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Governing Clincial Trials with Stem Cells in
Europe, the United States, and China:
Towards a Global Model?
Herbert Gottweis, Christian Haddad: Life Science Governance
Institute, Vienna
Haidan Chen: STS Research Center, Zhejiang University
REMEDiE meeting, June 2010
Governing Regenerative Medicine
low
high
hESC
Gene Transfer
Therapies
(Adult) Stem Cell
Therapies
iPS
siRNA
low
high
Clinical trials: are intended to develop drugs that are safe
and efficient.
 Research subjects need to be protected from harm
 Protocoll for clinical trials is build around these ideas.
Laboratory
preclinical
studies
Good quality
Safe in animals
Promising effects?
Safe for human
trials
20-80
healthy
volunteer
s
Up to
200/300
patients

Up to 3000
patients

 Hospital
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
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Phase 1
Phase 2
Phase 3
CLINICAL TRIALS
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




(Clinical use)
SOCIETY



safety
Proof of
concept
Does it
work?
Therapeutic
proof


 Pharmacy



Haddad, 2010
 Clinical trial protocols often vary greatly between settings, such as
between Europe, the United States, and China.
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)
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.
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 coproduce 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.
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).
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).
Geron
 First hESC-based investigational therapy, seeking IND approval to
start trials for years. FDA very reluctant.
 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)
 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”.
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.”
The US System
The Developer‘s View
MAA
Phase II
Phase III
Phase III
PrePhase I
Phase IV
Phase III
clinical
Phase II
<--------------------- Drug Development -------------------->
The FDA View
End of Phase II
MAA
Phase II
Phase III
Phase III
PrePhase I
Phase IV
Phase III
clinical
Phase II
Pre-IND
<--------------------- Drug Development -------------------->
14
The European System
The Developer‘s View
MAA
Phase II
Phase III
Phase III
PrePhase I
Phase IV
Phase III
clinical
Phase II
<--------------------- Drug Development -------------------->
The European Regulator‘s View
MAA
Preclinical
Phase II
Phase I
Phase III
Phase III
Phase IV
Phase II
Phase III
<--------------------- Drug Development -------------------->
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

 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.
USA versus Europe
FDA
EMA
Drug Development
Natl. CA
Clinical trials in
Member States
 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).
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).
 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).
 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))
 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.
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”)
Essential Differences
U.S.A
IND number – single active
substance
Europe
EUDRA-CTs
Tight quality requirements endof-phase II (EOP II)
GMP inspection at MAA
GMP certificate required for phase I
Continuous process (possibly
same review-team)
„Isolated“ clinical trials
Decision by precedents
Culture
Case-by-case decisions
Culture
Pre-IND Meeting, EOP II
Scientific Advice
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
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
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
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”
……
 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.
 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
 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.
 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.
 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.
China
MOH
SFDA
Drug Development
Clinical trials
Clinical application of
medical technology
 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.
 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.
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).
 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.
 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.
 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 coconstructed 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