The drivers and barriers for the adoption of

regenerative adult stem cell-based therapies

Author: Paula Salme Sandrak
Academic supervisor: Samer Yammine, PhD
Company representatives:
Emily Jordan, PhD, Jan Schaefer, MD, PhD
Degree Project, 30 Credits
Master Program in Bioentrepreneurship (2018)

Department of Learning, Informatics, Management and Ethics (LIME)
Examinator: Madelen Lek
ABSTRACT
Stem cells can be used to support the intrinsic regenerative mechanisms of the body to establish
the normal function of its diseased organs and tissues. Their therapeutic potential lies mainly
in indications where current treatments cause inconvenient side effects, offer temporary
resolve, or have been fruitless. Among different types of adult stem cells, mesenchymal stem
cells have been shown to have significant clinical potential, but their global adoption is
influenced by many complex and ever-changing commercial and regulatory factors. Therefore,
the aim of this study was to explore the global adoption of mesenchymal stem cell-based
treatments and their global market positioning. A qualitative research strategy was employed
whereby eight cross-sectional, semi-structured interviews were conducted with global key
opinion leaders from markets that have a major influence on the mesenchymal stem cell space
(the United States of America, Germany, Sweden, Japan, Thailand, and South Korea). The
findings indicate that the field is driven by the clinical safety and operational ease of
mesenchymal stem cell-based therapies, arbitration of local regulatory systems, emerging
precedent regulations, and patient-sourced financial donations. The main barriers that were
seen to hamper the adoption included insufficient cell biology and clinical knowledge, the lack
of adjusted global and country-specific regulations, and an inadequate education of authorities
and patients. Additional hurdles included the financial constraints of researchers and the
competing interests of the pharmaceutical industry. Key opinion leaders suggested that
companies and clinics should focus on consistent data gathering, consolidation of a global
regulatory framework, and the creation of an international registry infrastructure to aid
evidence collection and utilization. Besides that, stakeholders should position themselves
according to independent international organizations, academic institutions, and advocacy
groups to further collaboration and education. Global cooperation is required for the adoption
of MSC-based therapies and should be employed in establishing data registries, funding
streams, and harmonized regulations.

Keywords

Regenerative Medicine, Stem Cells, Regulations, Mesenchymal Stem Cell-Based Treatment

Adoption, Stem Cell Transplant
POPULAR SCIENCE SUMMARY
Regenerative medicine is an emerging field of healthcare that has the potential to relieve and
even solve an astounding variety of health problems. Stem cell therapies, the most substantial
part of this field, deploy special cells that are able to repair and replace old or damaged tissues
because they can develop into a range of cells that fulfill different useful functions in the body.
Mesenchymal stem cells are seen to have particular therapeutic potential as they are easily
accessible and demonstrate clinical benefits. On the other hand, therapies based on these cells
have not yet been widely embraced by clinicians and patients around the world due to various
commercial and legislative barriers that complicate the adoption process. This study aimed to
explore the diverse factors that influence the worldwide adoption of mesenchymal stem cell-
based treatment offerings and to understand how the companies and clinics prefer to respond
to these factors in pursuit of success. Eight interviews were conducted with clinical, scientific,
and industry experts from the United States of America, Japan, Thailand, South Korea,
Germany and Sweden. Multiple factors that influence the adoption were identified and key
findings indicated that although the studied therapies demonstrate various clinical advantages
over currently existing treatment options, further scientific and clinical evidence is needed. The
field is pressured by competitive interests and immature regulatory systems which raise the
need for globally consolidated legislations. Providers should focus on international
collaboration and build shared infrastructures to support the process of adoption on scientific,
financial, and educational levels. These findings indicate that clinicians and companies can
encourage the widespread endorsement of mesenchymal stem cell-based therapies by engaging
in global cooperation.
ABBREVIATIONS
ASC – adult stem cell
CAGR – compound annual growth rate
DTC – direct-to-consumer
EMA – European Medicines Agency
ESC – embryonic stem cell
EU – European Union
FDA – Food and Drug Administration
iPSC – induced pluripotent stem cell
ISSCR – International Society of Stem Cell Research
KOLs – key opinion leaders
MPSC – multipotent stem cell
MSC – mesenchymal stem cell
PMDA – Pharmaceuticals and Medical Devices Agency
PPSC – pluripotent stem cell
RCTs – randomized clinical trials
RMAT – regenerative medicine advanced therapy
SVF – stromal vascular fraction
USA – United States of America
TABLE OF CONTENTS
1. INTRODUCTION ............................................................................................................. 1
2. BACKGROUND ............................................................................................................... 1
2.1 Literature Review ......................................................................................................... 1
2.1.1 The Promise of Stem Cell-Based Treatment Options ......................................... 1
2.1.2 Supply and Demand Influences Stem Cell-Based Treatment Offerings .............. 2
2.1.3 Adult Stem Cells in the Context of Regenerative Medicine ................................ 2
2.1.3.1 The Current State of Clinical Development of MSC-Based Treatments .......... 3
2.1.4 National Authorities Shaping MSC-Based Treatment Landscape ....................... 4
2.1.4.1 The Direct Impact of Unharmonized Regulatory Landscape ........................... 4
2.1.4.2 Market Access Acceleration Schemes ............................................................. 5
2.1.5 The Effect of Direct-to-Consumer Marketing .................................................... 6
2.1.6 The Role of Medical Innovation Practice in Adopting New Treatments ............. 7
2.2 Problem Statement ....................................................................................................... 8
2.3 Study Value and Connection to Bioentrepreneurship .................................................... 8
2.4 Aim of the Study ........................................................................................................ 10
2.4.1 Research Questions ......................................................................................... 10
2.4.2 Delimitations ................................................................................................... 10
3. METHODS...................................................................................................................... 11
3.1 Research Design ......................................................................................................... 11
3.2 Data Collection .......................................................................................................... 11
3.2.1 Sampling of Study Participants ........................................................................ 12
3.3 Method of Analysis .................................................................................................... 14
3.4 Ethical Considerations ................................................................................................ 14
4. RESULTS ....................................................................................................................... 16
4.1 Public Awareness of Existing Options and Their Therapeutic Capacity ...................... 16
4.2. Scientific and Clinical Data Generation and Collection.............................................. 18
4.2.1 Data Generation Priorities ............................................................................... 18
4.2.2 Global Data Registry Infrastructure ................................................................. 19
4.3 Global Regulatory Harmonization Efforts................................................................... 20
4.3.1 Global Regulatory Arbitrage............................................................................ 20
4.3.2 Precedent Approvals to Guide the Industry ...................................................... 21
4.4. Financing of Research and Care ................................................................................ 21
4.4.1 Lack of Research Grants and Coverage ........................................................... 21
4.4.2 Controversies Associated with Financial Donations Collected from Patients ... 22
 4.5 Competing Interests of the Pharmaceutical Industry ................................................... 22
5. DISCUSSION.................................................................................................................. 24
5.1 Drivers and Barriers for the Adoption of MSC-based Treatment Options ................... 24
5.2 The Response to the Market Dynamics of MSC-based Treatment Options.................. 25
5.3 Implications and Areas of Future Research ................................................................. 26
5.4 Strengths and Limitations ........................................................................................... 27
6. CONCLUSION ............................................................................................................... 28
ACKNOWLEDGEMENTS ................................................................................................. 29
REFERENCES .................................................................................................................... 30
APPENDICES..................................................................................................................... 36
Appendix I. Invitation Letter................................................................................................ 36
Appendix II. Informed Consent and Interview Guide ........................................................... 37
Appendix III. Declaration on Ethics in Relation to Master’s Thesis Projects at LIME .......... 39
1. INTRODUCTION
Regenerative medicine holds the potential to greatly influence healthcare. Stem cell-based
treatments play a flagship role in this space thanks to their therapeutic capacity and possible
ability to alleviate various unmet medical needs. Such therapies offer both ethically and
clinically feasible commercialization pathways, particularly mesenchymal stem cells (MSCs),
a subtype of adult stem cells (ASCs) found in various parts of the body. The adoption of these
therapies is influenced by a variety of factors that can act as both drivers and barriers for the
introduction of innovative medical solutions. Such factors include (but are not limited to)
financing, marketing, and government support. In particular, the fragmented global regulatory
framework has both forced and allowed motivated patients to seek medical care from abroad,
which has placed countries under pressure to support stem cell-based innovation in a way that
ensures patient safety.

2. BACKGROUND
2.1 Literature Review
2.1.1 The Promise of Stem Cell-Based Treatment Options

Stem cell-based regenerative treatments offer promising opportunities for furthering medicine
and healthcare (1). Stem cells and their derivatives can be used to support the intrinsic repair
mechanisms of the body and to regenerate or even replace injured organs, tissues or cells to
establish normal function, which offers advancement opportunities for the treatment of a wide
variety of conditions - from neural diseases and spinal cord injuries to diabetes and skin
disorders (1, 2). Altogether, stem cell-based therapies comprise one of the largest segments of
the regenerative medicine market (3), and the overarching stem cell therapy pipeline includes
over 300 different products across all stages of development (3).
The therapeutic potential of stem cells lies in indications where current solutions, whether
surgical or pharmacological, have been fruitless, offer only temporary resolve, or cause
inconvenient side effects (3, 4). The lack of available treatment options for such diseases seems
to be one of the main reasons for the rising consumer (patient) demand and is reinforced by
public portrayals of stem cell-based treatments, as well as direct-to-consumer advertising (3).
Additionally, as the aging population increases globally, so does the demand for stem cell-based
therapies, as governments must find better ways to manage healthcare costs associated with the
burden of age-related chronic diseases (5, 6). What is certain, is that both industry and clinical
experts pronounce a significant demand for regenerative medicine solutions to solve these
health issues (7).
Indeed, industry analysts forecast a healthy growth curve for both the overall global
regenerative medicine market, estimating a compound annual growth rate (CAGR) of 12.7%
between 2015 to 2021 (8), as well as for the global stem cell therapy market that can boast with
an even steeper forecast – CAGR of 36.52% for the period of 2017 to 2021 (9). The cell therapy
industry (that includes the stem cell market) has proven to be a distinct healthcare sector that
demonstrates rapid development and capacity to feed a multibillion dollar industry (10).
In many countries around the world, physicians and scientists are currently on the path of
bringing stem cells and stem cell-derived products from “the bench to the bedside”. This
complex process has, slowly but steadily, started to produce increasing evidence of treatment

1
effectiveness as many candidates move into the final stages of clinical development and first
regulatory approvals incite discussions in top journals (3, 10, 11), paving the way for the
adoption of innovative therapies rooted in stem cell biotechnology.
2.1.2 Supply and Demand Influences Stem Cell-Based Treatment Offerings
Comprehending innovation adoption processes requires understanding the pressures behind the
demand and supply side of these activities (12). The development of stem cell-based therapies
is an innovation process and, as with any other similar process, it is steered either by a “demand
pull” and/or “science/technology push” (13). Some theorists see market demand as a dominant
player in shaping scientific and inventive activity. On the other hand, the proponents of the
“push” theory posit that internal scientific and technological developments, i.e. shifts on the
supply side, permit and influence modifications of the technology output (13). The existing
literature that handles the development of stem cell-based therapies offers ample evidence to
support both sides of the debate, indicating that these therapies evolve in a “hybrid” process,
disclaiming the more extreme viewpoints (13).
The reasons behind the enthusiasm for introducing stem cell-based therapies include unmet
medical needs, as well as technological advances which allow the medical community to
consider putting these technologies in clinical practice (1, 2, 14, 15). Therefore, the “pull”
theory can be exemplified by the growing patient demand and the “push” by evolving stem cell
technologies. The rest of the study background reviews these as well as other factors that, in
the publications, are seen to steer the adoption of stem cell-based treatment options.

2.1.3 Adult Stem Cells in the Context of Regenerative Medicine

The commercial and therapeutic potential of stem cells is influenced by biological

characteristics definitive to each cell. Stem cells can be divided into three main groups:
embryonic, fetal, and adult stem cells (ASCs), also known as tissue-specific stem cells (16),
since they produce only a set of specialized cells that fit into that certain tissue. Each of those
types can be characterized by their potency to develop into different functional/structural cells,
making toti-, pluri- and multipotent stem cells the most valuable since these cells offer options
for many treatment areas. Namely, totipotency stands for an ability to reproduce a whole
organism and all the cells within it, while pluri- and multipotency represents an ability to
generate many different types of cells, but not a whole organism. This, however makes them
more potent compared to unipotent stem cells which are deemed to differentiate into a single
cell type (16).
Nevertheless, the use of embryonic (ESC) and fetal stem cells is restricted in many countries
due to ethical concerns and deriving regulations (17). This has stimulated the development of
induced pluripotent stem cells (iPSCs) from ASCs that are in many biological ways similar to
ESCs but pose no ethical concerns (18). On the downside, both ESCs and iPSCs have been
associated with the formation of tumor known as teratoma (18), markedly curtailing their
clinical and, therefore, commercial potential.
Because of these limitations, science has turned to the use of ASCs which are involved in the
continual maintenance and repair of the tissues and organs throughout the individual’s life span
(19). These cells are both lineage-uncommitted or lineage-committed which means their
specialization capacity is broad: some ASCs maintain their pluripotency while others only
develop into a restricted number of cells and tissues. Therefore, these stem cells can be useful
for the treatment of various tissues, especially since they can be harvested from easily accessible
tissues and pose no ethical concerns associated with ESCs (19).

2
Although there are various types of ASCs, the greatest leaps in clinical research have been made
with mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells. MSCs are a
subset of ASCs that present no aforementioned ethical or tumorigenic problems (18), and are
widely available in almost all tissues of the body (17, 20). For instance, they have been isolated
from muscles, lung tissue, and bone marrow (21-23). MSCs can renew themselves, have a high
proliferation potential (24, 25), and are able turn into multiple different types of cells, from
chondrocytes and osteocytes that form cartilage and bone tissue, to various types of muscle
cells, including cardiac cells (26-29). This offers plenty of opportunities to explore treatment
options for diseases related to all of these tissues and organs.
2.1.3.1 The Current State of Clinical Development of MSC-Based Treatments
For a while, MSCs were isolated from the bone marrow (30) which is, however, an expensive,
highly invasive, and painful procedure with a low yield of isolated stem cells (31). Another
promising source of MSCs is the human umbilical cord. Harvesting umbilical MSCs is painless
and non-controversial compared to collecting ESCs (32), however it is constrained by the
availability of umbilical cord donations.
Nowadays, most MSCs used in regenerative medicine are derived from the adipose tissue that
is easier to access and presents plentiful harvesting locations (17). These cells can be isolated
in large numbers with the help of a typical cosmetic liposuction procedure or needle biopsy
and, if necessary, propagated under standard tissue culture conditions (33, 34). Indeed, the
abundance of MSCs in the adipose tissue (1 in 100) versus the bone marrow (1 in 100,000)
clearly indicates that former acts as a more optimal stem cell source (15).
The most common technique for isolating MSCs from fat is separating the stromal vascular
fraction (SVF) from the extracted fat by using either enzymatic digestion or mechanical
isolation techniques (with shear, centrifugal, radiation force, or simple pressure). SVF’s
regenerative clinical potential has been demonstrated in several studies, but it requires a
precisely defined purification procedure that would ensure the overall predictability and quality
of the final stem cell isolate (14). In drug development, the quality control of biological reagents
is frequently insufficient (35) but this very quality remains a precondition for the
reproducibility, and in turn, the safety and effectiveness of the final therapeutic agent (36).
However, no leading, commonly recognized isolation system has yet emerged for separating
MSCs from the SVF: the range of existing protocols for both enzymatic and mechanic isolation
is still very broad (14). This uncertainty may influence the variability and effectiveness, and in
turn the demand of MSC-based treatment offerings. In spite of uncertainties associated with
specific isolation protocols, the ease of obtaining adipose-derived MSCs adds to the commercial
attractiveness of MSC-based therapies (34, 37).
Next to isolation feasibility, MSCs demonstrate numerous biological properties that reinforce
their position in the clinical limelight. Since MSCs can be extracted with standard liposuction,
it is possible to use autologous (the patient’s own) cells that helps to avoid non-
immunocompatibility complexities, such as transplant rejection or the need for
immunosuppressive drugs (17, 34, 38, 39). Moreover, it has been discovered that MSCs
demonstrate immunosuppressive properties (34, 39-41), opening up opportunities to use
allogeneic (someone else’s than patient’s own) cells. This means that hundreds or even
thousands of patients can be treated with cultivated stem cells originating from one donor (42,
43), increasing economic savings and the potential customer segment considerably.
By adding all the above-mentioned factors up, it is evident that the market potential of adipose
tissue-derived MSC-based regenerative medicine is vast. Research groups around the world
have taken this into account and brought MSCs into clinical settings, with China, Europe, and

3
the USA spearheading the clinical development arena (18). Studies are being pursued in a
multitude of treatment areas: immune, cardiovascular, orthopedic, and other diseases (44, 45).
The most rapidly developing fields that are projected to have the smoothest market access
pathway (due to unmet need, economic or clinical considerations (42)), are orthopedics and
wound healing, followed by cardiology, diabetes, and neurodegenerative diseases (46, 47).

2.1.4 National Authorities Shaping MSC-Based Treatment Landscape

Besides the technological advances, the development of MSC-based treatment offerings is also
influenced by the presence of governmental support (5, 6). As regenerative medicine promises
improved health outcomes, various jurisdictions in North America (e.g. the US and Canada)
and Europe (e.g. Germany), as well as East-Asia (e.g. Japan) and Australia have provided
considerable financial support for stem cell research (6, 47). The potential curative abilities of
stem cell-based therapies are seen as a measure to contain expanding national healthcare costs,
underpinning the noteworthy economic potential of regenerative medicine (48, 49). Next to
anticipated return on these public investments, media coverage that has portrayed stem cell-
based therapies largely positively has only reinforced this demand for results (50). What is
more, these escalating expectations about economic returns are also confirmed by market
analysts who estimate an expansion of MSC-utilizing treatment market in the coming years,
forecasting it to reach 199 million US dollars by 2021 (51).
The demand for better health outcomes and return on investment has created a political need to
adapt the governance of translating stem cell science into clinical applications. Pressure for the
accelerated introduction of high priority medical solutions, including innovative stem cell
products has resulted in policy changes which are illustrated by, for example, the establishment
of fast-track frameworks in some countries (elaborated in Section 2.1.4.2) (50). One can argue
that updates in regulatory policies are essential to keep up with evolving science, however, the
commercialization pressure imposed on stem cell research may also exhibit negative influences
on the conduct of scientific research (52). The notoriously low success rate of biomedical
product development (around 10% of drug candidates that enter clinical development are
expected to receive the Food and Drug Administration’s (FDA) approval (53)) introduces
progressively higher costs that put researchers under pressure. Quite naturally, tight
investigation budgets are seen as a critical barrier to the progress of stem cell-based therapies
according to a recent survey conducted among key opinion leaders (KOLs) (3). The financial
dependency places priority on the fast commercialization of products and therapies (54) which
may result in poorly prepared clinical trials. In fact, experts point out that stem cell-based trials
are more likely to fail because of this than due to underlying science, based on previous
experiences with hurried or abandoned studies (10). On the other hand, budgetary
considerations may also evoke unethical behaviors to speed up the commercialization process
(e.g. deliberate disregard of data) and, consequently, undermine public trust in science (52).
2.1.4.1 The Direct Impact of Unharmonized Regulatory Landscape
While governments around the world recognize the importance of stem cell research, and some
of them invest remarkably in this emerging field of medicine (6), it has become conspicuous
that the pace of research has surpassed the attempts to govern the stem cell market. Global
policy development faces clear difficulties, chiefly due to the unique regulatory challenges
posed by stem cell-based therapies and products (55). Namely, stem cell-based product
candidates do not fit into the standard pharmaceutical regulatory framework, which means there
is extensive obscurity around what could be the best practice in introducing such products and
related therapies on the market (55). Regulations have direct implications on the adoption of
MSC-based therapies which are still in their infancy.

4
Global laws and regulations that oversee human stem cell studies form a “patchwork” of rules.
For instance, some countries require different level of trial oversight if studies use different
types of stem cells, or when these cells are manipulated, used for non-homologous purposes,
and combined with other (biological) substances (56, 57). Additionally, national variations exist
in the oversight of using human subjects in research and whether it is appropriate and allowed
to charge fees from the subjects in return for participating in the study (57). Literature
demonstrates clear differences even among markets with comparable socioeconomic indicators,
such as the USA, European Union, Japan, Australia, Canada, and Singapore. All of these
countries or federations are high-income economies and similar in a way how they prioritize
scientific research and the accessibility of healthcare, yet all of them have developed individual
regulatory frameworks for dealing with stem cell research and its clinical translation (56, 58).
Such country-specific variations have been seen to create challenges in developing international
registry tools that would aid global clinical trials on stem cell-based treatments (57).
Additionally, next to the absence of internationally harmonized regulations there are also great
differences in the effective bureaucratic application and administration of national regulations
governing the field, resulting in further confusion and delays in the adoption of stem cell-based
therapies (50, 55).
The differences in the oversight of clinical stem cell offerings are causing heterogeneity in
accessing these treatments: some countries cannot offer their citizens treatment options within
the existing regulatory frameworks (43). This leaves patients in situations ripe to cause harm,
as they look instead to under-regulated markets offering them services with uncertain quality
(43).

2.1.4.2 Market Access Acceleration Schemes

Before the widespread market access, patients can be introduced to new therapies through
clinical trials. In preparation for marketing authorization, researchers must conduct clinical
studies that help to generate safety and efficacy data, and this requires the recruitment of study
participants (57). However, the number of clinical trial participants is always limited, and the
patients who are “lucky” enough to be admitted in a study, often bear the “placebo group
problem”. Some of the patients are assigned to the control arms of the study because the ethics
of clinical research requires uncertainty on the part of the investigator to compare the healing
qualities of each study arm (59). This is known as clinical equipoise, a standard that recognizes
the authority of physician community over the individual physician in setting norms for clinical
practice (60). Therefore, even if a patient is able to secure a place in a trial, they cannot be
certain that the treatment they receive is superior. Yet, this poses ethical concerns for physicians
who follow the principle of doing what is best for their patients – if these physicians are certain
that one treatment option benefits their patients more than the other, they cannot participate in
a controlled trial. This certainty is the basis for ethical behaviour, regardless of the reason for
that certainty (which could be scientific studies, rules of thumb, or even just anecdotal evidence)
(60). Therefore, trials alone offer little relief for the patient population.

One of the ways regulators have responded to the intense demand for stem cell-based therapies
is to offer accelerated market access pathways for investigational drugs (61). For instance, in
Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) places stem cell products in
a fast track framework that aims to support the development of regenerative medicine. The only
condition for therapeutic options to be included in this specific framework is proven clinical
safety, while the efficacy and treatment benefits can be confirmed later, in the post-marketing
phase of the product life cycle (50).

5
On the other side of the Pacific Ocean, in the USA, one can find a selection of acceleration
schemes. There are three expedited review avenues of which the Fast Track pathway, meant to
speed up the availability of investigational biologics and cell products, is one of the most
relevant for stem cell-based therapies (56). The Fast Track pathway, however, is still a review
process that tends to consume too much time for patients with terminal illnesses.
As a response, the FDA has introduced a compassionate use program named “Expanded
Access”, where investigational medicinal products (including biologics), are given for the
patient on a case-by-basis with the drug manufacturer’s and the patient’s physician’s consent
(61). The downside of this program is that manufacturers are not always willing to risk taking
chances with an early product, since unexpected adverse events may compromise the
therapeutic agent’s approval process (61). Such behavior has triggered another legislative
movement called “right to try” in some of the states in the USA. The “right to try” is sought for
the terminally ill when any other expected timeline for product approval or access is
exceedingly lengthy, yet the product itself has demonstrated safety in an FDA-approved Phase
1 trial (56, 61). The legislation is seen by many as a state regulatory experiment which conflicts
with federal laws, that may, similarly to “Expanded Access”, compromise the future of an
investigational drug and rob resources from other clinical innovation efforts (56, 61, 62).
The latest development in the USA that aims to balance innovation and safety, is the
Regenerative Medicine Advanced Therapy (RMAT) designation, enacted as part of the 21st
Century Cures Act (63). This has partly emerged due to perception that the FDA has been
unproductive in reviewing and approving stem cell-based therapies (64). Given that preliminary
clinical data demonstrates efficacy proof for addressing an unmet need, RMAT provides
expedited access for regenerative medicine solutions in order to help patients with “serious or
life-threatening” conditions. Efficacy data can then be substantiated by various means, for
example through gathering real-world evidence from the clinics (63).
If we look into another major market, the European Union (EU), two main legislative initiatives
that provide faster access to new treatments, and therefore hopefully also to stem cell-based
treatments, are visible. The European Medicines Agency (EMA) has published a “Guideline on
the Compassionate Use of Medicinal Products” and the European Commission has introduced
a “Hospital Exemption Clause” (56, 65). The former is meant for providing pre-approval access
and the latter allows EU clinics to offer individually prescribed advanced therapy medicinal
products on a circumstantial basis (i.e. not routinely). In this way, the exemption clause supports
not just the quality and safety of stem cell-based (and other investigative) treatments but also
patient-centric care (65).

2.1.5 The Effect of Direct-to-Consumer Marketing

The relative ambiguity of national, not to mention global governance, has resulted in the
proliferation of companies engaged in direct-to-consumer (DTC) marketing of stem cell-based
therapies. Already in the early 2000s, companies utilized the strong public interest in the
medical potential of this field, along with the deferred (or simply slow) development of
government regulations, by marketing treatment options that could not demonstrate scientific
nor clinical evidence (66, 67). Similar patterns seem to continue up to this day, as stem cell
treatment providers opt not to wait for local regulatory authorities to guide them in DTC-
advertising, especially due to the lax of regulation in internet-based marketing which allows
providers target patients worldwide, regardless of local marketing laws (68-70). Clinics
engaged in DTC-advertising have been systematically witnessed declaring their clinical
readiness through featured publications, patents, as well as anecdotal patient testimonials and
news articles (71). With publications and patents, information on whether peer-review is in

6
place, is generally missing and the same tendency can be observed with allegedly running
clinical trials (72).
Although DTC-marketing has emerged in response to patient demand and can be viewed as a
contributor to patient education, possible false claims may damage the development and
reputation of stem cell-based treatments. Namely, offering a broad range of insufficiently
investigated therapies (37) may require significant financial and emotional investment from the
patient’s side but can result in simply ineffective or, worse, harmful medical care, bruising the
public credibility of regenerative medicine (43, 73). Secondly, such blemishes are recognized
as serious warnings for investors who would rather avoid taking financial risks to support
companies that do not comply with regulations governing human subjects research (37). Only
very recently have some of the major regulatory bodies (such as the FDA) articulated regulation
enforcement policies to address the problem of misleading DTC-marketing and the underlying
shadow economy, at least locally (63, 64).

Bioethicists find the public vigilance over DTC-advertising to be indispensable if we want to

safeguard the patients from undue risks, as well as better understand the myriad of relationships
between providers, researchers, customers (patients) and how these influence the development
and commercialization of stem cell-based treatments (37, 73). Furthermore, understanding the
role of a patient as a health consumer may be of utmost importance, given that DTC-advertising
has encouraged patients to take charge of decision-making while the absence of harmonized
global regulations allow them to ignore markets with more optimized regulations and buy
services from practices with dubious standards (7, 73). The patients who pay for treatments,
that they believe to be a part of genuine trials, shift roles, deliberately or not, from a study
participant to a health consumer, and understanding how this phenomenon directs the whole
field of regenerative medicine, including MSC-based therapies, is important (73). The value of
understanding this trend is also substantiated by the fact that “unproven” therapies stretch from
dishonest to legitimate (74-76) which means that these clinical experiments also offer a way to
accelerate access to care and may, in that way, speed up the development of new treatments as
“open trials” despite the obvious risks (73).

2.1.6 The Role of Medical Innovation Practice in Adopting New Treatments

Without a doubt, no high-quality stem cell clinic wants to be associated with unethical
behaviors. However, the intersection of high patient demand, evolving technologies, and
immature regulations has allowed the emergence of providers known as “rogue” clinics, a name
granted due to their practice of offering treatments in absence of supporting trial data (10, 73).
Although unethical at first sight, one could argue that this rushed adoption of experimental
therapies is a genuine response to an epidemic of unmet medical needs. In addition, certain
disciplines agree that next to the familiar science-based innovation where clinical studies play
a pivotal role in introducing new therapies, there are other ways to establish novel clinical
practices (50).

One such model of innovation (in addition to randomized, placebo-controlled, double blind
clinical trials (RCTs)) is medically innovative patient care. Such practice is driven by the ethics
of prioritizing the needs of the patient (as opposed to the search for broad scientific insight, as
is the case with RCTs) (50, 77). It is seen as an antidote for the problem of smothering
responsible innovative activities beyond trials, and has, in fact, proven to be a highly productive
approach in instituting new clinical practices. For instance, surgical care has advanced
immeasurably in the past 40 years, but only 10-20% of such techniques were ever tested in
scientific trial settings (78, 79). In the light of such leverage, medically innovative care could

7
play a legitimate role in the adoption of stem cell-based treatments. However, the global
regulatory and policy discussion around such therapies has first and foremost always revolved
around the structures of research, not innovative care governance (50). Such discord may act as
a barrier to the development and adoption of regenerative medicine since, as of now, stem cell-
related medical practice which includes human subjects but fails to comply with scientific
research regulations is seen as “rogue”. Innovative patient care, however, could act as a
responsible extension of routine clinical practice, and therefore, benefit from separate
guidelines and governance (50) that would help to promote safety and innovation, two factors
that are yearned to be acting hand-in-hand in the adoption of regenerative medicine (63).

2.2 Problem Statement

Experts foresee that the next few years will prove dynamic in the midst of the changing
regulatory and commercial landscape that caters and governs stem cell-based therapies (73).
Meanwhile, it is clear that stakeholders are worried about the current regulatory and commercial
trends and challenges not only because of patient safety but also because of the potential
influence of negative publicity on therapies which are developed for a genuine purpose but may
lose the support of investors and the public (73). On top of that, the market is tainted with
potentially misleading information about unauthorized products and lacks a consolidated
regulatory framework on both global and local levels. Research groups have authority over the
topic in the field of science, but the provision of MSC-based therapies occurs clearly in a
broader space (50, 73), offering various market participants, from patients to regulatory
authorities, to commercial and clinical stakeholders, opportunities to impact the adoption of
MSC-based therapies.
It is impossible to estimate the long-term circumstances of MSC-based treatment marketplace
due to its current immaturity. It is fairly apparent that shutting down clinics worldwide is not a
justified solution in the light of enormous global patient demand, therapeutic potential, and
arising commercial opportunities. However, it is possible to explore the perspectives of industry
KOLs who experience the situation directly and possess first-hand information about what
drives and restricts the adoption of regenerative MSC-based therapies, and more importantly,
how these aspects are taken into consideration currently and in the near future. It is unclear how
to position itself in relation to existing market and governance dynamics to enable innovative
practice while preventing the exploitation of patients. The literature presents a gap in this field
of qualitative information that could shed light on these complex circumstances, and perhaps
help to resolve or alleviate some of the problems associated with the stem cell marketplace, so
the field could progress for the benefit of everyone involved.

2.3 Study Value and Connection to Bioentrepreneurship

Bioentrepreneurship, the process of translating advances in life sciences into meaningful
commercial opportunities, rests upon management, capital, and technology (80). Characterizing
the current adoption process of MSC-based treatment options and its implications would help
stakeholders to understand the commercial landscape better and operationalize this knowledge
to support these three pillars. For instance, a clearer understanding of how to position oneself
in the light of the prevailing adoption drivers and barriers would inform bioentrepreneurs about
the factors they need to acknowledge in developing and accessing stem cell markets, to make
more efficient managerial and product commercialization decisions. This can, for instance,
relate to how the firm provides financial and medical value for its stakeholders (e.g.,
shareholders, patients) that, in turn, helps to formulate the company’s business model (81).

8
Additionally, a more explicit understanding of what modulates adoption can empower patients,
directly or indirectly (for example, with the support of patient advocacy groups) in finding most
suitable and high-quality clinics for their needs, ensuing in both meaningful commercialization
of MSC-based technology and capital inflow for the biotechnology company (80).
Finally, this research can offer potentially relevant information for authorities that formulate
medical regulations, contributing to an overall more ethical bioentrepreneurship space. This is
because medicinal products are regulated in virtually all aspects of the product life cycle and
the regulatory framework developed for pharmaceuticals (that has been mostly extended to
human biologic products) still needs to catch up with the development of stem cell science, to
ensure product safety and efficacy (55, 82). Since bioentrepreneurship handles the process of
translating scientific inventions into commercial opportunities (80), the regulation of factors
such as market access, manufacturing, and promotion (82) has a direct impact on
bioentrepreneurship.
Thanks to their conspicuous novelty and resulting incompatibility with the existing regulatory
and commercialization pathways (55), MSC-based therapies and their market adoption can also
serve as a useful precedent for other similar bioentrepreneurial situations. Since regenerative
medicine is a completely new, emerging field of healthcare (83), other solutions that aim to
replace or repair human organs, tissues, or cells to restore normal function (2) could, too,
subscribe to MSC-related insights, to achieve an accelerated yet responsible market
introduction. By the same token, this study could be applicable to even more disparate
biomedical solutions and possibly other subfields of bioentrepreneurship where emerging
technologies require novel market adoption measures, such as revamped regulations or product
development frameworks. Thus, this study would inform the general research field of
bioentrepreneurship of the hurdles related to the adoption of breakthrough technologies and
how to position oneself in the marketplace in response to these dynamics.

9
2.4 Aim of the Study
To explore the global adoption of mesenchymal stem cell-based treatments and their global
market positioning.

2.4.1 Research Questions

1. What are the perceived key drivers and barriers for the adoption of MSC-based
treatment options from the perspectives of industry KOLs?
2. How are MSC-based treatment space KOLs currently addressing these factors?
3. What key factors do these KOLs consider in positioning MSC-based offerings in the
global marketplace in the near future (in 1-5 years)?

2.4.2 Delimitations

The study is delimited to explore only short-term perspectives on the stem cell-based treatment
industry and will avoid long-term evaluations due to uncertainties present in this under-
regulated and young industry (55, 56). Aside from hematopoietic treatment options, other types
of stem cell-based treatments are still under pre-market investigation (63). Generating long-
term predictions would perhaps provide interesting discussion material but would remain highly
speculative due to low success rates in clinical trial outcomes (53) and the immature stem cell-
based treatment regulations. On the other hand, the delimitation to explore only short-term
perspectives offers a chance to explore actual and current paradigms that can offer
contemporary business intelligence.

The second delimitation is to explore the drivers and barriers for MSC-based treatment options
and disregard therapies that use other types of stem cells. The justification for this lies in the
broader therapeutic potential compared to competing offerings, and forecasted market size and
growth, discussed in Sections 2.2.1 to 2.2.4. MSC-based treatment options comprise the
majority of upcoming offerings (18, 84, 85) and, correspondingly, can be used as a model to
estimate the demand for other, still unapproved ASC offerings (18).

The third delimitation is to take a conscious choice to explore the perspectives of key opinion
leaders on a global level. As described in Section 2.1.4.1, the global regulatory framework still
comprises a patchwork of rules and laws that have turned the stem cell industry into a dynamic
marketplace where stakeholders, from patients and clinicians to scientists and lawmakers, are
left to seek support (e.g., therapeutic, financial, or regulatory) and experience beyond the
borders of their countries of residency. More specifically, this study is delimited to key global
geographies (see Table 1) that are currently shaping the stem cell marketplace, either with their
progressive regulatory systems, advanced science, or an abundance of stem cell clinics and
translational research centres.

10
3. METHODS
3.1 Research Design
The study will employ a qualitative research strategy to explore perceptions inductively to
understand how events take place in complex entrepreneurial settings (86), in this case how the
drivers and barriers for the global adoption for MSC-based treatments are perceived and taken
into account by relevant stakeholders. An inductive approach is suitable since the emphasis of
the thesis is on generating insights from various social perspectives and individual
interpretations (86) that would help to better understand the challenges of balancing innovation
and safety in the stem cell treatment space. This research can be used for more specific (e.g.
local market-bound) theories in future studies.

An exploratory cross-sectional research design is selected to probe study participants’

perspectives and gain a greater understanding about the market’s response to the specific
demand of MSC-based treatment options (86). The exploratory nature of the design serves to
find themes which clarify the understanding of the complex situation and, thereafter, contribute
to the insights generated as a part of this study (87, 88). A cross-section will help to enlighten
the situation at a single point in time (86) which, for this research, serves as a strength, as the
overarching purpose of the study is to update and advise decision-makers about the current
circumstances, enabling them to successively operationalize the findings. For instance, clinical
stakeholders such as physicians and clinic managers can be provided with better clarity about
why their services are (or are not) sought after and deliver improved offerings for their patients
in terms of consumer preferences and expectation management connected to treatment results.
Additionally, scientists who strive to commercialize their findings but struggle with
uncertainties such as changing regulations and patient preferences (89) can, through this work
and chosen research design, better understand the current adoption characteristics and
implement this knowledge, for instance, in designing clinical trials and processes for gathering
real-world evidence.

3.2 Data Collection

Data was collected via semi-structured interviews of 35-50 minutes in length. This data
collection method was deemed appropriate for the qualitative research strategy (87) as it puts
emphasis on the interviewees’ perspectives (as opposed to interviewer’s concerns). Moreover,
despite focusing on specific topics, semi-structured interviews allow deviation, consequently
revealing insights that would be otherwise left uncovered (87). Unstructured interviews were
regarded as unsuitable for this study due to their conversational style (87) which can introduce
an exceedingly great variety of topics unrelated to the aim of the research. Furthermore, it can
complicate the process of drawing patterns from information that is gathered to produce greater
clarity.

The interviews were conducted in English. This helped to avoid linguistic, sociocultural, and
methodological problems associated with translating interview data (90), therefore minimizing
possible bias. However, a possible bias could have been introduced by study participants whose
native language is other than English. Due to logistical limitations, phone calls were the
preferred method for reaching all except for one interviewee who preferred to be interviewed
in writing (this limitation will be further discussed in Section 4.4).

11
An interview guide (Appendix II) was prepared to cover topics that support the aim of the study
(87). The topics were developed in parallel to literature review, not only to ensure sufficient
knowledge and that the right questions were posed, but also to warrant the proper selection of
study participants and an appropriate interviewing approach that would establish trust and
understanding (88). To ensure the interview guide contributed to the aim of the study with the
right focus, questions were revised several times while subjected to a pilot test (87, 91) with a
stakeholder active in the stem cell industry. After the described test the initial version of the
guide and its focal points were modified to be used for the main interviews (88). The types of
questions included in the interview guide were informant factual questions and questions about
attitudes as well as normative standards (87). The reason for this was to gather knowledge about
the global stem cell-based regenerative medicine market from the perspectives of KOLs, in
order to explore the perceived treatment adoption drivers and barriers, as well as the current
and anticipated responses to these factors.

The same interview guide was used with all participants as it strengthened data comparability
(92). The interviews were recorded that allowed to be fully focused on the interviewing process
(87). Finally, the recordings were transcribed using a naturalistic verbatim approach (93), to
facilitate the accuracy and thoroughness of data analysis process (87).

The recruitment of interviewees and the interviewing process followed ethical principles
outlined in section “3.4 Ethical Considerations”.

3.2.1 Sampling of Study Participants

A non-probabilistic approach with inclusion criteria was used for participant sampling to reduce
bias and ensure a relevant sample for the aim of the thesis (87). Purposive sampling did not
allow to generalize to a broad population but it offered a strategic way to address the goal of
the research (87). In addition to direct purposive sampling, snowball sampling technique was
employed, since this increased the chance of including participants who, as global ASC-space
experts, are otherwise difficult to access, but with whom contacts can be established via their
peers (87). Sampling criteria were set to reduce bias and ensure relevance in the choice of study
participants (87). These criteria (visible in Table 1) were specified after background research to
ensure they were feasibly selective and, at the same time, supported answering the research
questions (87).

The aim of setting sampling criteria was to include study participants who can be considered to
be KOLs i.e. they can contribute to the study area with their high level of expertise on the stem
cell-based treatment space. The participants were screened to ensure they are knowledgeable
about the focus market, as well as about what influences the adoption of stem cell-based
therapies (criteria 1-3). Next to knowledge and experience, it was important that participants
represent key countries that play an influential role in shaping global MSC-based treatment
market (criterion 4). Such geographic scope was important in relation to results, as at the time
of the study, the stem cell market functioned on a global level, due to the heterogeneity of
regulations and arising relative availability of treatment options. Stakeholders within this
rapidly evolving marketplace need to adapt to both local and global changes on a continuous
basis and position their offerings in response to market dynamics.

12
Table 1. The study inclusion criteria for participant selection.

Criteria

1
Job title or level commensurate with expert status or sits on the advisory board of a
company/institution that reflects expert status
2
Length of professional experience in the stem cell-based treatment market exceeds 3
(preferably 5) years and past and/or current affiliation is related to adult (preferably
mesenchymal) stem cell-based treatments
3
Main professional affiliation connected to either a regulatory agency, clinic, research institution
(including clinics involved in performing MSC-based treatment studies), or an advocacy group
4
Represents key markets that shape the stem cell-based treatment space (either the USA,
Canada, Mexico, European Union countries, Japan, China, India, South Korea, Singapore,
Taiwan, Thailand, Indonesia, Malaysia, Russia, Israel, or Australia) (94-96)

Description of the participants sampled and interviewed for this study during spring 2018 is
displayed in the following table (Table 2). Each of these KOLs was assigned a letter (A-H)
which carries the purpose of reflecting the type of interviewee consistently in quotations.
Table 2. The anonymized interviewees with a corresponding letter (A-H, n=8), their current
and past professional affiliation related to stem cell-based offerings, and the country (market)
represented by each. The participants’ length of stem cell-related professional experience
ranged between 3 and 34 years (with an average experience of approximately 13 years).

Professional affiliation Which market

A Physician involved in the clinical MSC-based treatment space Germany

B Patient advocacy spokesperson on topics related to MSC-based United States/Thailand

treatments, former MSC clinic owner

C Spokesperson for stem cell science, academic researcher in the Japan

field of adult stem cell sciences, institutional leader,
bioentrepreneurial founder and executive

D Physician involved in the clinical MSC-based treatment space, United States

principal investigator in clinical research on MSCs

E Academic researcher in the field of adult stem cells sciences, Sweden

spokesperson and educator on topics related to stem cell sciences
and applications, including MSCs

F Physician, bioentrepreneurial executive, stem cell laboratory lead, United States

clinical researcher (work related to MSCs in all of these fields)

G Bioentrepreneurial executive of a MSC-related company, Japan

pharmaceutical industry expert, former academic scientist

H Bioentrepreneurial executive of a MSC-related company, former United States/South

academic scientist Korea

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3.3 Method of Analysis
Thematic analysis was employed to examine the collected data. This method is suitable as this
study aims to explore study participants’ perceptions. A search for themes in the transcripts
offers a flexible and available approach to explore these perceptions in further detail (97). As
described in the literature, thematic analysis is suitable for identifying, analysing, and reporting
various persisting themes and motifs across all transcripts (97). This is helpful to highlight the
main perceived adoption drivers and barriers for stem cell-based treatments and draw attention
to how the provider network intends to respond to these in commercializing their services.
The analysis will be conducted according to Braun and Clarke (97) who outline six necessary
phases for the recursive process. The phases are as following:
1) Familiarizing yourself with your data (transcription, reading and browsing, generation
of notions and raw concepts)
2) Generating initial codes (organized coding of transcripts, collection of similarly coded
data)
3) Searching for themes (laying out preliminary themes, based on assembled coded data)
4) Reviewing themes (analysis of their suitability in relation to coded data, and the overall
data set)
5) Defining and naming themes (continuous revision of each theme and overarching
statements, generation of explicit theme definitions and names)
6) Producing the report (the final extraction of interesting and appealing themes which are
analysed in relation to the aim of the study, research questions, as well as reviewed
literature)
The thematic analysis was done manually, using Microsoft Office software. Ultimately, the
results of the thematic analysis (themes found from collated data), were interpreted and
conclusions were drawn to instigate a discussion in the respective part of the thesis.

3.4 Ethical Considerations

The four main ethical considerations outlined by Diener and Crandall (98), harm to
participants, lack of informed consent, invasion of privacy, and deception, were paid attention
to in conducting this research. These principles carry importance in this context as study
participants are used to gather information about the topic of interest. Several steps were taken
to align the study with the aforementioned ethical considerations.

After receiving a positive confirmation to the electronic invitation letter (Appendix I), the
participants were sent an informed consent form (Appendix II) via e-mail and presented again
at the beginning of the interview together with an oral clarification of the form’s content. This
was done to explain the nature and aim of the research so they could autonomously decide if
they wished to participate (87). The participants were informed that they could opt not to answer
specific questions and leave the study at any point (87), to protect them from possible harm and
forced participation. Additionally, the researcher’s professional relationship with a private
company was explained, to disclose its possible influence on the research process. The explicit
approval of study participants was obtained before conducting and recording the interviews.

Additionally, the need for anonymity and confidentiality of participants was accounted for, to
protect them from (un)intended exposure that could compromise the interviewees or the
companies/institutions they represent. Thus, all the collected material was stored and handled
confidentially, and only the researcher had access to the interview recordings and transcriptions.

14
The names of the interviewees, as well as their respective companies, were anonymized in the
results analysis process. Additionally, any information that was seen as too sensitive,
inculpating, or invasive to privacy was excluded from the results. Finally, all recordings and
transcriptions were destroyed following the completion of the study.
For an overview of ethical considerations, including possible conflicts of interest, please see
Appendix III (“Declaration on Ethics in Relation to Master Thesis Projects at LIME”).

15
4. RESULTS
Various factors that influence the adoption of MSC-based treatment options were identified
from the thematic analysis of a total of eight interviews. The interview sample consisted of
global KOLs active in the MSC-based treatment market and it included physicians, advocacy
spokespeople, clinical as well as basic researchers, and industry experts (for more detail, refer
to Table 2).
The study identified five main themes that highlighted the current perspectives held by global
KOLs about the MSC-based treatment space. Additionally, the analysis pinpointed six
subthemes that further elucidate three of the themes. The thematic results structure is illustrated
in Figure 1 and outlined in the following sections of the study.

1. Public Awareness of Existing Options

and Their Therapeutic Capacity 2.1 Data generation priorities

2.2 Global data registry infrastructure

2. Scientific and clinical data generation
and collection

3.1 Global regulatory arbitrage

3. Global regulatory harmonization

efforts 3.2 Need for precedent approvals to
guide the industry

4. Financing of research and care 4.1 Lack of reimbursement and

research grants

4.2 Controversies associated with

financial donations collected from
patients
5. Competing interests of the
pharmaceutical industry

Figure 1. The five themes and six subthemes identified from the thematic content analysis of
eight KOL interviews. These themes illustrate the areas that were most emphasized when
exploring the drivers and barriers as well as the market positioning of given offerings.

4.1 Public Awareness of Existing Options and Their Therapeutic Capacity

The majority of study participants emphasized the encouraging medical potential of MSC-based
treatments as the grounding reason for the continuous development and appeal of the field.
First, several interviewees pointed out that MSC-based therapies offer surgery-free and drug-
free treatment routes, thus expressing superior technical characteristics over the current
standard of care.
“The market is driven, I said, by a desire for people to be treated without surgery.” (D)

16
Additionally, some participants mentioned that MSCs may contribute to preventive medicine,
underscoring the possibility of increasing people’s longevity through fending off diseases
before they even take place.

“We can collect some MSCs from frail patients and then we can conduct a [restoring
procedure] to the aged stem cells and /…/ auto-transplantation to the frail patient, /…/
to keep [them healthier for] longer. /…/ I think that is very-very big opportunity for
MSCs.” (G)

Secondly, participants agreed that the abundant proof of safety, as it is being published, is
reassuring the adoption of MSC-based treatment options.

“I think the one thing that drives [the field] is the consistent evidence of safety. /…/ I
think the safety is the key.” (F)

On the other hand, the clinical potential of cell (including MSC-based) therapies may be
outmaneuvered by new biotechnological solutions according to a splinter group of participants.

“There is a possibility, however, that cell therapy will be replaced in future by gene
therapy /…/, exosomes produced from stem or other cells, cytokines, or chemical
compounds.” (C)

Despite the existing awareness of therapeutic capacity, several KOLs were concerned by hypes
and claims that rest on outdated or anecdotal data. Excessively encouraging ideas that are not
grounded in clinical evidence could mislead patients as well as funding organizations, and this
may eventually harm the field’s credibility due to failed expectations.

There's a lot of lack of understanding of what this field is capable of, so we need to be
mindful about that /…/ When you continuously get these hypes and hot air with no
substance, the field will die, because people will finally realize that “Hey, you talked
about that five years ago, you talked about that ten years ago - what have you actually
done, you know, since then?” And people will start questioning /…/ [Providers] really
need to be mindful of delivering what they actually achieve, not just the hypes.” (H)

Interviewees from various geographical locations were perturbed by the possible shortfall of
knowledge patients have when undergoing conditionally approved MSC-based therapies. They
emphasized that patients need to be more inquisitive about the treatments they receive to protect
themselves from unscrupulous providers. Additionally, to make truly informed decisions about
their treatment options, patients should understand the ratio between the possible benefits and
risks better.

“If patients understand the potential benefit and risk or no effects of the new cell therapy
[then their participation in trials is acceptable] /…/ However, I have reservation
whether patients fully understand that [this] benefit is only potential.” (C)

The majority of KOLs saw patient advocacy groups as influential in empowering patients with
knowledge, as well as representing and protecting them in the governmental policy making
process.
“[The] perspective of patients should be involved in policy making. Individual patients,
however, may have not enough wide balanced knowledge and policy views /…/ we need
patient advocates for education and representing many patients.” (C)

17
However, all of the interviewees asserted that it is their own and the clinics’ responsibility to
raise public awareness about the existing treatment options and their realistic therapeutic
capacity. According to KOLs, a better understanding of what types of procedures and cells are
being used on patients, as well as whether the practicing physician is a suitable expert for the
conducted procedure would heighten the demand for more quality providers. Likewise, an
informed patient would inherently restrain the activities of practitioners that fail to demonstrate
scientific and clinical MSC-related expertise.
“I advise patients /…/ of what I think they might expect from treatment, both based on
our data, and data from other sources; patients should always be informed /…/ [and]
give informed consent before treatment. /…/ all respectable, all reputable practitioners
do that.” (D)

4.2. Scientific and Clinical Data Generation and Collection

In many countries, published and/or peer-reviewed scientific and clinical evidence is an
essential precondition for bringing new therapeutic options to the market. In the present study,
KOLs emphasized the need for further evidence on both the basic and clinical research levels,
as well as the need for increased publication of this data for the long-term success of MSC-
based therapies. Moreover, many KOLs highlighted the need for a unified data storage
infrastructure – a shared global registry that would help to consolidate the generated data and,
in this way, drive global scientific discussion and clinical research collaboration.

4.2.1 Data Generation Priorities

Many interviewees pointed out that even though evidence of safety exists, the field of MSC-
based treatments could be served well if more effort is invested in the basic cellular
characterization of MSCs.
“We need to go through single cell characterization/…/ so that we know what the hell
are we giving [to the patients]/…/ MSCs have gotten a bad reputation and it’s not their
fault. It has been too immature treatments and many not so serious players on the arena.
/…/ Really what has to be done, is better basic research, at first.” (E)
Next to a better cell biology understanding, study participants found it important to standardize
the technologies (e.g. culture systems) used for stem cell treatments, in order to achieve global
comparability of data. This, as of now, is hampered by the variety of methods used for MSC
processing and therapeutic delivery which, in turn, results in inconsistent clinical data.
“Huge difference [in results] by physicians and study groups… That’s why each clinical
evidence is so… Different between studies.” (G)
And, similarly:
“… to have the cells with consistent quality and quantity to be used in medical therapy
/…/ We need to simplify and unify a lot of technologies because there are a lot of
different ways to do things.” (H)
Besides basic research, most KOLs highlighted the crucial need for long-term thinking in
generating clinical evidence. In order to gather momentum for the future, researchers should
invest time and resources in conducting a larger number of well-designed studies to understand
which kinds of patients benefit the most from MSC-based therapies.

18
 “People have to get data, figure out who and how people get better, for this to ultimately
become a long-term benefit, and long-term industry and I don't see a lot of focus in that
space. /…/ We’ll treat a couple hundred patients and a couple hundred patients is data.
It may or may not be all on the same thing but over three or four years you're talking
about hundreds of patients. That’s not small.” (F)
In addition to conducting studies, KOLs were remarkably worried that even when clinical data
is gathered (and often it is not), it is frequently left unpublished, which smothers the global
scientific discussion. One of the main perceived reasons why this happens is that MSC-based
treatments are in their nature often procedures not products - it is difficult to conduct RCTs due
to patient aversion against participating in the placebo arm of procedures such as liposuction or
bone marrow extraction. Yet, it is hard to build scientific evidence just based on anecdotal
events related to single patients.
“I think the problem, right, is that there is no, nothing in between the occasional patient
and a clinical trial.” (E)
Interviewees from several markets pointed out the need for a compromise in the requirements
placed upon data collection in order to facilitate publications and the progress of the field. An
adjustment that was recommended was to focus on rigorous follow-up of all patients which
would compensate for not conducting complete clinical studies.
“I think that there can be a compromise in using historical controls or what's known
about the natural history of problem, /…/ And it, you know, it allows us to conduct
studies in the real world where people actually would participate.” (D)

4.2.2 Global Data Registry Infrastructure

The outstanding market revenue of MSC-based treatments may dangerously incentivize clinics
that focus on financial gains and are not interested in the scientific validity of their treatment
methods. According to the interviewees, such clinics do the field of MSC-based therapies a
disservice, since poor treatment results can incite public disapproval.
“… [the treatments of exploitative providers] fail, and then they disappear. This is the
way how you end up in a bad reputation.” (A)
KOLs emphasized the necessity for having a registry infrastructure that would not only
facilitate publishing and global data sharing between authorities and researchers, but also act as
an incentive system for the latter to share their data even in the absence of full-fledged RCTs.
“… we should only make it available to /…/ centers who have [a license to investigate]
from the [regulatory authority] /…/ [and only if an] institution agrees to put their data
in our registry, they don't have to do a placebo.” (F)
This theoretical registry was viewed as an opportunity for various small players (such as clinics,
research groups, and biotechnology companies) to consolidate their data in a shared regulatory
submission with sufficient sample size to gain market approval.
“To secure the safety and the efficacy, we need /…/ A large sample size, to analyze the
data/…/ such a databank is a very-very important infrastructure.” (G)

19
4.3 Global Regulatory Harmonization Efforts
According to KOLs, the current global patchwork of regulatory arrangements (or, in many
countries, their absence) that governs the stem cell-based treatment space has a significant effect
on the demand and breadth of adoption of MSC-based therapies. Although some of the markets
have recently introduced new laws that try to tackle the complexities associated with the
industry, the majority of interviewees were resolutely convinced the authorities lack adequate
knowledge about stem cell therapies to introduce pertinent regulations.
“It is still relatively young field /…/ they're not really sure how to regulate the therapies
/…/I was actually surprised that even the FDA and PMDA, they're very supportive of
your endeavors /…/ I think, the regulatory is really not hindering the process - they
really want to help you, but you really need to help them.” (H)
And, similarly, from another market:
“We have a higher knowledge about all this than the guys from the authorities. /…/ over
time, they will gain it, and once they will have it, the things will become easier.” (A)
Albeit frustrated by the absence of rules or regulatory forces that stifle innovation, several
stakeholders still insisted that they wish to follow consistent standards.
“I absolutely want to be reviewed. I want to be required to show data. /…/ And I want
to do it, above all, to be transparent.” (F)
Straightforward, unified global regulatory demands were viewed as desirable due to the global
nature of MSC-based therapies which incite patients to travel in search of potentially dangerous
therapies, unapproved in their own country of residence. Additionally, such consolidated
regulations would assist collaboration among researchers and providers.
“We have to [create consistent] regulatory pathways so that we can share the data and
we can collaborate in the clinical trials in the US, EU and Japan.” (G)
One acting body was suggested as a potential way to foster the introduction and enforcement
of such regulations - the International Society of Stem Cell Research (ISSCR), an independent
nonprofit that acts as a voice for stem cell-based therapies.
“… one thing that is underestimated, is the power of ISSCR /…/ ISSCR is still not taken
as seriously by the governments as they should /…/ Cause you have the top Japanese,
you have the top American, you have the top UK and Hong Kong, Sweden… Everybody
is there.” (E)

4.3.1 Global Regulatory Arbitrage

However, as of now, there is no globally harmonized regulatory system that would govern
specifically regenerative medicine. Herein, all KOLs agreed on the resulting phenomenon of
current as well as anticipated global regulatory arbitrage, meaning that the international
differences in laws allow MSC-focused providers and companies, depending on their goals, to
make strategic decisions about in which jurisdictions they wish to conduct either their studies
and/or business.
“… people are going to /…/ look at the different regulatory jurisdictions in the world
and pick where they want to do their first study/…/ the wild-wild west which is maybe
Panama /…/ the Bahamas where there is some regulation, but they'll be open minded

20
 about it; or do we want to go to the FDA or EMA /…/ [to] have that moniker /…/ and if
you go to Mexico, if you don't get shot, you'll get anything you want.” (F)
Similar trends were elucidated about patient behavior in relation to medical travel. Motivated
patients arbitrage the regulatory differences, knowingly or not, too, as they move between more
or less regulated jurisdictions.
“I just got a patient, came in from Japan, and he wanted to come to Thailand for
treatment. /…/ there’s a lot of science going on, but nobody's getting treated.” (B)
Although KOLs recognized the problems that originate from regulatory disparities, they saw
the arbitrage opportunity also as somewhat an appreciated flexibility to continue clinical
research.
“… until then, you go to the area where you can use it, where it’s legal, where you can
be open-minded, and there you can gain numbers [for data].” (A)

4.3.2 Precedent Approvals to Guide the Industry

Overall, many of the KOLs saw the development of regulatory systems to take place with the
support of precedent regulatory approvals in key markets, such as Japan.
“Japan is a recognized first world country with a recognized FDA, with a very-very
clean research policy. /…/ if this will be one of the first world countries /…/ to have
MSCs available, then this will be a sign to other first world countries to also reshape
the way they are going.” (A)
A KOL from Japan only accentuated this belief by expressing their thoughts on Japan’s
anticipated integrative role.
“I think Japan gets a big role to integrate regulatory pathways in major countries. /…/
patient access will become much better due to the Japanese regulatory law.” (G)
Although the important role of Japan was repeated, another KOL pointed out the avalanche of
international regulatory improvements that have followed Japan’s suite in the past few years.
“There is a trend that government regulatory bodies are really changing right now. I
think it might have started with Japan /…/ [PMDA’s new regenerative medicine law]
simplified the regulatory process /…/ [that] triggered the FDA’s response /…/ I think
that sort of a friendly competition is all a good thing and it sort of helps each nation to
model their system better.” (H)

4.4. Financing of Research and Care

Due to the high cost of researching and providing MSC-based therapies, the financing of this
field was seen as an important problem both practically and ethically, since the lack of research
grants and treatment coverage has pushed providers, in pursuit of funding, to turn to patients.

4.4.1 Lack of Research Grants and Coverage

The lack of research grants concerned several stakeholders, who saw such support as a strategic
necessity to sustain well-thought-out research and avoid setbacks due to weaknesses in data, a
possible consequence of hastily performed and poorly designed trials.

21
 “… think about it in a long-term perspective /…/ And that’s why the /…/ government
can play an important role. To actually look for endurance.” (E)
However, such support was still missing in the eyes of many KOLs.
“[The government does] not invest money into science because they don’t have it. They
just forbid it. /…/ I really don’t expect any more from them but not being in the way.”
(A)
The current absence of coverage of MSC-based therapies was pointed out as a clear-cut
limitation to providing treatment attempts that could also contribute to research. The minority
of stakeholders saw the reason for this being the controversy between insurance payments and
the chronically ill patient’s life span.
“… if they cover stem cells, there would be far fewer patients that were sick /…/
patient’s life span is shorter since he’s not treated with stem cells, [meaning] they don’t
have to pay for as many years [as they otherwise would for the chronically ill].” (B)
However, the majority of interviewees identified the shortage of cost-effectiveness data
necessary for health technology assessment as the main barrier for obtaining coverage and
setting a fair price.
“… still not clear whether the stem cell-based therapies are /…/ cost-effective
treatments for patients of difficult diseases.” (C)

4.4.2 Controversies Associated with Financial Donations Collected from Patients

Due to the lack of public or insurance-provided reimbursement, many clinics depend on so-
called patient “donations” (term used by several interviewees) that finance the treatment
attempts. Charging seriously ill patients was seen as ethically challenging, yet some KOLs
pointed out past precedents where patient donations helped to sustain the spread of therapeutic
options that, as of today, form the standard of care. They compared such cases with the current
circumstances governing MSC-based treatments.
“… if you look at HIV medication. It was there for a long time, and it was there for the
people who could afford it. /…/ [It] took another ten years till it was then in the first
world /…/ [and] another ten when it was available for everyone.” (A)
Yet, the ethical issues must be somehow tackled by applying institutional control over accepting
such donations, in order to find ways to sustain research and still protect patients.
“I think it will be accepted to make these kinds of donations. But it should be done in a
serious way, not some unserious, weird clinical… But to the universities, to the
university connecting clinics.” (E)

4.5 Competing Interests of the Pharmaceutical Industry

The pharmaceutical industry is a major supporting factor in advancing medical research due to
the sufficient budgetary and technological resources at the hands of such companies. Many of
the interviewees admitted this but pointed out that collaboration between the MSC-based
treatment space stakeholders and big pharmaceutical companies is lacking. One of the reasons
for this was seen to be the aspect that it is difficult for the pharmaceutical companies to package
autologous treatment procedures as commercially merchandisable products.

22
 “Using the patient's own tissue /…/ There’s just less opportunity for Pharma companies
to be involved /…/ it isn't mass-produced. /…/ there isn't a charge /…/ Because it's your
own tissue and you don't pay a fee to use your own tissue.” (D)

By supporting such treatments, the pharmaceutical industry is unable to leverage its regular
business model which is usually based on patents. The financial returns from a patented drug
or a device can be enormous while treatment options where native, genetically unmodified stem
cells are used, do not allow claiming intellectual property rights.

“Potential financial gains from a patented medical device or pharmaceutical treatment

are enormous /…/ huge financial payoff is something that, you know, that has to be
worried about a little bit.” (D)

Herein, by supporting MSC-based treatment options, pharmaceutical companies may avoid

supporting the regenerative medicine field since they face a serious threat of losing market share
and related profits that are currently captured by their own products but could be seized by
MSC-based treatment options.
“Honestly, I must be very crude and say, it’s money /…/ They’ll be quite careful when
it comes to stem cell therapies /…/ It’s all the size of the market.” (E)
And, similarly: “[When the] stem cells run wild, the drug companies’ profits will be cut in
half.” (B)
Several KOLs even pointed out that the pharmaceutical industry has lobbied against the
regenerative medicine field, including stem cell-based therapies, and this in turn, may influence
the adoption of MSC-based treatments.
“Lobbyism by the pharma industry which starts to be a barrier /…/ something we have
to understand /…/ Pharma lobby is huge and I’m not so sure they are not taking some
influence on the development of the stem cell treatment.” (A)
A minority of KOLs also discussed the opportunity of commercializing allogeneic solutions
which could be a more suitable product in the eyes of the pharmaceutical industry since such
cells could be cultivated and sold in large quantities through various distribution channels.
However, they also found that allogeneic cells provide less convincing clinical evidence
compared to autologous MSCs. Moreover, the maintenance of a biobank, necessary for storing
allogeneic cells, would place a significant burden on the healthcare system, hampering public
or private insurance coverage of allogeneic therapies.
“I think in the short run… autologous tissue is favored /…/ Because it's your own tissue
and you don't pay a fee to use your own tissue. /…/ The tissue which had to be gotten
from a tissue bank will generally cost [a lot]/…/ It's a tremendous stress on the health
system, economically /…/ the results [compared to autologous] are clearly against it.”
(D)

23
5. DISCUSSION
The aim of this study was to explore the global adoption of MSC-based treatment options and
their global market positioning. The research questions were pinning down the (1.) perceived
drivers and barriers for these phenomena and how KOLs within the explored industry would
recommend positioning oneself in response to these factors (2.) now and (3.) in the near future.
No previous study has shed light on the global adoption, market dynamics, and positioning of
MSC-based treatment offerings from the perspectives of KOLs involved in the field. However,
understanding these aspects is compelling since this information can support introducing
collective gains among patients and treatment providers.

5.1 Drivers and Barriers for the Adoption of MSC-based Treatment

Options
The interviews helped to identify multiple drivers of MSC-based clinical care which, while
confirming earlier studies, add focus to what factors are prioritized by industry stakeholders as
of today. The adoption of MSC-based therapies was strongly motivated by the possibility to
avoid drug-based treatment programs and more extensive surgeries that otherwise form the
standard of care. On top of that, MSC-based preventive medicine was identified as an adoption
catalyst since it would tackle diseases before their onset and would, therefore, provide
significant savings for the healthcare system. However, the fundamental driver of adoption
identified was the cumulating proof of safety of MSC-based therapies. These drivers suggest
that many of the providers avoid counting on drastic but insufficiently investigated therapies
that promise to solve completely unmet medical needs (37), often hoped to be addressed by
MSCs as reported by earlier publications (3, 6). Instead, it may be better to emphasize more
incrementally additive yet evidence-based improvements. This could also be ethically more
acceptable, given the KOL’s proposal to continue accepting patient donations to sustain
research and care in the face of tight investigation budgets (3).
Additional drivers that KOLs viewed as significant included regulatory factors. Emerging local
regulations, such as accelerated access pathways, were seen to act as trailblazers that could
possibly aid countries across the world to reshape their laws, in order to speed up the adoption
of MSC-based therapies in a responsible way. Likewise, the differences between the stringency
of existing legislations may boost the development of the field, since stakeholders can arbitrage
those disparities to better access patients and conduct more trials to gather evidence. Although
previous literature does delineate the regulatory opportunities opened up by expedited access
pathways (61), so far it has not been illumed that even ethically sound clinicians and companies
find it acceptable to arbitrage the global regulatory differences while anticipating local
legislative improvements. Although such behaviour may raise some ethical questions, it is also
somewhat explicable since data collection would aid stem cell research to progress, especially
since the traditional supporter of medical innovations, the pharmaceutical industry, is avert
about providing funds.
The study distinguished various MSC-based treatment adoption barriers which share both
similarities and differences with the factors outlined in past studies. Due to the time-consuming
process of introducing cell therapies, other competitive, possibly more affordable solutions like
gene and cytokine therapies may be approved before MSC-based therapies, harnessing their
potential market share. Such impediments are accentuated by the absence of finite cellular
characterization of MSCs, use of unstandardized culture systems that cripples data
comparability, and the shortage of publications that would otherwise advance scientific
discussion. In this light, it is interesting to see that although market analysts indicate an

24
encouraging trial pipeline (3), MSC-space KOLs assert the lack of published trials. The reason
for that may lie in the field’s slow progress, as the stakeholders are concerned about wasted
efforts if competing solutions would gain widespread approval before MSC-based options.
Such frustrations could be compounded by the public portrayal of regenerative medicine’s
health economic potential (48-50) and the actual state of MSC-based therapies’ cost-efficiency
evidence which has not been demonstrated yet.
The identified shortage of research grants, care coverage, and cost-efficiency data (a common
precondition for treatment coverage (99)) may hinder the field’s long-term success due to the
resulting deficiency of high-quality clinical evidence which can be generated only with
necessary funding. This paradoxical situation may be caused not only by the lack of
governmental support but also the strife between procedure-based regenerative medicine and
the patent-reliant pharmaceutical industry (100) with their alleged lobbyism. It could be feasible
to alleviate the situation by co-developing patentable technologies or processes for handling
stem cells to match the interests of both sides. This inclusivity may result in greater funding
and eventual sustainability of research. There is still, however, ambiguity in how exactly
pharmaceutical companies influence the development of stem cell therapies besides not
providing enough financial resources.
Although there are hundreds of stem cell clinics across the world, many of them are gains-
oriented and not focused on transparent research, which was clearly regarded as a barrier of
adoption due to the resulting reputational damage. Previous studies confirm these views. It has
been thoroughly argued that the proliferating presence of providers committed to DTC-
marketing and (quick) profit-making may have a negative influence on the public credibility of
MSC-related solutions (43, 73). Such behaviors have most likely emerged due to unharmonized
international regulations which have contributed to a lack of safety standards and created
different routes for how patients find their ways to experimental therapies (43, 50, 55).
Indeed, further barriers were identified from the field’s regulatory oversight. The lack of
adjusted global and country-specific legislations that would consider the unique character of
stem cell therapies hinder international collaboration as well as local adoption. This is the case
not only due to unscrupulous providers active in unregulated countries (10, 73), but also because
it makes it impossible for researchers to adhere to data transparency rules as often there simply
are no dedicated rules. It could be useful to strive for regulations that consider not just the
specific character of stem cell-based therapies but also incentivize providers to better adhere to
rules thanks to added benefits, such as a priority license to provide care coupled with a condition
to submit real world evidence for a defined period of time. An increase in licensed clinics would
possibly reduce the number of unethical providers and, as a result, protect the patients and the
field’s reputation.

5.2 The Response to the Market Dynamics of MSC-based Treatment

Options
The dynamics that shape the market of MSC-based therapies may require positioning efforts
that consider simultaneously the current time and the near future. KOLs distinguished the need
for further data generation as a precondition for the field’s long-term success. Thus, they
recommended to increase data comparability through standardized cell separation and
propagation systems, and to put more effort on the cellular characterization of MSCs as well as
on a larger number of clinical studies. Additionally, consistent patient follow-up was viewed as
crucial to achieve a compounded clinical sample, large enough to be leveraged by research
groups globally. This is in accordance with earlier adoption studies which recognize that

25
collaboration between clinics and companies can reduce overall costs of introducing cell
therapies (100). In the near future, KOLs saw a dire need to create an international registry
infrastructure that would facilitate sharing trial data, as well as historical and real-world
evidence. Such a registry would not only stimulate scientific discussion but also work as an
incentive mechanism for publishing: non-standard clinical studies are recognized as legitimate
(even without a placebo control) for a (shared) regulatory submission only if they are published
within this registry. This would possibly allow governments to also single out “rogue” and
“bona fide” researchers since the latter would, in this case, demonstrate reliability that has been
hard to determine up until today (101). Although KOLs identified the arbitrage of international
regulatory systems as a possible response to current circumstances, it would ultimately be better
for collaboration to create a global framework. This may possibly be achieved through
independent international organizations such as ISSCR that unify the involved markets.
Meanwhile, positioning one’s offerings according to precedent markets (such as Japan (50))
can be useful since their breakthroughs may incite corresponding regulatory revisions in other
countries, as suggested by recent comparative literature (102). Due to the fundamental role of
financing, it is important for providers to continuously populate cost-efficiency datasets to
achieve eventual reimbursement but, meanwhile, they should not shy away from accepting
financial donations from patients, although it can be advisable to streamline these donations to
clinics via recognized (academic) institutions. This can possibly be supplemented by
crowdfunding of trials, suggested by literature as a more ethical route to financing studies (103).
Finally, MSC-based treatment providers should focus on educating patients about the field
directly, and also collaboratively with patient advocacy groups. The latter could transpose
knowledge such as treatment risk-benefit ratio to patients, but also represent them in
governmental policy making processes.

5.3 Implications and Areas of Future Research

To the best of author’s knowledge, the findings of this study illustrate for the first time how
stakeholders in the MSC-based treatment space perceive the dynamics of the global
marketplace and how they would position MSC-related offerings in relation to this. Therefore,
these findings contribute a set of recommendations for which factors need to be considered by
players in the (adult) stem cell market, possibly offering pointers also for shaping other areas
of regenerative medicine. Additionally, the study provides an overview of the hurdles
experienced by KOLs which can be insightful for the regulatory authorities in designing
regulatory changes in the field of regenerative medicine.
This study uncovers several areas of interest for future research. First, since the emerged
registry topic seems to connect the needs for collaboration and necessary data leverage for
market access, it would be interesting to discern similar international registry infrastructures
from earlier times and analyze the results of such projects in terms of feasibility or insights that
could inform the creation of a framework for MSC regulation. Second, it could be insightful to
understand why international independent stem cell-related organizations such as ISSCR have
so far been ineffectual in aligning governments to collaborate more tightly with each other.
Third, it remains unclear how the alleged lobby work imposed by pharmaceutical companies
really influences the field of regenerative medicine and MSC-based therapies. Finally, the
study’s generalizability could benefit from a larger, more diverse sample. Moreover, it could
be intriguing to conduct a comparative analysis of countries to draw inferences about their role’s
scalability in the wider introduction of MSC-based therapies.

26
5.4 Strengths and Limitations
This study stands out for a couple of reasons. First, the sampling criteria and strategy rendered
a novel view on the field of research as they allowed to scope global perspectives from
European, American, and Asian markets that have a profound effect on the worldwide
expansion and development of stem-cell based therapies. Despite the pre-set criteria, it was
clear only after confirming the final interviews that the study will represent KOL perceptions
from several prominent markets. Although such scope may be seen as quite broad, it supports
the aim of the study as described under Delimitations (Section 2.4.2). The second strength of
this study was to accumulate elaborated insights beyond defined interview questions thanks to
the possibility to ask tailored follow-up questions which surfaced from the preceding answers.
Thus, the study recognized the singular perspectives of global KOLs by eliciting unprompted
discussion.
A considerable limitation of this study was that the sample did not include participants from
every market driving the global adoption of MSC-based therapies. This may bias the results
towards the perspectives of included participants. On the other hand, the aim of the study was
to explore the global perspective of KOLs, which eliminates the need for a specific comparison
of differences between countries. Additionally, the majority of participants (n=6) possessed
intercontinental work experience, which strengthens the global aspect of findings, and can
actually be considered as the third strength of this study.
The second limitation to be considered, is that even though all participants had experience with
MSC-based treatments, not all were active in this space at the time of the study (e.g. participant
C held an apex expertise of various kinds of stem cells but was working with another type of
ASC when this study was conducted). This may somewhat decrease the value of the results
since such participants may emphasize market factors, too general to be useful specifically for
MSC-based offerings. However, as the whole regenerative medicine, and particularly stem cell-
based industry is still relatively immature, it is probable that such findings do not alter the
results significantly.
The third limitation is that one of the interviewees (C) decided to be interviewed in writing due
to personal preferences. It is highly possible that this resulted in a briefer discussion which
possibly means that some aspects that could have been elucidated about the adoption of MSC-
based offerings, were left concealed. Thus, the findings of this thesis should be interpreted with
this feature in mind. However, due to the scarcity of experienced KOLs in the global stem cell-
based treatment space, this approach was still regarded as useful since it supported the aim of
this study.

27
6. CONCLUSION
The widespread adoption of MSC-based therapies could give ground to collective gains among
patients and treatment providers, whether clinicians or biotechnology companies. In spite of the
therapeutic potential, numerous clinical studies, and the worldwide interest in the topic, MSC-
based treatments are yet to be adopted by the global markets. Thus, the aim of this study was
to explore the factors that shape the global adoption of MSC-based treatments and their global
market positioning through the lens of KOLs within the field. The study unveiled various
drivers and barriers that impose significant influence on the adoption of MSC-based offerings.
These suggest that for the successful market introduction of such treatment options, further
basic and clinical evidence gathering should be prioritized, hand-in-hand with setting up a
shared registry infrastructure that would help to leverage collected data among researchers
across the world. The route to treatment adoption is barred by inconclusive scientific evidence,
financial constraints, scant education of patients and authorities, and the competing interests of
the pharmaceutical industry. In the light of these factors, MSC-space stakeholders should
prioritize collaboration through independent international organizations, patient advocacy
groups, and unifying academic institutions for the purposes of streamlining funding, education,
and stem cell research. Additionally, besides arbitraging the differences between national
regulatory systems and considering the activities of precedent markets in their strategies, it
should be taken into consideration that KOLs anticipate internationally consolidated regulations
specific to regenerative medicine as these would increase collaboration and scientific
transparency. Thus, the presence of global cooperation is crucial for the increased adoption of
MSC-based therapies and should be considered in establishing data registries, funding streams,
and harmonized regulations.

28
ACKNOWLEDGEMENTS
I would like to express my foremost gratitude towards Dr. Emily Rose Jordan and Dr. Jan
Schaefer who guided and accompanied me throughout this study. Thank you for giving me an
opportunity to work together with you and conduct my thesis work in collaboration with
MEDIGO GmbH.
Additionally, I would thank my academic supervisor Dr. Samer Yammine who, even though in
another country, kept me on course and provided useful feedback and a couple of good laughs.
Furthermore, I would like to acknowledge the help of all the study participants whose time,
support, and wisdom helped to significantly contribute in the results of this study. It was a great
honor to hear the thoughts of these global key opinion leaders.
Finally, I cannot miss a chance to say “Cheers!” to my family, all of my KI classmates, as well
as my MEDIGO colleagues who were always present when one was seeking for practical or
creative advice, thoughtful discussion partners, and someone to crack jokes with – it has been
a blast.

29
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APPENDICES
Appendix I. Invitation Letter
Dear …,

I am a current student in the master’s program in Bioentrepreneurship at Karolinska

Institutet in Sweden, conducting an internship at a digital health company MEDIGO GmbH in
Germany.

In conjunction with my program, I am conducting my thesis research on the subject of

global drivers and barriers for the adoption of regenerative adult stem cell-based
treatments. The outcome of this research should serve as an insight into the challenges
stakeholders experience when seeking to balance innovation and safety in the stem cell
treatment space.

Given your role as …, I would like to ask for 30-45 minutes of your time and invite you to
take part in an interview that would contribute to my research.

The research is qualitative and based on interviews. Participation is voluntary and

completely anonymous. All data gathered will be handled confidentially and your name or
organization will not be mentioned in any of the documents produced, unless explicitly wished
by you. Otherwise, all efforts will be taken to anonymize your participation.

The information provided will be used solely for academic reasons and only I will have access
to the raw interview data. You have the full right to answer only those questions that you want
to answer.

At the interview, we would discuss the following themes

• Your perspective on the current key drivers and barriers for MSC-based treatment
offerings
• Your perspective on how the providers are currently addressing these factors
• Your perspective on the near future (1-5 years) considerations that are key for the
increased adoption of adult stem cell-based treatments

The interview can be conducted via Skype or phone at your earliest convenience.

Please let me emphasize that the research is conducted independently from MEDIGO
GmbH and the collected raw data would be accessible only to myself.

I am looking forward to learning about this topic through the lens of your expertise.

Yours sincerely,
Paula Salme Sandrak

If you would like to read more about my academic program please click here.

36
Appendix II. Informed Consent and Interview Guide
Informed Consent
My name is Paula Salme Sandrak and I am a student in the Master’s program in
Bioentrepreneurship at Karolinska Institutet (KI) in Sweden, conducting an internship at a
digital health company MEDIGO GmbH in Germany. In conjunction with my program, I am
currently performing research for my final degree thesis and as a part of that, I will collect and
analyze data from interviews. The analysis of this material will be written into a degree thesis
as well as presented for an audience at KI as part of fulfilling the degree thesis course.

I am conducting my thesis research on the subject of global drivers and barriers for the
adoption of regenerative adult stem cell-based treatments. The outcome of this research
should serve as an insight into the challenges stakeholders experience when seeking to balance
innovation and safety in the stem cell treatment space.

If you have any questions, please contact my Program Director Madelen Lek
(madelen.lek@ki.se) at the Unit for Bioentrepreneurship, Karolinska Institutet.
The interview will take approximately 30-45 minutes. Participation is voluntary, and you can
choose to stop the interview at any time. All data collected will be handled confidentially.
Participation is anonymous - your name will not be mentioned in any document produced, and
only I will have access to the raw material. In order to facilitate the analysis, the interviews will
be recorded and transcribed. Afterwards I will delete the recording.
Is this clear and OK for you? Let’s start the recording then. And to repeat the question once
more, is it OK that we record this interview?

Interview Questions
Part 1. Background
1. Could you briefly describe your professional background as well your work
experience related to mesenchymal stem cell-based treatments?
2. How long have you been working in this area?
Part 2. Market adoption drivers and barriers
The stem cell-based treatment environment is currently influenced by many complex factors,
including an increasing patient demand and global regulatory challenges. Although the field is
evolving rapidly, patient access to therapies is still very limited and there are many uncertainties
about the widespread adoption of MSC-based treatments.
3. What do you believe to be the main influencing factors that drive the increased
adoption of MSC-based offerings?
4. What do you believe to be the main barriers and key challenges for the adoption
these treatment options?
5. In your view, how does the current global regulatory landscape affect the adoption
of MSC-based therapies?

37
Part 3. Response to market dynamics
6. In your view, how are the providers (either clinics or biotechnology companies) that
seek to increase the adoption of such therapies currently addressing the factors you
just described?
7. From your perspective, could these providers do something differently to better
address the current market dynamics?
Part 4. Forward-looking perspectives
8. When we are looking in to the future, what do you believe will be the key changes
in 1-5 years that will influence the adoption of MSC-based treatments? Why?
9. In your view, how should governance frameworks be adjusted to balance
innovation and patient safety in the MSC-based treatment space?
10. How would you recommend altering the process of finding evidence for novel
MSC-based therapies, to ensure responsible and faster adoption of such practices?
11. What do you believe to be the role of the patients in this developing landscape and
what rights should they have?
Part 5. Closing
12. Are there any other critical factors that influence the adoption of MSC-based
treatments that you think we did not discuss? Would you like to add anything?

38
Appendix III. Declaration on Ethics in Relation to Master’s Thesis
Projects at LIME
Project title:
“The drivers and barriers for the adoption of regenerative adult stem cell-based therapies”

Master’s student
Name: Paula Salme Sandrak
Program: Master’s in Bioentrepreneurship
Email address: paula.sandrak@stud.ki.se

Main supervisor
Name: Samer Yammine, PhD
Affiliation: Project Manager at LIME, KI
Email address: samer.yammine@ki.se

Short summary of the master thesis project (max 300 words):

Stem cells can be used to support the intrinsic regenerative mechanisms of the body to establish
the normal function of its diseased organs and tissues. Their therapeutic potential lies mainly in
indications where current treatments cause inconvenient side effects, offer temporary resolve,
or have been fruitless. Among different types of adult stem cells, mesenchymal stem cells have
been shown to have significant clinical potential, but their global adoption is influenced by
many complex and ever-changing commercial and regulatory factors. Therefore, the aim of this
study was to explore the global adoption of mesenchymal stem cell-based treatments and their
global market positioning. A qualitative research strategy was employed whereby eight cross-
sectional, semi-structured interviews were conducted with global key opinion leaders from
markets that have a major influence on the mesenchymal stem cell space (the United States of
America, Germany, Sweden, Japan, Thailand, and South Korea). The findings indicate that the
field is driven by the clinical safety and operational ease of mesenchymal stem cell-based
therapies, arbitration of local regulatory systems, emerging precedent regulations, and patient-
sourced financial donations. The main barriers that were seen to hamper the adoption included
insufficient cell biology and clinical knowledge, the lack of adjusted global and country-
specific regulations, and an inadequate education of authorities and patients. Additional hurdles
included the financial constraints of researchers and the competing interests of the
pharmaceutical industry. Key opinion leaders suggested that companies and clinics should
focus on consistent data gathering, consolidation of a global regulatory framework, and the
creation of an international registry infrastructure to aid evidence collection and utilization.
Besides that, stakeholders should position themselves according to independent international
organizations, academic institutions, and advocacy groups to further collaboration and
education. Global cooperation is required for the adoption of MSC-based therapies and should
be employed in establishing data registries, funding streams, and harmonized regulations.

39
Identify and specify possible problems of ethical character:
As the aim of the project is to explore the opinions, reasoning, and resulting behavior of studied
stakeholders, the main study participants (KOLs from the adult stem cell-based treatment space)
stand in the risk of being exposed. The information provided may contribute to a conflict of
interest and compromise them or their respective companies and institutions, for example in the
eyes of their investors or customers. Additionally, the study participants must be aware of the
voluntary character of this study and given a chance to give an informed consent, not to override
their right for autonomy, or deceive the study participants by any means.
The interviewees may be negatively influenced by certain questions which must be considered
during the process of designing the interview guide. For example, if the question is phrased in
a way that implies to explicit ethical controversies in the business activities of the interviewed
stakeholders, it may result in being offensive. Additionally, it must be considered that the
phrasing of questions may influence the answers and therefore bias the results of the study.
On the other hand, there is a possibility that interviews reveal unethical behaviors. This may
provoke the researcher to act (e.g., contact external parties to inform), which in turn can
compromise her reputation of confidentiality, or be invasive to the study participant’s privacy.
In those cases, a careful risk-benefit analysis must be conducted with the support of the
academic organization that governs this research, to see the potential harm and benefit caused
by the alternative ways of acting after the discovery of the information in question.

DATA HANDLING and RESULTS REPORT

How will the collected data be stored and protected?
All the collected material will be stored and handled confidentially. The interview recordings
and transcriptions will be stored electronically on a cloud drive that is password-protected. The
only person with direct access to the collected data is the author of this thesis. The interview
recordings and transcripts will be permanently deleted after the finalization of this study.

In what way will the integrity of the research respondents be guaranteed when the results
of the research will be made public?
Neither the institution nor the name of the study participant will be mentioned in the final thesis
to ensure anonymity and not evoke conflicts of interest regarding the information provided.
Any information that is seen as too sensitive, inculpating, or invasive to privacy is excluded
from the results. In addition, the interview recordings and transcripts will be permanently
deleted after the finalization of this study.

Do you intend to publish your results in a scientific journal or conference?

No.

If the project has ethical approval, please indicate the file number of the ethical approval
and the name of the Ethics Committee: N/A

40
DECLARATION OF CONFLICTING INTERESTS and FUNDING
ACKNOWLEDGEMENTS
In case of research commissioned by an external client, e.g. a company, please specify the
external client.

Name: MEDIGO GmbH (private company)

Contact persons: Jan Schaefer, PhD, MD (Chief Medical Officer at MEDIGO GmbH); Emily
Rose Jordan, PhD (Head of Medical Strategy at MEDIGO GmbH)
Contact emails: jan.schaefer@medigo.com; emily.jordan@medigo.com (respectively)

Please specify the relationship between the external client and the main supervisor and/or
master’s student, e.g. employment relation.
The author of this study, master’s student Paula Salme Sandrak holds an internship contract
with MEDIGO GmbH from 18.01.2018 to 18.06.2018. Jan Schaefer (MEDIGO GmbH’s Chief
Medical Officer) and Emily Rose Jordan (MEDIGO GmbH’s Head of Research) are her direct
company-affiliated supervising managers.
Acknowledge funding arrangements with external clients or other funders (name of the
funder and sum of funding)
The author of this study receives internship compensation from MEDIGO GmbH as part of her
contract. The size of the salary is regulated by statutory German laws governing mandatory
internship compensations.
Does there exist any other conflict of interest of the master’s student or any of the
supervisors?
No, the academic/working relationships between the author of this study and her direct
supervisors (Jan Schaefer, Emily Rose Jordan, and Samer Yammine) are the first and only
relationships between the named sides.

SIGNATURES

Main supervisor/research responsible

Date:
Signature:
Name in block letters:

Master student
Date:
Signature:
Name in block letters:

41