prepared industrially or manufactured by a method involving an industrial process”. • Excluded are • “advanced therapy medicinal products which are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient” (Office Journal of the European Union: L 324/121, (6))

23. First conclusion: substantial regulations, requirements and standards for bringing a stem-cell based product on the market are rather similar in the US and in Europe. • Both regulatory frames emphasize quality control (GMP) and offer a risk-based assessment and classification of these products. From this technical standpoint this is not surprising, because the European Medicines Agency and its regulatory scientists have looked at their colleagues at the FDA, and there are many telephone conferences and joint meetings where regulators and regulatory scientists discuss “technical” questions and exchange their experiences.

24. ReNeuron • Spinoff of KCL Psychiatry Department, found in 1998. Activity in US, now in UK (hurdles of FDA made them go to UK). • Many products in development, but crucial: Conditionally immortalized stem cell line derived from fetal tissues (aborted fetuses) – peculiar: „adult“ cell line • Intended for allogeneic use (and large scale product development) • Regulatory process: since 2005 ups/downs with US FDA, 2008 move to UK. MHRA approval within a year, GTAC (gene therapy advisory committee serving as ethical review board, also remit on SC therapies) was more reluctant. Final favorable opinion in early 2010. • Clinical trial conducted in Glasgow (Southern Hospital), start spring 2010. • Collaboration with GMP facility (Edinburgh), now involvement of a CRO for managing the clinical trial • Clinical (phase1 – safety) study 12 patients, indication: disability following an ischemic stroke, • If ever, will take years!! Before product • Clinical development process mainly under UK authority. IF (in years) phase 3 trials successful, then EMA centralized procedure for marketing authorization (“advanced therapy medicinal product”)

25. Europe EUDRA-CTs GMP certificate required for phase I „Isolated“ clinical trials Case-by-case decisions Culture Scientific Advice U.S.A IND number – single active substance Tight quality requirements end-of-phase II (EOP II) GMP inspection at MAA Continuous process (possibly same review-team) Decision by precedents Culture Pre-IND Meeting, EOP II Essential Differences

26. The European System Clinical Trials • … are regulated on a National Level within the European Framework • Informationsystems follow the trials (EUDRA-CT) • Assessments are done by Ethics committees and National Regulatory Agencies • The regulatory focus is on patient safety • Drug development is the responsibility of the Developer MAA for Biologics by Centralized Procedure • Case-by-case decisions

27. China: Stem Cell Clinical Trials as Reverse Engineering? • While in Europe the Advanced Therapies Regulation did not only regulate stem cell products, but was also a political technology to build Europe, in China the social role of stem cell regulation was not to stabilize or build a unified medical market, but to cut out a niche for Chinese companies and scientists to enter a medical market through competitive advantage. • Loosley speaking, the Chinese stem cells to patients model seemed to follow a strategy of “reverse innovation”: discussion in business studies on new model of innovation in emerging markets: • Take the needs of the consumers first and then work backwards • Classical model: revolutionary breakthroughs trickle-down and are increasingly taken up in different areas Tata motors has produced 2.200 BP car, and cellular phone companies like Nokia are producing cellular phones adapted to Third World needs, cellular phones that incorporate latest chip technology with functions useful in the particular developing context

28. Patients/citizens Mrs de Gregorio had her doubts before her husband and Corey left for China but she said she wanted Corey to have every possible chance in becoming an independent individual. "Like any parent, you want to do the best you possibly can with your child and at the end of the day you want to know that you’ve done and that you’ve tried everything,” the mother-of-three (cerebral palsy) said. “Even if that means going offshore and trying something experimental. " http://www.cairns.com.au/article/2009/04/18/38681_local-news.html accessed on November 7, 2009

29. Beike in the news • “Blind Girl’s Pioneering Operation” • “Paying for a Brighter Future” • “Revolution in China” • “China Trip Could Save My Life” • “Small Steps, Giant Leap” • ……

30. Beike Biotech: a Chinese company that has taken a leading position in administering stem cell treatments to patients from China and abroad (5000-6000 estimated treatments so far) • Patients presented on the web-sites of the company: all seem to share a similar story: typically diagnosed with diseases deemed non-treatable by their doctors at home, often a neurodegenerative disease, they were desperately looking for a cure elsewhere. This brought them at some point to contact the Chinese company Beike, that seemed to promise help for many illnesses for which no hope for cure existed in their home-countries. • Beike Biotech is not a singular phenomenon in the world of stem cell treatments. Administrating stem cell experimental or/and unproven stem cell therapies to patients is a practice that can be found in clinics around the world, and has recently turned into a topic of public concern.

31. Clinics offering stem cell therapies are located in China, India, Costa Rica, Dominican Republic, Germany, Mexico, Russia, and Turkey • International scientific community and medical doctors around the world have argued that the portrayal of the potential of stem cell treatments in a variety of clinics around the world tended to be overoptimistic and unsupported by published clinical evidence (Enserink, 2006; Lau et al., 2008). • ISSCR (2008) produced Guidelines for the Clinical Translation of Stem Cells and Patient Handbook on Stem Cell Therapies to protect patients from potential physical, psychological and financial harm, and hoped that the handbook would prompt regulators and governments to stick to the guidelines so that fewer would get

32. Beike Biotech is a biotechnology company that was founded in 2005 with financial, political and academic support from Peking University, Hong Kong University of Science and Technology, and the Shenzhen City Hall. • Company, located in the Shenzhen Hi-tech Industrial Park, has been approved as a hi-tech enterprise of Shenzhen which hoped to become a world leader through the development of a global network and platform for R&D and clinical application of stem cell technology. • Beike’s ambitious business model was to build a network connecting research institutes, hospitals and the company together in the field of stem cell research and treatment. First, it set up cooperations with hospital centers, provided them with stem cell technology and equipments, arranged patients at these hospitals for stem cell treatment, and shared profit with treatment centers at certain ratio.

33. In China, there are two different regulatory approaches to stem cell clinical trias as there are two different definitions on stem cells: one is defined as stem cell-based product and the other is defined as medical technology. • Early on, China coped with stem cell-based products as investigational new drugs of biologics, and stem cell clinical trials should follow the State Food and Drug Administration (SFDA)’s guide, laws and regulation, such as the SFDA’s application and approval procedure for clinical trials, Drug Administration Law of the People's Republic of China, Regulations for Implementation of the Drug Administration Law of the People's Republic of China, Provisions for Drug Registration. • This regulation is similar with the American FDA model.

34. However, during the first review processes in 2005 and 2006, the SFDA found it difficult to regulate stem cell–based products as drugs. At the same time companies and hospital treatment centers had begun stem cell application, which had already aroused the international criticisms and concerns. • To stop the unproven stem cell application in China, and to accelerate the development of the stem cell-based therapies, the Ministry of Health (MOH) issued the Regulations on Clinical Application of Medical Technology on 1 March, 2009 and stem cell clinical application was regulated as Category 3 medical technology under the MOH. • Stem cell clinical trials should be under the regulation of the Department of Science, Technology and Education, MOH, after the clinical trials have been done and approved by this department, then stem cell medical technology can begin its clinical application, which will be under the regulation of the Department of Medical Administration, MOH.

35. China MOH SFDA Clinical trials Drug Development Clinical application of medical technology

36. However, so far the MOH hasn't worked out the detailed guidelines and regulations on stem cell clincial trials, that's why all the applications of stem cell clinical application has been suspended. It is still not clear whether there will be unified regulation in this field. • Attraction of untried stem cell treatment for patients as it is in the case of Beike Biotech reflects a larger transformation in the global bio-economy in which the competition for scientifically and technologically advanced treatment options and therapeutic success operates in a regulatory patchwork situation and constellation of uncertainty that fundamentally transforms the role of the patient and the research subject in contemporary society. • Newly emerged actors and actor constellation such as the Beike stem cell treatment medical network are part of this constellation and benefit from it. The rise of the “e-patient” operating independently and skillfully in the Web 2.0. landscape has led to a situation of patients much stronger engaged than in the past in globally searching and exploring medical treatment options.

37. While entering this new bio-economical/therapeutic constellation as “patients”, these patients often are not only actors seeking treatments, but also, simulatenously, operate as voluntary research subjects and funders of research. Part of this development is the emergence of forms of interaction between patients and treatment centers, who are now actively engaging in interacting with patients, patient communities and potential research subjects through the Web. 2.0. architecture. Process of patients becoming involved in unproven therapies administered in clinics criticized by the medical community is a complex one and thus raises important questions concerning the role of patients in the context of health care and medical research.

38. Conclusions • Both Europe and the US constitute highly risk averse regulatory environments • industry representatives as well as some parts of organized patient groups have been lobbying for more streamlined and decreased regulatory efforts. • although clinical trials protocols (at least in the realm of more conventional pharmaceutical products and randomized controlled trials/RCTs) have been subject to increased efforts of global harmonization since the 1990s the regulatory regimes in the US and Europe still vary significantly. For industry, the US constitutes a more or less single “technological zone“ with a single regulatory authority, the FDA. In Europe clinical trials authorization and oversight still is in the hands of the Member States’ competent authorities. Despite efforts to harmonize European clinical trials (EU Clinical trials Directive 2001/20/EC), regulatory requirements persist to be highly divergent (O’Donnell 2007).

39. In April 2010, the European Commission even describes the Clinical Trials Directive as “arguably the most criticized piece of legislation” passed by the Community on medicines ever since (EurActiv 22-04-2010)). • In contrast to the US, in Europe – especially in Germany – the role of medical professions and their institutionalized practices of self-regulation also contribute to European efforts to regulate the sector by means of independent regulatory agencies at arm’s length. We will discuss this in more detail below.

40. Major concern for all actors involved in clinical trials is the inherent risks of human subjects’ research. Clinical trials are medical experiments and there resides at least a nuance of indeterminacy in each trial, a chance that something could go wrong. GCP guidelines and ethical review serve the purpose to guarantee the maximum of safety for the trial participants. • Institutions in this field operate political technologies that enable the proceduralization of risk assessment and governance as well as the proceduralization of ethics. With the rise of a bureaucratized bioethical apparatus, ethics has been transformed into a “workable document”. Besides risks to the research subjects, the conduct of clinical trials also involves a series of other social and institutional risks.

41. The highly publicized cases of companies such as US-Geron and UK-ReNeuron are interesting case studies to scrutinize the intertwined dimensions of risk in the governance of advanced biomedicine. • Both the US and the UK can be perceived as highly risk averse regulatory environments. Both are regulatory states with a high level of delegation in regulatory issues to specialized independent regulatory agencies and a tradition of fastidious regulatory science (REFs). • Clinical trials regulations do not only regulate risks, but are co-constructed in complex socio-political and cultural settings. • US: normalizing stem cell trials through institutional continuity • Europe: Governing Europe through creating special institutions for stem cell trial regulation • China: double strategy of regulation and non-regulation describes China´s position in the global economy between taking on global responsibilities and securing competitive advantages