Stem Cell Reports Commentary - Inclusivity and diversity: Integrating international perspectives on stem cell challenges and potential
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Stem Cell Reports
Commentary
Inclusivity and diversity: Integrating international perspectives on stem cell
challenges and potential
Robin Fears,1,* Hidenori Akutsu,2 Lara Theresa Alentajan-Aleta,3 Andrés Caicedo,4 Antonio Carlos Campos de
c,6 Jillian Cornish,7 Giulio Cossu,8 Patrice Debré,9 Geoffrey Dierckxsens,10
Carvalho,5 Miodrag Coli
Nagwa El-Badri, George Griffin,12 Patrick Chingo-Ho Hsieh,13 Maneesha S. Inamdar,14 Pradeep Kumar,15
11
Consuelo Macias Abraham,16 Romaldas Maciulaitis,17 Mamun Al Mahtab,18 Fergal J. O’Brien,19
Michael Sean Pepper,20 and Volker ter Meulen1
1InterAcademy Partnership, ICTP Campus, c/o TWAS, Trieste 34151, Italy
2Center for Regenerative Medicine, National Center for Child Health and Development, Tokyo 157-8535, Japan
3Department of Internal Medicine, University of the Philippines, Manila, Philippines
4Escuela de Medicina, Universidad San Francisco de Quito, USFQ, Quito, Ecuador
5Instituto de Biofisica Carlos Chagas Filho, Universidade Federal, Rio de Janeiro Rj21941-902, Brazil
6Department of Medical Sciences, Serbian Academy of Sciences and Arts, Belgrade, Serbia
7Department of Medicine, University of Auckland, Auckland 1142, New Zealand
8Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester M13 9PL, UK
9Departement d’immunologie, Hopital Pitie Salpetriere, 75013 Paris, France
10Institute of Philosophy of the Czech Academy of Sciences, 110 00 Prague 1, Czech Republic
11Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, 12578 Giza, Egypt
12Institute for Infection and Immunity, St. George’s, University of London, London SW17 ORE, UK
13Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
14Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India
15Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, University of the Witwatersrand, Johannesburg 2193,
South Africa
16Institute of Haematology and Immunology, ‘‘Dr C. Jose Manuel Ballester Santovenia’’, Havana 10400, Cuba
17Institute of Physiology and Pharmacology, Medical Faculty of the Lithuanian University of Health Sciences, 49264 Kaunas, Lithuania
18Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka 1000, Bangladesh
19Tissue Engineering Research Group, Department of Anatomy & Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland
20Institute for Cellular and Molecular Medicine, Department of Immunology, and South African Medical Research Council Extramural Unit for Stem Cell
Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
*Correspondence: robin.fears@easac.eu
https://doi.org/10.1016/j.stemcr.2021.07.003
SUMMARY
Regenerative medicine has great potential. The pace of scientific advance is exciting and the medical opportunities for regeneration and
repair may be transformative. However, concerns continue to grow, relating to problems caused both by unscrupulous private clinics of-
fering unregulated therapies based on little or no evidence and by premature regulatory approval on the basis of insufficient scientific
rationale and clinical evidence. An initiative by the InterAcademy Partnership convened experts worldwide to identify opportunities
and challenges, with a focus on stem cells. This was designed to be inclusive and consensus outputs reflected the diversity of the global
research population. Among issues addressed for supporting research and innovation while protecting patients were ethical assessment;
pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the
public. The InterAcademy Partnership (IAP) identified options for action for sharing good practice and building collaboration within the
scientific community and with other stakeholders worldwide.
Introduction ensuring that research studies collec- 1. To use advances in research
Scientific advances in regenerative tively address therapeutic priorities and development as rapidly as
medicine continue to offer great and have the potential to benefit all possible, safely and equitably,
promise in our attempts to tackle patients. to provide new routes to patient
intractable diseases, including those In 2020, the InterAcademy Partner- benefit worldwide.
presented by aging populations and, ship (IAP), the global network of 2. To support medical claims by
potentially, to reduce health care more than 140 academies of science, robust and replicable evidence
costs. These advances will be appli- engineering, and medicine, consti- so that patients and the public
cable worldwide. However, as noted tuted a working group on regenerative are not misled.
in a recent editorial (Pera, 2020), there medicine to integrate perspectives
is still much to be done to involve from researchers worldwide on the op- This IAP work focused on stem cells
hitherto underrepresented groups in portunities and challenges in this field for unmet medical needs but it is ex-
their contribution to research and in with the following objectives: pected that many of the conclusions
Stem Cell Reports j Vol. 16 j 1847–1852 j August 10, 2021 j ª 2021 The Authors. 1847
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Stem Cell Reports
Commentary
would be relevant more broadly ing disease causes rather than the principles that must be embedded
for regenerative medicine. In this symptoms. The pace of science has in information for patients contem-
context, regenerative medicine is continued to advance rapidly, and plating such offerings. One crucial cri-
described as comprising various novel one of the key messages from the acad- terion is emphasized for patients
interdisciplinary approaches to health emies is that it is vital to grow invest- deciding on whether to consent. Pa-
care, including the use of cell and ment worldwide in basic science to tient consent must be fully informed
gene therapies, aimed at tissue regen- understand cell and tissue biology in terms of the information on risk
eration, repair, restoration, and reor- and to provide the resource for future and effectiveness. In addition, pa-
ganization. Regenerative medicine innovation. However, enthusiasm tients should not be expected to pay
strategies depend upon harnessing, about the broad potential of regenera- to participate in clinical research on
stimulating, guiding, or replacing tive medicine applications has led to a regenerative medicine until it be-
endogenous development and repair disconnect between expectations and comes an approved treatment that
processes. In this commentary we the realities of translating technolo- may be reimbursed according to the
take the opportunity to draw atten- gies into clinical practice. The acade- specific procedures of each country’s
tion to some key points from the mies endorsed a call for substantial health system, whether public or pri-
statement (IAP, 2021) and discuss rethinking of the social contract vate. However, this payment is now
emerging messages in the context of (Cossu et al., 2018) that enables public happening in some countries. A
recent developments. support for research and clinical prac- requirement to pay to participate is
Scientists, nominated by IAP mem- tice. It is vital to tackle multiple issues not unique for the field of regenerative
ber academies, provided inputs from for poor-quality science, inconsistent medicine, despite restraints offered by
Bangladesh, Brazil, Cuba, Czech Re- ethical and regulatory policies, un- current safeguards by regulatory au-
public, Ecuador, Egypt, France, Ger- clear funding models, unrealistic thorities and institutional review
many, India, Ireland, Italy, Japan, hopes, and unscrupulous commercial committees and the standards of med-
Lithuania, New Zealand, Philippines, clinics. In the social contract, citizens ical professionalism. The ethical issues
Serbia, South Africa, Taiwan, and the pay tax and/or insurance to get the may be complex (Shaw et al., 2017)
UK, with expertise in medical disci- best available treatment for diseases and it is crucially important that the
plines, biosciences, and ethics. At the that may affect them. They expect research oversight system is suffi-
time of writing this commentary, that therapy will constantly improve, ciently robust to ensure that all trials
the consensus statement has been but this requires research, especially satisfy the standards of ethical
endorsed by the majority of IAP acad- on basic mechanisms of diseases, research (Lynch and Joffe, 2019).
emies. One of the starting points for which funding agencies are less in- Second, there is an evidence crisis as
preparation of the IAP statement was clined to fund than translational a result of premature marketing
a comprehensive joint report by the research. Moreover, incurable diseases approval and commercialization of
academies of science and medicine lead patients to uncritically accept any expensive approaches based on
across the European Union (EU) proposed therapy, exposing them- some, but insufficient, scientific ratio-
(Cossu et al., 2020; EASAC and selves to possible clinical risks and nale and clinical evidence, facilitated
FEAM, 2020) that incorporated discus- certain economic damage. The conse- by regulatory authority initiatives
sion from an academies-organized ses- quences of not tackling the challenges for accelerated access. Conditional
sion at the World Science Forum in and finding the right balance for approval or other accelerated access
2019. research and innovation would be to mechanisms have been introduced in
waste investment and researchers’ the EU and in other countries,
IAP global statement main time, as well as to undermine patient including Japan, the United States,
messages trust and protection. and Canada. Efforts to provide acceler-
Although stem cell therapy has There are two main problems. First, ated access to innovation are welcome
proved itself, so far, in the treatment in many countries, commercial clinics in principle, and it is acknowledged
of only a limited number of approved offer unregulated products and ser- that, when the number of available
clinical indications, there is very vices promising a wide range of patients is low, there may be a need,
active research and development un- benefits using poorly characterized for example, to combine work on
derway for many others, including treatments with little or no evidence proof of concept with dose finding. It
neurological, hepatic, cardiovascular, of efficacy, with safety concerns, must also be generally recognized
retinal, and musculoskeletal disorders, misleading scientific rationale, and that there is an accelerating pace in
as well as cancers. There is potential with the primary intention of profit. moving from research discovery to
for transformative change in address- The IAP statement offers guidance on human applications: this has been
1848 Stem Cell Reports j Vol. 16 j 1847–1852 j August 10, 2021Stem Cell Reports
Commentary
noteworthy recently during the coro- therapeutic effect; the reason cannot example, in Iran (Afshar et al., 2020).
navirus disease 2019 (COVID-19) be that there is no other therapeutic IAP has previously published general
pandemic and will be discussed later. option. In 2017, a child affected by ep- guidance (IAC and IAP, 2012) for
However, granting early access trans- idermolysis bullosa, already consid- promoting responsible science, with
fers financial costs and the burden ered a terminal patient, was returned recommendations for researchers,
of medical uncertainty from drug de- to a normal life thanks to the auto- research institutions, research fun-
velopers to health care systems and transplantation of autologous, geneti- ders, and journals. These broad recom-
from trial participants (who should cally corrected epidermis (Hirsch mendations are relevant to the
be required to undergo rigorous et al., 2017). Although this treatment conduct of regenerative medicine
informed consent procedures) to was outside of a regular clinical trial, when integrated with community
health care consumers (who are not). it was supported by a previous proof- standards of medical practice. Acade-
Further discussion on early access, for of-concept study (Mavilio et al., mies, with their power to convene ex-
example on problems related to surro- 2006) and by 40 years of successful perts from many scientific disciplines,
gate endpoints and weak post-market- clinical practice of epidermis auto- can also help by building inclusivity
ing obligations, is provided in the Eu- transplantation in large burns. to tackle the interdisciplinary weak-
ropean academies’ work (EASAC and Within the EU there is substantial ness that may hinder the pace of prog-
FEAM, 2020). variation in national hospital exemp- ress in this field (Cheuy et al., 2020).
In this era of increasing pressure for tion provisions relating to the criteria A second pervasive theme is for
international competitiveness, where for unmet medical needs and benefit/ setting the balance between promo-
some medicines regulatory frame- risk balance (Hills et al., 2020). Thus, tion of innovation and the obligation
works become increasingly permis- there are considerable challenges for to put patients first. For example, the
sive, it is important that countries do using hospital exemption consistently objective to increase investment in
not lower their regulatory thresholds as a mechanism in support of innova- basic and clinical research must be
without fully considering the conse- tion, while also safeguarding public accompanied by solutions to the prob-
quences for patient safety, health health and ensuring that evidence- lem of how expensive therapies can be
care budgets, and public trust in sci- based clinical trials are not circum- reimbursed, otherwise medicine pipe-
ence, and without ensuring that com- vented (EASAC and FEAM, 2020). In lines will be filled with innovation
mitments on post-marketing studies EU member states and elsewhere, it is that cannot be afforded. Expensive
are respected. Undesirable practices important to counter the perception therapies appear inequitable but it is
inherent in stem cell tourism in that hospital exemption should necessary to take a long-term health
some countries (e.g., Skeen et al., be used as a cheaper and quicker economic perspective. Advanced
2019; Julian et al., 2020) are one approach for therapies that would technologies in regenerative medi-
consequence of the relative laxity in typically be approved under a market cine, if treating the cause of disease,
some national regulatory frameworks. authorization. may bring sustained and substantial
cost savings and may eliminate the
Supporting responsible science long-term costs of poorly efficacious
HOSPITAL EXEMPTION and innovation current therapies.
PROCEDURES The IAP statement assessed a range of The issues for responsible science
issues for supporting responsible sci- and its applications are illustrated by
In some countries, unlicensed medical ence and innovation (Table 1). One the experience of the COVID-19
products in development can be used cross-cutting issue is the need to do pandemic. Although there is a need
under certain regulated procedures to more to facilitate internationally for urgent intervention with novel
allow named patients early access to agreed frameworks for robust, inter- therapies, proposed use of stem cells
innovation in situations of unmet disciplinary assessment of research during a pandemic must also be based
clinical need. For example, in the protocols and evidence collection. on rigorous evidence of safety and
EU, there is the hospital exemption This has implications for research efficacy following strict research
provision (regulation 1394/2007/EC). infrastructure and for sharing (and protocols that address the ethical is-
While it is important not to preclude possibly certifying) skills worldwide, sues and characterize the cells used,
any accelerated procedures such as particularly for low- and middle-in- focusing on a defined stage of the dis-
hospital exemptions and compas- come countries (LMICs). There is also ease and in the hands of a team
sionate use, they must be carefully interest worldwide in ethical guide- with capacity to undertake the inter-
scrutinized and authorized when suffi- lines for research on regenerative med- vention. Unfortunately, as the US
cient evidence suggests a possible icine (Table 1), including recently, for Food and Drug Administration (FDA)
Stem Cell Reports j Vol. 16 j 1847–1852 j August 10, 2021 1849Stem Cell Reports
Commentary
Table 1. Supporting research and innovation in regenerative medicine while protecting patients
Priorities Summary of points covered in IAP statement
Ethical assessment Ethical issues relate to uncertainty, patient consent, professional responsibilities,
equity, and fairness. Concerns are evaluated further by Hermeren (2021) amid increasing
momentum worldwide to discuss ethical issues. There are implications for professional
training and constitution of ethics committees
Research in vitro and in animal models Need for robust scientific foundation for clinical research and for ensuring consistency
in composition and viability of a novel agent as it moves through successive stages of
research and development
Clinical trials Should be conducted according to approved design and monitoring procedures with
transparency in data collection. The orphan nature of some rarer applications must be
recognized in trial design to ascertain the acceptable level of evidence for safety
and efficacy
Regulatory authorization and access to new medicines Proportionate and consistent regulation must be based on replicable science and
international development of standards as a step toward necessary regional and
global regulatory coordination in addressing discrepancies (Qiu et al., 2020). LMICs
must be included in global convergence on quality, efficacy, safety, and post-marketing
surveillance (WHO, 2020)
Engaging with patients, policy makers, and the public Notwithstanding the excellent work of the International Society for Stem Cell Research,
there is more to be done to describe the difference between evidence-based practice and
unproven, erroneous, and illegitimate practices. This requires an informed public and
well-advised health professionals and regulators worldwide
For the IAP statement, see IAP (2021).
observed early during the pandemic form a starting point for larger, collab- mation so as to discourage unproven
(Marks and Hahn, 2020), some of the orative trials designed to evaluate effi- practices.
same clinics that have been offering cacy. A publication by IAP (https:// First, although there is a long his-
unproven stem cell therapies for www.interacademies.org/sites/default/ tory of valuable comment from re-
diverse conditions are now offering files/2021-05/IAP_strenghtening_ searchers in developed economies
unproven treatments for the compli- research_0.pdf), on the challenges for (e.g., McMahon and Thorsteinsdottir,
cations of COVID-19. There is the strengthening research on COVID-19 2011) about the priorities for LMICs
additional concern during the more broadly, discusses the general is- in building their research capacity
pandemic that if such approaches are sues associated with improving and addressing their research prior-
used outside of the conventional hos- research questions, study design, trial ities, less has been heard from the re-
pital setting, then the unproven conduct, and reporting (all areas searchers themselves in LMICs in
claims for efficacy may encourage pur- where some COVID-19 research has contributing to engagement world-
chasers to refrain from taking other been of insufficient quality to inform wide. The IAP statement aims to
steps, such as wearing face masks and practice; Glasziou et al., 2020). help redress this lack of inclusivity
social distancing, to protect them- and diversity. This requires further
selves and others from COVID-19. Engaging within the scientific discussion—and action—on research
While the early claims were premature community and with stakeholders and innovation priorities and capa-
and risked undermining confidence in worldwide bilities worldwide, and on their
regenerative medicine approaches, Scientific and medical communities connection with policy and practice.
recent assessment is helping to clarify worldwide have a responsibility to In seeking to catalyze the raising of
the scientific rationale and limitations provide reliable sources of informa- community awareness of the value
of stem cells to halt the inflammatory tion and ensure that discussions and of greater inclusivity (Pera, 2020),
cascade in COVID-19 (Durand et al., decisions are evidence based and that IAP also builds on earlier work in
2020; Monguio-Tortajado et al., voices, previously muted, are now LMICs with other academy networks
2021). It remains the case that stem heard. In conclusion, we emphasize and national academies, for example
cells might prove to be of value, and two overarching points: building in training and mentoring African
well-designed experimental medicine research capacity to address unmet scientists in stem cell and regenera-
studies (Lanzoni et al., 2021) can medical needs, and tackling misinfor- tive medicine, and there is scope to
1850 Stem Cell Reports j Vol. 16 j 1847–1852 j August 10, 2021Stem Cell Reports
Commentary
do more in collaboration with profes- and medical device regulations, Samani, R.O., Ashtiani, M.K., Azin, S.-A.,
sional societies. including those appertaining to regen- Hajizadeh-Saffar, E., et al. (2020). Ethics of
Second, previous guidelines by erative medicine (Executive Commit- research on stem cells and regenerative
scientific societies and others, while tee on Global Health and Human Secu- medicine: ethical guidelines in the Islamic
Republic of Iran. Stem Cell Res. Ther. 11,
of great importance, have provided rity, 2020), includes objectives for
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insufficient guidance to curtail the capacity building in regulatory science
01916-z.
rise of the use of stem cells of un- as well as in clinical development infra-
Cheuy, V., Picciolini, S., and Bedoni, M.
proven benefit. It is time here also for structure and other opportunities for
(2020). Progressing the field of regenerative
renewed and inclusive efforts world- developing academia-industry-govern-
rehabilitation through novel interdisci-
wide involving multiple stakeholders ment collaboration. The specific re- plinary interaction. NPJ Regen. Med. 5,
and researchers, regardless of their quirements for skills and training in 16. https://doi.org/10.1038/s41536-020-
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formation go deeper than possible considered in the wider context of Cossu, G., Birchall, M., Brown, T., De
harm to individual patients—crucially responsible science (IAC and IAP, Coppi, P., Culme-Seymour, E., Gibbon, S.,
important though that is—because 2012) and alongside other efforts to Hitchcock, J., Mason, C., Montgomery, J.,
there is wider potential to harm the improve research governance, report- Morris, S., et al. (2018). Lancet Commis-
credibility of research and scientific ing, and dissemination. For example, sion: stem cells and regenerative medicine.
integrity. Academies have strengths IAP has a current project on combatting Lancet 391, 883–910. https://doi.org/10.
in public outreach and education predatory academic journals (https:// 1016/S0140-6736(17)31366-1.
and can help to support the scientific www.interacademies.org/project/pre Cossu, G., Fears, R., Griffin, G., and ter Meu-
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mation. However, this is not enough IAP encourages its academy mem- lenges and opportunities. Lancet 395,
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(Matthews and Iltis, 2017); scientists bers and their regional networks to
6736(20)31250-2.
must also engage with policy makers. continue to engage worldwide, in
Durand, N., Mallea, J., and Zubair, A.C.
The commitment by scientific ex- advising on formulation of guidelines
(2020). Insights into the use of mesen-
perts to this IAP project has identified for research and its reduction to prac-
chymal stem cells in COVID-19 mediated
several opportunities where the rela- tice; in appraisal of the evidence base acute respiratory failure. NPJ Regen. Med.
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scientific societies can be augmented, safety; in engaging in public debate 00105-z.
at national and regional levels, and about the value of innovation; and in EASAC and FEAM (2020). Challenges and
where, collectively, the scientific com- helping policy makers to decide on pri- Potential in Regenerative Medicine (EASAC
munity can support national regulato- orities for pursuing health and equity. and FEAM).
ry agencies and their international con- Executive Committee on Global Health and
nectivity The significant potential for AUTHOR CONTRIBUTIONS Human Security (2020). A UHC Approach to
academies worldwide can be exempli- Initial drafting of the manuscript was by R.F. Harmonizing Asian Pharmaceutical and
fied by the follow-up in Europe, where All authors contributed to the discussion Medical Device Regulations (Japan Centre
academy advice was delivered earlier and revision of the manuscript draft and to for International Exchange). https://www.
(EASAC and FEAM, 2020). European the response to reviewers. All authors also jcie.org/programs/global-health-and-human-
academies and their experts continue contributed to the working group discussion security/executive-committee-on-global-
health-and-human-security/task-force-for-
to engage with the European Medicines that led to the preparation of the IAP State-
ment on Regenerative Medicine (IAP, 2021). promoting-pharmaceutical-medical-device-
Agency and with other stakeholders
regulatory-harmonization-in-asia/.
and policy makers, e.g., in the new Alli-
Glasziou, P.P., Sanders, S., and Hoffmann,
ance for Transformative Therapies,
T. (2020). Waste in COVID-19 research. Br.
with particular interests in the educa- CONFLICT OF INTERESTS
Med. J. 369, m1847. https://doi.org/10.
tion of patients and health care profes- 1136/bmj.m1847.
A.C. is CEO of Dragon BioMed-USFQ and
sionals (https://rpp-group.com/files/ M.S.P. is founder of the biotech company Hermeren, G. (2021). The ethics of regener-
eaftt/index-lp.html) as well as in other Antion biosciences (https://antion.ch/#1). ative medicine. Biol. Futura https://doi.
established networks of researchers, pa- Other authors declare no competing interests. org/10.1007/s42977-021-00075-3.
tients, educators, and regulators (e.g.,
Hills, A., Awigena-Cook, J., Genenz, K.,
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