Achim Rosemann University of Sussex ar253@sussex.ac.uk

1. Regenerative medicine research as global collaborative project: opportunities, challenges, conflicts Achim Rosemann University of Sussex ar253@sussex.ac.uk

2. Key terms • “Stem Cells” • Sources • Therapeutic potential • Broad range of medical applications • “Regenerative Stem Cell Medicine” • Evolving medical paradigm • New types of risks • Regulatory challenges / no international harmonization yet • “Clinical translation” • Translation of new therapeutic application from bench to bedside to market • Very divergent forms.

3. Outline Presentation • Part I: Overview Literature on clinical translation in stem cell (SC) field • Identification of analytical gaps • Theoretical relevancy of the study of international stem cell clinical trial partnerships • Part II: Introduction of Case Study – The China Spinal Cord Injury Net • Geographic scope and objectives • Part III: Standardization and scientific self-governance: forms and challenges • Part IV: Key-Findings in relation to theme of ‘standardization’ in context of China SCI Net • Situation and and context specificity of transnational research zones • Advantages of operating across heterogeneous forms of clinical experimentation • Forms of resistance and Alter-standardization • Conclusions

4. Part I: Overview Literature and Gaps

5. Clinical translation in regenerative stem cell medicine: ethnographic studiesFour central study directions • (1) Preclinical Development (that precede first in human applications) - Cribb, A., et al. (2008). Towards the applied: the construction of ethical positions in stem cell translational research. Medicine, Health Care & Philosophy. - Martin, P., Brown, N., and A. Kraft (2008). From Bedside to Bench? Communities of Promise, Translational Research and the Making of Blood Stem Cells, Science as Culture. - Wainwright, S.P., et al., 2006a. From bench to bedside? Biomedical scientists’ expectations of stem cell science as a future therapy for diabetes. Social Science & Medicine - Wainwright, S.P, and Williams, C. (2009) Spaces of speech and places of performance: an outline of a geography of science approach to embryonic stem cell research and diabetes, New Genetics and Society. • (2) The uptake of randomized controlled trials (in Europe and USA) - Webster, A., et al. (2011). Experimental heterogeneity and standardization: stem cell products and the clinical trial process.Biosocieties - Wilson-Kovacs DM, Hauskeller C. 2011. The clinician-scientist: professional dynamics in clinical stem cell research. Sociology of Health & Illness - Wilson-Kovacs DM, Weber S, Hauskeller C. 2010. Stem cells clinical trials for cardiac repair: regulation as practical accomplishment. Sociol. Health Illn. • (3) Experimental for-profit stem cell treatments (especially in Asia) - BharadwajA, Glasner P. 2009. Local Cells, Global Science: The Rise of Embryonic Stem Cell Research in India. London: Routledge - PatraPK, Sleeboom-Faulkner M. 2009. Bionetworking: experimental stem cell therapy and patient recruitment in India. Anthropological Medicine - PatraKP, Sleeboom-Faulkner M. 2011. Recruiter-patients as ambiguous symbols of health: bionetworkingand stem cell therapy in India. New Genet. Soc. - Song, P. (2011) The proliferation of stem cell therapies in post-Mao China: Problematizing ethical regulation. New Genetics and Society 30(2): 141–153. - Chen, H. (2009). Stem cell governance in China: from bench to bedside?. New Genetics and Society, 28(3), 267–282. • (4) International flows and exchanges - Chen, H.D., and H. Gottweis (2011). Stem Cell Treatments in China: Rethinking the patient role in the global bio-economy. Bioethics - Kent, K. (2012) Regenerating bodies: tissue and cell therapies in the 21st century, Routledge - Sleeboom-Faulkner, M. and P.K. Patra (2011). Experimental stem cell therapy: Biohierarchies and bionetworking in Japan and India, Social Studies of Science • WaldbyC, Mitchell R. 2006. Tissue Economies: Blood, Organs and Cell Lines in Late Capitalism. Durham, NC: Duke Univ. Press

6. Gaps in Literature Three unexplored dynamics • (1) Increasing significance of randomized controlled clinical trials (RCTs) in Asian societies • Aiming to formal approval of SC-based medicinal products, under review of drug regulatory agencies • (2) Increasing formation of multi-country clinical trial partnerships in regenerative SC medicine • (3) Trend of Clinical Trial “Mimicry” • Uptake of clinical trial methodology, by providers of unproven therapies Focus in this presentation: theme 2 First clinical trials network in SC field USA/ Asia

7. Theoretical Relevancy: Of the study of international clinical trial collaborations in regenerative stem cell medicine field • (1) Global Distribution of Evidence Based Medicine Standards • (2) Processes of Standardization, Scientific Self-governance, and International Harmonization • (3) Development of large scale international collaborations • (4) Implications of the increasing scientific significance of societies in Asia (in this study especially, China)

8. Part II: Introduction of Case Study

9. Introduction China SCI Net and SCI Net USA: • China SCI Net founded in 2005 by HK born researcher from USA, under umbrella of HKU • (2) Close ties to US (parallel network in USA (since 2010 – 8 hospitals), but: • - Leadership of China SCI Net – from HK, and ML China • - Targeting benefits in first place for SCI researchers and patients in China • (3) Transnational flows: • Transfer of data and clinical experience from China to USA • Data in China shall be used for application at US FDA (4) Several phase I & II trials have been conducted Phase II and III trials are in preparation, in both US and China

10. Clinical Rationale and Approach Organization tests a stem cell-based combination therapy of: (1) Injection of Umbilical Cord Blood Mononuclear Cells into spinal cord, following surgery (2) Six week course of lithium (3) One time high-dose injection of

11. Central Objective of Network:Creation of a transcontinental standardized multi-center clinical trial infrastructure • Creation of multi-center clinical trial network that is able to: • Create fully standardized clinical data, that can be accepted by: • Drug regulatory authorities in China, Hong Kong, Taiwan and the USA • Goal: Realize maximum scope of access to SCI patients

12. Part III: Standardization and scientific self-governance

13. Standards / Standardization & Scientific Self Governance • International standards: (Timmerman and Epstein 2011) • Crucial instruments for organization and governance of modern science • Construct uniformities across time and space • Create homogenized international research zones • Allows for validation of data and findings, from highly dispersed communities • Are controlled through gate-keeping institutions: • drug regulatory authorities, editorial boards of scientific journals, peer-review, scientific societies, ethics committees, etc • Scientific Self-governance (in transnational contexts) “Project-internal forms of self-regulation and capacity building that aim for the creation of a standardized trans-institutional research infrastructure that is compliant with multi-country regulatory requirements and/ or other international scientific standard systems.” • China SCI Net – must meet regulatory requirements of : • the SFDA (China), the DOH (HK), the TFDA (Taiwan), and the FDA (USA)

14. Brief illustration: Modes of clinical translation among associated hospitals (to China SCI Net) • China SCI Net (as a whole) • Hospitals A, B, C • Hospital D • Hospital E • Differences with regard to: • (1) Approval / Review • (2) Research methodologies • (3) Access to treatment (target population) • (4) Forms of capitalization

15. Standardization 1. Standardization of time: medical interventions, physical examinations, lab tests, etc 2. Standardization of Surgery 3. Standardization of Injection 4. Standardization of Cells

16. Standardization II: 5. Standardization of in- and exclusion criteria 6. Standardization of rehabilitation protocols 7. Standardization of outcome measures

17. Methods and techniques of standardization • (1) Selection procedures (of hospitals): • External assessment parameters: • GCP qualifications of hospitals, GTP qual. of labs • Practice Based assessment parameters • Observation Trial • (2) Training • in clinical trial design and methodology • in standardized procedures (surgery, injection, etc) • (3) Implementation of control and supervision structure • Web based monitoring system • Supervisor- head of department – double signing system • Work with CRO (contract research organization) in phase IIII trial

18. Part IV: Key-Findings related to themes of standardization and scientific self-governance

19. The situation and context specific character of:Trans-continental standardized research zones • Andrew Barry (2005): Technological zones “A space within which differencesbetween technical practices, procedures, and forms have been reduced, or common standards have been established.” • Standardized research zone China SCI Net: • Only existent in context of network’s clinical trials • Not permanent or enduring • Standardized zones can be switched on and off • Depending on situational requirements, partners, regulatory agencies involved, objectives of research, etc. • Multiple forms of clinical research co-exist side by side • In same hospital, department, under supervision of same researcher

20. The co-existence of multiple forms of clinical experimentation: opportunities and forms of knowledge transfer • Coexistence of multiple forms of clinical experimentation, in context of regulatory flexibility: • Allows the tapping of experiences and knowhow, not existent in USA • Allows knowledge transfer from low to high regulated countries • This forms: • Alteration of dominant regulatory paradigm, through which clinical research is regulated in USA • Poses some questions about ethics, and regulation of international partnerships

21. Standardization and Resistance • Standards stratify social realities and practices • i.e. standards function as mechanisms of in- and exclusion • Restructure existing normative systems • Restructure livelihoods • (for instance – if SC clinics are closed down) • Definitions of what counts as “international” are highly contested • Aura of universality, but: • grounded in particular localities • disguises local and trans-local power-play • disguises the interests of particular stakeholders • Result: Resistance and Alter-standardization

22. Alter-standardization and pluralization • Resistance to international standards: • Pronounced in clinical stem cell field in China • Rigidadoption of “international” regulation would mean: • Devaluation of various existing practices • Closing down of clinics • Loss of livelihoods • What is at stake is: • Clash between an evolving and in many respects imported form of regulatory authority, with • Local forms of professionalism and research validation • These local forms are based on: • Historically evolved conceptions of medicine and medical research • New forms and opportunities of capitalization and profit making • Processes of ‘alter-standardization” (as counter strategy) • i.e. the formation of novel transnational networks of institutional spaces, knowledge sharing and publication • These evolving transnational spaces of ‘alter-standardization: • Endorse and validate alternative forms of experimental research • With ethical and research protocols that – in numerous respects – • Diverge from current international scientific standard cannon.

23. Case – The International Association of Neurorestoratology (IANR) • IANR: good example of “alter-standardization” • International Society founded by neurosurgeon from Beijing • New sub-branch of the neurosciences: neurorestoratology • Many members of IANR offer – experimental for-profit applications • Neurorestoratology: • Combines various medical approaches • (cell and SC based approaches feature high) • Patient Centered. Aims to: • Restore neurological functions in patients • Improve quality of life • Focus – on patients wellbeing used to: • Endorse the use of efficacy and safety assessment procedures other than randomized controlled clinical trials (RCTs) • To legitimize less rigorous forms of medical experimentation • Such as self-comparison of patients

24. Case – The International Association of Neurorestoratology • IANR: • Creates platform for global sharing of knowledge – of research conducted outside of international standard system • Does so by • (1) Creating new possibilities for publication • (2) Organization of large scale conferences • Plays a pivotal role in gradually transforming previously marginalized forms of experimental clinical research from: • Being unacceptable and critical • To a slowly tolerated component of the ordinary

25. Conclusions • Clinical research collaborations across contexts of regulatory diversity • Perils: • Daunting Tasks, multiple challenges • Intensive forms of trans-national scientific self-governance required • Need to compensate / fill the gaps of state regulation • Advantages: • Tapping of unprecedented experiences • Access to low cost environment, large numbers of patients • The fragility / polymorphous character of transnational technological zones • Internationalization and its discontents: • Processes of alter-standardization • Pluralisation of the international / of international standard systems • Dilemma: notions of suppressed “subalterns” that need a “voice” through a well-intended anthologist doesn’t work here; • we are dealing with risky and highly profit oriented forms of experimental medicine • Formation of alternative transnational networks and platforms of knowledge sharing