Expert Opinion on Orphan Drugs

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieod20

Current state of developing advanced therapies

for rare diseases in the European Union

Tingting Qiu , Yitong Wang , Monique Dabbous , Eve Hanna , Ru Han ,

Shuyao Liang & Mondher Toumi

To cite this article: Tingting Qiu , Yitong Wang , Monique Dabbous , Eve Hanna , Ru Han ,
Shuyao Liang & Mondher Toumi (2020) Current state of developing advanced therapies for
rare diseases in the European Union, Expert Opinion on Orphan Drugs, 8:10, 417-429, DOI:
10.1080/21678707.2020.1835640

To link to this article: https://doi.org/10.1080/21678707.2020.1835640

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EXPERT OPINION ON ORPHAN DRUGS
2020, VOL. 8, NO. 10, 417–429
https://doi.org/10.1080/21678707.2020.1835640

ORIGINAL RESEARCH

Current state of developing advanced therapies for rare diseases in the European
Union
Tingting Qiua, Yitong Wanga, Monique Dabbousa, Eve Hannab, Ru Hana, Shuyao Liang a
and Mondher Toumi a

a
Department of Public Health, Aix-Marseille University, Marseille, France; bDepartment of Price, Reimbursement and Market Access, Creativ-
ceutical, Paris, France

ABSTRACT ARTICLE HISTORY

Objective: Advanced Therapy Medicinal Products (ATMPs) present significant therapeutic advantages Received 25 June 2020
for inherited rare diseases. However, the development of orphan ATMPs is challenging due to their Accepted 8 October 2020
complexity and unpredictable biological activity. This study aims to comprehensively describe the
KEYWORDS
current state of orphan ATMPs in Europe.
Advanced therapy medicinal
Methods: Orphan drugs (ODs) granted by European Commission until March 2020 were investigated. products; european union;
The characteristic of diseases and ATMPs were extracted from the public summary reports of ODs from landscape; clinical trials;
Committee for Orphan Medicinal Products. The methodology for the pivotal studies of ATMPs was methodology
extracted.
Results: A total of 274 ATMPs were identified, covering 116 rare diseases, with metabolic, optical, and
oncologic diseases being the most targeted. A total of 158 ATMPs were indicated for life-threatening
diseases, 129 ATMPs targeted diseases currently lacking authorized or satisfactory treatment available.
Twenty-eight ATMPs are being investigated in the phase II/IIII or phase III studies. The median patient
size of pivotal studies was 127, 15 were open-label studies, 8 were single-arm trials, and 14 reported
surrogate outcomes.
Conclusion: There are rapid growths in developing ATMPs for life-threatening diseases with high
unmet clinical needs. Optimizing the study methodology and exploring innovative design to facilitate
the market access is paramount.

1. Introduction distinct regulatory programs for ATMPs have been established

in several countries in order to facilitate the MA of these
Rare diseases are increasingly considered a high public health
innovative therapies. For instance, the regenerative medicine
priority in many countries. Legislation for rare diseases has
advanced therapy (RMAT) designation has promoted exten­
been established in order to offset the potential losses of
sive interactions with the FDA beginning in very early stages
developing drugs in such a niche market, including non-
of drug development [8,9]. A steady market growth in the field
financial and financial incentives to pharmaceutical compa­
of ATMPs is being witnessed and the global ATMPs market is
nies, national rare disease initiatives, and expedited market
predicted to exceed 35.4 USD billion by 2026 [10].
authorization (MA) programs [1,2]. Such strategies have sig­
ODs have gained great attention from pharmaceutical
nificantly stimulated the research efforts, with more than 600
companies due to the supportive regulatory environment.
orphan drugs (ODs) approved worldwide [3] and the global
More importantly, the high prices of ODs, in order to recover
ODs market estimated to reach 209 USD billion by 2022 [4].
the development investment from small patient pool, also
The fast growth in the development of ODs is partly driven
have generate large revenue potential [11,12]. Compared to
by the improved knowledge of underlying genetic causes of
traditional ODs, ATMPs could result in extra costs driven by
rare diseases, given that approximately 80% of rare diseases
the personalized nature of the medicines, meaning that
are composed of genetic components [5]. The technological
some ATMPs cannot be prepared, tested, and manufactured
progress in advanced therapy medicinal products (ATMPs)
in bulk and, therefore, involve higher costs for clinical deliv­
represents great opportunity to treat rare and inherited dis­
ery [13]. Furthermore, ATMPs are associated with additional
eases, even for those previously perceived as incurable illness
value elements to those of ODs due to its curative potential
[6]. According to the European regulation EC No. 1394/2007
through the limited-time administration [14]. Undoubtedly,
[7], ATMPs were classified as gene therapy medicinal products
orphan ATMPs hold both pronounced importance for dis­
(GTMPs), somatic cell therapy medicinal products (sCTMPs),
ease treatment and enormous commercialization potential.
tissue-engineered products (TEPs) and combined products.
For example, nusinersen (Spinraza®), the first treatment
Like ODs, ATMPs addressing high unmet clinical needs possess
approved for spinal muscular atrophy (SMA), costs 750,000
a high potential for expedited MA pathways. Furthermore,
USD in the first year and 375,000 USD annually afterward.

CONTACT Tingting Qiu tingting.qiu@etu.univ-amu.fr Department of Public Health, Aix-Marseille University, Marseille, France
Supplemental data for this article can be accessed here.
© 2020 Informa UK Limited, trading as Taylor & Francis Group
418 T. QIU ET AL.
This placed Spinraza® amongst the priciest drugs in the
world post-market launch [15]. However, onasemnogene
abeparvovec-xioi (Zolgensma®), as the first gene therapy
approved for SMA, was priced at 2.1 USD million per patient
for a single injection administration [16], making it the most
expensive drug on the global market.
The purpose of this study was to conduct a comprehensive
analysis for the ATMPs granted with OD designation in Europe.
This study aimed to enhance the knowledge on which ther­
apeutic areas having high unmet clinical needs attracted the
greatest number of ATMP developers to participate in.
Furthermore, the current development status of the ATMPs
was investigated to gain a preliminary perspective on the
products representing high promises for market launch in
the near future. Finally, pivotal clinical trial methodology for
ATMPs that are currently in the late-stage of development
were studied to understand potential challenges faced in
clinical evidence collection for ATMPs.
2. Method
2.1. Data source
The official website of the European Commission (EC) was
searched to identify designated ODs as of 1 March 2020. The
official website of the European Medicines Agency (EMA) was
searched to obtain the public summary reports on orphan
designation published by the Committee for Orphan
Medicinal Products (COMP), as well as the scientific recom­
mendations of ATMPs published by the Committee for
Advanced therapies (CAT) [17].
The company websites and press releases for ATMPs spon­
sors were searched to understand sponsor characteristics and
the current development status of their products. The United
States National Library of Medicine’s ClinicalTrials.gov data­
base and the European Union’s (EU) Clinical Trials Register
were searched to supplement information where information
related to clinical trials of ATMPs was not completely pre­
sented on the company websites.
2.2. Data extraction and analysis
Specific extraction forms were established using Microsoft
Excel to extract data.
2.2.1. Product-related data
Product-related data including product name, product cate­
gory, cell type, gene vector, indication, prevalence of target
rare disease in EU, available treatment authorized, date of ODs
designations, and current development phase were searched
and extracted. The ATMPs were classified based on regulation
EC No. 1394/2007, under which, gene-modified, cell-based
therapy, including chimeric antigen receptor T (CAR-T) immu­
notherapy, was defined as GTMPs.
The therapeutic areas of targeted diseases were identified by
searching the International Classification of Disease (ICD)-11 data­
base. Diseases were classified as debilitating diseases, life-
threatening diseases, or debilitating and life-threatening diseases
according to the description of rare diseases in the COMP reports.
The current development phases were defined as pre-clinical,
phase I, phase I/II, phase II/III, phase III, under evaluation, author­
ized, rejected, and withdrawn from the EU market. Phase II/III
studies and phase III studies were regarded as late-stage devel­
opment. The study designs for ATMPs in phase II/III or phase III
studies were further investigated in relation to randomization
method, masking, comparator selection, report of outcomes,
patient number, follow-up duration and study centers.
The primary outcomes were classified into four cate­
gories: 1) patient-relevant outcomes were endpoints well
defined which could be measured objectively, such as mortal­
ity and overall survival for oncology, 2) patient-reported out­
comes (PROs) were any reports of the status of a patient’s
health condition originating directly from the patient, such as
the Health Related Quality of Life (HRQoL), 3) clinician-
reported outcomes (ClinROs) were considered as rating scales
of patients’ status conducted on the basis of clinicians’ evalua­
tion, and 4) surrogate outcomes were endpoints used to pre­
dict clinical benefits and support faster market approval, such
as biomarkers.
Two analysts conducted independent searches and extrac­
tions of ODD-ATMP information. Any discrepancies identified
were resolved by a senior researcher specialized in pharma­
ceutical science and biologics.
2.2.2. Sponsor-related data
Sponsor-related data extracted included: sponsor name, spon­
sor type (commercial or noncommercial organization), and
sponsor regions. Commercial organizations referred to phar­
maceutical companies (including biotech company), consult­
ing companies, contract research companies or other science
companies. Noncommercial organizations referred to the fol­
lowing categories: private individual, medical centers (includ­
ing hospitals), academic institutions (e.g., universities), charity
organizations, and governmental agencies. The EMA-small and
medium-sized enterprises (SMEs) database was searched to
identify whether a company held an SME status in the EU.
For pharmaceutical companies originating outside of the
EU, a legal representative in one of the EU Member States
(including the United Kingdom (UK)) must be established for
administrative reasons. Therefore, both regions for ODs
holders and regions for original ODs developers were studied.
Parent organization regions were considered if the ODs
holders were subsidiary companies.
3. Results
3.1. Description of orphan ATMPs and rare diseases
targeted
A total of 1,670 products were designated as ODs as of
March 2020. Among them, 274 products met the definition
of ATMPs and were investigated in this study. The number of
ATMPs has significantly increased over the past 10 years: there
were only 28 ATMPs between 2001 and 2009 in comparison to
243 ATMPs between 2010 and 2019 (Supplementary
Material 1).
GTMPs (N = 160, 58.39%) represented the largest number
of ATMPs, most of them used adeno-associated virus (AAV)

(N = 110, 68.75%), lentiviral (N = 29, 18.13%) or retroviral
(N = 11, 6.88%) as gene vector. Among them, four products
adopted gene editing technology, including EDIT-101 (CRISPR/
Cas9-based), SB-318 (zinc finger nucleases-based), SB-913 (zinc
finger nucleases-based), and CTX-001 (CRISPR/Cas9-based).
Five products, BB2121, JCAR017, KTE-X19, CTL019, and
SLAMF7, were CAR-T cell-based gene therapy. sCTMPs
(N = 107, 39.05%) accounted for a relatively smaller percen­
tage compared with GTMPs, with the majority of them (55,
51.40%) manufactured using allogeneic cell. TEPs represented
the smallest number of ODDs-ATMPs (N = 7, 2.55%).
3.1.1. Country distribution of ATMPs developers
Considering ODs holders in the EU, England (N = 69, 25.18%)
had the largest number of ATMPs, followed by France (N = 43,
15.69%) and Germany (N = 29, 10.58%). When considering the
Figure 1. Number of ATMPs in member states of European Union.
Figure 2. Classification of ATMPs holders (data in percentage).
EXPERT OPINION ON ORPHAN DRUGS 419
origin of ODDs developers, 156 (56.93%) ATMPs were origin­
ally developed by European Member States. Among these,
France (28, 17.95%) held the largest number of ATMPs, fol­
lowed by England (27, 17.31%) and Germany (21, 13.46%)
(Figure 1). A total of 115 (41.97%) ATMPs were developed by
sponsors originating outside the EU, with over three-quarters
of manufacturers from the United States (N = 91, 79.13%).
Other countries with manufacturers having ATMPs in Europe
included Switzerland (N = 11), Japan (N = 4), Israel (N = 3),
India (N = 2), South Korea (N = 2), Canada (N = 1), and
Australia (N = 1).
3.1.2. Characteristics of ATMPs holders
The majority (N = 243) of ATMPs holders were commercial
organizations, only a small number (N = 31) of ATMPs holders
were noncommercial organizations Figure 2. For 156 ATMPs
420 T. QIU ET AL.

originally developed in EU Member States, 125 (80.13%) of a narrow patient group. Twenty-three (8.39%) ATMPs were
them were developed by commercial organizations, and 74 indicated for diseases only having symptom-relieving treat­
(59.20%) of these companies were registered as SMEs in ments available. Thirty-one (11.31%) ATMPs were indicated
the EU. for diseases with replacement treatments available, such as
The companies or agencies with more than 5 orphan plasma factor for hemophilia, and alglucosidase alfa for glyco­
ATMPs included Promethera Biosciences (15 designations for gen storage disease type II.
9 indications), Fondazione Telethon (9 designations for 8 indi­ The therapeutic areas with the largest number of ATMPs
cations), Kite Pharma (7 designations for 7 indications), were metabolic diseases (64 designations for 33 diseases),
Orchard Therapeutics (7 designations for 6 indications), ophthalmology (41 designations for 12 diseases), oncology
UniQure Biopharma (6 designations for 5 indications), (28 designations for 7 diseases), neurology (25 designations
Abeona Therapeutics (5 designations for 4 indications), for 11 diseases), and hematologic malignancies (25 designa­
MeiraGTx (5 designations for 4 indications), and Novartis tions for 12 diseases) (Supplementary Material 2).
Europharm (5 designations for 5 indications). The diseases holding the greatest number of ATMPs were
retinitis pigmentosa, followed by epidermolysis bullosa,
glioma, Duchenne muscular dystrophy, and graft-versus-host
3.1.3. Target therapeutic areas of ATMPs disease Table 2.
A total of 116 types of rare diseases were targeted by 274
ATMPs. Among them, 158 (57.66%) ATMPs were indicated for
diseases perceived as debilitating and life-threatening diseases
Table 1. The greatest number (N = 126, 45.99%) of ATMPs 3.2. Current development stages of ATMPs
were indicated for diseases with a prevalence of 0.1 ~ 1/10,000 A total of 12 ATMPs for 16 rare diseases have received MA
people in the EU Table 1. worldwide of all the ATMPs investigated. Seven products were
Seventy-three (26.64%) ATMPs were indicated for diseases approved in the EU, including darvadstrocel (Alofisel®), auto­
currently having no authorized treatment available, while logous CD34+ cells encoding βA-T87Q-globin gene
patients were only treated with surgery, or other supportive (Zynteglo®), tisagenlecleucel (Kymriah®), axicabtagene ciloleu­
strategies. Thirty-three (12.04%) ATMPs were indicated for cel (Yescarta®), voretigene neparvovec (Luxturna®), ex vivo
diseases having authorized, but not satisfactory treatments expanded autologous human corneal epithelial cells contain­
available, such as in the case where treatments only targeted ing stem cells (Holoclar®), and autologous CD34+ cells trans­
duced with a lentiviral vector containing the human ADA gene
(Strimvelis®). Five products were approved in other countries
Table 1. Characteristic of targeted rare diseases of ATMPs.
outside of Europe, including remestemcel-L (Prochymal®) in
Disease
Therapeutic areas Disease characteristic* prevalence Existing Canada, autologous mesenchymal stem cell (MSC)
(N) (N) (N) treatments (N) (NeuroNata-R®) in South Korea, autologous adult live-
Metabolic Life-threatening disease ≤ 0.1 (64) No authorized cultured osteoblasts (Ossgrow®) as well as allogeneic bone
diseases (64) (19) treatment marrow derived MSC (Stempeucel®) in India, and Zolgensma®
(73)
Ophthalmological Debilitating disease (58) > 0.1–1 Not satisfactory in the US. Allogeneic adipose-derived adult MSC contained in
diseases (41) (126) treatment a fibrin-based bioengineered dermis (SkinMed) was used
(33) under the ‘Hospital Exemption’ rule in the EU. One anti-
Oncological Debilitating and life- > 1–2.5 Symptomatic-
diseases (28) threatening disease (26) relieving Epstein-Barr virus (EBV) cytotoxic T-cell therapy, developed
(158) treatment by Scotland National Health Services, was accepted by the
(23) Medicine and Healthcare Products Regulatory Agency
Neurological Debilitating and > 2.5 (58) Replacement
diseases (25) potentially life- therapy (31) (MHRA) for the application of this unlicensed medicinal pro­
threatening disease duct under the direct personal responsibility of the prescriber.
(30) The development of four products, INGN 201, ATIR101,
Hematologic Disability and life Authorized
Malignancies threatening disease (8) therapy SAR421869, and SAR422459, were terminated due to re-
(25) (satisfactory) prioritization of clinical development strategies. Alipogene
(99) tiparvovec (Glybera®) was withdrawn from the EU market
Immunological Negative impact on the Neutralizer or
diseases (21) QoL (1) chelating when the manufacturer did not apply for MA renewal.
agent (15) Human heterologous liver cells (Heparesc®) and sitimagene
Blood diseases ceradenovec (Cerepro®) were rejected for MA from EMA due
(21)
Dermal diseases to insufficient efficacy evidence.
(13) The majority of ATMPs (N = 192, 70.07%) were still in the
Transplantation- early development stages: 60 (21.90%) in pre-clinical phase, 12
related (8)
Digestive diseases (4.38%) in phase I clinical trials, 87 (31.75%) in phase I/II clinical
(6) trials, and 33 (12.04%) in phase II clinical trials. Only 28
Infectious diseases (10.22%) ATMPs were in phase II/III or phase III clinical trials.
(5)
Other diseases Among them, all clinical trials were multi-center studies
(17) (Figure 3), with the exception of 2 clinical trials, EB-101 for
N number, QoL quality of life epidermolysis bullosa and FLT180a for hemophilia B, which
 EXPERT OPINION ON ORPHAN DRUGS 421

Table 2. Rare diseases with more than 5 ATMPs granted by the European medicines agency.
Therapeutic ATMPs Disease Availability of
Disease name areas Number prevalencea treatment The ATMPs after pre-clinical development (Number of products)
Retinitis pigmentosa Ophthalmology 14 3 Luxturna® GS030; HORA-PDE68; HORA-RPE65; AAV-RPGR; NSR-RPGR; AAV2-hRPE65v2;
UshStat; RST-001; Expanded hRPC from neural retina (N = 9)
Epidermolysis bullosa Dermatology 11 0.5 None EB-101; KB103; SkinMed; Holostem: COL17A1, COL7A1 and LAMB3-based
therapy; Allogeneic dermal fibroblasts; Allogeneic skin-derived ABCB5-
positive mesenchymal stem cells (N = 8)
Glioma Oncology 11 2.6 Chemotherapies AV0113; DNX-240; ICT-107; VB-111; DCVax-L; Toca 511; Autologous ex-vivo-
expanded leucocytes treated with 5-aza-2ʹ-deoxycytidine (N = 7)
Duchenne muscular Neurology 8 0.5 Translarna® PF-06939926; SGT-001 (N = 2)
dystrophy
Graft-versus-host Immunology 8 0.5 Immuno- Allogeneic bone-marrow derived ex-vivo expanded multipotent adult
disease suppressants progenitor cells (N = 1)
Pancreatic cancer Oncology 7 2.4 Chemotherapies GVAX; LOAd703; VCN-01; Cytochrome P450 isoform 2B1 gene transfected
human embryonic kidney 293 cells encapsulated in polymeric cellulose
sulfate (N = 4)
Leber congenital Ophthalmology 6 1 Luxturna® AAV-RPE65; AAV2-hRPE65v2; EDIT-101; GS010 (N = 4)
amaurosis
Hemophilia B Hematology 6 0.3 Factor IX FLT180a; PF-06838435 (SPK-9001); AMT-061 (N = 3)
Hemophilia A Hematology 5 0.8 Factor VIII TAK-754; BMN 270; SPK-8011; SB-525 (N = 4)
Mucopolysaccharidosis Metabolic 5 0.1 None ABO-102; EGT-101; LYS-SAF302; SAF-301 (N = 4)
type IIIA disease
Ornithine Metabolic 5 0.1 Ravicti® DTX301; MRT5201 (N = 2)
transcarbamylase disease
b
Achromatopsia Ophthalmology 5 0.15 ~ 0.3 None AAV-CNGA3; ACHM A3; AAV-CNGB3; ACHM B3 (N = 4)
Severe combined Immunology 5 0.01 ~ 0.1b None OTL-101; Autologous CD34+ cells transfected with retroviral vector
immunodeficiency containing adenosine deaminase gene (N = 2)
ATMPs advanced therapy medicinal products, hRPC human retinal progenitor cell
Luxturna® Voretigene neparvovec, Ravicti® Glycerol phenylbutyrate, Translarna® Ataluren
aper 10,000 European citizens
bprevalence varied according to the disease subtypes.

were conducted in a single center in California and the UK,
respectively.
Phase III studies were completed for four products, among
them, GS010 showed clinically meaningful improvement in
vision against placebo in the 96 week cutoff data. However,
the clinical results of the phase III study for the other three
products were not as promising as anticipated: VB-111 for
recurrent glioblastoma did not demonstrate clinical benefits
in either overall survival or progression-free survival versus
Bevacizumab group, Cx401 for complex perianal fistulas failed
to show significant difference in healing rate compared to the
control group, and ECCS-50 for the treatment of impaired

Figure 3. Current status and study centers for phase II/III and phase III clinical trials.
422 T. QIU ET AL.
hand function in patients with systemic sclerosis missed both
the primary and secondary outcomes s against placebo.
Phase III studies were terminated for three products, auto­
logous osteoblastic cells (Preob®) for non-traumatic osteone­
crosis, ELAD for acute liver failure, and Toca 511 for glioma, all
due to interim results suggesting that primary outcomes could
be unlikely to achieve in the final analysis. Phase III studies
were suspended for two products, ICT-107 and BPX-501,
because the sponsors were unable to secure sufficient finan­
cial resources.
The recruitment of phase III studies was not yet initiated for
2 products, SPK-8011 and Neuro-Cells. SPK-8011 was being
investigated in a lead-in, observational study prior to phase
III clinical trial. Neuro-Cells planned to start patient enrollment
in June 2020.
The recruitment of phase II/III or phase III studies for the
remaining 17 products is underway, with the exception of
autologous MSC-NTF cells (NurOwn®) having completed their
recruitment with 261 patients included. The interim analyses
of ongoing phase II/III or phase III studies were disclosed for
five products, all of them showed encouraging results: Lenti-D
targeting adrenoleukodystrophy, JCAR017 targeting follicular
lymphoma, autologous dendritic cells (DCVax-L®) targeting
glioma, AMT-061 targeting hemophilia B, and BMN 270 target­
ing hemophilia B. No interim data were released for the rest of
11 products. The MA application of BMN270 was submitted to
EMA and FDA in the last quarter of 2019.
3.3. Study design of the pivotal studies for ATMPs
The median patient size is 127 (ranging from 15 to 414), with
12 (42.86%) studies having estimated enrollments less than
100 patients. Among them, 15 (55.56%) studies were open-
label studies, while the remaining 12 studies were blinded
(Table 3).
Single-arm studies were conducted for 8 (29.63%) products
(Supplementary Material 3). Among them, BMN207, FLT180a,
SPK-9001, and AMT-061 were indicated for hemophilia with
plasma factor replacement therapy available. Lenti-D, EB-101,
LYS-SAF302, and ATA129 were indicated for diseases currently
having no available treatments. The natural history study of
mucopolysaccharidosis type IIIA was being conducted in parallel
with the ongoing phase III studies investigating LYS-SAF302.
Randomized clinical trials (RCTs) using active comparators
or standard-of-care (SoC) as control groups were conducted
for seven products: ELAD, BPX-501, omidubicel (NiCord®),
Cx401, JCAR017, Toca511, and BB2121. Randomized, sham-
controlled studies using placebo or untreated patients as
control groups were conducted for 11 products: Preob®,
NurOwn®, Ery-Dex, NSR-REP1, ICT-107, VB-111 (for the treat­
ment of glioma and ovarian cancer), DCVax-L, GS010, Neuro-
Cells, ECCS-50, and NT-501. The natural history study of
Leber’s hereditary optic neuropathy was being conducted in
parallel with the ongoing phase III studies investigating
GS010.
Patient-relevant outcomes were used for five products:
overall survival for ELAD, BPX-501, ICT-107, VB-111 (for the
treatment of glioma and ovarian cancer), and Toca511. PROs
were used for two products: Amyotrophic lateral sclerosis
functional rating scale (ALSFRS-R) for NurOwn® and the
Cochin score for ECCS-50. ClinROs were used for three pro­
ducts: Modified International Cooperative Ataxia Rating Scale
(mICARS) for Ery-Dex, Development quotient (DQ) for LYS-
SAF302 and International Standards for Neurological
Classification of Spinal Cord Injury (ISNCSCI) motor scores for
Neuro-Cells. Surrogate outcomes were used for 14 products: 1)
progression-free survival or event-free survival for Lenti-D,
JCAR017, DCVax-L and BB2121, 2) treatment response rate
for Preob®, Cx401, EB-101, and ATA129, 3) plasma factor activ­
ity for BMN 270, FLT180a, SPK-9001 and AMT-061, and 4)
visual acuity for NSR-REP1 and GS010. The validity of primary
outcomes for two products, the time to neutrophils engraft­
ment for NiCord® and the rate of change in Ellipsoid Zone (EZ)
Area Loss for NT-501, were not well established.
4. Discussion
4.1. ATMPs potential to treat rare diseases lacking
satisfactory therapy
The fast growth in the development of orphan ATMPs could
be attributed to the benefits associated with ODs, such as the
guarantee of development support from the EMA and faster
patient access with high prices [18,19]. The UK and France
were shown as the pioneering countries amongst the EU
Member States in this market [20]. The UK has been perceived
as the leading country with over 70 ATMPs companies actively
participating in this field. Biotech companies in France were
consistently strong contributors in ATMP development, such
as GenSight Biologics, Vivet Therapeutics, Lysogene and
TxCell [21].
As shown in this study, around 50% of the ATMPs investi­
gated were indicated for rare diseases currently lacking effec­
tive treatments or having therapies unsatisfactory to patients’
needs. This suggested that orphan ATMPs in development
might provide new treatment opportunities for patients suf­
fering from life-threatening rare diseases.
A large number of ATMPs were used for the treatment of
inherited metabolic disorders that mostly could be alleviated
only by adherence to strict diet management. Enzyme repla­
cement therapy (ERT) was applied for enzyme deficiency dis­
eases, such as mucopolysaccharidos (MPS), toward supplying
the functional enzymes to accelerate the degradation of accu­
mulated toxic substances. Whereas ERT was associated with
persistent complications as well as the risk of developing anti-
drug antibodies to ERT, which could significantly affect clinical
outcomes [22]. The advantages of gene therapies for meta­
bolic diseases included their ability to deliver normal genes to
generate therapeutic enzyme in sufficient quantities through
one-time administration and their precise localization and
rapid delivery to affected organs, including the central ner­
vous system (CNS) [23].
Similar to enzyme deficiency diseases, hemophilia, as an
X-linked monogenic blood disorder, relies on frequent (every
2 ~ 3 days) coagulation factors replacement therapy to reduce
the incidence of spontaneous bleeding [24]. However, the
formation of anti-drug antibodies has restricted the long-
term effectiveness of such therapies. Encouragingly,
 EXPERT OPINION ON ORPHAN DRUGS 423

Table 3. ATMPs (N = 28) being investigated in the phase II/III or phase III clinical trials.
Estimated
Product Patient completion Follow-up
name Indications Study design Comparator Primary outcomes numbera date duration
Preob® Non-traumatic Triple Placebo Percentage of treatment responders 55 Terminated 24 months
osteonecrosis blinded,
RCT
ELAD Acute liver failure Open label, Standard of care Overall survival 151 Terminated 91 days
RCT
BPX-501 HSCT Open label, CTX Overall survival 178 December 2023 3 years
RCT
NiCord® HSCT Open label, Unmanipulated Time to neutrophil engraftment 124 December 2019 42 days
RCT cord blood unit
Lenti-D Adrenoleukodystrophy Single arm NA Proportion of subjects who are alive and have 32 February 2023 24 months
trial no 6 major functional disabilities
NurOwn® ALS Double Placebo Amyotrophic lateral sclerosis functional rating 261 October 2020 28 weeks
blinded,
RCT
Cx401 Anal fistula Double Fibrin adhesive Closure of fistulas 214 Completed 26 weeks
blinded,
RCT
Ery-Dex Ataxia telangiectasia Triple Placebo Modified International Cooperative Ataxia 180 December 2019 12 months
blinded, Rating
RCT
NSR- Choroideremia Single Untreated Corrected visual acuity 169 March 2020 12 months
REP1 blinded, patients
RCT
EB-101 Epidermolysis bullosa Single arm NA Wound healing 15 March 2021 12 weeks
trial
JCAR017 Follicular lymphoma Open label, Standard of care Event free survival 262 May 2023 3 years
RCT
ICT-107 Glioma Double Placebo Overall survival 414 Suspended 46 months
blinded,
RCT
VB-111 Glioma Open label, Add on therapy Overall survival 252 June 2023 10 years
RCT
DCVax-L Glioma Quadruple Placebo Progression free survival 331 Unknown Unknown
blinded,
RCT
Toca 511 Glioma Open label, Standard of care Overall survival 403 December 2019 4 years
RCT
BMN 270 Hemophilia A Single arm NA Median FVIII activity 130 December 2022 52 weeks
trial
SPK- Hemophilia A NA NA NA 55 July 2020 12 months
8011
FLT180a Hemophilia B Single arm NA Factor IX activity levels 50 December 2035 5 years
trial
SPK- Hemophilia B Single arm NA Annualized bleeding rate; Vector derived FIX: 55 November 2021 12 months
9001 trial C level
AMT-061 Hemophilia B Single arm NA Factor IX activity levels 56 March 2020 26 weeks
trial
GS010 Leber’s hereditary optic Quadruple Placebo ETDRS visual acuity 37 Completed 48 weeks
neuropathy blinded,
RCT
LYS- SAF302 MPS type IIIA Single arm trial NA Development 20
quotient
January 2022 24 months
BB2121 Multiple myeloma Open label, Standard of care Progression free survival 381 June, 2025 5 years
RCT
VB-111 Ovarian cancer Double Placebo Overall survival 400 December 2022 5 years
blinded,
RCT
ATA129 Post-transplant Single arm NA Objective response rate 33 November 2020 2 years
lymphoproliferative
disorder
Neuro- Spinal cord injury Double Placebo Physical changes; Increase of ISNCSCI motor 70 January 2021 12 months
Cells blinded, scores
RCT
ECCS-50 Systemic sclerosis Quadruple Placebo Cochin score (24 weeks) 88 Completed 48 weeks
blinded,
RCT
NT-501 Macular telangiectasia Double Placebo Rate of Change in Ellipsoid Zone Area Loss 112 March 2022 24 months
type 2 blinded,
RCT
ALS amyotrophic lateral sclerosis, AML acute myeloid leukemia, ATMPs advanced therapy medicinal products, CTX cyclophosphamide, ETDRS Early Treatment Diabetic
Retinopathy Study, HSCT hematopoietic stem cell transplantation, ISNCSCI International Standards for Neurological Classification of Spinal Cord Injury, MPS
mucopolysaccharidosis, NA not applicable, RCT randomized controlled trial
NiCord® omidubicel, NurOwn® autologous-cultured mesenchymal bone marrow stromal cells secreting neurotrophic factors, Preob® autologous osteoblastic cells
aActual patient number was presented if the study has completed, otherwise, estimated patient number was presented.
424 T. QIU ET AL.
hemophilia was considered well suited for correction by gene
therapy as the bleeding phenotype was seen to be responsive
to a wide range of factor levels, thus a precise regulation was
not required [25]. Valoctocogene roxaparvovec (BMN270) for
hemophilia A has submitted a market authorization applica­
tion to the EMA and FDA in November and December of 2019,
respectively, based on data from a phase 1/2 trial showing
reduced bleeding episodes and need for factor VIII infusions.
Remarkably, the levels of clotting factor VIII remained stable
over the course of 3 years following treatment [26].
Inherited retina diseases, such as retina pigmentosa and
Leber’s congenital amaurosis, also attracted a attention from
ATMP developers. The retina has been considered an excellent
target for gene therapy since the accessibility to the retina
allows for relatively noninvasive procedures, the treatment
effects can be easily monitored, and the blood–retinal barrier
could minimize the systemic immune response [27].
Luxturna®, a treatment delivering a normal copy of the
RPE65 gene directly to retinal cells, was approved as the first
therapy to treat patients with retinal dystrophies caused by
‘biallelic’ RPE65 mutations, with the potential to restore sight
and improve vison at low light levels as compared to the
control group.
4.2. Challenges in the patient access to orphan ATMPs
4.2.1. Challenges in conducting clinical trials for ATMPs
Despite extensive interests for developing orphan ATMPs, the
number of ATMPs approved as well as the ATMPs in late stage
of development globally is still limited. Small patient size
constitutes the biggest obstacles in conducting clinical trials
of ODs. Insufficient knowledge about rare diseases leads to
a delay in correct diagnosis [28], thus candidates also miss the
ideal opportune time to be enrolled and treated earlier [29].
Placebo-controlled studies face ethical hurdles in rare diseases,
while rare diseases usually lack commonly agreed upon SOC,
posing challenges to conduct RCTs with accepted active com­
parators. Heterogeneity in pathophysiology of rare diseases
leads to great variations in drug responses [6]. This situation
has become even more complex when it comes to ATMPs for
rare diseases, which generally require complicated manufac­
turing processes. Maintaining the high quality and minimizing
the batch-to-batch variation of ATMPs are crucial to ensure
adequate patient response [30]. Additionally, as one-time
administration therapies, ATMPs will exclude the patients
from eligibility in future clinical trials [31,32].
Innovative methods to strengthen the evidence quality for
ATMPs have been proposed [33]. Natural history study, exter­
nal prospective cohort, or patient registry to serve as the
control group of the single-arm trial have been utilized to
gain regulatory approval. Pragmatic RCTs incorporating
a cluster randomization design based on study centers [34]
may provide a robust design. Other strategies to deal with
small sample sizes include adaptive study design [35], employ­
ing genetic testing to reduce individual’s variability, and
selecting continuous endpoints [29]. Moreover, data-sharing
among multiple companies developing ATMPs for the same
patient group could be a practical and ethical solution [36].
This analysis has shown that surrogate outcomes were
commonly selected as primary outcomes for ATMPs.
However, surrogate outcomes raised questions regarding
their appropriateness to support MA [37]. It was advisable
that the validity of surrogate outcomes be established early
before deciding to use surrogate outcomes in the pivotal
studies. PROs can provide powerful evidence for patient per­
ceptions that clinical measures are unable to capture [32].
Composite outcomes including multiple types of outcomes
could be considered to evaluate treatment outcomes for
patients with heterogeneous disease characteristics [36,38].
Early engagement of patient groups could be applied to
capture the additional values of ATMPs [39].
4.2.2. Market access for ODs and ATMPs in Europe
The high prices for ODs, combined with the great uncertainties
in clinical evidence, can result in the incremental cost-
effectiveness ratio (ICER) of ODs exceeding the payer ‘willing­
ness to pay’ threshold. Several EU countries have established
special pathways to overcome the challenges in the HTA of
ODs. For example, ultra-ODs may be eligible to undergo Highly
Specialized Technology evaluations in England, which raises the
ICER threshold to £100,000 per QALY gained [40]. Approved
ODs were presumed to have additional benefit by law, granting
with reimbursement along with MA automatically in Germany
[41]. A variety of managed entry schemes is increasingly imple­
mented across the European countries to address the uncer­
tainties of ATMPs, ranging from the simple discount to
coverage with evidence development programs containing
pay-for-performance elements [42].
Although ATMPs may benefit from the above-mentioned
specific HTA pathways for ODs established in EU countries,
there remains inherent uncertainties unique to ATMPs. The dur­
ability of treatment benefits and potential risks in the long run is
impossible to predict based on the limited evidence at the time
of market launch [36]. Traditional HTA pathways may fail to
capture the broader societal values associated with ATMPs,
including the age of onset (priority given to children), lifetime
disease burden for patients [13], productivity, improvement in
adherence and the impact on the future drugs development
[42]. The recent sanitary COVID-19 crisis supports the additional
value of one-time therapies over chronic treatments on regular
basis in terms of reducing the contamination risk at hospital
level. Further explorations are needed regarding how best to
measure and include the additional value elements into the
QALY calculation would be informative and useful [43,44].
4.3. Business Model for ATMPs in rare conditions
This study has indicated that the development of ATMPs was
dominated by commercial sponsors rather than noncommer­
cial sponsors. This was partly because noncommercial organi­
zations signed licensing agreements with pharmaceutical
industries to achieve the translation from scientific discoveries
to ultimate commercialization. Public–private partnership
complementarily harnessed the capabilities of each party,
thus ensuring a faster development of ATMPs [45,46].
Biotech stocks have far outpaced the average stock market
 EXPERT OPINION ON ORPHAN DRUGS 425

during the last quarter of 2019, following a 195 USD billion 5.2. Regulatory requirements
biopharma acquisition witnessed among pharmaceutical
The FDA predicts that they will be approving between 10 and
giants [47]. The rapid progress on ATMPs and the extensive
20 cell and gene therapy products a year based on an assess­
pipelines in biotech companies have urged interested big
ment of the current pipeline and the clinical success rates by
pharma to act quickly in order to catch the opportunity to
2025. Fast growth in ATMPs will enhance the knowledge
arrive early on the market.
about effectiveness and safety of ATMPs, thus regulators
Due to the paucity of clinical evidence, it is still prema­
may take advantage of insights gained from already approved
ture to predict the magnitude and sustainability of clinical
products to impose more clarified and strict requirements on
benefits of ATMPs in the long run. On the most optimistic
the collection of clinical evidence. The sustainability of the
assumptions, there are gene replacement therapies target­
effectiveness of ATMPs will be better understood, leading to
ing monogenic conditions may bring a ‘cure’ opportunity, or
requirements for clinical trial durations to be sufficiently long
at least, patients may have symptoms relieved for many
enough to investigate the patient outcomes. The require­
years after one administration. Under such circumstance,
ments for comparative studies may be more demanded in
once the limited number of prevalent patients have been
the existence of alternative therapies with reasonable efficacy,
presumably cured, only incident patients remain available to
such as chemotherapies for large B-cell lymphoma. Historical
treat. Therefore, future competitors must differentiate and
comparisons will be accepted only when rigorous methodolo­
highlight their respective clinical advantages as comparisons
gical protocols are in place to guarantee the validity of such
to initially approved products. Otherwise, they will probably
comparisons. Post-approval commitment for effectiveness evi­
end up with ‘no added benefits’ against existing product,
dence generation will be unavoidable. The difficulties inherent
left with no options but lower prices as the only leverage to
to all ODs development will continue to apply, and an increas­
win the already depleted market. In another scenario closer
ing number of ultra-orphan drugs targeting monogenic dis­
to reality, ATMPs would not all be ‘miracle’ to fundamentally
eases will likely emerge and may struggle to generate robust
reverse disease progression, but show great variations in
pre-approval evidence.
clinical benefits for heterogeneous ATMPs and diverse dis­
While all biopharmaceutical industries have been
eases. For example, CAR-T cell therapy will not be cure for
affected by the COVID-19 pandemic, many gene or cell
blood cancers, as shown in the clinical trials that 47% of
therapy companies, especially biotech and start-up compa­
patients receiving Yescarta® had a complete response.
nies, have been disrupted particularly heavily due to their
Under such circumstances, first ATMPs, therefore, will not
complex manufacturing, supply, and funding mechanisms.
exhaust all the prevalent patients and still leave rooms for
Research and preclinical development activities were slo­
following products with different modes of actions. Even if
wed down due to less than normal operation capacity.
products with better efficacy or less safety concerns reach
Patient recruitment become ever challenging in small com­
the market later on, they may take up the leading position
munities with ultra-rare diseases, where international
of available products.
recruitments were suspended and engagements with
patients for follow-up assessment also suffered [32]. Some
companies have implied that their launch plans were mod­
5. Future prospect
ified or postponed, with delays in regulatory approval and
5.1. Advancement in technology patient access to ATMPs expected. Close connections with
regulators will be helpful to timely communicate the rele­
ATMPs hold new clinical promises in the treatment of devast­
vant modifications made in the manufacturing process and
ing diseases through its unique mechanism of action, yet
clinical trial protocols. Regulators, such as the FDA, have
substantial challenges remain in the manufacturing of auto­
also claimed that their work to advance treatments for rare
logous ATMPs. It requires an individual approach for each
diseases and ensure continuity of care for people with rare
patient, raising barriers in terms of complex logistics, lengthy
diseases remain top priorities during the COVID-19 out­
wait times, and variable product potency [48]. Therefore,
break, along with their endeavors to establish ‘Rare
developing allogeneic products would represent benefits to
Disease Clinical Trial Networks’ as a global clinical trial
eliminate the complex manufacturing logistics and inconveni­
platform for a wide range of rare diseases [52].
ence caused by in-patient administration [49]. For instance,
Companies with more efficiency and resilience will demon­
allogeneic induced pluripotent stem cell (iPSC)-derivatives
strate their advantages to absorb the damage and get back on
have been suggested as a unique platform for human disease
track more quickly, while fragile, small biotech will need to re-
modeling, target validation, drug screening, preclinical assess­
assess their portfolio and prioritization strategies to decide where
ment, and development of personalized medicine [50]. The
to invest further [53].
progress in gene-editing technologies, such as CRISPR-CAS9,
ZINC Finger, and Transcription activator-like effector nucleases
(TALENs) have enabled the possibility of developing engi­
5.3. Reexamine the reimbursement of ATMPs
neered constructs to create universal cellular therapies to be
used as ‘off-the-shelf’ [51]. Additionally, gene-editing technol­ Historically, most ATMPs have succeeded to gain reimbur­
ogy represents the potential to reduce the off-target activities sement in EU countries. While ATMPs themselves, relying
by target and kill cancer cells while also distinguishing and solely on its innovative nature, may not constitute
preserving healthy cells [50]. a sufficient reason to justify their cost-effectiveness
426 T. QIU ET AL.
considering the significant evidence gaps in terms of their
‘curative’ nature and long-term advantages at the time of
market launch. Rather, rare diseases featured with substan­
tial unmet needs that are targeted by ATMPs remain the
primary drivers for favorable reimbursement decisions.
However, it must be recognized that ODs have triggered
continuous debates surrounding whether the societal pre­
ference toward rare disease really exists, and to what
extent the healthcare system should give priority to ODs
[41]. One example is Glybera® for ultra-rare condition
named lipoprotein lipase deficiency (LPLD), which was
approved based on the scarce evidence from single-arm
trials recruiting less than 20 patients. However, it was
withdrawn from the EU market because its 1 USD million
price caused extremely limited usage in major EU countries
where reimbursement was lacking. This is indicative that
the price of orphan ATMPs must be determined by finding
the right balance between medical needs, clinical benefits,
appropriate commercial returns, and healthcare affordabil­
ity [54].
Furthermore, although the cost burden of existing
orphan ATMPs is likely to be relatively small in the short
term, the cumulative effects of multiple ATMPs expanding
indications from rare diseases to more prevalent diseases
has raised financial concerns for the long term. Not sur­
prisingly, payer acceptance for the evidence limitations for
ATMPs may not be sustained in the long run. Payers will
further emphasize the importance of comprehensive evi­
dence collection to confirm the sustainability of treatment
benefits, relative effectiveness profile, and the impact on
patient-relevant outcomes. Innovative payment mechan­
isms (e.g. outcome-based payment and install payment)
will be increasingly adopted to mitigate the financial risks
in relation with evidence limitations of orphan ATMPs, thus
better informing on their respective strengths and draw­
backs. Real-world evidence (RWE) collection will be increas­
ingly appreciated to provide important insights into the
post-launch performances to bridge evidence gaps at time
of launch, to support future reimbursement decisions, and
to strengthen the implementation of outcomes-based pay­
ments. Widespread adoption of RWE may only materialize
when its inherent shortfalls, including potential confound­
ing, incomplete data, lack of universally accepted metho­
dological standards, have been overcome [55].
In particular, affordability and sustainability of the
healthcare system become more evident and urgent issues
in the current COVID-19 pandemic, when constrained
healthcare resources must be prioritized to combat this
catastrophic emergency. More than ever before, ATMP
developers will need to demonstrate that the costs of
their treatments are offset by long-term, measurable
patient benefits [53].
5.4. Patient engagement and clinical adoption
Collaborations involving all relevant stakeholders are of para­
mount importance for orphan ATMPs. Early communication,
not restricting to manufacturers, regulators, and payers, but
also inclusive of patient advocacy groups and clinicians, will
promote the obtention of support and expertise that are
essential to succeed. Patients have expressed their willingness
to be in partnership with manufacturers throughout the whole
development lifecycle instead of passive participants of clinical
trials. The advantages of patient contribution in terms of
deepening knowledge on the natural history of rare diseases,
facilitating collection of patient-relevant outcomes, informing
the understanding of patient perception on the value of
ATMPs, and facilitating the long-term patient tracking must
be highlighted [56].
The level of commercial returns generated by ATMPs is
expected to be highly dependent upon what proposition (i.e
supports/services) is provided in addition to the product itself
[57]. As multiple ATMPs will gain approval over the following
years, hospital systems are at risk of becoming overloaded
with managing multiple training programs and administration
protocols. It is valuable in having manufacturers and third-
party suppliers come together and align on standardized pro­
cesses to reduce complexity for hospitals [58]. Strategies to
facilitate clinical adoption will be needed to ensure ATMPs are
as easy as possible to integrate into healthcare delivery/
patient pathway. Additionally, clinicians may need support to
secure health claims for patient administration are correctly
and efficiently collected to satisfy the data requirements of
public and private health insurers.
Under the COVID-19 crisis, vulnerable patients suffering
from rare diseases will face the difficult choice between risking
COVID-19 exposure and postponing clinician visits. Clearly,
urgent actions are required to transform healthcare delivery
and to update current systems by making the most use of
digital technologies, such as the use of teleconference to
deliver remote healthcare services [59]. Manufacturers of
ATMPs will need to have the right IT infrastructures in place
to facilitate the digitization of documentation and the disse­
mination of training materials. If implemented appropriately,
digital health may be impactful to improve the healthcare
access for patients desiderating orphan ATMPs in the
future [60].
6. Conclusion
As shown in this study, ATMPs will bring substantial promises
to a variety of rare diseases currently out of treatment options.
It is predicted that a rising number of orphan ATMPs will arrive
in the foreseeable future, with some products currently in the
late stages of clinical trials. However, challenges in the gen­
eration of compelling and robust evidence for orphan ATMPs
cannot be neglected due to small patient numbers, open-label
designs, absence of suitable comparators, inappropriate surro­
gate outcomes, and short follow-up durations. Regulators tend
to embrace orphan ATMPs through initiatives of accelerated
approval pathways eligible for ODs and breakthrough thera­
pies. Conversely, payers scrutinize the high price of ATMPs
making the cost-effectiveness unjustified in relation to the
evidence uncertainties surrounding long-term performances.

Undoubtfully, with ATMPs targeting both rare diseases and
prevalent diseases emerging, more strict evidence require­
ments will become a necessity for both regulators and payers.
The rising number of ATMPs competing in a niche market will
require developers to highlight the respective therapeutic
advantages of their products, especially for the products
launched later on. The success of orphan ATMPs will also
rely on collaborative strategies to streamline market launch
and commercialization processes. Public–private partnerships
and cooperative agreements between biotechs and major
pharmaceutical companies could strengthen the capacities of
each party and increase the efficiency of developing ATMPs.
The early engagement of relevant stakeholders, including
patients, clinicians, regulators, and payers, may be paramount
in order to understand the needs of each one, and therefore,
enable developers to be better prepared to remove potential
barriers. Additionally, collaborations and communications are
evermore critical during the COVID-19 outbreak when
research and development activities for ATMPs have been
heavily disrupted. The benefits of a digital revolution to trans­
form the paradigm of healthcare deliver must be amplified to
ensure that timely patient access to orphan ATMPs will not be
severely delayed.
Author contributions
M Toumi, TT Qiu and E Hanna: contributed to the study conception and
design; TT Qiu, YT Wang, R Han and SY Liang: material preparation,
data collection and analysis. TT Qiu, M Toumi and M Dabbous: wrote
the first draft of the manuscript. All authors commented on previous
versions of the manuscript. All authors read and approved the final
manuscript.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Funding
This paper was not funded.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Shuyao Liang http://orcid.org/0000-0002-0627-8922
Mondher Toumi http://orcid.org/0000-0001-7939-7204
EXPERT OPINION ON ORPHAN DRUGS 427
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