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CELL & GENE THERAPY INSIGHTS
CLINICAL TRIAL DESIGNS FOR
ADVANCED THERAPIES
EXPERT INSIGHT
Enrico Fritsche, Magdi Elsallab, Michaela Schaden,
Spencer Phillips Hey, Mohamed Abou-El-Enein
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-
-
Cell & Gene Therapy Insights
CELL & GENE THERAPY INSIGHTS
DOI: 10.18609/cg.2019.156
Evaluating a marketing-authori-
zation application under the con-
ventional centralized procedure of
the European Medicine Agency
(EMA) can be a lengthy process,
taking up to 210 days (and that
is excluding any additional time
required for applicants to respond
to EMA requests for additional in-
formation). In an eort to support
drug development, the EMA has
devised several early access routes
for drug developers in the EU [1]
where some of them can be uti-
lized via the PRIority MEdicine
(PRIME) scheme [2]. e PRIME
scheme was launched in March
2016, specically to support the
more rapid translation of products
targeting an unmet medical need
by enhancing the early interaction
and dialogue with regulators before
submission of marketing authori-
zation application (MAA), as well
as accelerating the regulatory as-
sessment procedure of MAA [3,4].
While such regulatory tools can
help to more expeditiously satisfy
unmet medical needs, this comes
at the cost of having a less com-
prehensive data set, and therefore,
greater uncertainty about the prod-
uct’s benet-risk balance at the
time of marketing authorization.
However, to oset this initial lack
of data, EMA obligates product
developers to perform extensive
post-marketing studies in order
to generate more robust evidence
supporting the overall safety and
ecacy prole of these products.
Similar policies are adopted by the
US Food & Drug Administration
(FDA) in cases when new drugs are
approved on the basis of limited
evidence [5,6]. Developers of ad-
vanced therapy medicinal prod-
ucts (ATMPs) have proactively
integrated PRIME and other such
regulatory tools into their product
development strategies [7–9]. For
example, by mid 2019, three AT-
MPs (Kymriah®, Yescarta®, and
Zynteglo®) were approved under
the PRIME scheme (although
only Zynteglo beneted from the
accelerated assessment; assessment
of Kymriah and Yescarta were re-
verted to the standard timetable
since major objections were raised
during the regulatory evaluation
and could not be resolved within
the accelerated timetable).
However, the uncertainty about
the benet-risk prole of new-
ly-approved ATMPs is not merely
due to regulatory exibility. ere
are several other features of clini-
cal trials for ATMPs that can leave
critical gaps in the evidence base
concerning product safety and ef-
cacy [10–15]. For example, since
ATMPs often target rare diseases
[16], the pre-market clinical trials
are mostly small, single-arm trials
that face an increased risk of bias
and other translational challenges
[17]. Surveys among ATMP-devel-
opment companies in Europe have
shown that for many rare diseases
of interest, little is known about
disease progression or the chal-
lenges associated with creation and
interpretation of reliable endpoints
for new indications [18]. Selection
of endpoints is of particular impor-
tance since ATMP trials mainly rely
on surrogate endpoints due to the
lack of clinically meaningful ones
for many indications, such as vari-
ous cardiac cell therapy approaches
[19]. However, relying on surrogate
endpoints in pre-market trials only
amplies the uncertainty for how
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to appropriately use these products
in the clinical setting [20].
To make up for this epistemic
shortfall, post-marketing stud-
ies are therefore a critical tool for
gathering the much-needed fol-
low-up data, as well as allowing
for additional evidence synthesis
eorts to inform appropriate use
of such products [21,22]. In order
to better understand the character-
istics of the post-marketing studies
associated with ATMPs approval,
we examined the regulatory land-
scape of post-marketing studies
and performed a systematic review
of the European Public Assessment
Reports (EPAR) that is describing
the evaluation of ATMPs autho-
rized via the centralized procedure.
Data on post-marketing clinical
studies (planned and ongoing) of
authorized ATMPs were extracted
from the respective specic Eu-
ropean public assessment report
(EPAR) and the corresponding
page in clinicaltrials.gov registry
for each product. e EPAR search
was based on the “nd medicine”
search function on the EMA web-
site www.ema.europa.eu/en/med-
icines. e cut-o-date for data
entry is November 1, 2019. Rele-
vant data were extracted from the
pharmacovigilance plan that, upon
marketing authorization, each mar-
keting authorization holder MAH
has to provide within a detailed
Risk management plan. Detailed
information on this can be found
within the EPAR, chapter “Risk
Management Plan”, sub-chapter
“Pharmacovigilance Plan”, which
includes a table describing “type
of study/ status”, “categorization
1-3”, “objectives”, “safety concerns
addressed”, “date for submission of
interim or nal reports (planned or
actual)” and optional “milestones”
or separate information on “sta-
tus”. is sub-chapter represents
‘additional pharmacovigilance ac-
tivities’, a regulatory term that en-
compasses all pharmacovigilance
activities not considered as routine,
and can include clinical studies or
non-interventional post-authori-
zation safety studies (more details
provided in Box 1). ese activities
can be assigned at the time of mar-
keting authorization to one of three
categories that need to be followed
when implementing post-market-
ing authorization studies on AT-
MPs. Category 1 is mandatory and
comprises post-marketing studies
that are imposed as conditions to
the marketing authorization. ese
studies should provide key infor-
mation to the benet-risk prole
of the product. Category 2 is also
mandatory and entails specic ob-
ligations only in case of a condi-
tional marketing authorization or
a marketing authorization under
exceptional circumstances. Final-
ly, any other studies for investi-
gating a specic safety concern or
evaluating the eectiveness of risk
minimization activities fall under
category 3. Category 3 comprises
activities which are conducted or
nanced by the MAH for investi-
gating specic safety concerns, but
‘do not include studies which are
imposed or which are specic ob-
ligations’ (i.e. excluding categories
1 or 2) [23].
Categorization of each ATMP
to “Gene-“, “Somatic cell-“, or
“Tissue-engineered” was based on
information extracted from the
EPAR of the respective authorized
CELL & GENE THERAPY INSIGHTS
DOI: 10.18609/cg.2019.156
ATMP [24–33]. According to EMA
classication, gene therapy prod-
ucts function by inserting ‘recom-
binant’ genes into the body, usu-
ally to treat a variety of diseases,
including genetic disorders, cancer
or long-term diseases. Somatic-cell
therapy products contain cells or
tissues that have been manipulat-
ed to change their biological char-
acteristics or cells or tissues not
intended to be used for the same
essential functions in the body. Tis-
sue-engineered products contain
cells or tissues that have been mod-
ied so they can be used to repair,
regenerate or replace human tissue
[34,35].
e last published information
on the post-marketing studies
was collected by searching Clin-
icaltrials.gov database using the
tradename, international non-pro-
prietary name or, if available, clin-
icalTrials.gov identiers (Data-cut-
o: November 1, 2019).
e results of our data extraction
for the 10 EMA-aproved AT-
MPs are presented in Table 1. e
composition of the post-authori-
zation studies of ATMPs was an
equal split between interventional
studies (50%) and observational
studies (50%) (Figure 1). 35% of
the interventional studies includ-
ed were already ongoing at the
time of marketing authorization
(MA), and the applicant would
be required to provide an update
on the results of the studies, while
15% were newly designed studies.
e newly planned interventional
trials have generally adopted de-
signs that resemble pre-market tri-
als—eg., using single-arm designs,
small sample sizes, or short-term
follow-up periods with primary
outcomes often focused on answer-
ing hypothesis from pre-marketing
scenarios, focusing on a narrow
study population rather than test-
ing real-world scenarios in a broad-
en population (Table 1). Observa-
tional trials were either long term
fBOX 1
The regulatory framework for post-markeng studies.
-
-
-
[57,58]
[35]
-
[57]
[59]
[36]
-
-
[35]
[59] -
-
-
[25,26]
-
-
[60]
EXPERT INSIGHT
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fTABLE 1
Overview of addional pharmacovigilance acvies in post-markeng sengs for all currently marketed ATMPs within Europe.
Class of ATMP Name of ATMP
(# of PMAS) Category Study design Idener Pivotal
(main study)
Sample
size
Follow-up
length Study objecves to full PMAS requirement Status at
me of MA
X
1-
X
X
X
2 X 170
1 X
X
X 920
X
X
X
1
X
1 X
1 🗸
1 X
X 1250
1-
X
1
X
1
X 50
🗸
X
X
1 X
X
🗸290
X 105
X 125
Intervenonal studies planned at me of markeng authorizaon, Intervenonal studies ongoing at me of markeng authorizaon, Observaonal studies planned at me of markeng authorizaon, Observaonal studies ongoing at
me of markeng authorizaon.
EXPERT INSIGHT
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1510 DOI: DOI: 10.18609/cg.2019.156 Cell & Gene Therapy Insights - ISSN: 2059-7800
fTABLE 1 (CONT.)
Overview of addional pharmacovigilance acvies in post-markeng sengs for all currently marketed ATMPs within Europe.
Class of ATMP Name of ATMP
(# of PMAS) Category Study design Idener Pivotal
(main study)
Sample
size
Follow-up
length Study objecves to full PMAS requirement Status at
me of MA
X 100
X
X
X
1 X
2 🗸
2 🗸15
2 🗸
Tissue-
2 X
X
X
🗸102
🗸75
Intervenonal studies planned at me of markeng authorizaon, Intervenonal studies ongoing at me of markeng authorizaon, Observaonal studies planned at me of markeng authorizaon, Observaonal studies ongoing at
me of markeng authorizaon.
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follow up of the patients treated
in premarketing studies or mostly
a registry study to collect data on
particular safety and ecacy pa-
rameters in real-world settings.
e number of total post-mar-
keting studies ranged from two to
nine across the 10 ATMPs (Fig-
ure 2). e sample size of the trials
ranged from 15 to 1250 patients
(Table 2), with most of the tri-
als intending to enrol fewer than
200 patients (Figure 3). Duration
of follow-up in trials ranged from
12 to 180months (Table 2), which
is mostly dependent on the use
of viral vectors in the treatment
since these products require lon-
ger follow-up for safety-related
fFIGURE 1
Percentage of post-markeng authorizaon study types at MA for all
marketed ATMP.
fFIGURE 2
Number and types of post-markeng authorizaon studies submied by each applicant.
CELL & GENE THERAPY INSIGHTS
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parameters. Half of applicants
(50%) included Phase III interven-
tional trial designs that tradition-
ally focus on product ecacy as a
primary endpoint and usually form
the basis of the regulatory submis-
sions and authorization (Figure 4).
Most of these trials (86%) were
initiated before the MA but only a
few of them represent pivotal trials
upon which the MA was acquired
and the rest continued to perform
these trials as part of the post-mar-
keting surveillance phase which
would have traditionally been in-
cluded in a MA submission pack-
age (Table 1).
Our analysis suggests that a high
degree of variability between trial
designs of ATMPs in post-market-
ing settings cthat can be explained
by the wide range in evidence gen-
erated from clinical studies at the
time of MAA, the rarity of the in-
dication and the specic character-
istics of the product itself (whether
fFIGURE 4
Frequency of study phases submied as post-markeng authorizaon studies.
fTABLE 2.
Summary stascs of post-markeng authorizaon design pa-
rameters among ATMPs.
Sample size Follow-up (months)
25
2 0
15 12
1250
fFIGURE 3
Frequencies of sample sizes specied in the post-markeng studies of
ATMPs.
EXPERT INSIGHT
Cell & Gene Therapy Insights - ISSN: 2059-7800
it is genetically modied or not).
is inherited variability requires
developers to devise a post-mar-
keting strategy based on a case-by-
case scenario. Moreover, many of
the post-marketing trials, intended
to address the critical benet-risk
knowledge gaps for ATMPs, are
phase III interventional trials that
may not be well suited to inform
routine clinical use of the products.
e sample sizes of post-marketing
trials are relatively small for studies
that should aim to reect real-life
situations. Further analysis of the
data also showed high variability in
the follow-up periods specied for
each study (Figure 5). ese obser-
vations add the challenge of iden-
tifying a clear cut-o between pre-
and post-marketing studies and the
exact added value of PMAS.
e dominant trial paradigm
for decades has been explanatory
in its orientation—which is to say
that trials have been designed to
test experimental interventions un-
der “idealized” or “laboratory-like”
conditions that are optimized to
detect a treatment eect. Explana-
tory trial designs thus generally in-
volve strict intervention protocols,
many patient inclusion/exclusion
criteria, and high-resourced settings
in an eort to control for system-
ic errors (e.g. confounding, bias)
and deliver statistically credible re-
sults of high internal validity [36].
In the pre-market setting, this ap-
proach to trial design makes good
sense, since the primary question
from a regulatory perspective may
be of the form: How will this new
intervention work for this particular
patient in a controlled setting? By
contrast, in the post-market setting,
the primary question is a dierent
form: “Can this new intervention
be benecial once available to the
wider population?” Addressing this
question requires a more pragmat-
ic orientation to trial design, which
often involves more exible proto-
cols, broader and more heteroge-
neous patient populations, and a
mix of dierent healthcare settings.
For instance, early evidence of the
real-world ecacy performance of
Yescarta, a CAR T cell-based prod-
uct used in treatment of non-Hod-
gkin lymphoma (NHL), showed
that the ecacy signals generated
once the product was used in clin-
ical practice, applied to more het-
erogeneous population are slightly
inferior to that generated from the
clinical trial [37].
is raises the question of
whether it is more sensible to
continue reproducing data in
post-marketing settings within the
framework of phase III-type trials
or rather introduce more exible
designs that would account for re-
al-world heterogeneity.
fFIGURE 5
Frequencies of follow-up periods specied in the post-markeng studies of
ATMPs.
CELL & GENE THERAPY INSIGHTS
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Pragmatic trials are meant to in-
form a clinical or policy decision
by evaluating the eectiveness of
interventions in real-world clini-
cal practice [38]. We believe that
the distinction between explana-
tory and pragmatic trial concepts
may be valuable here when de-
signing post-marketing trials that
are needed to ensure safe and re-
liable use of ATMPs and full the
requirements of multiple stake-
holders (regulators, HTA bodies,
payers etc.) [39].
For ATMPs, the major draw-
backs of an explanatory orientation
are the small sample size due to low
incidence levels, a short time frame
of observation, limited or com-
plete exclusion of distinct patient
population such as vulnerable pop-
ulations (e.g., children, elderly and
pregnant women) and patients with
comorbidities (e.g., neurological or
hematological disorder, autoim-
mune disease or infections) [40].
More heterogenic outcome data
would be of particular value for
these products, due to commonly
underlying heterogenic baseline
parameters immanent to the types
of rare diseases that are frequent-
ly of interest. us, it seems that
more pragmatic trials would be
suitable for ATMP post-market-
ing safety and ecacy surveillance.
Although the data from pragmatic
trials is noisier, it can nevertheless
provide a more representative pic-
ture of whether an intervention ac-
tually has utility in clinical practice
(or how its utility may vary from
one set of conditions to the next).
However, when characterizing
explanatory and pragmatic trial
concepts, it is crucial to observe
that the explanatory/pragmatic
distinction is not a dichotomy, but
a multi-dimensional continuum.
In recognition of this point, or-
pe et al. implemented the PRag-
matic-Explanatory Continuum In-
dicator Summary (PRECIS) tool,
which breaks down a trials prag-
matism (or lack thereof) along 10
dierent dimensions as described
in their published report [41].
As a result of subsequent ex-
tensive discussion on the concept
of pragmatism within clinical re-
search methodology [40,42–50],
the requirements for characteriz-
ing a study as pragmatic trial were
optimized and validated, leading
to the implementation of PRE-
CIS-2 [51]. is improved tool
represents a nine-spoked ‘wheel’
with nine domains based on trial
design decisions. e features of
PRECIS-2 were summarized in
Box 2.
fBOX 2
The Pragmac-Explanatory Connuum Indicator Summary 2
(PRECIS-2) wheel (adapted from Loudon et al., 2015 [51]).
1. “Eligibility” domain
2. “Recruitment” domain
3. “Seng” domain
4. “Organisaon” domain
5. “Flexibility: delivery” domain
6. “Flexibility: adherence” domain
“Follow up” domain
8. “Primary outcome” domain
9. “Primary analysis” domain
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To concretely illustrate how we
believe pragmatic, post-market-
ing trials for ATMPs should be
designed, we applied a PRECIS-2
analysis to hypothetical trials for
the two marketed CAR-T cell ther-
apies, tisagenlecleucel (Kymriah®,
Novartis) and axicabtagene cilo-
leucel (Yescarta®, Kite Pharma/Gil-
ead). In what follows, we discuss
particular PRECIS-2’s dimensions
that are relevant to our case study
and how we believe trials of Kymri-
ah and Yescarta should be oriented
along the pragmatic spectrum.
Eligibility criteria
Current post-marketing studies
for Yescarta and Kymriah relied
on restricted enrollment according
to the authorized indication with
deliberate consideration of contra-
indications, special warnings, and
precautions for use (see Annex I,
Summary of product characteris-
tics) [52,53]. An exception to this
was given in case of enrolling spe-
cial patient populations not covered
at marketing authorization, there-
by addressing missing information
according to the RMP (e.g. use in
HBV/HCV/HIV infection, use in
patients with active Central Ner-
vous System (CNS) involvement in
malignancy). However, to be more
pragmatic and better inform clini-
cal use, we believe that there should
be greater exibility in the eligibil-
ity criteria, for example, allow for
patients with dierent schemes of
pre-conditioning lymphodepleting
therapies. is exibility will enable
further exploration of the eects of
dierent treatment schemes on the
product outcome, and thereby ll-
ing some of the critical information
gaps for distinct patient popula-
tions, e.g. co-morbidities, variable
pre-treatment or age groups. e
EBMT registry could be useful here
as well since it enables entering stan-
dardized data that can be analyzed
in larger post-marketing studies.
Organizaon
To deliver clear information on
what kind of expertise and resources
are needed to deliver the interven-
tion of interest, current approach-
es to post-marketing trials tend to
focus on interventions being only
performed by physicians/hospitals
that are specially trained within the
control distribution program as a
risk minimization measure. Given
the risks associated with Kymriah
and Yescarta, we believe that this is
the right approach and that a more
pragmatic design along this dimen-
sion is not necessary.
Flexibility of delivery
Relating to mechanisms on how
to deliver the intervention, cur-
rent post-marketing concepts for
Kymriah and Yescarta CAR-T cell
products focus on administration
only within the authorized dosing
regimen. However, clinicians may
often have to adjust dosing in prac-
tice, for example, for patients with
low baseline T-cell concentrations
in leukapheresis starting materials.
A more pragmatic approach would
thus include administration of
products that do not meet the com-
mercial specications. However, an
CELL & GENE THERAPY INSIGHTS
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important pre-requisite to allow
for this kind of approach would be
that no overwhelming safety con-
cerns have been identied during
manufacture and release of such
out-of-specication (OSS) product.
is would enable a deeper inves-
tigation of the dose-response rela-
tionship for OSS concentration lev-
els of the CAR-T cell product. For
instance, the authorized dosage of
Kymriah is 0.2-5x106 CD19+ CAR
T-cells (body weight-based), with
a maximum dose of 2.5x108 CAR
T-cells (non-body weight-based).
However, even lower dose ranges
(e.g. ≤0.03 x 106) in acute lympho-
blastic lymphoma trials showed a
clinical response [54].
Flexibility of adherence
A pragmatic approach here would
ideally deviate as little as possible
from standard practice by avoid-
ing highly stringent time frames for
study visits, thus increasing exi-
bility and patient adherence. Less
stringent follow-up visits may be
also motivating for practitioners, in
reducing the associated monitoring
and workload without jeopardizing
patients safety.
Follow up
e procedure for follow up under
current post-marketing settings re-
lies on an evaluation period of up to
15 years for safety and ecacy sur-
veillance after CAR-T cell adminis-
tration. When applying pragmatic
trial concepts in the post-marketing
settings, post-market studies need to
interface with the patient registries
and rely on them, which in turn will
be the most pragmatic ‘information
engine’ in the long-run. is has the
potential to enhance patient compli-
ance and commitment for a longer
follow up period and promote pa-
tient consent to register data in the
EBMT registry and use it, for in-
stance, as a source of external con-
trol data for comparative purposes.
Primary outcome
e current post-marketing trials
for Kymriah and Yescarta aim at
further characterization of safety
proles, specically related to Cy-
tokine Release Storm (CRS), neu-
rotoxicity, infections, prolonged cy-
topenias, growth and development,
reproductive status and pregnancy
outcomes. Some trials aim to char-
acterize further the ecacy prole
related to Overall Response Rate
(ORR), CD19 CAR T-cell level,
incidence/exacerbation of pre-exist-
ing comorbidities, relapse/progress
disease, incidence death and moni-
toring of replication-competent len-
tivirus. A pragmatic approach along
this dimension could apply a more
concise set of outcomes, particularly
the ones that interfere with patients’
daily productivity and quality of life
while keeping additional tests or vis-
its to a minimum. In order for the
pragmatic approach to provide add-
ed value outside of the controlled
environment of an explanatory trial,
it should also incorporate relevant
patient decision-making criteria to
provide meaningful evidence and
build upon the evidence generated at
the time of MAA.
Primary analysis
ere was no access to detailed sta-
tistical analysis plans to evaluate
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primary analysis mechanisms under
the current conventional post-mar-
keting setting for Kymriah and Yes-
carta. For a pragmatic trial approach
here, including a heterogeneous
patient population and planning
for sub-group analyses would al-
low for detecting clinically-relevant
safety and ecacy signals. Indeed,
given the limited data that is often
available for ATMPs, we would rec-
ommend a maximally pragmatic
approach to the primary analysis of
post-marketing trials to try and in-
clude as much patient-relevant data
as possible.
While the new regulatory tools de-
veloped by EMA to facilitate rapid
marketing authorization in cases
of major public health interests are
warranted, these tools must be ac-
companied by sound post-autho-
rization strategies to generate long
term evidence for safety and ecacy.
e current regulatory landscape
for conducting post-authorization
studies is very complex and demands
an enormous eort from the MAH
to navigate. As we have shown,
there is a wide variety in post-mar-
ket study designs for ATMPs, both
for studies that are required by the
regulatory authorities and for those
studies conducted voluntarily by the
MAH to investigate a specic safety
concern or to evaluate the ecacy/
eectiveness of risk minimization
activities (classied in category 1, 2
and 3). However, within that variety,
we observed that many post-mar-
keting surveillance trials for ATMPs
adopt explanatory trial design fea-
tures and are focusing on answering
hypotheses that a more suitable to
pre-market trials. us, we believe
that there is room for improvement
in terms of designing (or mandating)
post-market trials of ATMPs that
will better meet the information-
al needs of patients, clinicians, and
payers.
We have suggested that applying
the tools of pragmatic trial design
(as made explicit by the PRECIS-2
framework) may help to ll this
gap. In particular, RWD generated
from registry-based pragmatic trials
would have great potential to gen-
eralize ndings and better inform
the use of ATMPs across diverse
patient populations. However, there
are certainly challenges regarding
data quality, as patient populations
will become more divergent, thus
increasing the risk for confounding
and a higher degree of diuse data
generated. On the other hand, the
aggregation of clinical data collected
from RWD can increase the robust-
ness of meta-analyses derived from
post-marketing studies. In a recent
report, regulators from the Swedish
Medical Products Agency called for
more attention to methodological
basics of post-marketing studies
that can help generate reliable re-
sults and armed the regulatory
value of the pragmatic trial concept
regardless of labelling the studies as
‘pragmatic’ or ‘real-world evidence’
[55]. Moreover, the eld of ATMP
may learn from medical device eval-
uations, where regulatory agencies
already implemented guidance on
how to apply real-world data for
regulatory decision-making [56].
While all aspects of the approach
of a pragmatic trial do not need to
be implemented at once, working on
improving the current post-market-
ing study methodology and supple-
menting it with new ideas can help
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to enhance the current practice (Box
3). We believe that such an approach
would not only be benecial for
MAHs but also for regulators and
health insurance providers, to obtain
real-world data from clinical routine
faster after marketing authorization
for ATMPs.
fBOX 3
Consideraons for using pragmac trial concepts for
post-authorizaon safety and ecacy studies (both
observatonal and intervenonal).
Contribuons: All named authors take responsibility for the integrity of the work as a whole, and have given their approval
for this version to be published. Fritsche E, Elsallab M and Schaden M contributed equally as authors on this arcle. Hey SP
and Abou-El-Enein M contributed equally as senior authors.
Acknowledgements: None.
Disclosure and potenal conicts of interest: The authors declare that they have no conicts of interest.
Funding declaraon: MS received funding from the Erasmus SMT Mobility Program during her work on this project.
ME received funding from the Arab-German Young Academy of Sciences and Humanies (AGYA), a project of the Ber-
lin-Brandenburg Academy of Sciences and Humanies, funded by the Federal Ministry of Educaon and Research (BMBF).
The project was parally funded from the European Union’s Horizon 2020 research and innovaon programme under grant
agreement No. 825392 (Reshape) and No. 820292 (Restore)
Copyright: Published by Cell and Gene Therapy Insights under Creave Commons License Deed CC BY NC ND 4.0 which
allows anyone to copy, distribute, and transmit the arcle provided it is properly aributed in the manner specied below.
No commercial use without permission.
Aribuon: Copyright © 2019 Fritsche E, Elsallab M, Schaden M, Hey SP, Abou-El-Enein M. Published by Cell and Gene
Therapy Insights under Creave Commons License Deed CC BY NC ND 4.0.
Arcle source: Invited; externally peer reviewed.
Submied for peer review: Oct 2 2019; Revised manuscript received: Nov 2 2019; Publicaon date: Nov 18 2019.
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Enrico Fritsche
-
Magdi Elsallab
-
Michaela Schaden
Spencer Phillips Hey
-
Mohamed Abou-El-Enein
-
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-
