Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Study on sustainable and resilient supply
of medical radioisotopes in the EU
Therapeutic Radionuclides

Ligtvoet, A., Scholten, C., Davé, A., King, R., Petrosova,
L., Chiti, A., Goulart De Medeiros, M., Joerger, A.

2021

EUR 30690 EN

This publication is a Science for Policy report by the Joint Research Centre (JRC), the European Commission’s science and knowledge
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concerning the delimitation of its frontiers or boundaries.
Contact information
Name: Margarida Goulart
Address: European Commission
B-1049 Brussels
Email: margarida.goulart@ec.europa.eu
Tel.:
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https://ec.europa.eu/jrc

JRC124565
EUR 30690 EN

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ISBN 978-92-76-37422-0

ISSN 1831-9424

doi:10.2760/642561

Luxembourg: Publications Office of the European Union, 2021
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How to cite: Ligtvoet, A., Scholten, C., Davé, A., King, R., Petrosova, L. and Chiti, A., Study on sustainable and resilient supply of medical
radioisotopes in the EU, Goulart De Medeiros, M. and Joerger, A. editor(s), EUR 30690 EN, Publications Office of the European Union,
Luxembourg, 2021, ISBN 978-92-76-37422-0, doi:10.2760/642561, JRC124565.

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Contents
Abstracts __________________________________________________________________________________ 1
Executive summary __________________________________________________________________________ 2
Résumé exécutif_____________________________________________________________________________ 4
1 Introduction: Supply shortages in radionuclides for medical diagnostics lead to questions about
radiopharmaceuticals for therapy ____________________________________________________________ 6
1.1 Reactor shutdowns at the core of supply shortages around 2008-2010 ___________________________________ 7
1.2 With the growth in therapeutic use shortages may increase in the future _________________________________ 7
1.3 A wide range of methods was used to uncover information at member state level __________________________ 7
1.4 The focus in this report is on radiopharmaceuticals ___________________________________________________ 8

2 Current and emerging use of radiopharmaceuticals _____________________________________________ 9
2.1 Radiopharmaceuticals, their indication and use _____________________________________________________ 11
2.2 Current use is a proxy for current demand _________________________________________________________ 13
2.2.1

Demand in terms of activity_______________________________________________________________ 14

2.2.2

Demand in terms of procedures ___________________________________________________________ 16

2.3 Incidence – population growth greatest for prostate cancer ___________________________________________ 18
2.4 Good examples of data collection in EU-27 _________________________________________________________ 20

3 Regulation, reimbursement, finance and guidelines ____________________________________________ 21
3.1 EU Regulation and licensing _____________________________________________________________________ 21
3.2 Reimbursement and Finance ____________________________________________________________________ 23
3.3 Health systems resources and capacity ____________________________________________________________ 25
3.4 Staff expertise and knowledge ___________________________________________________________________ 25
3.5 Medicine shortages ____________________________________________________________________________ 26
3.6 Guidelines – a preference for European level _______________________________________________________ 26
3.7 Radiopharmaceuticals prices vary, especially “high potentials” _________________________________________ 28

4 Supply chain capacity is becoming a pressing issue _____________________________________________ 31
4.1 Overview of the international radiopharmaceutical supply chain _______________________________________ 31
4.2 Production of therapeutic radionuclides ___________________________________________________________ 33
4.2.1

Production routes for therapeutic radionuclides ______________________________________________ 34

4.2.2

European production of radionuclides in an international supply chain ____________________________ 37

4.3 Specific European supply chains __________________________________________________________________ 39
4.3.1

Suppliers for radionuclides and radiopharmaceuticals__________________________________________ 39

4.3.2

Characteristics of the supply chain before irradiation and during transport _________________________ 43

4.4 Production capacity for therapeutic radionuclides in Europe ___________________________________________ 44
4.4.1

Installed production and processing capacity _________________________________________________ 44

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

4.4.2

Planned production and processing capacity _________________________________________________ 46

4.4.3

Potential to increase production and processing capacity _______________________________________ 48

4.5 Stability of supply in Europe _____________________________________________________________________ 49
4.5.1

Supply disruptions to European hospitals ____________________________________________________ 49

4.5.2

Impact of disruption on patient treatments __________________________________________________ 50

4.5.3

Causes of supply disruptions ______________________________________________________________ 51

4.6 Critical issues and foreign dependencies in the supply chain ___________________________________________ 53
4.6.1

Before irradiation phase _________________________________________________________________ 54

4.6.2

In irradiation phase _____________________________________________________________________ 55

4.6.3

After irradiation phase ___________________________________________________________________ 55

4.6.4

During transport ________________________________________________________________________ 56

5 Future demand may rise, depending on market developments ___________________________________ 57
5.1 Characteristics of the therapeutic radiopharmaceutical market ________________________________________ 57
5.2 Expected development of demand in Europe _______________________________________________________ 58
5.2.1

Therapeutic radionuclides ________________________________________________________________ 58

5.2.2

Therapeutic radiopharmaceuticals _________________________________________________________ 60

5.3 Developments in the therapeutic radiopharmaceutical market _________________________________________ 62
5.3.1

Drivers _______________________________________________________________________________ 62

5.3.2

Challenges: production, regulation, market asymmetries, and political decisions ____________________ 63

5.3.3

Matching supply and (expected) demand is difficult under current situation________________________ 64

5.3.4

Adequacy and resilience of the supply chain cannot be maintained _______________________________ 64

6 Policy recommendations __________________________________________________________________ 66
6.1 Recommendations on monitoring demand _________________________________________________________ 66
6.2 Recommendations on securing future supply _______________________________________________________ 66
6.3 Recommendations on the factors influencing demand and supply ______________________________________ 67
6.4 Recommendations on regulation, reimbursement, finance and guidelines ________________________________ 67

Reimbursement models _________________________________________________________ 68
Financing healthcare in Europe __________________________________________________________________ 68

Methodological notes and caveats ________________________________________________ 71
Analysis of radionuclide therapy clinical trials _______________________________________________________ 71
Methodology to calculate current demand _________________________________________________________ 74
Validation of acquired information and calculated data _______________________________________________ 75
Involved stakeholders and experts in interviews, workshop and national data requests _____________________ 76
Delphi survey respondents ______________________________________________________________________ 79

Country factsheets _____________________________________________________________ 82
Glossary_____________________________________________________________________ 170
View of the EANM ____________________________________________________________ 172

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Abstracts
English
This report presents an overview of the current use of radionuclides for medical therapy in Europe as well as an
estimate on the amounts being used. It also provides the expert opinion of more than 200 professionals in the
field of nuclear medicine and radiopharmacy on future growth potential of the use of therapeutic radionuclides.
The research signals the paucity of information, and reiterates the call for joint European efforts for more reliable
data. While historical practice in radionuclide therapy has not led to major supply concerns, the imminent
approval of certain treatment options (for example PSMA linked to Lutetium-177 for prostate cancer) may lead
to a rise in demand for Lutetium and other radionuclides that may pose challenges to European radionuclide
producers. The shutdown of European research reactors without immediate replacement capacity, as well as a
general ageing of the infrastructure is an unsolved issue that also requires concerted European action.
While the market for therapeutic radionuclides is currently still small in comparison to the market for diagnostic
radionuclides, the use of radiopharmaceuticals promises advances in the treatment of cancer. At the same time,
technological developments for the production of these radionuclides are still uncertain and in early stages of
market readiness. Supply is not fully secured, as the market is new and volatile. Future market developments are
influenced by national reimbursement systems in reaction to radiopharmaceutical pricing, as well as complicated
regulations that are determined by both radiation protection and pharmaceutical directives.

Français
Ce rapport présente un aperçu de l'utilisation actuelle des radionucléides en thérapie médicale en Europe, ainsi
qu'une estimation des quantités utilisées. Il présente également l'avis de plus de 200 professionnels experts dans
le secteur de la médecine nucléaire et de la radiopharmacie sur le potentiel de croissance de l'utilisation des
radionucléides thérapeutiques. L'étude souligne le manque d'informations disponibles et renouvelle l'appel à
des efforts européens communs pour collecter des données plus fiables. Si la pratique historique de la thérapie
par radionucléides n'a pas soulevé de problèmes majeurs en matière d'approvisionnement, l'approbation
imminente de certaines options de traitement (le PSMA lié au Lutétium 177 pour traiter le cancer de la prostate,
par exemple) pourrait entraîner une hausse de la demande en Lutétium et autres radionucléides qui pourrait
confronter les fabricants européens de radionucléides à des défis. L'arrêt des réacteurs de recherche européens
sans capacité de remplacement immédiate, ainsi que le vieillissement général des infrastructures, est un
problème qui nécessite également une action européenne concertée.
Si le marché des radionucléides thérapeutiques est actuellement encore peu développé par rapport au marché
des radionucléides diagnostiques, l'utilisation des produits radiopharmaceutiques promet des avancées dans le
traitement du cancer. Parallèlement, les développements technologiques pour la production desdits
radionucléides sont encore incertains et se trouvent à un stade préliminaire de préparation au marché.
L'approvisionnement n'est pas pleinement assuré, car ce marché est nouveau et encore volatile. L'évolution
future du marché est influencée par les systèmes nationaux de remboursement en réaction à la tarification des
produits radiopharmaceutiques, ainsi que par les réglementations complexes qui sont déterminées à la fois par
les directives sur la radioprotection et par les directives pharmaceutiques.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Executive summary
This report was prepared on request of the European Commission's Joint Research Centre, following calls for
action from the Council of the European Union, to provide insight in the use of radionuclides for medical therapy
in the European Union. Radionuclides use for therapy currently is small as compared to radionuclides use for
diagnosis: the market for therapeutic radionuclides is about 100 times smaller than for diagnostic radionuclides.
However, in the coming decade significant growth is expected for the use of selected therapeutic radionuclides.
More national level information is required to properly assess future issues of supply and demand.
Large and unexpected outages in research reactors in 2008-2010 have led to shortages in radionuclides used for
medical diagnostics, which increased policy attention to the supply of notably Molybdenum/Technetium and to
the search for alternatives to these radionuclides. Several European and international activities have been
undertaken to (at least) increase the exchange of information regarding the supply of radionuclides for
diagnostics.
In the last decade, innovations in the use of radioligands in radiopharmaceuticals have opened up potential
applications in targeted radionuclide therapy – which led to the questions whether promising therapeutic
innovations may face the same supply risk as the diagnostic radionuclides. Unfortunately, information to answer
such questions is not publicly available and this report is a (first) attempt to provide further insight.
There are very high expectations regarding Lutetium-177 and Actinium-225 linked to PSMA (prostate-specific
membrane antigen) which may result, when approved, in a soaring demand. While in this study more than 98%
of the consulted experts expect growth in the demand for Lutetium-177-PSMA, 63% expect this growth to be
larger than 15% over the next decade. This expectation follows from cancer incidence statistics: the target
population of prostate cancer patients (incidence of ~335,000 in 2020 in the EU) is an order of magnitude larger
than the population of cancer patients for which therapeutic radionuclides are currently used (for example, nonHodgkin lymphoma incidence of ~86,000 in 2020 in the EU). Other high-potential radiopharmaceuticals that
emerged from this study are several other Lutetium-177-combinations (for neuroendocrine tumours, nonHodgkin lymphoma – more than 80% of respondents expect growth), as well as Holmium-166 (bone metastases,
head and neck squamous cell carcinoma, hepatocellular carcinoma) and Thorium-227 (non-Hodgkin lymphoma,
ovarian cancer and mesothelioma, prostate cancer) both for which more than 60% of respondents expect
growth. In this report we focus on the radionuclides and indications for which growth is expected.
Radionuclides are produced in what could be called a quasi-market environment – production facilities for
radionuclides remain in the hands of, or are financially supported by, governments while commercial
organisations exploit the radiopharmaceuticals – characterised by information asymmetries.
However, the indications and therapeutic potential are not the only factors affecting whether a
radiopharmaceutical is accepted in the market. There are national differences in healthcare systems and
healthcare markets, including differences in reimbursement and access of radionuclides to the market, which
stem from the fact that healthcare largely is a Member State competence. This means that access to radionuclide
therapy is not uniform across the Union, but even within countries differences in access to facilities and trained
healthcare professionals exist. Further investigation of appropriate treatment modalities through Health
Technology Assessment is advised.
Furthermore, there are supply factors that need to be taken into consideration when assessing the future of
radiopharmaceuticals. These factors will become more pressing as demand for radionuclides increases.
There are only few European or international production facilities that are able to provide radionuclides. Most
of the available production capacity is in nuclear research reactors. Several of these mainly state-sponsored
facilities are scheduled to close within the next decade without clarity on new research/production capacity.
Although some information exchange regarding these facilities exists, there is no coordination on the allocation
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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

of radionuclide production capacity. Furthermore, some of the enrichment and irradiation facilities are not
available in Europe, which leads to additional worries about security of supply or self-sufficiency and dependence
on foreign sources.
In spite of the current situation in radiopharmaceuticals, there seems to be little worry among healthcare
professionals and other consulted experts regarding the supply of radionuclides. However, this will likely change
due to the aforementioned increased demand for treatments related to cancer and ageing irradiation
infrastructure in Europe. It is therefore advisable to remain observant of the developments in the radionuclides
field, both for diagnostics and therapy.
Insight in the current situation regarding supply and demand is problematic, since very little information is
available or disclosed at any level, save with the pharmaceutical companies. A more concerted effort to gather
critical information regarding radionuclides is therefore advised, both at national and at European level. Good
practices for gathering radionuclide and/or radiopharmaceutical information can be found in a number of
Member States, notably Belgium, the Czech Republic, and Sweden, and could be harmonised and extended to
all EU Member States. We recommend efforts to make the therapeutic market more transparent and to improve
official data collection on the use (demand) of radiopharmaceuticals.
Concerted and timely European action is necessary now to ensure the continued resilient supply of therapeutic
radionuclides in Europe for the future. This might include better monitoring of the progress of building new
facilities, supranational attention for removing possible barriers and organising fallback options in these
processes, and negotiating guaranteed levels of production of radiopharmaceuticals (for the medical market)
with both existing and new facilities.
Furthermore, research and innovation actions, including health economic evaluations, could contribute to exploit
the potential of therapeutic radionuclides and provide solutions to observed challenges in the
radiopharmaceutical supply chain. Ultimately, the goal is to promote an equitable, efficient, and high-quality
health system.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Résumé exécutif
Le présent rapport a été préparé à la demande du Centre Commun de Recherche (JRC) de la Commission
Européenne suite aux appels à l’action du Conseil de l’Union Européenne, pour fournir un aperçu de l'utilisation
des radionucléides pour la thérapie médicale au sein de l'Union Européenne. Actuellement, l'utilisation des
radionucléides à des fins thérapeutiques est moindre par rapport à l'utilisation des radionucléides à des fins de
diagnostic : le marché des radionucléides thérapeutiques est environ 100 fois moins important que celui des
radionucléides à des fins de diagnostic. Toutefois, il est prévu que l’utilisation de certains radionucléides
thérapeutiques augmente considérablement au cours de la prochaine décennie. De plus amples informations au
niveau national sont nécessaires pour évaluer précisément les futurs problèmes de l'offre et de la demande.
Les arrêts importants et imprévus des réacteurs de recherche en 2008-2010 ont entraîné des pénuries de
radionucléides destinés aux diagnostics médicaux, ce qui a renforcé l'attention politique portée à
l'approvisionnement, notamment en molybdène/téchnétium, et à la recherche de solutions de substitution à ces
radionucléides. Plusieurs activités européennes et internationales ont été entreprises pour intensifier (au moins)
l'échange d'informations concernant l'approvisionnement en radionucléides pour les diagnostics.
Au cours de la dernière décennie, les innovations dans l'utilisation des radioligands dans les produits
radiopharmaceutiques ont généré des applications potentielles dans la thérapie par radionucléides ciblée - ce
qui a conduit à la question de savoir si les innovations thérapeutiques prometteuses pourraient être confrontées
au même risque d'approvisionnement que les radionucléides de diagnostic. Malheureusement, les informations
permettant de répondre à ces questions ne sont pas disponibles publiquement et le présent rapport est une
(première) tentative pour éclaircir ces questions.
Les attentes sont très fortes en ce qui concerne le lutétium-177 et l'actinium-225 liés au PSMA (antigène
membranaire spécifique de la prostate), ce qui pourrait entraîner, une fois approuvés, une forte hausse de la
demande. Cette étude montre que plus de 98 % des experts consultés s'attendent à une croissance de la
demande de lutétium-177-PSMA, 63 % d’entre eux prévoient que cette croissance sera supérieure à 15 % au
cours de la prochaine décennie. Cette prévision découle des statistiques sur l'incidence du cancer : la population
cible des patients atteints d'un cancer de la prostate (incidence d'environ 335 000 en 2020 au sein de l'UE) est
plus importante que la population des patients atteints d'un cancer qui sont déjà traités avec des radionucléides
thérapeutiques (par exemple, l'incidence des lymphomes non hodgkiniens est d'environ 86 000 en 2020 dans
l'UE). Les autres produits radiopharmaceutiques à fort potentiel qui ont émergé de cette étude sont différentes
combinaisons de Lutétium-177 (pour les tumeurs neuroendocrines, les lymphomes non hodgkiniens – plus de 80
% des répondants prévoient une croissance), ainsi que le Holmium-166 (métastases osseuses, carcinome
épidermoïde de la tête et du cou, carcinome hépatocellulaire) et le Thorium-227 (lymphomes non hodgkiniens,
cancer des ovaires et mésothéliome, cancer de la prostate), tous deux pour lesquels plus de 60 % des répondants
prévoient une croissance. Dans ce rapport, nous nous concentrons sur les radionucléides et les indications pour
lesquels une croissance est attendue.
Les radionucléides sont produits dans ce que l'on pourrait appeler un environnement quasi-marché - les
installations de production de radionucléides étant aux mains des gouvernements ou soutenues financièrement
par ces derniers, tandis que des organisations commerciales exploitent les produits radiopharmaceutiques - se
caractérisant par des asymétries d'information.
Toutefois, les indications et le potentiel thérapeutique ne sont pas les seuls facteurs qui déterminent
l'acceptation d'un produit radiopharmaceutique sur le marché. Il existe des différences nationales dans les
systèmes et les marchés des soins de santé, y compris des différences dans le remboursement et l'accès au
marché des radionucléides, qui découlent du fait que les soins de santé relèvent en grande partie de la
compétence des États membres. Cela signifie que l'accès à la thérapie par radionucléides n'est pas uniforme dans

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

tous les pays de l'Union, et qu'il existe des différences au sein même des pays dans l'accès aux structures et aux
professionnels de santé formés. Il est conseillé de poursuivre l'étude des modalités de traitement appropriées
par le biais de l'évaluation des technologies de la santé.
En outre, certains facteurs liés à l'offre doivent être pris en considération lors de l'évaluation de l'avenir des
produits radiopharmaceutiques. Ces facteurs deviendront plus astreignants à mesure que la demande de
radionucléides augmentera.
Il n'existe que peu d'installations de production européennes ou internationales capables de fournir des
radionucléides. Les réacteurs de recherche nucléaire sont la principale source des capacités de production.
Plusieurs de ces installations, principalement parrainées par l'État, devraient fermer au cours de la prochaine
décennie sans que l'on sache exactement quelles seront les nouvelles capacités de recherche/production. Bien
qu'un certain échange d'informations concernant ces installations ait lieu, il n'existe aucune coordination sur la
répartition de la capacité de production de radionucléides. En outre, certaines des installations d'enrichissement
et d'irradiation ne sont pas disponibles en Europe, ce qui suscite de vives inquiétudes concernant la sécurité de
l'approvisionnement ou l'autosuffisance et la dépendance vis-à-vis des sources étrangères.
Malgré la situation actuelle dans le domaine des produits radiopharmaceutiques, les professionnels de la santé
et les autres experts consultés semblent peu préoccupés par l'approvisionnement en radionucléides. Toutefois,
cela va probablement changer en raison de la hausse de la demande en traitements contre le cancer et du
vieillissement des infrastructures d'irradiation en Europe. Il est donc conseillé de rester vigilants et attentifs aux
évolutions dans le domaine des radionucléides, tant pour le diagnostic que pour la thérapie.
La connaissance de la situation actuelle de l'offre et de la demande est problématique, car très peu
d'informations sont disponibles ou diffusées à quelque niveau que ce soit, sauf en ce qui concerne les entreprises
pharmaceutiques. Il est vivement recommandé de déployer des efforts plus concertés pour recueillir des
informations critiques sur les radionucléides, tant au niveau national qu'au niveau européen. Les bonnes
pratiques pour la collecte d'informations sur les radionucléides et/ou les produits radiopharmaceutiques sont
implantées dans un certain nombre d'États membres, notamment en Belgique, en République tchèque et en
Suède, et pourraient être harmonisées et étendues à tous les États membres de l'UE. Nous recommandons des
efforts pour rendre le marché thérapeutique plus transparent et pour améliorer la collecte de données officielles
sur l'utilisation (la demande) des produits radiopharmaceutiques.
Une action européenne concertée et en temps utile est nécessaire pour garantir la continuité durable et future
de l'approvisionnement en radionucléides thérapeutiques en Europe. Cela pourrait inclure un meilleur suivi de
la progression de la construction de nouvelles installations, une attention supranationale pour éliminer les
obstacles éventuels et organiser des options de repli dans ces processus, et la négociation de niveaux garantis
de production de produits radiopharmaceutiques (pour le marché médical) avec les installations existantes et les
nouvelles.
En outre, les actions de recherche et d'innovation pourraient contribuer à exploiter le potentiel des
radionucléides thérapeutiques et apporter des solutions aux problèmes observés dans la chaîne
d'approvisionnement radiopharmaceutique. En fin de compte, l'objectif est de promouvoir un système de santé
équitable, efficace et de haute qualité.

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1

Introduction: Supply shortages in radionuclides for medical diagnostics lead to
questions about radiopharmaceuticals for therapy

The use of radionuclides for medical purposes is an important pillar of healthcare systems around the globe,
including those in European member states. Nuclear (molecular) medicine involves using radionuclides injected
into patients at low doses for functional imaging to detect diseases and using (usually) other radionuclides for
the targeted therapy of tumours. Imaging is of primary importance to enable making correct diagnoses and
providing treatments. For the purpose of imaging, the workhorse radionuclide is Technetium ( 99mTc, used in
Single-photon emission computed tomography or SPECT), which is used in the European Union (including the
UK) roughly 10 million times per year (this represents ~25% of global demand). 1
In the last decades, the use of radionuclides for therapy has increasingly received attention in research,
development and clinical trials. By binding radionuclides to other molecules or antibodies they can be guided to
a target tissue, to provide local treatment of (primarily) cancers. This targeted approach, which is known as
radioligand therapy, or unsealed source radiotherapy, can be combined with imaging techniques to provide
theragnostics (therapy + diagnosis). Given the prevalence of cancer in Europe and worldwide, there is still much
to be gained by improving diagnosis and treatment through these means.
While the importance of radionuclides for medical diagnostics and therapy is very large, there is relatively little
information available on the use/demand and production/supply of the most relevant radionuclides. Until today,
this branch of medicine largely depends on nuclear research infrastructures that were built in the 1950s, 1960s
and 1970s to provide knowledge for nuclear energy and nuclear weaponry. The concerns on nuclear security led
to some of the information being sensitive or classified (state secrets). At the same time, it should be noted that
there are very large private interests at stake that are best preserved by maintaining information asymmetry
(trade secrets). Both reasons may be deemed legitimate, but lead to a situation in which relatively little
information is known on important medical modalities.
The European Commission as well as the Council of the European Union 2 have recognised the importance of
more information on the uses of nuclear technology and nuclear medicine in particular. The responsible
Commission’s Directorate-General for Energy, in coordination with the DGs for Health, Research & Innovation
and Economic Growth, has started a strategic initiative to assess medical, industrial and research applications of
nuclear technology, called SAMIRA, in 2017.3 This has led to a comprehensive overview report4 as well as a range
of conferences and workshops organised by the Commission. Further in-depth research has been performed on
the diagnostic uses of radionuclides. However, insights in the use, demand and supply of therapeutic
radionuclides has been very limited and fragmented at European level.
This report, commissioned by the European Commission’s Joint Research Centre, focuses on the supply and
demand of radionuclides for therapy. Its content is based on public or disclosed information.
Below we provide more information on the importance of the issue, the scope of this report, and the research
approach.

1 NucAdvisor and Technopolis Group (2019). European study on medical, industrial and research applications of nuclear and radiation

technology (SAMIRA). Brussels: European Commission, 2019.
2 See: https://data.consilium.europa.eu/doc/document/ST-9437-2019-INIT/en/pdf
3 The SAMIRA agenda is expected to be published in Q1 2021.
4 Ibid.

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1.1

Reactor shutdowns at the core of supply shortages around 2008-2010

The supply of radionuclides for medicine has relied on existing research infrastructure for decades with relatively
few disruptions. Research reactors5 currently produce the majority of both diagnostic and therapeutic
radioisotopes, including the most used imaging radioisotope 99Mo/99mTc. European research reactors, among
them HFR (The Netherlands), BR2 (Belgium), Maria (Poland) and LVR-15 (Czech Republic), are important 99Mo
producers, delivering more than about 60% of the global demand. Although both alternative production methods
as well as alternative radionuclides for imaging and therapy are being developed, the demand for 99Mo/99mTc is
expected to remain significant for the next decade. 6
The fragility of the supply chain was however demonstrated in the years 2008-2010, when planned and
unplanned reactor shutdowns led to difficulties in supply and cancelled or delayed diagnostic tests around the
globe. This led to the establishment of the OECD-NEA High-Level Group on the Security of Supply of Medical
Radioisotopes (HLG-MR) as well as the European Observatory on the Supply of Medical Radioisotopes by the
European Commission.7 Focusing mainly on 99Mo/99mTc, these bodies have repeatedly indicated that the small
number of ageing reactors are increasing supply risks and the planned shutdown of both HFR and BR2 would
lead to acute shortages of 99Mo/99mTc.

1.2

With the growth in therapeutic use shortages may increase in the future

While the current use of radionuclides for therapeutic purposes remains a fraction of the radionuclide use for
imaging and diagnostics, there are strong reasons to suspect that its use may increase in the near future.
Especially the success of clinical trials for [177Lu]Lu-PSMA for prostate cancer and its imminent (expected in 2021)
EU marketing authorisation is expected to expand the market drastically. The severity and health impacts of
cancers and their prevalence in the European population provide room for more targeted treatments. Large
pharmaceutical companies’ moves in this market (e.g. Bayer – Xofigo®, Novartis – Lutathera®) also show that
commercial opportunities are identified.
The European market for therapeutic radionuclides is characterised by large uncertainty due to the relative
novelty of the field, the constant innovation taking place, and the differences in nuclear medicine practice as well
as differences in the healthcare system (both in terms of organisation as in terms of financing) in each separate
member state. The potential growth of therapeutic radionuclides also faces many challenges. To properly assess
the challenges to the deployment of therapeutic radionuclides, a clearer picture of the current status is needed,
which is the purpose of this report.

1.3

A wide range of methods was used to uncover information at member state level

The research presented in this report relied on mixed methods to provide both top-down (at European level) as
well as bottom-up (at Member State level but starting from individual therapy centres) data on supply and
demand. Where possible, we relied on official statistical data and research reports. However, as indicated above,
this information is not readily available for most member states. We further based our findings on interviews or
written correspondence with international and national experts, including pharmaceutical companies, reactor
operators, nuclear medicine associations, national authorities and specialists. While inviting more than 800

5

Research reactors are nuclear reactors that are primarily used or have originally been built for research, development, education, and
training activities. They are different from nuclear power reactors/plants that are purpose-built for energy production. Research reactors
produce neutrons for research activities and are equipped with several instruments for research and other irradiation activities. Many
research reactors also use a part of their capacity to perform industrial activities such as the production of medical radionuclides or silicon
(neutron transmutation) doping.

6 Ibid. 1
7 See: https://ec.europa.eu/euratom/observatory_radioisotopes.html

7

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

experts directly and, with the help of nuclear medicine associations many more indirectly through newsletters
and online platforms, we gathered full responses from 194 (mainly nuclear medicine) experts in a two-phased
Delphi survey in the spring and summer of 2020. This has allowed us to provide a rough estimate of radionuclide
use in 26 countries (while always preferring official statistics over our own estimates); this information was sent
to representatives of national nuclear medicine associations and/or national health care institutes for
verification. In addition, findings were put forward for validation (cross-check) to suppliers of
radiopharmaceuticals. A workshop with relevant stakeholders from government, academia, and industry was
held in January 2021 to discuss findings, policy implications and further recommendations. Further details on the
research approach can be found in the appendices of this report.
Our research team was supported by prof. Arturo Chiti (Humanitas University, Italy) and overseen by an expert
advisory board consisting of prof. Ken Herrmann (Universitätsklinikum Essen, Germany), prof. Gabriel Krestin
(Erasmus University Medical Center Rotterdam, the Netherlands), and prof. Dominique Vandijck (Ghent
University, Belgium).

1.4

The focus in this report is on radiopharmaceuticals

The three main medical specialties using ionising radiation are radiology, radiotherapy and nuclear medicine. In
these three domains, innovation to improve healthcare is a constant driver. A weighing of the merits of each
speciality goes beyond the scope of this report. Radiology uses low energy external electron beams for imaging.
Radiotherapy involves higher energy external electron beams, γ-rays or ion beams, or internal (sealed)
radioactive sources (“brachytherapy”) for treating tumours. Nuclear medicine involves using radionuclides
injected into patients at low doses for functional imaging (SPECT/PET) to detect diseases and using other isotopes
at high doses for the targeted therapy of tumours. This report specifically focuses on the therapeutic use of
nuclear medicine, i.e. the use of radionuclides in radiopharmaceuticals to treat patients (primarily patients with
cancer) because of the promising developments taking place in this field.
In chapter 2 we provide further explanation on the topic and discuss the current use of radionuclides for therapy
in Europe. Chapter 3 describes European regulations and healthcare reimbursement systems that may affect
future uptake of radionuclides. Next, chapter 4 describes the supply end and the issues that may become
important in the near future. Chapter 5 discusses future market developments while chapter 6 provides policy
recommendations based on the previous chapters.
The annexes give additional information on methods used, the data quality per country and an overview of
country factsheets that were used for the different analyses.

8

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

2

Current and emerging use of radiopharmaceuticals

Although having become widely spread relatively recently, nuclear medicine plays a vital role in cancer care today
as it has shown to improve overall survival and quality of life for many people. As the understanding of the biology
of cancer has grown, the science of nuclear medicine has evolved to deliver targeted, safe and effective
diagnostics and treatments.8 Compared to almost all other systemic cancer treatment options, nuclear therapy
has shown efficacy with minimal toxicity, and typically requires shorter cycles of therapy while showing
significantly fewer (both in terms of number and severity of) side effects. The use of nuclear medicines,
however, is in early stages of development and deployment and is therefore expected to expand to yield benefits
to patients.
Overview of the main conclusions of the chapter:
•

Using a retrospective estimate of the annual use of radionuclides in various EU countries (and the UK) as a
proxy of the demand for radionuclide use shows that 131I, 177Lu and 90Y are the most used radionuclides in
terms of activity at time of administration (TOA).

•

The same data shows that [131I]-NaI, [177Lu]Lu-DOTATATE, [177Lu]Lu-PSMA, 90Y- microspheres (both glass
and resin) and 90Y-colloids are the most used radiopharmaceuticals (in that order) as per activity at TOA.

•

The same radiopharmaceuticals account for the highest numbers of procedures delivered with the addition
of [223Ra]RaCl2 which ranks third following [131I]-NaI and [177Lu]Lu-DOTATATE.

•

[131I]-NaI is the most commonly used radiopharmaceutical and far outstrips use of other
radiopharmaceuticals in terms of both activity (two-fold compared to next most used radiopharmaceutical)
and procedures (almost seven-fold compared to next most used radiopharmaceutical).

•

131

•

Data availability and quality are major limiting factors in terms of calculating and understanding the use of
and demand for therapeutic radionuclides across the EU. Only a few countries have detailed insights into
the use of therapeutic radionuclides in their country. Belgium, the Czech Republic and Sweden are
examples of good data collection in this regard.

I and 223Ra are the most ubiquitously used radionuclides in Europe, being used in almost all the countries
we have data for. 177Lu, 90Y, 153Sm and 186Re are also widely used across more than 10 countries.

Nuclear medicine encompasses both diagnostic and therapeutic applications of radioactive isotopes. This study
focuses on the therapeutic application of nuclear medicine, namely use of radionuclide and radiopharmaceutical
therapy, i.e. the delivery of radioactive isotopes emitting alpha (α), beta (β) and/or gamma (γ) radiation to
tumour associated targets (see section 4.2). This type of radiation is called ionising radiation. Especially alpha
and beta radiation are important for radionuclide therapy, as these constitute of particles that can kill cancer
cells and have a short range of action. Gamma radiation, constituting of high-energy photons, is not contributing
much to the (open source) therapeutic purpose, but can be used for imaging.
The beta radiations, most prevalently used in the therapeutic purposes, consist of electrons or positrons
(positively charged electrons) which are derived from unstable atoms. These beta particles have a relatively long
path length and lose their kinetic energies as their follow their path, eventually coming to a stop. The linear

8 Merkel, C., Whicher, C.H., Bomanji, J. et al. (2020). Realising the potential of radioligand therapy: policy solutions for the barriers to

implementation across Europe. Eur J Nucl Med Mol Imaging 47, 1335–1339: https://doi.org/10.1007/s00259-020-04745-7

9

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

energy transfer (LET, which is the amount of energy deposited per path length) is very low, leaving little tissue
damage. For beta-emitters to be effective, a high concentration of radionuclides is necessary. 9
The alpha radiation consists of positively charged helium nuclei, which in fact are two protons and two neutrons.
Alpha particles are derived from the decay of the heaviest radioactive elements, they have a relatively short path
length and a high LET, meaning that they cannot travel far but lead to a more substantial amount of tissue
damage along their path than beta particles. Given their path length and LET specifics, alpha-emitters are
especially suitable for the treatment of small tumours, however, due to its high toxicity, administration of alphaemitting radionuclides requires accurate dosimetry calculations, so the estimated absorbed dose is in line with
toxicity considerations.10
Only therapeutic applications of radioactive isotopes are in the scope of this study, however, several therapeutic
radionuclides are used in theragnostic (both diagnosis and treatment) as well. Several therapeutic radionuclides
(e.g. 177Lu, 153Sm, 67Cu, 47Sc) emit both alpha and/or beta radiations as well as gamma radiation, which can be
imageable using for instance gamma cameras. Some radiopharmaceuticals (e.g. 166Ho-microspheres) also bear
magnetic properties allowing for MRI imaging.
Isotopes emitting beta and/or alpha particles can be used in radiopharmaceutical therapy. Some administered
radionuclides can also be visualised by nuclear imaging techniques which allows for precise targeting,
substantially more advantageous as compared to other existing therapeutic approaches to cancer.11 A recent
and highly promising innovative branch of nuclear therapy, radioligand therapy is currently used in a small
number of cancers, however there is evidence that a similar approach can be used in other cancer and noncancer conditions.
Figure 1

Types of radionuclides and their characteristics

Source: Nitipir et al. (2017)

9 Poty, S., Francesconi, L. C., McDevitt, M. R., Morris, M. J., & Lewis, J. S. (2018). α-Emitters for Radiotherapy: From Basic Radiochemistry to

Clinical Studies-Part 1. Journal of nuclear medicine: official publication, Society of Nuclear Medicine, 59(6), 878–884.
https://doi.org/10.2967/jnumed.116.186338
10 Ibid Poty et al. (2018)
11 Sgouros, G., Bodei, L., McDevitt, M.R. et al. (2020). Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev

Drug Discov 19, 589–608: https://doi.org/10.1038/s41573-020-0073-9

10

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

2.1

Radiopharmaceuticals, their indication and use

While a substantial number of radioisotopes (less than 50) are already used in clinical therapeutic applications
(incl. external radiotherapy and sealed sources), many more have the potential of being successfully used for
therapeutic purposes.12 In this study we look at the use of radionuclides in the form of radiopharmaceuticals for
treatment purposes – this excludes external radiotherapy and sealed sources (as used in brachytherapy). This
reduced the number of radionuclides that are marketed, used in clinical trials or used for compassionate use to
the 18 included in the table below. Table 1 presents an overview of the radionuclides that are in the scope of
this study, along with their main characteristics and use indications.
Table 1
Radionuclide
32P

Overview of radionuclides included in the study
Full name
Type of
Indications for use (in
emission*
Europe)

Radiopharmaceutical
name in Europe (if
available)

Remarks

n/a

The first
radionuclide
used in
therapeutic
applications
more than 50
years ago.

Phosphorous32

β

47Sc

Scandium-47

β

Under investigation for
liver metastases

67Cu

Copper-67

β

Under investigation for
meningioma and
neuroblastoma

89Sr

Strontium-89

β

Bone pain palliation arising
from skeletal metastasis

Metastron®

90Y

Yttrium-90

β

90Y-glass and resin

TheraSphere®

Myeloproliferative disease
Bone metastases

microspheres
(TheraSphere®/SIRSpheres®) are used in
intra-arterial treatments in
the liver
90Y-colloids are used in

Zevalin®
SIR-Spheres®
Ytracis®
Yttriga®

radiation synovectomy
[90Y]Y-ibritumomabtiuxetan (Zevalin®) is used
in B-cell lymphoma and
non-Hodgkin lymphoma

Yttrium-90 is
effective in
forming
complexes
with a variety
of agents and
can be broadly
used in therapy
for various
indications.

90Y-somatostatin is used

for treatment of
neuroendocrine tumours
131I

Iodine-131

β

[131I]-NaI is used in benign
thyroid diseases, thyroid
remnant ablation and
thyroid cancer
[131I]I-mIBG (IOBENGUANE)
is used in neuroblastoma

12 Ibid Sgouros et al. (2020)

11

Generics and Theracap®

One of the
most
important and
widely used
radionuclides

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Full name

Type of
emission*

Indications for use (in
Europe)

Radiopharmaceutical
name in Europe (if
available)

and adult neuroendocrine
tumours

Remarks

for thyroid
diseases.

153Sm

Samarium-153

β

Bone metastases

Quadramet®

166Ho

Holmium-166

β

166Ho-microspheres are

QuiremSpheres®

used in intra-arterial
treatment in the liver and
against recurrences of
head and neck squamous
cell carcinoma
[166Ho]Ho-chitosan is used
in hepatocellular
carcinoma (HCC)
[166Ho]Ho-DOTMP is used
in bone metastasis
169Er

Erbium-169

β

169Er-colloids are used in

n/a

radiation synovectomy
177Lu

Lutetium-177

β

177Lu-antibodies

Betalutin®

(Betalutin®) are used in
non-Hodgkin lymphoma

Lutathera®

[177Lu]Lu-DOTATATE
(Lutathera®) is used in
gastroentero-pancreatic
neuroendocrine tumours
(GEP-NETs)

EndolucinBeta®

[177Lu]Lu-PSMA is used in
therapy of castration
resistant prostate cancer
(pc) and pc-metastases
[177Lu]Lu-somatostatin is
used in neuroendocrine
tumours (NETs))
186Re

Rhenium-186

β

Radiation synovectormy

188Re

Rhenium-188

β

Treatment of nonmelanoma skin cancer

Rhenium-SCT®

[188Re]Re-HEDP used in
painful bone metastases
211At

Astatine-211

α

Under investigation for a
range of tumours

212Pb

Lead-212

β

Under investigation for a
range of tumours

213Bi

Bismuth-213

α, β

Under investigation for a
range of tumours

223Ra

Radium-223

α, β

Castration-resistant
prostate cancer
Symptomatic bone
metastases and no known
visceral metastases

12

Xofigo®

Lutetium-177 is
a therapeutic
radioisotope of
rapidly
increasing
importance.

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Full name

Type of
emission*

Indications for use (in
Europe)

225Ac

Actinium-225

α, β

[225Ac]Ac-PSMA is used for
metastatic castration
resistant prostate cancer

Radiopharmaceutical
name in Europe (if
available)

Remarks

[225Ac]Ac-Lintuzumab is
used for acute myeloid
leukemia (AML)
227Th

Thorium-227

α

227Th-conjugate is used for

(CD22 positive) nonHodgkin lymphoma
227Th-antibody is used for

ovarian cancer and
mesothelioma
[227Th]Th-PSMA is used for
metastatic castration
resistant prostate cancer
*Y-rays are omitted from this description as they are used in imaging and are therefore not in scope of the study.

2.2

Current use is a proxy for current demand

While there is some difference between the demand for therapeutic radionuclides and the current use of
radiopharmaceuticals, we have approached the demand for radionuclides in terms of activity from the number
of procedures using radiopharmaceuticals. The demand in terms of number of procedures is directly related to
the deployment of the radiopharmaceutical in which the radionuclide is used. This is measured at the level of
the patient/hospital. For the demand in terms of activity a reference point is needed, as activity decreases
exponentially over time. We express demand in terms of activity at the patient/hospital level at time of
administration (TOA). We do this, as (1) information is best available at this level (i.e. procedures), (2) activity
and procedures are now expressed at the same level and (3) to avoid uncertainties/differences in time (thus
affecting activity) from irradiation to application.
Measuring true demand for radionuclides in the EU is fraught with difficulty given the fragmented nature or often
complete lack of data collection between countries. Additionally, suppliers of radionuclides and
radiopharmaceuticals do not provide such (strategic) market information. For these reasons, a retrospective
estimate of annual use of radionuclides may serve as the best proxy of the demand for radionuclides. It should
be noted that true demand for radionuclides may be higher than current use, as there may be other reasons (e.g.
cost, availability, knowledge) for using fewer radionuclides. It should also be noted that the demand at the
irradiator is higher: due to inefficiencies, processing and transport times, higher activities need to be produced
in order to meet the needed activities at the time of administration to patients.
To establish an overall estimate of current demand (using current use as proxy), annual country level demand
for radionuclides was calculated first on a more granular level by radiopharmaceutical and indication. These were
then summed to give a national and EU level estimate for a given radionuclide/radiopharmaceutical.
Demand at the radiopharmaceutical and indication level was estimated using two main methods. The first
method makes use of national statistical data from publicly available sources or from national nuclear medicine
societies, whilst the second uses Technopolis survey data to estimate demand. The first method was preferred
where data were available as these were believed to be more robust than survey data. The exact methodology
and important assumptions associated with current demand calculations are provided in Appendix B.2. We also
asked national nuclear medicine societies and suppliers of radiopharmaceuticals to validate the final current

13

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

demand calculations. However, not all nuclear medicine societies and radiopharmaceutical suppliers provided
responses. We indicate the countries with validated responses below and in the appendices.
The majority of the current demand calculations (14 countries) are based on our validated survey data and/or
national statistics; however, a large share of countries have not validated the calculated figures. As such, the
current demand calculations have to be treated with caution. Nonetheless, the figures do give an indication of
the most in demand radionuclides/radiopharmaceuticals in Europe in terms of both activity and procedures.

2.2.1

Demand in terms of activity

As would be expected, 131I and 223Ra are the most ubiquitously used radionuclides in Europe, for example, they
are used in 26 and 25 countries respectively out of the 26 countries we have data for (Figure 2 and Figure 3 –
note that the scales are different). 131I and 223Ra are typically used as [131I]-NaI and [223Ra]RaCl2 in the case of
various thyroid-related conditions (both benign and malignant) and bone metastases respectively. 177Lu, 90Y and
153
Sm (at high activity levels in Figure 2) and 186Re (at lower activity levels in Figure 3) are also widely used across
more than 10 countries.
Figure 2

Current demand for radionuclides (1000 GBq activity) across Europe

N.B. The data labels at the end of a bar indicate the number of countries reporting use of a particular radionuclide. Data for
Denmark was not available.
Figure 3

Current demand for radionuclides (GBq activity) across Europe

N.B. The data labels at the end of a bar indicate the number of countries reporting use of a particular radionuclide. Data for
Denmark was not available.

14

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

177

Lu and 90Y are used as different radiopharmaceuticals for different indications, most prominently as 90Y
microspheres (both glass and resin) for intra-arterial treatments in the liver, 90Y-colloids for radiation
synovectomy, [177Lu]Lu-DOTATATE for neuroendocrine tumours, and [177Lu]Lu-PSMA for castration-resistant
prostate cancer and metastases (Figure 4).
Figure 4

Current demand for radiopharmaceuticals (1000 GBq activity) across Europe

N.B. The data labels at the end of a bar indicate the number of countries reporting use of a particular radiopharmaceutical.
Data for Denmark was not available.
Figure 5

Current demand for radiopharmaceuticals (GBq activity) across Europe

N.B. The data labels at the end of a bar indicate the number of countries reporting use of a particular radiopharmaceutical.
Data for Denmark was not available.

Suppliers of radiopharmaceuticals were asked to validate the collected data for their product. From the
responses received, we understand that the current demand for 177Lu-antibodies is in line with the suppliers’
estimate. For [177Lu]Lu-PSMA suppliers estimate a 25-30% higher current European demand – which still leaves
[177Lu]Lu-PSMA the third radiopharmaceutical most in demand in terms of activity. For [177Lu]Lu-DOTATATE the
European demand is probably somewhat less, based on a crude patient number obtained during validation.
Overall, this supports the conclusion that 177Lu is currently high in demand, second after 131I.

15

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

2.2.2

Demand in terms of procedures

In terms of number of procedures (i.e. individual treatments or doses) delivered [131I]-NaI far outstrips other
radiopharmaceuticals as well. The next most popular radiopharmaceuticals in terms of procedures required are
[177Lu]Lu-DOTATATE and [223Ra]RaCl2, both of which account for about eight-fold fewer procedures compared to
those delivered for [131I]-NaI (16k each respectively as opposed to 120k for [131I]-NaI).
Figure 6

Current demand for radiopharmaceuticals (1000 annual procedures) across Europe

N.B. Data for Denmark was not available.
Figure 7

Current demand for radiopharmaceuticals (annual procedures) across Europe

N.B. Data for Denmark was not available.

Drawing conclusions from country-level data has limitations as data for some countries was not validated by the
respective national nuclear medicine society. From the countries with validated data, Estonia (781), Poland (648)
and Slovakia (591) deliver the greatest number of radionuclide therapy procedures per million inhabitants, which
includes 131I. The UK (25k), Poland (24k), and Spain (16k) deliver the greatest number of procedures in total.
To focus on the upcoming radionuclides, we have created Figure 8 which excludes 131I (the top panel for validated
data and bottom panel for indicative data that has not been validated). Here we see that per million inhabitants
UK (205), Sweden (186) and Belgium (169) deliver the most radionuclide therapy procedures per million
inhabitants.

16

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Further, in per capita terms, use of 90Y appears more common in Hungary, the Czech Republic and Spain than in
other European countries (based on validated data; see Figure 8 top panel). The use is largely in the form of 90Ycolloids in Hungary and Czechia, while in Spain 90Y-microspheres account for almost 60% of the procedures. On
the other hand, the relatively higher rate of use of 177Lu in the UK and Italy is down to [177Lu]Lu-DOTATATE. 223Ra
is quite heavily used in Sweden, Belgium and the UK despite it being a more costly radionuclide. On the other
hand, 166Ho use is most prominent in Hungary, Spain and the Netherlands.
Figure 8

Number of annual radionuclide therapy procedures by country and radionuclide (excluding 131I)

N.B. The top panel shows countries for which data were validated by the relevant national nuclear medicine society (as
indicated by an asterisk), while the bottom panel shows indicative data for the remaining countries. Data for 131I are not shown
as it is used across all countries represented in the data and in very high amounts. Austria, Denmark, Germany, Greece, Latvia
and Romania are not represented in the graph. Data was not available for Denmark. We received a very low number of
responses from Austria, Germany and Greece. Romania only uses 131I and while Latvia uses 131I as well as 223Ra, the procedure
numbers are very low.
17

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

2.3

Incidence – population growth greatest for prostate cancer

Incidence data may be used as an indicator of the new patient population eligible for treatment with a given
medicine. Here we define incidence as the number of new cases per 100,000 people in a given year, and absolute
incidence gives the new cases for an entire population. A crucial caveat with the use of incidence data for this
analysis is that it is the eligible, or potential, population – i.e. not the number of new patients that will be treated
with radiopharmaceuticals. A proportion of these new patients will for example, receive alternative or competing
treatments in practice, or in some instances die before treatment can be given.
Incidence rates for relevant cancers are calculated from the European Cancer Information System (ECIS) 13 and
given in Table 2. Data from 2010 was used as the latest incidence data, from 2014, was not considered
representative of enough countries across Europe. Using data from 2010 drew incidence information from 128
cancer registries across 27 different countries across the EU across all ages for both males and females. The
average incidence per 100,000 people in 2010 was calculated for each therapeutic area from the available
registries. The incidence for each therapeutic area relevant to a given radiopharmaceutical was summed to give
the total new people eligible for treatment with that radiopharmaceutical in 2010. Absolute numbers were
calculated assuming an EU population of 441 million in 2010. 14 Certain therapeutic areas, such as B-cell
lymphoma and head and neck cancers did not have incidence data available.
Table 2
EU incidence of cancers occurring in therapeutic areas for radiopharmaceuticals in 2010
Therapeutic area(s)
Average annual incidence rate
Radiopharmaceutical
relevant to a
in EU countries per 100,000
radiopharmaceutical (as
people
given in ECIS)

Absolute incidence
in EU countries

[177Lu]Lu-PSMA

Prostate

171*

376,671

[225Ac]Ac-PSMA

Prostate

171*

376,671

[227Th]Th-PSMA

Prostate

171*

376,671

[90Y]Y-ibritumomab-tiuxetan

Non-Hodgkin lymphoma
(B-cell lymphoma n/a)

19

84,276

227Th-conjugate

Non-Hodgkin lymphoma

19

84,276

177Lu-antibodies

Non-Hodgkin lymphoma

19

84,276

90Y-resin microspheres

Liver and intra-heptic bile
ducts

15

68,121

90Y-glass microspheres

Liver and intra-heptic bile
ducts

15

68,121

166Ho-microspheres

Liver and intra-heptic bile
ducts

15

68,121

[166Ho]Ho-chitosan

Liver and intra-heptic bile
ducts

15

68,121

[225Ac]Ac-Lintuzumab

Leukaemia

14

62,467

[131I]-NaI

Thyroid gland

12

52,655

13 ECIS - European Cancer Information System (2021). From https://ecis.jrc.ec.europa.eu, accessed on 11/01/2021. European Union.
14 Statista data (2021). From https://www.statista.com/statistics/253372/total-population-of-the-european-union-eu/. Accessed on 11/-

1/2021

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radiopharmaceutical

Therapeutic area(s)
relevant to a
radiopharmaceutical (as
given in ECIS)

Average annual incidence rate
in EU countries per 100,000
people

Absolute incidence
in EU countries

[131I]I-mIBG

Endocrine and Brain and
other CNS

10

41,977

32P-sodium-phosphate

Myeloma and Bones and
Joints

9

37,565

227Th-antibody

Mesothelioma

2

10,096

90Y-colloids

Bones and joints

1

4,507

[89Sr]SrCl2

Bones and joints

1

4,507

[223Ra]RaCl2

Bones and joints

1

4,507

[188Re]Re-HEDP

Bones and joints (non
melanoma skin cancer data
n/a)

1

4,507

186Re-colloids

Bones and joints

1

4,507

[177Lu]Lu-DOTATATE

Endocrine

1

2,588

169Er-colloids

Bones and joints

1

4,507

[166Ho]Ho-DOTMP

Bones and joints

1

4,507

[153Sm]Sm-EDTMP

Bones and joints

1

4,507

166Ho-microspheres

Head and neck

n/a

n/a

Source: European Cancer Information System and Technopolis 2020. *calculated per 100,000 males only

It is clear from Table 2 that prostate cancer has by far the greatest average incidence rate (171/100,000 males)
in cancers relevant to radiopharmaceuticals used in Europe. Despite being applicable to only half the population
(males only), the absolute number of prostate cancers still far outweighs any absolute numbers of other relevant
cancers. When combined with the expected market approval of PSMA radiopharmaceuticals 15 following on from
current clinical trials in the coming months and years, it appears that use of these medicines will greatly increase
over the coming decade.
Non-Hodgkin lymphoma was the therapeutic area that had the second greatest incidence rate according to ECIS
data, therefore radiopharmaceuticals that treated this ([90Y]Y-ibritumomab-tiuxetan, 227Th-conjugate, 177Luantibodies) ranked high in the eligible new population for treatment. Those radiopharmaceuticals that treat
endocrine or bone and joint cancers ranked the lowest in terms of eligible new people for treatment.
By far, the most commonly used radiopharmaceutical, [131I]-NaI, ranked relatively low in terms of incidence rates
for its therapeutic areas. However, importantly 131I does not have competing treatments for hyperthyroidism
and thyroid cancer. We would therefore expect a large proportion of this ‘potential’ population to in fact receive
treatment with 131I – for other radiopharmaceuticals that have more competing treatments this proportion may
be lower.
It should be noted that this analysis makes use of incidence data (the number of additional people in a given unit
of time) rather than prevalence data (the total population of interest). Prevalence data was not available for
analysis. Current incidence data in 2020/21 is also likely to be higher than the figures given here owing to the

15 For example, the progress being made in the VISIONS study https://clinicaltrials.gov/ct2/show/NCT03511664

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

population demographics becoming more skewed towards older age brackets where cancer incidence is greater.
Although incidence rates and absolute numbers are likely greater now for all cancers than in 2010, this data still
demonstrates that prostate cancer has by far the greatest incidence rate of relevant cancers, this will hold true
for 2020/21 also.

2.4

Good examples of data collection in EU-27

Data regarding the use of therapeutic radionuclides is fragmented across the EU. Only a few countries have
detailed insights in the use of therapeutic radionuclides in their country and information can be obtained from
official bodies. In this study we found that Belgium, the Czech Republic and Sweden are examples of good data
collection in this regard. For these countries official bodies were able to provide the requested data. Here we
shortly describe their approach to data collection.
•

In Belgium, the federal agency for nuclear control FANC collects data on the imported activity of
radiopharmaceuticals used in Belgium. This data concerns the activity per radiopharmaceutical delivered to
the Belgian departments for nuclear medicine. In addition, in Belgian health insurance data, the number of
units administered and invoiced of (reimbursed) radiopharmaceuticals is collected. Also, price information
of reimbursable radiopharmaceuticals is monthly updated and published at the website of the national
health insurance institute RIZIV. These three sources provide a reliable and fairly complete overview of
radionuclides used in Belgium and their costs.

•

In the Czech Republic, the State Institute for Drug Control contains databases of medicinal products and
pharmacies and the comprehensive statistics it collects include the amount of radiopharmaceuticals (in Bq)
used in clinical praxis. The number of patients receiving radionuclide therapy by indication is available from
National Registers maintained by the Institute of Health Information and Statistics of the Czech Republic
which collect the numbers of patients diagnosed each year and the type of treatment they receive. The
number of procedures delivered including dose per procedure can be evaluated from statistics of health
insurance companies and the Institute of Health Information and Statistics of the Czech Republic. Not all
these data are publicly available, and some can be made available on request for research purposes. The
Czech Society of Nuclear Medicine has access to these data.

•

In Sweden, the Swedish Radiation Safety Authority (SSM) provides national data on radiopharmaceuticals.
All administrations of radiopharmaceuticals are reported annually. Data collected include how many
treatments each radiopharmaceutical has been used for, if the treatment is for adults or children and the
average activity (MBq) of those treatments. The number of patients treated is not collected and this number
may differ from the total number of treatments.

In some other countries we have seen that data on the use of radiopharmaceuticals is collected for
reimbursement or radiation protection, but that the purpose and aggregation level of this information does not
allow trace-back to specific radiopharmaceuticals or radionuclides. For instance, data registered at the level of
indication does not discriminate between several candidate medicines or treatments. Also, radiopharmaceuticals
that have not received marketing authorisation but are used in clinical trials, used compassionately, or produced
in-house (magistral preparation/compounding), or that are not reimbursed, are generally not visible in official
data or not specific enough to monitor (e.g. as category ‘Other nuclear medicine treatments’).
To gain better insights and to monitor European demand for therapeutic radionuclides and radiopharmaceuticals
better official national data collection is needed. Current approaches for bottom-up data collection through
surveys to individual healthcare professionals or nuclear medicine societies do provide some insights, but these
are never complete and inherently introduced uncertainties, resulting in best estimates. Furthermore, a fatigue
for such bottom-up data collection exercises is observed among nuclear medicine professionals and national
associations. The examples above may provide inspiration for improving and standardising these data collection
mechanisms to strengthen the European overview through national data.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

3

Regulation, reimbursement, finance and guidelines

There are many different future pathways for the use of radiopharmaceuticals, and they are determined by a
range of factors. The presence of radiopharmaceutical guidelines on when and how they should be used, such as
those published by the EANM, do not guarantee their use. Similarly, a lack of guidelines also does not necessarily
mean that a radionuclide will not be used as a part of treatment. The Technopolis survey has shown that
treatment using radionuclide therapy is done often as part of clinical trials, prior to the development of clinical
guidelines. Yet even when treatments are established, there are still a number of broad factors, clinical and
non-clinical, that can determine the use of radionuclide therapy. We explore these factors in more detail
throughout this chapter. These factors may also be applicable to medicine use more broadly, however; evidence
specific to radiopharmaceuticals is included where available from the study.
Overview of main conclusions of this chapter:
•

When being granted a licence for the European market, the Centralised procedure is the most relevant
for radionuclide therapy medicines. Medicines that treat cancers must go via this procedure.

•

Sharing radiopharmaceutical HTAs via the EUnetHTA may be of particular help to countries with less wellresourced healthcare bodies that lack capacity to conduct HTAs.

•

Referral systems and communicative networks are necessary to help ease geographical inequalities in
terms of patient access to treatment with radionuclide therapy.

•

Clinical staff education can affect if alternative or competing therapies are chosen over treatment with
radiopharmaceuticals.

•

Radionuclide therapy may be at particular risk of shortages due to the complex supply chain required to
manufacture a radiopharmaceutical and get it to the hospital bedside.

•

The prices of radiopharmaceuticals are negotiated by hospitals, regions or countries (e.g. by ministries).
These negotiations differ per country which can lead to a range of prices paid for the same
radiopharmaceutical.

3.1

EU Regulation and licensing

Until 1989 the unique properties of radiopharmaceuticals had seen them treated differently to other medicinal
products in legislative terms in the EU. However, in May 1989 the Council Directive 89/343/EEC came into action
which extended the scope of Directives 65/65/EEC and 75/319/EEC on the regulation or administrative action
relating to proprietary medicinal products, laying down additional provisions for radiopharmaceuticals. The
result was that regulation of radiopharmaceuticals became more harmonised with more general medicines. In
2001 Directive 2001/83/EC further harmonised radiopharmaceutical legislation by stating that marketing
authorisation was required for industrially manufactured radiopharmaceuticals, with exemptions in certain
instances.16
Market authorisation may be given on the European market via a number of different routes: (1) the centralised
procedure, (2) the decentralised procedure (DCP), (3) the mutual recognition procedure (MRP) and (4) national
authorisation procedures.17 The first three of these routes to market authorisation can give a company approval

16

Verbruggen et al (2020). Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU. See:
https://www.eanm.org/publications/guidelines/gl_radio_phct_259_853.pdf

17

Lægemiddelstyrelsen (2016). Marketing authorisation for a medicine. See: https://laegemiddelstyrelsen.dk/en/licensing/licensing-ofmedicines/marketing-authorisation/

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

to market in all or several member states at once, whilst the latter national authorisation procedure only gives
authorisation to market in a single country.
Central authorisation is a key benefit to EU member states and EEA members that gives patients timely access
to new and innovative medicines. It is required that certain products, such as oncology medicines, go through
the central authorisation procedure18 making it of particular relevance to radionuclide therapy medicines. The
European Medicines Agency (EMA) evaluates centrally authorised single market authorisation applications and
recommends authorisation to the European Commission who ultimately decides which medicines are granted
market authorisation to EU and EEA members. 19 Xofigo® ([223Ra]RaCl2) is one example of a radiopharmaceutical
that has gained access to the EU via a centrally authorised procedure. In 2013, Bayer was granted market
authorisation for Xofigo® by the European Commission for the treatment of adults with castration-resistant
prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastases. This decision followed
a positive recommendation by the EMA’s Committee for Medicinal Products for Human Use (CHMP) to the EC.
The MRP is used when a product has already received national market authorisation in one member state or
country and another member state wishes to use their evaluation of the product to grant market authorisation
in their own country. The EU holds Mutual Recognition Agreements (MRAs) for radiopharmaceuticals with
countries outside the EU including Australia, Canada, Israel, New Zealand, Switzerland and the USA. 20 The DCP is
similar to this process but can be used when a product is yet to receive market authorisation in any member
state. In this case a member state must act as the Reference member state (RMS) to conduct an initial evaluation
of the product.21 The product may then gain market authorisation to multiple member states through the DCP,
also distinguishing it from the national authorisation procedure.
Variation in national legislation also contributes to differences in how radiopharmaceuticals can be used in
different member states. France and Hungary, for example, have policies that only allow radiopharmaceuticals
to be used only after authorisation has been granted or when a clinical trial has started.22 More relaxed
approaches are taken in other member states, most notably Germany. Technopolis expert interviews have
suggested that Germany takes a progressive approach regarding compassionate use of radiopharmaceuticals
(and other medicines in general). Compassionate use allows a promising technology that may not yet be in clinical
trials to be used on a case where therapeutic need is adequate. Consequently, Germany is considered particularly
innovative with a broad palette of radiopharmaceuticals in use – even though these are not yet on the market.
Other countries, like The Netherlands, Belgium, Austria and Sweden for example, also take progressive
approaches. Certain radiopharmaceuticals without market authorisation can be prepared based on ‘pharmacy
practice’ whereby hospital pharmacies take responsibility. However, scrutiny over radiation protection and Good
Manufacturing Practice is required with in-house production.
New radiopharmaceuticals may also come into use in Europe as part of a clinical trial. Legislation surrounding EU
clinical trials is currently undergoing a transition with the aim of simplifying the process. 23 The new Clinical Trials

18 Medpace (2020). The evolving landscape of therapeutic and diagnostic radiopharmaceuticals. See: https://www.medpace.com/wp-

content/uploads/2020/07/Article-The-Evolving-Landscape-of-Therapeutic-and-Diagnostic-Radiopharmaceuticals.pdf
19

EMA (2020). What we do. See: https://www.ema.europa.eu/en/about-us/what-we-do

20

EMA Mutual recognition agreements (MRA) https://www.ema.europa.eu/en/human-regulatory/researchdevelopment/compliance/good-manufacturing-practice/mutual-recognition-agreements-mra

21

HMA Medicines Approval System. See:
https://www.hma.eu/medicinesapprovalsystem.html#:~:text=The%20decentralised%20procedure%20(%20DCP%20)%20is,for%20MRP%2
0to%20be%20used

22 Schwarz et al. (2019). Harmonization of U.S., European Union, and Canadian First-in-Human Regulatory Requirements for

Radiopharmaceuticals: Is This Possible? See: http://jnm.snmjournals.org/content/60/2/158.full#ref-17
23 Ibid.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Regulation EU 536/2014 repealed the Directive 2001/20/EC with the ambition of creating a single application
and authorisation procedure via a central EU portal and database. This will replace the older Directive where
each participating country must individually make a clinical trial application. Although the new regulation was
due to come into force in 2016 it has been delayed; the EMA management board has proposed a new ‘go-live
date’ of December 2021.24 Technopolis believes the use of the central portal for clinical trials may see shorter
times to approve the use of novel radiopharmaceuticals in clinical trials in Europe in the future.

3.2

Reimbursement and Finance

Although a pivotal milestone for medicine availability, licensing of radionuclides via regulators such as the EMA
does not guarantee clinical use. Decision makers must still decide whether to grant reimbursement taking both
clinical and financial considerations in mind. Reimbursement may occur on a national or regional level, where
pharmaco-economic evaluations are used, or on an individual case-by-case basis. Factors that need to be
considered are therapeutic need, if the technology is lifesaving, if an alternative technology available or not, the
total number of patients that can be treated with the new technology, if only a certain sub-cohort of the eligible
population will be treated and also price (which involves manufacturer negotiations).
Over recent decades Health Technology Assessments (HTAs) have been established as important instruments
for reimbursement decisions. HTAs provide systematic literature reviews of clinical data and health economic
analysis that inform if a new treatment or regimen is both more clinically and cost effective than a comparator
(what is already used). These studies may typically take a national perspective, with models tailored towards a
specific health system (e.g. healthcare costs). Regarding radionuclides, HTAs are more suited to interventions on
the radiopharmaceutical level, whereby a specific indication can be explored.
Given the variation in healthcare systems between countries, HTAs can lead to differing reimbursement
recommendations from one country to the next. Taking 223Ra for the treatment of metastatic prostate cancer
(mPC) for example, a HTA for the Irish National Centre for Pharmaco-economics (NCPE) did not recommend 223Ra
for reimbursement following findings of an incremental cost-effectiveness ratio (given by the additional cost of
a treatment divided by the additional health benefit) of €79,948, which was deemed to be too costly for the
additional clinical patient benefit.25 Concurrent findings that 223Ra to treat mPC was not cost-effective were found
in other national HTAs (Germany, England and Wales, Scotland and Sweden) 26. However, as demonstrated
through the survey conducted in this study, despite uncertainty regarding the cost-effectiveness of 223Ra it is still
used in practice to treat mPC in many European countries. This may come down to individual negotiations on
price at the national level between manufacturers/suppliers and purchasers. The National Institute for
Healthcare Excellence (NICE) in England and Wales only recommended that 223Ra is used if “company provides
Radium-223 dichloride with the discount agreed in the patient access scheme”. 27 Discount negotiations such as
these are more often than not kept confidential, as such no further analysis on the relationship between
discounting and reimbursement was possible.
In recognition of (a) the effort national health agencies need to generate HTAs and (b) that often evidence in a
HTA is either generalisable or adaptable to other European countries, the EU set up the EUnetHTA (European

24

Highlights of Management Board: June 2020 meeting: https://www.ema.europa.eu/en/documents/press-release/highlightsmanagement-board-june-2020-meeting_en.pdf

25 NCPE (2014). Cost Effectiveness of Radium-223 (Xofigo®) for castration-resistant prostate cancer with symptomatic bone metastases and

no known visceral metastases. See: http://www.ncpe.ie/wp-content/uploads/2013/12/Xofigo-12122014_final.pdf
26 See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873580/#ref18
27 See: https://www.nice.org.uk/guidance/ta412/chapter/1-Recommendations

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Network for Health Technology Assessment) as part of Directive 2011/24. 28 A Technopolis review of the
EUnetHTA assessment list showed that no specific radionuclides or radiopharmaceuticals have been included.
Although outside of the scope of this study, Stereotactic Body Radiation Therapy (SBRT) has been included on
the EUnetHTA Prioritisation List (EPL) for “Other Technologies”. 29 Given the increasing importance of HTAs in
reimbursement decisions, increasing dialogue with EUnetHTA and appropriate radionuclide related bodies may
help to share HTA radiopharmaceutical resources between European countries. Supplying radiopharmaceutical
HTAs via the EUnetHTA may be of particular help to countries with less well-resourced healthcare regulatory
bodies that lack capacity to conduct HTAs from scratch.
Given the high prices often attached to radiopharmaceuticals and costs to health care systems, the number of
procedures reimbursed may be limited. In Hungary, for example, reimbursement of radiopharmaceuticals occurs
via the National Health Insurance Fund, as is the case for other medicines. However, the decision process for
reimbursement differs. The reimbursement decision is made by a special medical expert committee on a patientby-patient basis. The effect of having a special committee taking more granular decisions works as a cost control,
limiting the number of very expensive procedures,
Reimbursement and pricing strategies of radiopharmaceuticals in Europe vary significantly between member
states. The variation seen is a consequence of reimbursement and pricing being decided at a national level.
Generic models of reimbursement commonly used in healthcare settings are shown in Table 3. Reimbursement
trends in secondary care have seen a shift in recent years from primarily ‘unbundled’ fee for service models
towards ‘bundled’ payments where a lump sum covers a patient pathway, diagnosis or disease, for example.
Bundling has previously been defined as the degree to which the components of healthcare are grouped together
for payment.30 For example, where a fee for service model is employed radiotherapy planning and rehabilitation
may need to be reimbursed separately to radiotherapy treatment itself. However, these units of care could be
reimbursed in one payment if a model of payment per pathway is utilised. Fee for service reimbursement has
been criticised for incentivising high volume of care, perhaps at the expense of quality, whilst not encouraging
integrated care.
Table 3
Model

Reimbursement models used in European healthcare settings
Description

Fee-for service

Payment for each unit of service and patient contact

Payment per day

Payment per day that patient stays in hospital

Payment per case / diagnosis
/ procedure

Payment per case based on grouping of patients with similar diagnoses /procedures or
resource needs

Payment per pathway

Payment for all services required for a defined patient pathway

Budget

Global lump sum paid irrespective of the number of patients treated

Source: Nuffield Trust Reforming payment for health care in Europe to achieve better value

There is a strong lack of published literature regarding reimbursement of radiopharmaceuticals. However, some
parallels may be drawn from the (also scant) literature that is published regarding other radiotherapy services
and reimbursement.

28 See: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32011L0024
29 See: https://eunethta.eu/assessments/eunethta-prioritisation-list-epl-other-technologies/
30 See: https://www.nuffieldtrust.org.uk/research/reforming-payment-for-health-care-in-europe-to-achieve-better-value

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

For example, Lievens et al. (2020) found that fee-for-service radiotherapy financing is seen in nine European
countries (Belgium, Estonia, France [private and public], Germany, Greece [private], Lithuania, Luxembourg, the
Netherlands, and England). Only 5 countries (Bulgaria, Finland, Portugal, Romania, and Spain) used bundled
payments that correspond to a payment per case, diagnosis or procedure. The study also found that where a
budget is used, the budget is defined by either number of treatments delivered or investment in equipment.
These findings may serve as an approximation as to the reimbursement models also used for
radiopharmaceuticals.

3.3

Health systems resources and capacity

Treatment with radionuclide therapy may require considerable investment in infrastructure. For example,
there may need to be dedicated radiotherapy centres that provide inpatient and outpatient facilities. The
investment required for such facilities may not be covered under national reimbursement schemes.
Consequently, smaller peripheral hospitals are less likely to have such infrastructure to administer most
nuclear medicine therapies. Where patients reside closer to smaller peripheral hospitals, they may be referred
to a larger hospital or specialist radiotherapy centre, or an alternative course of treatment could be prescribed.
One Belgian national expert indicated that in response to the problem of geographical resource availability,
nuclear medicine is run via a hub and network system that will eventually channel patients to 7 national
radionuclide therapy centres. A further expert from the UK described ability to receive radionuclide therapy as a
‘post code lottery’ in the country, where larger cities have better equipped hospitals with highly trained staff.
As can be seen from these examples, difficulties with resources and capacity can lead to geographical
inequalities of health. These inequalities may become particularly pronounced where expensive infrastructure
is required, as is the case with radionuclide therapy. Referral systems and communicative networks are
necessary to help ease geographical inequalities.

3.4

Staff expertise and knowledge

In practice it is usually nuclear medicine departments who perform the treatment with radiopharmaceuticals in
conjunction or on referral from oncologists. Although these departments are staffed with experts in their fields,
additional expertise may be required due to the clinical complexity of certain indications. Expertise and a
multidisciplinary team of oncologists, radiologists, surgeons and more are all needed to revolve around patients.
One Dutch expert highlighted that treating neuroendocrine tumours (NETs) with radionuclide therapy is
particularly difficult due to the complications that can arise, consequently endocrinologist expertise must also
be brought on board the team where not already present.
Where staff expertise and knowledge of radionuclide therapy is lacking it can be expected that alternative or
competitive courses of treatment may be chosen. The majority of radiopharmaceuticals are utilised in clinical
settings where multiple drugs are used. In practice the course of treatment used where competing therapies are
available will be influenced by what the treating physician is able to directly manage. Therefore, the education
of clinical staff has a direct effect on whether radiopharmaceuticals are used. One exception to this is the use of
iodine-131 for thyroid cancer and hyperthyroidism, where there is a lack of competing therapies.
One expert in Belgium suggested that doctors often first choose what is available in their hospital leading to
inefficiencies. Chemotherapy may be a viable alternative for many hospitals to treat certain cancers, for example.
The reasons for choosing what is available to them may be to avoid referral away thus maintaining turnover in
the hospital. The outcomes of staff lacking expertise in radiotherapy may be similar to those arising from a lack
of resources and capacity – Increased use of alternative therapies and geographical health inequalities.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

3.5

Medicine shortages

In cases where staff expertise, resources and capacity to deliver radionuclide therapy are sufficient there may
still be instances where it is not possible to use it as a course of treatment. Medicine shortages, which have been
a growing problem in the EU, can force triaging of patients in order to decide who gets treatment, or in the case
of severe shortages force the use of alternative treatments for all patients. A 2019 survey of 400,000 community
pharmacies across Europe conducted by the Pharmaceutical Group of the European Union (PGEU), found that all
responding countries (24 Member States) experienced medicine shortages in the past 12 months. 31 From a
patient perspective medicine shortages present a major problem as it may lead them to switch to alternative
therapies, potentially resulting in increased risks of adverse effects, decreased treatment effectiveness,
medication errors, non-compliance and disease progression. In addition to potentially decreasing quality of care
and worsening patient outcomes, medicine shortages may represent a serious problem to the efficiency and
quality of healthcare institutions.
Radionuclide therapy may be at particular risk of shortages due to the complex supply chain required to
manufacture a radiopharmaceutical and get it to the hospital bedside. Unique to radiolabelled medicines,
compared to other medicines, is the need to consider the half-life of the product. Radionuclides with shorter
half-lives need to be produced as locally as possible to prevent decay, which renders the medicine unusable.
Robust supply chains are therefore critical to prevent supply side related shortages. A specific example of supply
side related shortages was reported in the Technopolis survey which occurred in Cyprus. The Cypriot example
was reported as occurring due to connecting flights carrying radionuclide cargo that either arrived late or not at
all. This example is demonstrative that supply chains need to be adapted and robust to the unique geographies,
if any, of individual countries.

3.6

Guidelines – a preference for European level

The complexity of treatment with radiopharmaceuticals necessitates specific clinical knowledge. As such, clinical
guidelines are useful to help harmonise and disseminate best practice. Information that clinicians may look to
clinical guidance for assistance may be, for example, dosimetry of radiopharmaceuticals for certain subpopulations.
Guidelines can be published on varying levels from an organisation, to the national or European level. Drawing
on data from the Technopolis survey and supporting interviews, there is a clear preference among countries in
Europe to make use of European level guidelines. At this level the guidelines that tend to be used are published
by the European Association of Nuclear Medicine (EANM). A total of 22 of 28 countries reported using European
level guidelines for radiopharmaceutical treatment (see Table 4).
Additional guidelines are also requisite given that the EANM does not publish guidelines that cover all
radiopharmaceuticals that are used on the European market. Slightly less (15 out of 28) countries reported using
national guidelines, of these 14 reported using a combination of European and national level guidelines. Only
Ireland reported using national level alone, however, this may be due to a lack of reporting through the survey,
as opposed to the European level not being used (this is also the case for all instances of “Not reported” in Table
4). Use of guidelines at the organisational level were not well reported, with only Bulgaria, Denmark and Poland
suggesting their use.

31 PGEU (2020). PGEU Medicine Shortages Survey 2019 Results. Available at https://www.pgeu.eu/wp-content/uploads/2019/03/PGEU-

Medicine-Shortages-Survey-Results-2019-1.pdf. Accessed 09/04/2020

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

There was 1 reported instance of a country – Romania – using non-European guidelines from the USA. The
specific organisations were the American Thyroid Association and the National Comprehensive Cancer Network;
their guidance is used for treating thyroid malignancies and hyperthyroidism with 131I.
Table 4
Level of radiopharmaceutical guidelines used by country
Country
National clinical guidelines
European clinical guidelines
(e.g. from the EANM)

Organisation clinical
guidelines

Austria

Yes

Yes

Not reported

Belgium

Yes

Not reported

Not reported

Bulgaria

Not reported

Not reported

Yes

Croatia

Yes

Yes

Not reported

Cyprus

Yes

Not reported

Not reported

Czech Republic

Yes

Not reported

Not reported

Denmark

Yes

Not reported

Yes

Estonia

Yes

Yes

Not reported

Finland

Yes

Yes

Not reported

France

Yes

Yes

Not reported

Germany

Yes

Yes

Not reported

Greece

Yes

Yes

Not reported

Hungary

Yes

Yes

Not reported

Ireland

Not reported

Yes

Not reported

Italy

Yes

Yes

Not reported

Latvia

Not reported

Not reported

Not reported

Lithuania

Not reported

Not reported

Not reported

Luxembourg

Yes

Yes

Not reported

Malta

Yes

Not reported

Not reported

Netherlands

Yes

Yes

Not reported

Poland

Not reported

Not reported

Yes

Portugal

Yes

Not reported

Not reported

Romania

Yes*

Not reported

Not reported

Slovakia

Yes

Not reported

Not reported

Slovenia

Yes

Not reported

Not reported

Spain

Yes

Yes

Not reported

Sweden

Yes

Yes

Not reported

United Kingdom

Yes

Yes

Not reported

Total (Yes)

23

15

3

Source: Technopolis survey and interviews. *also reported using US guidelines

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

3.7

Radiopharmaceuticals prices vary, especially “high potentials”

Prices for therapeutic radiopharmaceuticals are generally not publicly available and not shared by suppliers.
Only in Belgium detailed price data for radiopharmaceuticals were found online. 32 To obtain insights in the prices
of radiopharmaceuticals nuclear medicine experts and professionals have been asked in the Technopolis survey
to provide ranges of prices: minimum and maximum prices of the radiopharmaceutical in their countries. Based
on an analysis of this data we have obtained some relevant price information on most of the
radiopharmaceuticals included in this study, although not for all.
The prices of radiopharmaceuticals are negotiated by hospitals, regions or countries (e.g. by ministries). These
negotiations differ per country and the outcomes are therefore different. In addition, for some countries the
transport of radiopharmaceuticals is more costly due to further distance from suppliers or more expensive
transporting (e.g. air transport instead of road transport). As a result, prices of radiopharmaceuticals are
different among countries for most radiopharmaceuticals. The minimum and maximum prices that have been
provided by respondents to the survey are therefore spread over a certain range (depending on the number of
respondents). The results of the survey are provided in Figure 9 and Figure 10.
Figure 9

Reported prices of radiopharmaceuticals per patient dose across Europe – high end

Source: Technopolis survey, figures are based on estimates and data, N is number of respondents

The figures show that the among the most expensive radiopharmaceuticals are some of the highest growing
radiopharmaceuticals in terms of demand. The average price per patient dose is highest for [177Lu]Lu-DOTATATE,
around €18k (if only responses based on data are considered). This radiopharmaceutical, also commercially
known as Lutathera®, is expected to rise in demand in the next ten years. The price of this radiopharmaceutical
spans a wide range, as some hospitals in Europe (esp. in the Netherlands) produce this medicine in-house,
which results in a considerably lower price than paid to the supplying pharmaceutical company (€4k per patient
dose versus ~€23k per patient dose excl. €2.5k transport costs in the Netherlands) 33. In the Netherlands, where
[177Lu]Lu-DOTATATE was developed, the Dutch minister has stimulated to continue in-hospital (magistral)

32 Public data from RIZIV (2020), the Belgian institute for health and disability insurance. See: https://www.riziv.fgov.be/nl/themas/kost-

terugbetaling/door-ziekenfonds/geneesmiddel-gezondheidsproduct/terugbetalen/radiopharma/Paginas/vergoedbareradiofarmaceutische-referentielijsten-referentiebestanden.aspx
33 Lucien Hordijk (2019). Reconstructie lutetium-octreotaat. NTVG, 09-01-2019. See: https://www.ntvg.nl/artikelen/reconstructie-lutetium-

octreotaat/volledig

28

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

preparation in response to the price difference for this radiopharmaceutical after marketing approval and orphan
drug designation34 by the EMA.35
Radiopharmaceuticals based on 90Y- and 166Ho-microspheres are also among the most expensive
radiopharmaceuticals and are expected to grow in demand. The average price for these products per patient
dose is between €9k-€12k. The spread in prices is lower for these medicines, though in Germany a low minimum
price for [90Y]Y-ibritumomab-tiuxetan was reported – which is likely due to in-hospital preparation.
Figure 10 Reported prices of radiopharmaceuticals per patient dose across Europe – low end

Source: Technopolis survey, figures are based on estimates and data, N is number of respondents

Most other radiopharmaceuticals are considerably lower priced, with average prices ranging between €250€4.000 per patient dose. The radiopharmaceutical [131I]-NaI is one of the oldest and cheapest
radiopharmaceuticals, being a side product from the production of the commonly used diagnostic 99Mo/99mTc.
Prices in the same range are paid for 169Er-colloids, 90Y-colloids and 186Re-colloids, with prices being closer to the
cost of the radionuclide.
Several 177Lu radiopharmaceuticals are currently priced in the mid-range, but these are not commercially on the
market and still used in clinical trials (esp. [177Lu]Lu-PSMA) or used compassionately. Preparation of these
radiopharmaceuticals is mainly in-house, resulting in varying prices per hospital in the order of several thousand
euros per patient dose. Once these products receive marketing authorisation an increase in price is to be
expected. The price of the commercially available and marketed [223Ra]RaCl2 is on average €4k per patient dose
and is thus more expensive than in-hospital prepared medicine, although priced in a somewhat similar mid-price
range.
The price for the radionuclides used in these radiopharmaceuticals was hard to obtain due to confidentiality and
little information was found. From the information we received, the prices of radionuclides are in the order of
several hundreds of euros per patient dose, with lower prices for 131I and higher prices for the more novel
therapeutic radionuclides such as 90Y and 177Lu. Generally, interviewees state that the prices for most
therapeutic radionuclides are higher than prices for diagnostic radionuclides (esp. 99Mo/99mTc). Origins lie in

34 Meaning 10 years of market exclusivity in the EU.
35 See: https://www.tweedekamer.nl/kamerstukken/moties/detail?id=2019D17566

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

different production volumes, as well as in legacy prices: irradiators have become more commercial/business
minded and there has been a stronger focus on full cost recovery for novel radionuclides.
In interviews, some insights have been provided in the cost structure of radiopharmaceuticals. The price of more
novel radiopharmaceuticals is for roughly 10-15% related to the price of the radionuclide: irradiation, processing
and margin for irradiator and processor. Which indeed suggests prices of several hundreds of euros per patient
dose, but also higher. Another rough 20-25% of the price is related to the radionuclide labelling to produce the
final radiopharmaceutical including margin. The remaining 70-60% of the price is related to transport, recovery
of investments (incl. R&D costs), marketing of the products and margin of the radiopharmaceutical company.
Radiopharmaceuticals produced in-hospital and for experimental or compassionate use are generally cheaper
and have a different cost structure. For in-hospital production, expert estimates are that 50-60% of the price is
attributable to the price of the radionuclide and about 20-30% to the price of the vector and the rest to other
costs, such as labour costs for in-hospital preparation.
Table 5

Average prices of radiopharmaceuticals per patient dose in Europe
Average price per patient dose in
Europe

Radiopharmaceuticals

Number of respondents from which average
is calculated

[177Lu]Lu-DOTATATE

€ 18.056

7

[90Y]Y-ibritumomab-tiuxetan

€ 11.923

6

90Y-glass microspheres

€ 11.500

5

90Y-resin microspheres

€ 9.214

7

[223Ra]RaCl2

€ 4.041

26

[177Lu]Lu-PSMA

€ 3.050

2

177Lu-peptides

€ 3.050

2

177Lu-antibodies

€ 2.200

2

[131I]I-mIBG

€ 2.150

10

[153Sm]Sm-EDTMP

€ 1.426

9

186Re-colloids

€ 661

4

90Y-colloids

€ 562

10

169Er-colloids

€ 431

2

[131I]-NaI

€ 255

27

Source: Technopolis survey, calculated from responses that were based on data (estimates excluded)

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

4

Supply chain capacity is becoming a pressing issue

Therapeutic radiopharmaceuticals consist of radionuclides often labelled with a carrier molecule that target
specific cells (often cancer cells). Only a few radionuclides target the right cells directly, such as 131I, and do not
have to be labelled with a carrier molecule for the specific therapy. The production of these radiopharmaceuticals
contains of several steps, which we describe in this chapter. In our description we focus on the time-sensitive
ingredient of the radiopharmaceutical: the radionuclide. We first provide an overview of the general production
process of the carrier molecule before we delve into specific supply chains.
Overview of main conclusions of this chapter:
•

Most therapeutic radionuclides are most effectively produced in nuclear reactors, only a few are most
effectively produced in accelerators (e.g. cyclotrons).

•

Currently, Europe has multiple local suppliers for most therapeutic radionuclides often used to date, an
exception seems 223Ra. For most long-lived therapeutic radionuclides foreign suppliers exist as well.

•

Cyclotron-produced therapeutic radionuclides (e.g. 67Cu and 211At) have limited supply and very few
suppliers in Europe, limiting research and adoption. Also, the current supply of 225Ac (which could be
produced in cyclotrons, but now obtained from US stockpiles) is a concern for its further development.

•

For the supply of radiopharmaceuticals about 20 different suppliers have been identified, for some
(generic) radiopharmaceuticals multiple suppliers exist. Radiopharmaceutical companies, especially those
with a (novel) patented product, manage and protect their supply chain actively and tend to vertically
integrate their supply chain to secure supply.

•

In Europe, seven research reactors currently produce most therapeutic radionuclides. Their capacity to
produce therapeutic radionuclides competes with capacity for their other (irradiation/research) activities.

•

Most of these European research reactors that produce therapeutic radionuclides are over 50 years old.
Many of them are planned to stop operations within the next 10-20 years, while there is limited potential
to increase production capacity of younger installations

•

Several plans for new build capacity to replace these research reactors exist, but it is uncertain whether
these will be realised (in time) and can provide sufficient capacity for the variety of therapeutic
radionuclides to match demand expectations. This poses a risk for the future security of supply of
therapeutic radionuclides in Europe.

•

Overall, the supply of therapeutic radionuclides has been reasonably stable in the past five years, although
disruptions of supply do occur, mainly caused during external production or transport. This directly
impacts the treatment of patients, causing delays in their treatment.

•

Several critical issues and foreign dependencies exist in the supply chain. These include foreign
dependencies for the supply of raw material and enrichment of LEU and stable isotopes, and issues such
as ageing European irradiation capacity and uncertain future irradiation capacity.

4.1

Overview of the international radiopharmaceutical supply chain

An overview of the general supply chain for therapeutic radiopharmaceuticals is provided in Figure 11. This
supply chain starts at the mining of the raw material for the radionuclide and ends at patient delivery in the
hospital. The most important steps in the supply chain are highlighted. Between each step transport occurs. The
exact processes that are performed in each step differs per radiopharmaceutical – here we describe the more
general or common processes.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Figure 11 Supply chain for therapeutic radiopharmaceuticals

Technopolis Group, 2020

The first step is mining the raw material to produce the desired radionuclide. Although we do not describe this
step in great detail, it is important to note that not all isotopes needed for the production of therapeutic
radiopharmaceuticals are naturally abundant. For instance, rhenium is one of the scarcest materials in the earth’s
crust. Also, the isotopes needed for targets are sometimes only a fraction of the natural occurring material: 176Lu
is <3% abundant and only traces of 226Ra and 229Th can be found in nature as these elements have no stable
isotopes36. Many of these materials are not mined in Europe, but imported from abroad, including uranium.
The second step is conversion. This process is relevant for radionuclides that are produced from enriched targets
(instead of targets from materials that have sufficiently high isotopic abundance in nature). In this step the raw
material is prepared for enrichment. The conversion depends on the enrichment process. For instance, for
uranium, used to produce 131I (among others), the uranium ore is converted to uranium hexafluoride gas that
can be used for gaseous enrichment.
In the enrichment step, the concentration of a certain isotope is increased. Methods to separate undesired
isotopes from the source material are used. These methods are based on the mass difference between isotopes,
such as centrifugal separation, diffusion separation or electromagnetic separation (applied in calutrons – a type
of mass spectrometers). Enrichment facilities exist in Europe (e.g. Urenco applying centrifugal separation for
stable isotopes), but enrichment is also done outside Europe (e.g. Russian calutrons for 176Yb enrichment).
Enrichment delivers materials that can be used for both the fabrication of targets and reactor fuel. The reactor
fuel is generally fabricated from low enriched uranium (LEU) powder, pressed into pallets that are stacked into
rods. This is only relevant for the production of radionuclides through a reactor. The target production is key to
produce virtually all therapeutic radionuclides, as it is also used in accelerators (such as cyclotrons). The target is
bombarded with elementary particles (electrons, protons or neutrons) or alpha particles to establish a nuclear
reaction of which the product is the desired radionuclide (as the only or one of the products). This process occurs
during irradiation. In a nuclear reactor irradiation of the target is done with neutrons (generated with the reactor
fuel). In an accelerator, which can be a linear accelerator or a cyclotron, charged particles are used for irradiation

36 CIAAW (2020). Isotopic compositions of the elements 2019. Available online at www.ciaaw.org.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

of the target. For example, to produce 211At alpha particles (positively charged) are used, while for the production
of 67Cu protons (positively charged) are used for irradiation. The desired product of the nuclear reactions, that
are thus established in the target, remains within the target. These radionuclides need to be extracted from the
target material and other (undesired) reaction products that reside within the target.
Processing is the activity in which the desired radionuclide is extracted from the target. Different methods have
been established for this extraction, of which most are chemical processes. Processing can be difficult and costly.
For example, the extraction of 177Lu from 176Yb is notoriously difficult as both have very similar chemical
properties.37 During processing the radionuclide is converted into a chemical form that allows transport and
further preparation of the radiopharmaceutical. For radionuclides such as 212Pb and 213Bi, a generator is used: a
device from which users can locally elute the desired radionuclide from a longer-lived parent radionuclide. This
allows for longer transport times for short lived radionuclides.
The radiopharmaceutical is prepared by pharmaceutical companies or in hospital and/or commercial
radiopharmacies. In this preparation the radionuclide can be chemically bound to a carrier molecule that acts as
a targeting agent to specific cells in the human body. These carrier molecules are often called vectors and can –
for instance – be peptides, proteins, antibodies or particles.38 The radiopharmaceutical can be delivered in
multiple forms (e.g. solution for injection, powder for in capsules) to the hospital. Radiopharmacies may use
precursors, generators or kits to prepare in-house the final radiopharmaceutical.
When the radiopharmaceutical is prepared for therapy, it can be delivered to the patient in the hospital. This
might require specific beds and facilities to safely administer radiopharmaceuticals and to deal with the
radioactive waste associated with the procedure (both leftover radiopharmaceutical as well as body excretions).
Routine radiopharmaceuticals, such as [131I]-NaI can be administered in a wide range of hospitals, while more
recent radiopharmaceuticals such as [177Lu]Lu-DOTATATE, require more advanced facilities and expertise (e.g.
related to waste and regulation). Treatment may require multiple injections at the hospital, spread over several
weeks, such as with [223Ra]RaCl2 and [177Lu]Lu-DOTATATE.

4.2

Production of therapeutic radionuclides

Therapeutic radionuclides are unstable isotopes that emit radiation while decaying into a stable isotope
(eventually). The radiation is used for therapeutic purposes, e.g. for damaging cancerous tissue. The radiation
type is often β-radiation – electrons or positrons – and sometimes α-radiation – helium nuclei, 2 protons and 2
neutrons – that consists of larger particles. In addition, γ-radiation – high energy photons – can also be produced,
although these are not contributing much to the therapeutic purpose but may be used for imaging. These
radionuclides generally decay within several hours or several days.
The production of these therapeutic radionuclides occurs in the irradiation phase of the supply chain after which
(chemical) processing occurs to extract the radionuclide. Here we first describe the production routes of
therapeutic radionuclides in the irradiation phase, which determines the technology/infrastructure needed for
irradiation. Next, we describe the international context in which production occurs, highlighting the position of
Europe in this part of the supply chain.

37 A. Dash, R. Chakravarty, F.F. Knapp and A.M.R. Pillai (2015). Indirect Production of No Carrier Added (NCA) 177Lu from Irradiation of

Enriched 176Yb: Options for Ytterbium/Lutetium Separation. Current Radiopharmaceuticals 8: 107.
38 F.F. Knapp and A. Dash (2016). Radiopharmaceuticals for Therapy. New Delhi: Springer.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

4.2.1

Production routes for therapeutic radionuclides

To produce these unstable therapeutic radionuclides, nuclear reactions are needed. Stable nuclides react with
an elementary particle (neutrons, protons, electrons, or photons) to create the desired unstable radionuclide (as
one of the reaction products). Such reactions can be created by irradiating the stable nuclide with neutrons,
resulting in unstable neutron-rich radionuclides, or by irradiating with charged particles (electrons or protons),
resulting in neutron-poor radionuclides. The first is typically done in nuclear reactors – but can also be achieved
using spallation in accelerators – while the latter is done with linear accelerators or cyclotrons.
Sometimes no nuclear reactor or accelerator is needed. Some therapeutic radionuclides are a product of
spontaneous nuclear reactions, such as 225Ac. The radionuclide is then a result of the decay of another (longliving) radionuclide. An extraction method is then needed to separate the useful decay product from its parent
nuclide. When the therapeutic radionuclide is chemically different from its parent, generators can be used for
this separation. The therapeutic radionuclide can then be eluted from the generator.
Most therapeutic radionuclides are most effectively produced using nuclear reactors. In most cases the
common/commercial production route is through the irradiation of prepared targets with neutrons in a nuclear
reactor. This holds for the most widely used therapeutic radionuclides. Some of these radionuclides are indirectly
produced in nuclear reactors, as they are eluted from generators. Examples are 212Pb and 213Bi. Sometimes also
alternative production routes exist using accelerators or cyclotrons, for instance to produce 186Re, 223Ra or 225Ac
– although these are often not widely applied or still being tested.
A few therapeutic radionuclides are most effectively produced using accelerators or cyclotrons. These are 67Cu
and 211At, which are currently not widely used.
Table 6 provides an overview of the production routes all therapeutic radionuclides that are included in this
study. It indicates whether the production method leads to a carrier added (CA) product or a no-carrier-added
(NCA) product, which is generally easier to process. NCA means that precautions are taken to minimise
contamination with stable isotopes39 of the element in question, resulting in a higher specific activity.40 The table
also provides some basis properties of these radionuclides, including half-life and emission.
Table 6
Radionuclides, their properties and production routes
Radionuclide
Production
Half-life
32P

Nuclear reactor (inefficient through
cyclotron):

Emission

14.26d

Single β- (pure
emission)

3.35d

Multiple β- and
multiple γ
(imageable)

Remarks

Irradiation of 32S targets
47Sc

Nuclear reactor:
NCA: irradiation of enriched 47Ti target
(high flux, lower cost process)

Theragnostic

NCA: irradiation of enriched 46Ca target
(expensive process, possibility of
47Ca/47Sc generator)

39 The difference between NCA and CA is especially relevant in the case of 177Lu where the direct production route results in 177Lu CA with

the coproduction of 177mLu (160.1d half-life) which causes significant waste issues at hospitals (laboratory waste and waste from
excretions) and additional radiation dose.
40 A. Dash, M.R.A. Pillai and F.F. Knapp (2015). Production of 177Lu for Targeted Radionuclide Therapy: Available Options. Nucl. Med. Mol.

Imaging, 49(2). See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463871/

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Production

Half-life

Emission

Remarks

67Cu

Accelerator/cyclotron (most effective
route):

2.6d

Single β- and
multiple γ
(imageable)

Theragnostic

50.5d

Single β- (pure
emission)

64.1h

Single β- (pure
emission)

8.02d

Multiple β- and
multiple γ
(imageable)

Theragnostic

46.27h

Multiple β- and γ
(imageable)

Theragnostic

26.83h

Multiple β- and
multiple γ
(imageable)

9.4d

Multiple β-

6.65d

Multiple β- and
multiple γ
(imageable)

High-energy proton irradiation of
natural Zn targets (typical route)
89Sr

Nuclear reactor:
Irradiation of highly enriched 88Sr target
(high flux)

90Y

Nuclear reactor:
CA: irradiation of stable/natural 89Y
(100% abundant) target (high flux)
NCA: decay of 90Sr (fission product of
235U in reactors) to 90Y following
separation from 90Sr (elution from
industrial generator)

131I

Nuclear reactor:
CA: extraction of 131I from 235U fission
product (by-product from 99Mo
production, similar processing)
CA: irradiation of (enriched) 130Te target

153Sm

Nuclear reactor:
CA: irradiation of enriched 152Sm targets

166Ho

Nuclear reactor:
CA: Irradiation of 165Ho (100%
abundant) target (common route)

By-product from 99Mo
production, the
workhorse for SPECT
diagnostics with 99mTc

NCA: elution of 166Dy/166Ho generator,
with 166Dy produced by irradiation of
enriched 164Dy with high flux
(experimental, not yet available)
169Er

Nuclear reactor:
CA: irradiation of (enriched) 168Er target
(fairly scarce)

177Lu

Nuclear reactor:
CA: irradiation of highly enriched 176Lu
targets (direct route, efficient, but
contains long-lived 177mLu impurity)
NCA: irradiation of 176Yb targets
(indirect route, requires elaborate
processing)

Theragnostic
Direct route through
176Lu has issue of
separating 177Lu from
176Lu: as this is difficult
carrier (176Lu) is still
present in the final
product, incl. 177mLu.
This results in lower
specific activity and
177mLu causes waste
issues at hospitals.41

41 The 177mLu impurity has a half-life of 160.1 days and will be excreted by patients. It results in an additional dose to patients and excretions

that need to be stored and processed as radioactive waste. Concerns are that this waste exceeds activity limits in European radiation

35

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Production

Half-life

Emission

Remarks
NCA will also be
produced in Canadian
CANDU nuclear power
plants for German ITM
supplier.

186Re

Nuclear reactor (commonly used):

90.64h

Multiple β- and γ
(imageable)

16.9h

Multiple β- and
multiple γ
(imageable)

7.2h

Multiple α (during
therapy)

Theragnostic

10.4h

Multiple β- and
single γ emission of
parent for 212Bi
(decaying in α, βand imageable γ)

Scalable production,
easier to transport due
to generator, receives
strong research
interest in NL and FR

45.6m

Single α, multiple βand single γ
(imageable)

Theragnostic

CA: Irradiation of metallic enriched
185Re target

Theragnostic

Accelerator/cyclotron:
NCA: proton or deuteron irradiation of
186W target (arising)
188Re

Nuclear reactor:
CA: irradiation of (highly) enriched 187Re
target
NCA: elution of 188W/188Re generator,
with 188W produced by irradiation of
enriched 186W in (very) high flux
reactors

211At

Accelerator/cyclotron:
Alpha particle irradiation of natural
209Bi (100% abundant) targets

212Pb

Generator:
Elution from 224Ra/212Pb generator

213Bi

Generator:
Elution from 225Ac/213Bi generator
(limited availability, high costs, see also
225Ac production)

Short half-life requires
very short time-to
patient
Requires 225Ac which
has limited
supply/availability

223Ra

Nuclear reactor:

11.43d

Multiple α, multiple
β- and multiple γ
(imageable)

10.0d

Multiple α and
multiple β-

NCA: Irradiation (high flux) of 226Ra
target, resulting in 227Ac which days into
223Ra (industrial generator)
Accelerator/cyclotron:
Proton irradiation of 232Th (naturally
abundant) target (not yet
industrialised)
225Ac

Nuclear reactor:
Extraction from natural decay of 229Th,
obtained from fissile 233U, originally

Limited supply and
difficult to make, only
from aged sources

safety regulations and that many regular hospitals cannot deal with this waste properly. See for instance: A. Dash, M.R.A. Pillai and F.F.
Knapp (2015). Production of 177Lu for Targeted Radionuclide Therapy: Available Options. Nucl. Med. Mol. Imaging, 49(2).

36

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Production

Half-life

Emission

Remarks

reactor produced by irradiation of
natural 232Th targets (limited, too small
amounts to serve market)

Currently provided at
no/low costs for
medical research

Extraction from natural decay of 229Th,
obtained from 233U legacy waste from
US weapon programme (limited,
inefficient, costly, long half-life)

Very radiotoxic due to
long half-life and
multiple α’s – main
challenge in use

Accelerator/cyclotron:
Proton irradiation of 226Ra target (few
producers)
227Th

Nuclear reactor:

17.72d

Irradiation of 226Ra target

Single α and multiple
γ (imageable)

Not much produced
yet, but experts say
production is scalable

Source: F.F. Knapp and A. Dash (2016). Radiopharmaceuticals for Therapy. New Delhi: Springer.

4.2.2

European production of radionuclides in an international supply chain

Therapeutic radionuclides are used across the globe. The production of therapeutic radionuclides is therefore
not limited to Europe but occurs in reactors and accelerators in many countries. Figure 12 provides an overview
of the number of research reactors across the globe producing specific therapeutic radionuclides. Although based
on several sources, this picture is likely not fully complete, but provides some relevant insights.
Figure 12 Therapeutic radionuclides produced by research reactors across the globe

Sources: IAEA RRDB (2016-2020), C.D. Ferguson, T. Kazi and J. Perera (2003), RIVM (2020) and interviewees. (*half-life less
than 72h)

First, it shows that Europe (in contrast to other continents) has multiple local suppliers for most therapeutic
radionuclides that are commonly used, including the short-lived therapeutic radionuclides (marked in the figure
with an asterisk). The latter group is not (well) suited for transport across continents. The fact that there are
multiple reactors producing these radionuclides in Europe would in principle allow for diversification of supply

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

and makes the supply chain more robust. However, figures on the amount of a radionuclide supply by each of
the reactors, and to whom they supply for what use, is not clear.
Second, for most long-lived therapeutic radionuclides foreign (non-European) suppliers exist. This would in
principle allow for international transport of therapeutic radionuclides to Europe. For some therapeutic
radionuclides, specifically 177Lu and 223Ra, we know such international transport exists. For the latter, no
European source was disclosed. Whether transport of other long-lived therapeutic radionuclides to Europe
would occur, depends on contracts with pharmaceutical companies, excess of supply for local use – on which we
do not have data – and economic factors such as price and demand.
Lastly, we note that the most produced therapeutic radionuclide worldwide is 131I, which is one of the most
established radionuclides in medicine. It is produced in research reactors in every continent and generally linked
to the production of the diagnostic 99Mo/99mTc pair – of which supply is actively monitored and coordinated (e.g.,
through the OECD NEA and the EU Observatory). Currently not so widely produced therapeutic radionuclides
are 89Sr, 169Er, 213Bi (experimental use), 223Ra and 212Pb (experimental use). For some we could only identify one
or two suppliers worldwide, which may in practice be more, but nonetheless signals a weaker supply chain in
terms of diversity of supply.
For the therapeutic radionuclides produced in accelerators no up-to-date information was available. These
radionuclides are novel and not routinely applied in clinical practice. Based on the IAEA’s 2006 Directory of
Cyclotrons used for Radionuclide Production in Member States42, some insights are available, although outdated.
Nevertheless, Figure 13 provides an overview of the number of cyclotrons listed by the IAEA as producer of 67Cu,
211
At, and 186Re.
Figure 13 Therapeutic radionuclides produced by cyclotrons across the globe

Source: IAEA (2006). Directory of Cyclotrons used for Radionuclide Production in Member States: 2006 Update. IAEA: Vienna.
Report number: IAEA-DCRP/2006.

For 211At, there are likely multiple sources available in Europe, while for 67Cu and 186Re no current sources are
available in Europe. Still, 211At is reported as being only limited available, which is considered as the most
important barrier to the clinical use of 211At. Several cyclotrons installed are capable of producing 211At, also in
Europe. Copenhagen University Hospital and Arronax in France have been reported as pursuing production of

42 IAEA (2006). Directory of Cyclotrons used for Radionuclide Production in Member States: 2006 Update. IAEA: Vienna. Report number:

IAEA-DCRP/2006. See: https://www-pub.iaea.org/MTCD/Publications/PDF/dcrp2006-cd/start.pdf

38

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

211

At at a regular basis in Europe, several sites in Japan and two in the USA are reported as having similar
ambitions.43
The availability of 67Cu is very limited, with only a few producers outside Europe, and has been reported as
limiting its potential use.44 There have been issues with steady supply, acquiring sufficient amounts for clinical
studies and high costs.45 No current source for 67Cu could be identified in Europe, although the Paul Scherrer
Institute (Swiss) previously produced 67Cu for research purposes. This activity has however halted over a decade
ago and cannot be scaled for commercial use, as the IP2 Irradiation station is only used for about 9
months/year.46
The therapeutic radionuclide 186Re is produced with cyclotrons in Asia. In Europe several reactors produce this
radionuclide, as well as in Asia and North America.

4.3

Specific European supply chains

The supply chain for each therapeutic radiopharmaceutical is completely different. On a conceptual level, as
discussed in section 4.1, the components of the supply chain are identical, but the organisations involved, the
resources, processes and equipment needed are different. Therefore, in fact, we have to consider multiple supply
chains: one for each therapeutic radionuclide.
Here we consider the radionuclide specific supply chains in Europe, zooming in on the most relevant and timesensitive phases of the supply chain: irradiation, processing and preparation of the radiopharmaceutical. We
identify the producers and processors of therapeutic radionuclides in Europe and the radiopharmaceutical
producers and suppliers.

4.3.1

Suppliers for radionuclides and radiopharmaceuticals

The supply chain for the therapeutic radionuclides included in this study is further detailed in Table 7. For each
radionuclide and associated radiopharmaceutical(s) we have indicated the main organisations in Europe that
produce (irradiate) and/or process the radionuclide and that produce/supply the radiopharmaceutical.
For the most used radiopharmaceuticals suppliers across Europe were identified, resulting in a list of almost 20
different suppliers of radiopharmaceuticals. For the more recent therapeutic radiopharmaceuticals only the
patent holder supplies the radiopharmaceutical. Examples are AAA/Novartis supplying [177Lu]Lu-DOTATATE,
Bayer supplying [223Ra]RaCl2 and Boston Scientific supplying 90Y-glass microspheres. For most other (generic)
therapeutic radiopharmaceuticals multiple suppliers exist in Europe. Especially for 131I pharmaceuticals there is
a diversity of suppliers available. Suppliers for novel or still experimental radiopharmaceuticals, such as 213Bi and
211
At, could not be identified. We expect that these radionuclides are generally prepared/labelled within the
hospital.
On the level of radionuclide producers and processors about 20 different suppliers of radionuclides were
identified across the continent. For each radionuclide multiple producers and processors exist in Europe. The

43 S. Lindegren et al. (2020). Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure. Cancer Biotherapy &

Radiopharmaceuticals, 35 (6). See: https://doi.org/10.1089/cbr.2019.3055
44

T. Ohya et al. (2018). Small-scale production of 67Cu for a preclinical study via the 64Ni(α,p)67Cu channel. Nucl. Med. Biol, 59. See:
https://pubmed.ncbi.nlm.nih.gov/29475187/

45 N.A. Smith, D.L. Bowers and D.A. Ehst (2012). The production, separation, and use of 67Cu for radioimmunotherapy: A review. Applied

Radiation and Isotopes, 70. See: http://dx.doi.org/10.1016/j.apradiso.2012.07.009
46 N.P. Van der Meulen et al. (2019). The use of PSI’s IP2 beam line towards exotic radionuclide development and its application towards

proof-of-principle preclinical and clinical studies. 22nd Int. Conf. on Cyclotrons and their Applications. See:
http://accelconf.web.cern.ch/cyclotrons2019/papers/tua03.pdf

39

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

only exception is 223Ra where no European supplier could be identified/disclosed. Bayer is the only supplier of
the 223Ra-based radiopharmaceutical and has secured supply for 10 years from the USA. The irradiators among
this list are all research reactors. Processors are often the same organisations as the radiopharmaceutical
producer/supplier or are affiliated with them or the irradiator.
Interviews reveal that radiopharmaceutical companies have vertically integrated supply chains in Europe to
secure the supply of radionuclides for their products as much as possible. They have long-term contracts with
suppliers ensuring delivery of radionuclides matching their demand projections. Where possible, radionuclides
are produced as close as possible to the customer, to reduce transport and thus loss of product (activity). Supply
is diversified to limit risks and backups are created in the supply chain, the specifics of which are not disclosed.
Table 7
Suppliers of radionuclides and radiopharmaceuticals in Europe
Radionuclide
Radiopharmaceutical
Radionuclide producer/
processor
32P

32P-sodium-phosphate

([32P]-Na3PO4)

Radiopharmaceutical
producer/ supplier

POLATOM (PL)

Curium Pharma

BRR (HU)

GE Healthcare

Comments

47Sc

47Sc

Institut Laue-Langevin
(FR)

Unknown: likely
hospital preparation as
still experimental

67Cu

67Cu

unknown

Unknown: likely
hospital preparation as
still experimental

Accelerator
produced

POLATOM (PL)

GE Healthcare

SCK-CEN (BE)

MGP

Commercial name:
Metastron®

89Sr

[89Sr]SrCl2

Has in the past
been produced by
the Paul Scherrer
Institute (Swiss)

POLATOM
90Y

90Y-colloids

POLATOM (PL) precursor

Curium Pharma/CIS
Bio

NRG (NL)

GE Healthcare

SCK-CEN (BE)
90Y-glass microspheres

BRR/IZOTOP (HU)

Boston Scientific

CIS Bio also
supplies 90Yprecursor under
the commercial
name Ytracis®
NRG irradiator for
Boston Scientifc
Commercial name:
TheraSphere®

[90Y]Y-ibritumomabtiuxetan

Bayer
Curium Pharma
Eckert & Ziegler
IBA

90Y-resin microspheres

Sirtex Medical
Curium Pharma

131I

[131I]I-mIBG

POLATOM (PL)

40

GE Healthcare

Commercial name:
Zevalin®
Eckert & Ziegler
also supplies 90Yprecursor under
the commercial
name Yttriga®
Commercial name:
SIR-Spheres®
(SIRT)

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Radiopharmaceutical

[131I]-NaI

Radionuclide producer/
processor

Radiopharmaceutical
producer/ supplier

SCK-CEN (BE)

Curium Pharma

IRE (BE)

POLATOM

BRR/IZOTOP (HU)

GE Healthcare

CVŘ Řež (CZ)

Curium Pharma

Comments

IZOTOP
POLATOM
Monrol Europe
153Sm

[153Sm]Sm-EDTMP

POLATOM (PL)
SCK-CEN (BE)
BBR/IZOTOP (HU)

Curium Pharma/CIS
Bio

Commercial name:
Quadramet®

GE Healthcare

CVŘ Řež (CZ)
166Ho

[166Ho]Ho-chitosan

NRG (NL)

Unknown

[166Ho]Ho-DOTMP

ITM/FRMII (DE)

Unknown

166Ho-microspheres

POLATOM (PL)

Quirem
Medical/Terumo
Europe

(HoMS)

BRR/IZOTOP (HU)
CVŘ Řež (CZ)

169Er

169Er-colloids

NRG (NL)

NRG irradiator for
Quirem Medical
Commercial name:
QuiremSpheres®

Curium Pharma

CVŘ Řež (CZ)
Institut Laue-Langevin
(FR)
177Lu

177Lu-antibodies

[177Lu]Lu-DOTATATE
177Lu-peptides

[177Lu]Lu-PSMA

POLATOM (PL) – CA,
precursor
NRG (NL)

ITM
Nordic Nanovector
AAA/Novartis

SCK-CEN (BE)
FRMII/ITM (DE) – NCA
BRR/IZOTOP (HU)

ITM
ITM in collaboration
with Edocyte/Novartis

Eckert & Ziegler (DE, GMP
in 2021)

Institut Laue-Langevin
(FR)
186Re-colloids

POLATOM (PL)
SCK-CEN (BE)

ITM and Monrol
Europe also
provide the
precursor 177Lu-Cl3
for hospitals
Commercial
names: Betalutin®
(antibodies),
EndolucinBeta®
and Luthatera®
(DOTATATE)

CVŘ Řež

186Re

NRG largest
producer of 177Lu
in Europe

Curium Pharma/CIS
BIO

CVŘ Řež (CZ)
NRG (NL)
188Re

188Re

[188Re]Re-HEDP

POLATOM (generator)
(PL)
SCK-CEN (generator) (BE)

41

Curium Pharma
Curium Pharma

Commercial name:
Rhenium-SCT®
Requires very high
flux, therefore few

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Radiopharmaceutical

Radionuclide producer/
processor

Radiopharmaceutical
producer/ supplier

CVŘ Řež (generator) (CZ)
211At

211At

NPI Řež cyclotron (CZ)
University Hospital
Copenhagen (DK)

irradiators
available
Unknown: likely
hospital preparation as
still experimental

CNRS/CERI (FR)
Forschungszentrum
Karlsruhe cyclotron (DE)

JRC IHCP Ispra cyclotron
(IT)

NRG (NL) – production

Production seems
limited, not only
produced for
medical
applications

Radionuclide
producer
information from
2006 (IAEA), no
recent information
available

HNIP cyclotron Krakow
(PL)

212Pb

Accelerator
produced

Only some have
limited routine
production

Medizinische Hochschule
Hannover cyclotron (DE)

212Pb

Comments

Orano Med/Roche

Orano Med (FR)

In development,
not clinical
practice
Easy transport as
can be sold as
generator

213Bi

213Bi

JRC Karlsruhe (DE)

Unknown: likely
hospital preparation as
still experimental and
very short half-life

Supply limited due
to limited 225Ac
supply, currently
not possible to
enlarge supply

223Ra

[223Ra]RaCl2

IFE (NO)

Bayer (NO)

IFE in Kjeller
prepares product
for Bayer

Supply from abroad, only
disclosed source:
Oakridge National
Laboratory, part of US
DOE

Bayer has 10-year
supply contract of
227Ac for
production with
US DOE
Commercial name:
Xofigo®

225Ac

[225Ac]Ac-Lintuzumab

JRC Karlsruhe (DE)
Eckert&Ziegler (DE)

[225Ac]Ac-PSMA

Rest of suppliers abroad
in US and Russia

Unknown: likely
hospital preparation as
still experimental

Not used in EU

Unknown: likely
hospital preparation as
still experimental

Only supply for
several hundred
patients
Limited supply
worldwide, strong
interest from
producers, several
studies for
alternative

42

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Radiopharmaceutical

Radionuclide producer/
processor

Radiopharmaceutical
producer/ supplier

Comments
production routes,
supply less than
demand, expected
to grow, currently
only
compassionate use
in EU

227Th

227Th-antibody

Irradiator unknown

227Th-conjugate

Eckert&Ziegler (DE)

Bayer (NO)

227Th is obtained

from the same
source as 223Ra

[227Th]Th-PSMA
Based on multiples sources: websites and documents of producers, information received for country factsheets, IAEA
databases for research reactors and cyclotrons, reports and this study’s survey

4.3.2

Characteristics of the supply chain before irradiation and during transport

The supply chain before irradiation is less time-critical, as the activity of the desired product is not yet decaying
in this phase. In many cases the used raw material is a stable isotope, so that time is no longer a limiting factor.
Therefore, usually the supply chain is analysed from irradiation and beyond. The supply chain before irradiation
is very international.
As part of their vertically integrated supply chain, pharmaceutical companies manage the supply chain actively.
Irradiators are in many cases service providers, who get their targets for radionuclide production delivered from
the radiopharmaceutical company. Strategic reserves of the enriched target material are created to ensure
production continuity, but also to set competition aside. As an example of the latter, 99% enriched 176Yb has
been bought from the market for several years by one of the pharmaceutical companies delivering 177Lu
radiopharmaceuticals to strengthen its competitive position.
Enrichment and fabrication of the target material and the nuclear fuel is in part done in Europe. Orano enriches
uranium (reactor fuel and target material for 131I) in France and Urenco in the Netherlands and UK. Urenco also
enriches several stable isotopes for medical applications. The latter is done in the Netherlands by the Urenco
Stable Isotopes subsidiary, producing for instance 186W (for 188Re production) and 47Ti (for 47Sc production).47
However, about 40% of the world’s production of stable isotopes is from Russia, using old calutrons. 48 Russia is
the go-to supplier for “difficult-to-source” stable isotopes and the only producer of enriched 176Yb (by the
Electrokhimprebor and Kurchatov Institute, sold by JSC Isotope from ROSATOM). These calutrons are built during
and shortly after the Second World War and need to be replaced within one or two decades. 49 Information on
initiatives for replacements of such equipment, e.g. ROSATOM’s and US Oak Ridge Laboratory’s plans to use gas
centrifuge to produce such stable isotopes, is scarce and not up to date.50
In addition to enrichment for stable isotopes, Europe also relies on the US and Russia for high-assay low-enriched
uranium (HALEU) that is used as fuel in research reactors. HALEU is obtained from Russia or from down-blending

47 Urenco (2019). Urenco Stable Isotopes Brochure. See: https://www.urenco.com/cdn/uploads/supporting-

files/Urenco_Stable_Isotopes_brochure_2019.pdf
48 NSAC Isotopes Subcommittee (2015). Meeting Isotope Needs and Capturing Opportunities for the Future: The 2015 Long Range Plan for

the DOE-NP Isotope Program. See: https://www.asc.ohio-state.edu/physics/ntg/6805/readings/2015_NSACI_Report_to_NSAC_Final.pdf
49 L.P. Roobol and I.R. de Waard (2019). Marktontwikkeling en leveringszekerheid voor medische radionucliden. RIVM. See:

https://www.rivm.nl/bibliotheek/rapporten/2019-0101.pdf
50 NIDC (2019). ORNL’s Enriching Isotopes Again. See: https://www.isotopes.gov/node/335

43

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

US’ highly-enriched uranium stocks. A recent ESA-report51 highlights the risk that foreign supply of HALEU cannot
be guaranteed beyond 2030-2040, impacting medical radionuclide production.
The French Orano is involved in the fuel mining and conversion. Mining activities are not done within Europe,
but in North America, Middle East and Africa.52 For most raw materials used for fuel and targets Europe relies on
mining in other continents. The conversion of Uranium is done by Orano in France. 53
The produced radionuclides in Europe are transported by specialised companies. Transport needs to be efficient
and is bound by regulations. Europe has at least 16 specialised transporters across Europe to timely distribute
radionuclides to hospitals in Europe and beyond.54 Transport requires just in time delivery and therefore uses
both road transport as well as air transport. Special regulations and administration exists to regulate safe and
timely transport and to prioritise medical radionuclides in air transport (using mainly cargo flights but also
passenger fights).55,56

4.4

Production capacity for therapeutic radionuclides in Europe

4.4.1

Installed production and processing capacity

Although most therapeutic radionuclides are produced in nuclear reactors, only a limited number of nuclear
reactors produce therapeutic radionuclides. Unlike nuclear power plants for energy, there are currently no
single-purpose nuclear reactors to produce radionuclides. Commercial production of radionuclides occurs in
research reactors, which are also used for several other research or industrial applications.57 The capacity to
produce therapeutic radionuclides in these research reactors thus competes with capacity for other
(irradiation/research) activities, including the production of diagnostic radionuclides (larger market). However,
depending on the production route and irradiation cycle, different instruments within the reactor are needed –
this determines in practice the current production capacity. Increasing production capacity for a specific
radionuclide thus not only requires changing production schedules, but also instruments (i.e. reactor set-up) –
the latter can be a major process taking several years.58
The radioactive decay of therapeutic radionuclides results in a short shelf-life of the radionuclide and the
radiopharmaceutical. The time to patient should therefore be optimised. Distance and transport are crucial
factors in optimising the time to patient. Therefore, only radionuclides with a half-life of several days, or that can
be eluted from generators, are suitable for transport across continents. Production in Europe for European
patients is thus clearly beneficial.

51 Euratom Supply Agency (2019). Securing the European Supply of 19.75% enriched Uranium Fuel. A revised Assessment. May 2019. See:

https://ec.europa.eu/euratom/docs/ESA_HALEU_report_2019.pdf
52 Orano Website (2020). See: https://www.orano.group/en/nuclear-expertise/orano's-sites-around-the-world/uranium-mines
53 Orano Website (2020). See: https://www.orano.group/en/nuclear-expertise/orano's-sites-around-the-world/uranium-transformation
54 European Isotopes Transport Association (2020). See: http://www.eita.org/members
55

J.S. Hughes and S.J. Watson (2004). A survey of the transport of radioactive materials by air to, from and within the UK. PATRAM 2004,
Berlin. See: https://inis.iaea.org/collection/NCLCollectionStore/_Public/37/088/37088554.pdf?r=1&r=1

56 EITA (2016). The transport of radiopharmaceuticals – a race against the clock. See:

https://www.youtube.com/watch?v=qUoSA0WSJZw&t
57 A recent and notable exception (October 2020) are the CANDU reactors of Bruce Power in Canada that will have an Isotope Production

System installed during ongoing life-extension works of the reactors. After installation, these reactors will produce 177Lu NCA for ITM
(worldwide distribution) starting 2022. According to experts interviewed, only this type of CANDU reactors would be suitable for
radionuclide production. See: https://www.brucepower.com/2020/10/29/agreement-signed-to-advance-lutetium-177-isotopeproduction-to-meet-global-demand-for-critical-cancer-fighting-therapies/
58 As indicated by interviewees and as the case of Bruce Power in footnote 57 shows (addition of instruments during life-extension works,

planned already several years before).

44

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

In Europe seven research reactors currently produce most therapeutic radionuclides 59. These are:
•

The MARIA (1974) reactor in Poland, operated by POLATOM

•

The HFR (1961) in the Netherlands, owned by the EC/JRC and operated by NRG

•

The BR2 (1961) in Belgium, operated by SCK-CEN

•

The FRMII (2004) in Germany, operated by the Technical University of Munich

•

The ILL (1971) reactor in France, operated by Institute Laue-Langevin

•

The LVR-15 (1957) in the Czech Republic, operated by CVŘ Řež

•

The BRR (1959) in Hungary, operated by BNC/AEKI

In addition, the JRC in Karlsruhe (Germany) supplies some alpha emitters for (pre-)clinical trials and research use.
Figure 14 provides an overview of the therapeutic radionuclides 60 that are produced by these research reactors
in Europe. The figure contains information collected from several sources but may not be fully complete. Also,
some reactors may not routinely produce a therapeutic radionuclide, as is for instance the case with the
production of 177Lu in the LVR-15. Also, these reactors are only a limited number of days (between 100-270) each
year available for irradiation services.61
The figure shows that many of the therapeutic radionuclides considered in this study are produced in Europe,
especially those that are commonly applied in clinical practice. The only exception is 223Ra for which no European
source was found in available data. For the more novel therapeutic radionuclide 227Th also no European supplier
could be identified, while for the novel/experimental therapeutic radionuclides 47Sc, 212Pb, 213Bi and 225Ac only
one supplier could be identified among these reactors. For the other therapeutic radionuclides multiple suppliers
seem to exist in Europe, although it is unclear what their production capacity is for each radionuclide.
Figure 14 Radionuclides produced by current research reactors in Europe

IAEA RRDB (2016/2020), C.D. Ferguson, T. Kazi and J. Perera (2003), RIVM (2020) and interviewees.

Most of the research reactors that produce therapeutic radionuclides in Europe are over 50 years old. The only
exception is the FRMII reactor, which only produces a limited amount of therapeutic radionuclides ( 177Lu and
166
Ho). The other reactors – including the largest radioisotope producers MARIA, BR2 and HFR – reach their end
of lifetime within the next 10-20 years. The expected end of operation for the BRR is 2023, for the HFR 2026, for
the LVR-15 2028, for MARIA 2040 and the BR2 will at least be operational until 2026 but is investigating the

59 IAEA (2020). Research Reactor Database. See: https://nucleus.iaea.org/RRDB/RR/ReactorSearch.aspx
60 The radionuclides 67Cu and 211At, which are not produced with reactors, are not included in the figure.
61 For example, the HFR has 270 days or operation, FRMII 240 days, MARIA 200 days, BR2 147 and ILL 100 days. Source: L.P. Roobol,

C.E.N.M. Rosenbaum and I.R. de Waard (2020). Leveringszekerheid voor medische radionucliden – aanvullingen 2020. RIVM. See:
https://www.rivm.nl/bibliotheek/rapporten/2020-0153.pdf

45

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

possibility to operate until 2036.62 This means that most of the radionuclide producers in Europe will stop
operations, even within the next 10 years (cf. Figure 15), if the lifetime of these facilities will not be extended
or when these facilities will not be replaced.
Figure 15

Timelines of current and planned infrastructures for radionuclide production in the EU

Based on websites of infrastructures, information from representatives and OECD NEA (2019)

4.4.2

Planned production and processing capacity

As most European research reactors producing therapeutic radionuclides are ageing, new production facilities
are being planned. Most of these facilities are intended to take over the activities of current research reactors.
Apart from new facilities, replacing the current fleet, existing facilities can to some extent increase the supply of
some therapeutic radionuclides.
Currently, three new research reactors are being planned in Europe (cf. Figure 15). These are the MYRRHA
reactor (scheduled to be operational in 2036) 63 to replace the BR2 in Belgium and the Pallas reactor (scheduled
to be operational in 2025)64 to replace the HFR in the Netherlands. Both plan to produce therapeutic
radionuclides – for Pallas this is even a major part of its business case – but construction has not yet started. The
only research reactor that is currently being built in Europe, and that plans to produce medical radionuclides, is
the Jules Horowitz Reactor (JHR/RJH) in France. However, the JHR is planning to produce 131I only – there are no
concrete plans to produce other therapeutic radionuclides (although this is possible and not explicitly
excluded).65 The focus of the JHR will be on research.
In addition, some novel concepts are planned – and currently being piloted – to produce therapeutic
radionuclides. One of these is ASML’s and IRE’s SMART/LightHouse project in Belgium, where a high-power
superconducting linear electron accelerator is used to produce radionuclides. Another is SHINE, a US initiative
that is planning to build a plant in Europe, where an accelerator-based neutron source is used to produce

62 Several sources, including OECD NEA (2019). The supply of Medical Radioisotopes. 2019 Medical Isotope Demand and Capacity Projection

for the 2019-2024 Period. See: https://www.oecd-nea.org/jcms/pl_19912/2019-medical-isotope-demand-and-capacity-projection-forthe-2019-2024-period
63 Website MYRRHA (2020): https://www.myrrha.be/myrrha-project/myrrha-phased-implementation/
64 Website Pallas (2020): https://www.pallasreactor.com/en/en-pallas-van-levensbelang-voor-miljoenen/
65 L.P. Roobol and I.R. de Waard (2019). Marktontwikkeling en leveringszekerheid voor medische radionucliden. RIVM. DOI: 10.21945/RIVM-

2019-0101.

46

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

radionuclides. Both are focussed on the production of the diagnostic radionuclide 99Mo but explore or plan the
production of therapeutic radionuclides.
Foreseen new production capacity or extension of current production capacity (cf. Figure 15):
•

Pallas reactor in the Netherlands (Petten): a research reactor that is planned to replace the current HFR,
with a strong focus on the production of diagnostic and therapeutic radionuclides. The key radionuclide that
will be produced is the diagnostic 99Mo/99mTc. Other radionuclides planned, include the therapeutic 177Lu,
131 166
I, Ho, 153Sm and 89Sr. Pallas is still evaluating the potential production of 188Re and 186Re.66 Pallas is still
in a preparatory phase and should be the first privately financed research reactor. Recently the Dutch
government has indicated that this ambition is not realistic, and that public financing may be needed or even
extension of the lifetime of the HFR. 67 There has been no final decision on the build of Pallas, but officially
Pallas is scheduled for operations in 2025.

•

Myrrha reactor in Belgium (Mol): is an innovative research reactor that consists of a subcritical nuclear
reactor driven by a high-power linear accelerator as external neutron source. It thus consists of a nuclear
reactor and a linear accelerator. Myrrha will be used to produce 99Mo, taking over the role of the BR2. In
addition, the reactor and accelerator will be used to produce other radionuclides as well, including
therapeutic radionuclides – although which ones are not specified.68 Myrrha is planned to start operations
in 2036.

•

Jules Horowitz Reactor in France (Cadarache): The JHR is currently being built by an international
consortium mainly for research purposes, but also plans to produce Uranium-based medical radionuclides.69
This will be primarily the diagnostic pair 99Mo/99mTc, but also the therapeutic radionuclide 131I will be
produced. There are no concrete plans to produce other radionuclides, although this option is reported to
be not excluded.70 JHR is planned to start operations between 2026 and 2028.

•

SMART/LightHouse in Belgium (Fleurus): Based on technology that spun-off from ASML, a novel
accelerator-based facility to produce radionuclides is developed in Belgium. A high-power superconductive
linear electron accelerator is used to produce primarily 99Mo. Lighthouse is however investigating the
possibility to produce therapeutic radioisotopes; it is unclear which exactly. 71 Commercial production of
99
Mo should start in 2025.72

•

SHINE in US/Europe: Shine is currently testing and preparing a novel accelerator-based concept to produce
medical radionuclides in the US and plans to build a plant in Europe (Groningen, The Netherlands is named
as a potential location). The focus is on the production of 99Mo through a low-energy accelerator-based
neutron source using a liquid lowly enriched uranium target. SHINE is also producing 177Lu NCA, where they
claim to control the whole supply chain, including own enrichment of 176Yb and processing of the targets. 73
SHINE does this in cooperation with GE Healthcare and the Czech Institute of Organic Chemistry and
Biochemistry. Supply started in 2020. Additionally, SHINE plans to produce 131I and 90Y using the 99Mo facility

66 PWC (2018). PALLAS/LightHouse Review. Extract of final report.
67

Dutch Ministry of Health, Welfare and Sport (2020). Kamerbrief over stand van zaken Pallas-reactor. 9 December 2020. See:
https://www.rijksoverheid.nl/binaries/rijksoverheid/documenten/kamerstukken/2020/12/09/kamerbrief-over-stand-van-zaken-pallasreactor/kamerbrief-over-stand-van-zaken-pallas-reactor.pdf

68 Website MYRRHA (2020): https://www.myrrha.be/science-and-myrrha/nuclear-medicine/
69 JHR/CEA website (2020): http://www-rjh.cea.fr/radio-isotopes.html
70

L.P. Roobol and I.R. de Waard (2019). Marktontwikkeling en leveringszekerheid voor medische radionucliden. RIVM. DOI: 10.21945/RIVM2019-0101.

71 PWC (2018). PALLAS/LightHouse Review. Extract of final report.
72 IRE (2019). The SMART project: accelerator based production of Mo-99. Presentation. See:

https://ec.europa.eu/energy/sites/ener/files/documents/s1-3_ekollegger_ire.pdf
73 SHINE website (2020): https://shinemed.com/177Lu/

47

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

and intends to install additional irradiation ports for neutron activation, planning to produce 177Lu and
166
Ho.74 SHINE also claims to investigate 225Ac production. The commercial operation of the shine plant in
the US is planned for 2022, while construction of the European plant is planned for 2023 with operations
starting 2025.75
•

Institut Laue-Langevin in France (Grenoble): At the ILL reactor a new irradiation system is developed that
should be operational in 2024.76 This would enlarge the capacity to produce therapeutic radionuclides at the
ILL reactor.

•

Bruce Power CANDU reactors in Canada: the German ITM is currently working with Bruce Power to produce
177
Lu in their CANDU nuclear power plants. These reactors will be upgraded and receive an Isotope
Production System to produce 177Lu NCA that will be supplied to ITM for global distribution. With this
upgrade the production of 177Lu should start in 2022.77

In addition, the European Spallation Source (ESS) in Sweden (Lund) has started a project to explore the potential
of the ESS to produce medical radionuclides. 78 The ESS is an accelerator producing high-flux neutrons through
spallation. This could potentially be used to produce medical radionuclides, although the current focus of the ESS
is very much on research. In the project the diagnostic radionuclide 99Mo/99mTc and the therapeutic radionuclides
131 177
I, Lu, 225Ac are considered.79 It is unclear whether or when the ESS will indeed produce therapeutic
radionuclides and whether prices will be competitive. As indicated before, decision criteria for production are
not available; the priority use of facilities for research or medical purposes is a political decision.
There are no official plans to replace the MARIA reactor in Poland or the LVR-15 in the Czech Republic. It is unclear
whether their lifetime will be extended with upgrades. Both produce a variety of radionuclides. If the listed
foreseen production capacities will not be realised or take over the supply from these reactors, supply in Europe
will likely be reduced. In that situation, there will also be fewer suppliers, reducing the redundancy in supply and
thus weakening the supply chain.

4.4.3

Potential to increase production and processing capacity

Building new facilities for radionuclide production and processing is expensive and has so far not successfully
been taken up by the market. Pharmaceutical companies interviewed rely on existing research reactor
infrastructure to produce therapeutic radionuclides. Although some new production capacity is planned, there
are also options to extend the current production capacity – which may also take time but is less expensive than
building new facilities. With the ageing of current research reactors, this seems to be only a solution on the short
or medium term (next decade).
Interviews with suppliers of therapeutic radionuclides reveal that there is some potential to increase current
production capacity. Some reactor cores do have space for additional instruments for the irradiation or
therapeutic radionuclides. This would however require changing and optimising the reactor setup, which will
take easily five years and is a costly project – which would require timely decision making and investments.

74 L.P. Roobol, C.E.N.M. Rosenbaum and I.R. de Waard (2020). Leveringszekerheid voor medische radionucliden – aanvullingen 2020. RIVM.

See: https://www.rivm.nl/bibliotheek/rapporten/2020-0153.pdf
75 Ibid.
76 L.P. Roobol, C.E.N.M. Rosenbaum and I.R. de Waard (2020). Leveringszekerheid voor medische radionucliden – aanvullingen 2020. RIVM.

See: https://www.rivm.nl/bibliotheek/rapporten/2020-0153.pdf
77 Bruce Power website (2020): https://www.brucepower.com/2020/10/29/agreement-signed-to-advance-lutetium-177-isotope-

production-to-meet-global-demand-for-critical-cancer-fighting-therapies/
78 The ESS is since 2015 officially a European Research Infrastructure Consortium (ERIC) and a landmark research infrastructure in the ESFRI

Roadmap 2018. In this European roadmap for research infrastructures also the JHR and the Myrrha are listed as projects.
79 Y.J. Lee and M. Jensen (2019). Isotope Production at European Spallation Source. A potential new access to neutrons. 30 April 2019. See:

https://indico.cern.ch/event/782482/contributions/3413625/attachments/1836380/3009684/INFRAIA_kickoff_ESS.pdf

48

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Therefore, this would only be an option for younger research reactors, such as the FRMII. At the FRMII production
capacity for 177Lu production could technically be increased with factor 4 and for 166Ho with factor 5 using current
instruments. Personnel is a limiting factor in this. At the LVR-15 irradiation capacity could be further expanded
as well, but this would limit the use of the reactor for scientific purposes. 80 At the HFR there is also some capacity
left to increase the production of 177Lu. However, the expected demand growth for 177Lu is higher than the
potential increase of available production capacity in these installations.
The production of certain radionuclides could be prioritised within the available reactor capacity and
instruments. This would mean that, in order to avoid supply shortages of important medical radionuclides, other
radionuclides would be produced less or less reactor capacity will be available for scientific research. From a
commercial perspective, an irradiator would prioritise radionuclides that are more profitable. From a scientific
perspective, a research reactor would prioritise the research activities for which it was build and funded.
Therefore, such prioritisation requires openness, coordination and collaboration, and a framework to make such
prioritisation decisions.
Additional increase of supply can be realised by further increasing the efficiency of the post-irradiation supply
chain.81 Especially shortening transport times would be beneficial. Due to radioactive decay the activity of the
product decreases over time, meaning that less product remains for clinical use if the time between production
and administration to patients is longer. The effective supply can thus be increased if the supply chain is
optimised and the distance between producer and user is shortened. This is one of the benefits of having a
European supply. It is however unclear how much further efficiency increase is still possible within the current
supply chain; more openness and coordination could contribute to insight in further efficiency potential.
Overall, the expectation is that meeting the projected demand for specifically 177Lu will be difficult in the longer
term with current (ageing) installations. In the next decade it is expected to be possible to double the current
production capacity for 177Lu, especially through optimising processes and prioritising 177Lu production. This
would only be sufficient to sustain a 3% demand growth 82, while the projected demand for 177Lu is in fact higher
(see section 5.2)

4.5

Stability of supply in Europe

4.5.1

Supply disruptions to European hospitals

As therapeutic radionuclides cannot be stocked due to their short shelf lives (because of radioactive decay), a
continuous and undisrupted supply is essential for patient treatments. Across the supply chain disruptions may
occur that affect the supply to patients, but especially the steps from irradiation to pharmaceutical preparation,
with transport in between, are time sensitive and disruptions there affect the supply. The Moly-crises, during
which several reactors were (temporarily) shut-down, has shown the vulnerability of the medical radionuclide
supply chain.
Overall, the supply of therapeutic radionuclides has been reasonably stable in the past five years, although
unplanned disruptions of supply do occur. Such disruptions are fairly limited, based on Technopolis’ survey
among relevant clinical experts. Most respondents indicated no disruption of supply in five years’ time for most
therapeutic radionuclides considered in this study. Exceptions are 131I, 166Ho, 169Er and 186Re, for which a majority

80 L.P. Roobol, C.E.N.M. Rosenbaum and I.R. de Waard (2020). Leveringszekerheid voor medische radionucliden – aanvullingen 2020. RIVM.

See: https://www.rivm.nl/bibliotheek/rapporten/2020-0153.pdf
81 Ibid.
82 Ibid.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

of respondents indicate at least some disruptions in the last five years. Interestingly, 131I is one of these
radionuclides, being one of the most widely used therapeutic radionuclides.
The commonly used therapeutic radionuclides 131I and 90Y have been most reported by surveyed experts as being
often short in supply – meaning that there have been supply shortages more than four times in five years. These
shortages were reported from across Europe, but as these are widely used, the absolute numbers give a distorted
view. Relative numbers (percentages) show that 169Er – relative to the amount of users of this radionuclide among
the survey respondents – is most mentioned as being often short in supply, followed by 131I, 186Re and 90Y. Still,
for any of the radionuclides included in this study less than 12% of the respondents indicate that often (>4 times
in 5 years) supply issues occur, while less than 30% of the respondents indicate that they are sometimes (3-4
times in 5 years) faced with supply issues.
Figure 16 Supply chain shortages or long-term production disruptions in the last five years

Source: survey among experts across Europe (numbers in bars are # of respondents)

4.5.2

Impact of disruption on patient treatments

Supply shortages always have impacts on the treatment of patients, resulting in delayed treatments. As the
treatment is with a radiopharmaceutical, we have explored the impact of shortages of specific radionuclides per
radiopharmaceutical. However, we asked experts participating in the survey to indicate the severity of supply
disruptions for the treatment of patients. The result is displayed in Figure 17.
The impact of supply shortages on treatments strongly differs per radiopharmaceutical. For 166Ho-microspheres
respondents indicate that supply shortages impact the treatment of patients to a great extent. In contrast, for
[89Sr]SrCl2 , 177Lu-petides, 169Er-colloids, [153Sm]Sm-EDTMP and 186Re-colloids most respondents believe
disruptions have only impact on treatments to a small extent or not at all. The difference in impact of supply
shortages on treatment per radiopharmaceutical is also clear for 131I, where respondents indicate that a shortage
of [131I]I-mIBG has a stronger impact on treatments than a shortage in [131I]-NaI.

50

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

A few radionuclides have the unfavourable combination of being reported by experts as being often or
sometimes short in supply and having a great or some impact on the treatment of patients. Among these are the
widely used 131I and 90Y radionuclides, for which ~30% of respondents indicate >3 shortages in 5 years’ time and
~50% of respondents indicate a great or some impact on the treatment of patients. The less applied 166Ho is also
important to note, for this radionuclide about 24% of respondents indicate >3 shortages in 5 years’ time and all
respondents indicate a great impact on the treatment of patients.
We emphasise that this is a first estimate of the severity of impacts on treatment; further details on treatment
specifics would have to be investigated to provide more detailed findings.
Figure 17 Impact of supply disruptions on the treatment of patients

Source: survey among experts across Europe (numbers in bars are # of respondents). NB: the boxes indicate whether a
radionuclide has been indicated as often or sometimes short in supply in Figure 16

4.5.3

Causes of supply disruptions

Most of the reported supply chain disruptions (79%) occur during external production. These are the phases of
irradiation, processing and preparation of the radiopharmaceutical by pharmaceutical companies. Another 14%
of all disruptions occur during transport after irradiation and 7% of all disruptions occur during procurement in
the hospital.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Figure 18 Position in supply chain where supply issues originate

Source: survey among experts across Europe (numbers are # of respondents)

The causes of supply disruptions are often related to quality control issues, maintenance/outage of reactors
or delayed shipping, although causes are not always reported to hospitals. Table 8 specifies the causes of
experienced supply issues per radionuclide based on responses to the survey.
Table 8
Reported supply causes of supply issues per radionuclide
Radionuclide
Causes of experienced supply issues
•

Product failed quality control

•

Reactor maintenance or outage

•

Shipping delayed (esp. air travel)

153Sm

•

Reactor maintenance or outage

166Ho

•

Reactor maintenance or outage

•

Product failed quality control

•

Reactor maintenance or outage

•

Product failed quality control

•

Problems with labelling (PSMA/DOTATATE)

•

Reactor maintenance or outage

•

Shipping delayed (esp. air travel – flight
activity limit reached)

•

Miscommunication with supplier

•

131I

169Er

177Lu

186Re

223Ra

Solutions suggested for supply issues
•

Improve quality control throughout value
chain

•

Better anticipation of demand/orders

•

Increase the number of suppliers/sources for
the radionuclide

•

As demand is low, supply is less (frequent),
which makes supply chain weaker. Higher
demand could solve these issues, but
depends on needs.

•

Expand the network of suppliers/sources for
the radionuclide

•

Optimising transport/flight bookings by
better monitoring flight activity limits

Changes in production schedule

•

Better coordination within supply chain

•

Product failed quality control

•

Increase number of suppliers/sources for the
radionuclide

•

Long delivery times

•

•

Reactor maintenance or outage (for parent
radionuclide)

Increase number of suppliers/sources for the
radionuclide (capacity has increased after
long delivery times)

•

Shipping delayed (esp. air travel)

32P

•

Product no longer offered

89Sr

•

Product no longer offered

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Causes of experienced supply issues

90Y

•

Product failed quality control

•

Vector
for
labelling
(ibritumomab-tiuxetan)

Solutions suggested for supply issues

unavailable

Source: survey among experts across Europe

Especially during the COVID pandemic, transport has been an important cause of disruptions and turned out to
be the weakest link in the current supply chain. Cross-border transport, especially using (commercial) flights, had
been severely disrupted. Countries that rely on flight transport for radionuclides often mentioned flight issues in
the past five years: Cyprus, UK, Portugal and Italy reported flight issues. Flights did not arrive, were delayed
(resulting in less activity delivered or delay of procedure) or flights reached their activity limit. To better
coordinate this during the COVID pandemic, a corona response team was set-up during the pandemic. 83 The
pandemic has shown that road transport is less vulnerable to disruptions than flight transports. Countries that
rely on cross-continental flights experienced more (complex) supply disruptions than countries that could be
supplied by road transport. As Europe has irradiation facilities, processing facilities and pharmaceutical
companies located within its continent, road transport is for many countries feasible and disruptions have been
relatively mild.84 This shows that having such irradiation and post-irradiation facilities within Europe adds to the
robustness of the European supply chain.

4.6

Critical issues and foreign dependencies in the supply chain

The supply chain for therapeutic radionuclides is international by nature and has some critical issues. NonEuropean, foreign, supply is part of this supply chain, especially before irradiation. Generally, this is not a critical
issue, but some weak links/dependencies are identified. Below we describe the critical issues and foreign
dependencies in general, but we first provide an overview of identified critical issues and foreign dependencies
per radionuclides. This is given in Table 9.
Supply chains are specific to each therapeutic radionuclide. For the currently most used therapeutic
radionuclides no significant critical issues exist, but there are some foreign dependencies. For 223Ra supply seems
to rely for a significant part on the US and the NCA production of 177Lu relies on enrichment in Russia. In the longterm, the expected demand for 177Lu seems difficult to be met. For several novel or experimental radionuclides,
that are not much used in clinical practice, dependencies and supply issues exist. Once demand for these
radionuclides increases, some of these dependencies are likely to be solved, but these take time and may delay
clinical uptake. For 225Ac and 213Bi, supply issues are more fundamental, as new industrial production processes
need to be developed – for 213Bi also close to the patient.
Table 9
Overview of identified critical issues and foreign dependencies per radionuclide
Radionuclide
Critical issues and foreign dependencies
32P

-

47Sc

Experimental, limited sources available. Only one irradiator in Europe identified.

67Cu

Currently limited supply for medical use, experimental only, but small quantities. No European source
was identified. Short lifetime for foreign supply.

83 World Nuclear news (2020). Air transport improves for medical radioisotopes. 28 April 2020. See: https://world-nuclear-

news.org/Articles/Air-transport-bottleneck-easing-for-medical-radioi
84 L.P. Roobol, C.E.N.M. Rosenbaum and I.R. de Waard (2020). Leveringszekerheid voor medische radionucliden – aanvullingen 2020. RIVM.

See: https://www.rivm.nl/bibliotheek/rapporten/2020-0153.pdf

53

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

89Sr

Phased out: limited use and reduced supply. Reported to be not available anymore.

90Y

- (short lifetime for foreign supply)

131I

-

153Sm

- (short lifetime for foreign supply)

166Ho

- (short lifetime for foreign supply)

169Er

-

177Lu

Sufficient supply in Europe for short term, although very limited supply of NCA. Shortage on longterm expected. Several initiatives to improve supply, mainly in North America (SHINE & Bruce
Power). When ageing European reactors decommission, stronger foreign dependency is likely. Relies
on ageing Russian calutrons for enrichment of non-carrier added 177Lu. Current business continuity
plans from pharmaceutical companies rely on US.

186Re

-

188Re

Requires very high flux reactors for production, not many available and most of these are ageing in
Europe.

211At

Very limited supply for medical use, experimental only, but small quantities. There are cyclotrons in
Europe that could technically produce 211At in the future. Short lifetime for foreign supply.

212Pb

Experimental, currently limited supply for medical use. Short lifetime for foreign supply.

213Bi

Relies on availability of 225Ac, which has limited supply, currently reliant on US DOE.

223Ra

No European supply disclosed (if available). Likely strong dependency on US. Only one
pharmaceutical company has a radiopharmaceutical using 223Ra on the market, which has supply
secured for projected demand in next 10 years. This holds risk of monopolised supply of 223Ra.

225Ac

Very hard to obtain. Limited supply, currently largely reliant on US DOE. Other production routes
need to be developed. When clinical trials successful, additional (European) sources are needed for
clinical application.

227Th

Experimental, not much produced yet. No European irradiation source identified but has potential to
be scaled.

Source: synthesis of information in this report.

4.6.1

Before irradiation phase

Before the irradiation phase there are some inherent foreign dependencies. First of all, the raw material for
reactor fuel (mostly Uranium) and most targets are mined outside Europe. The French Orano is involved in
mining activities for reactor fuel. Sources are in multiple countries; there is no dependency on a single nonEuropean country. Most Uranium is mined in Kazakhstan, Canada and Australia, although there is a relatively
small amount mined in Ukraine. Some raw material for targets are mined in Europe, such as Sulphur (for 32P
production), Strontium (for 89Sr production) and Tungsten (for 186Re and 188Re production).85 Some raw material
for targets is however very scarce limiting its availability, such as Rhenium. Similarly, for some isotopes, such as
176
Lu, the natural abundance is low.
Europe has limited facilities for enrichment. Most of these facilities are used for the enrichment of uranium as
reactor fuel (power plants). These include the enrichment facilities of Urenco (NL, DE, UK) and Orano (FR).
However, for the fuel of research reactors (high-assay low-enriched uranium – HALEU) Europe relies on the US

85 Minerals Education Coalition website (202): https://mineralseducationcoalition.org/mining-minerals-information/periodic-table-of-the-

elements/

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

and Russia. This is a clear foreign dependency, for which ESA suggested several actions and explored potential
business cases for European supply with Orano and Urenco.86
Urenco has also facilities for the enrichment of stable isotopes that can be used in targets. For the enrichment
of lanthanides, including lutetium and ytterbium, foreign enrichment facilities are needed. Especially Russian
calutrons are used, which are old and need replacement in the next decades. This is a critical element in the
supply chain and a clear foreign dependency. As demand for enriched isotopes for therapeutic radionuclides
will remain, it is likely that such facilities will be replaced or that innovative alternatives will appear.

4.6.2

In irradiation phase

Irradiation capacity in Europe seems currently sufficient, although future capacity issues depend on new
irradiation facilities replacing the ageing fleet of current research reactors. In Europe a wide range of
radionuclides are produced, limiting foreign dependencies. The HFR, BR2, MARIA and LVR-15 reactors are
currently the largest suppliers of radionuclides, but all are planned to be decommissioned in the next 10-20 years.
Most therapeutic radionuclides are most efficiently produced using such research reactors. Replacement
capacity is needed in order to sustain supply in Europe and to avoid foreign dependencies – which are possible
for longer-lived radionuclides. Outage of research reactors have been reported in many European countries as
causes of supply disruptions of therapeutic radionuclides.
To that end several replacement irradiation facilities are planned in Europe. These are planned to become
operational in the next decade – although planned dates have in the past been delayed. Not all of these facilities
will be built with 100% certainty: there is no final decision on the build of Pallas and SHINE in Europe seems also
not certain. For most planned facilities it is unclear what therapeutic radionuclides they will produce, for example
for Myrrha and SMART/LightHouse this is not specified. The JHR that is currently being built, currently has only
the production of 131I in scope. As building new facilities takes time and are prone to delays, this uncertainty is a
risk for securing European supply.
Interviewees indicate that there is a role for governments in building new reactors. Risks and investments in such
facilities are high and – in a young and volatile market such as for therapeutic radionuclides – the market is not
likely to take such risks and make the required investments themselves. Pallas has embarked on a mission to be
fully privately funded, but has recently seized this pursue. European could play a role in coordinating future
capacity needs and initiatives.
Across Europe several cyclotrons and accelerators could produce the therapeutic radionuclides 67Cu and 211At87,
but supply is currently low. As these are currently experimental and not widely used in clinical practice, demand
is also low. The lack of supply is however reported to hold back the development and uptake of these
radionuclides. As the half-life of these radionuclides is rather short a network of cyclotrons across Europe that
produce these radionuclides seems to be important should these become widely adopted in clinical use.

4.6.3

After irradiation phase

The current irradiators of radionuclides are associated with processors that are located near irradiation facilities.
In Europe, no imminent lack of current processing capacity for therapeutic radionuclides was reported or
conveyed during the study. Yet, the demand for such facilities, especially for labelling, is expected to increase
significantly should [177Lu]Lu-PSMA receive marketing authorisation following a successful VISION clinical trial.

86 Euratom Supply Agency (2019). Securing the European Supply of 19.75% enriched Uranium Fuel. A revised

Assessment. May 2019. See: https://ec.europa.eu/euratom/docs/ESA_HALEU_report_2019.pdf
87 M.R. Zalutsky and M. Pruszynski (2011). Astatine-211: Production and Availability. Curr. Radipharm. 4(3). See:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503149/#R39

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Interviewees indicate that – although this will involve significant investments and planning several years ahead
– this will likely be picked up by the market to follow demand. New processing capabilities are for instance
planned in the Netherlands (the Nuclear Health Centre) on the site of the HFR and the planned Pallas reactor. 88
There is no significant foreign dependency in this phase.

4.6.4

During transport

Transport post-irradiation is very time-sensitive: the longer transport takes; the more activity is lost. Flight
transport has proven to be the weakest link in the current supply chain during the COVID pandemic.89
Interviewees indicate that during the pandemic a lot of effort was put in place to ensure the international
transport of radionuclides, establishing a special working group to coordinate this.90 European countries that are
dependent on cross-country or cross-continental flights for their radionuclide supply have reported most
disruption of supply. Overall, Europe has had limited disruptions compared to Asia and North America, as many
irradiators and processors are based in Europe. For many European countries road transport of therapeutic
radionuclides is possible, which has been less sensitive for disruptions than air travel.91 This is a clear benefit
of having important parts of the supply chain in Europe, with multiple suppliers across Europe.

88

Pallas (2020). Focus on Pallas. Edition 3. See: https://www.pallasreactor.com/focus-on-pallas/3/22/

89 World Nuclear News (2020). Air transport improves for medical radioisotopes. 25 April 2020. See: https://world-nuclear-

news.org/Articles/Air-transport-bottleneck-easing-for-medical-radioi
90 Nuclear Medicine Europe (2020). How the COVID crisis has affected the transport of radiopharmaceuticals. See:

http://nuclearmedicineeurope.eu/wp-content/uploads/2020/11/Transport_WG.pdf
91 L.P. Roobol, C.E.N.M. Rosenbaum and I.R. de Waard (2020). Leveringszekerheid voor medische radionucliden – aanvullingen 2020. RIVM.

See: https://www.rivm.nl/bibliotheek/rapporten/2020-0153.pdf

56

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

5

Future demand may rise, depending on market developments

The market for therapeutic radionuclides is in development. Current demand is likely to change in the next
decade. In this chapter we describe the characteristics of the therapeutic radionuclide and radiopharmaceutical
market, including expected developments of demand. We also discuss the drives and challenges for the
development of this market.
Overview of main conclusions of this chapter:
•

The market for therapeutic radionuclides is much more volatile than the market for diagnostic
radionuclides with new products that entered the market in the last five years and that are on the brink
of entering the market.

•

Driven by its therapeutic potential and the promise of growth in demand, the therapeutic
radiopharmaceutical market has caught the interest of big pharmaceutical companies.

•

The demand for 177Lu, 225Ac, 227Th and 166Ho is expected to increase in the next ten years. Especially the
demand for 177Lu is expected to rise strongly, outgrowing current demand capacity.

•

The demand for PSMA pharmaceuticals is expected to increase strongly. An increase or even strong
increase is also expected for several targeted alpha therapies.

•

The demand for 90Y, 131I and 169Er is expected to remain stable in the next ten years, while the expected
demand trend for 223Ra is inconsistent among experts.

•

The demand for 89Sr, 32P, 153Sm and 188Re and related radiopharmaceuticals is expected to decrease in the
next ten years.

•

Challenges for the development of the therapeutic radionuclide/radiopharmaceutical market revolve
around competition with alternative treatments, supply capacity not sustaining demand growth,
regulatory barriers, market intransparency and asymmetry, and political decisions.

•

As the market for therapeutic radionuclides/radiopharmaceuticals is volatile and intransparent, matching
supply and demand is difficult. It is not likely that in such a market supply and demand will be optimally
met.

•

The current European supply chain for radiopharmaceuticals currently used in clinical practice seems
adequate, but fragile, and not resilient. The development of several new radionuclides is hindered by
insufficient current supply.

5.1

Characteristics of the therapeutic radiopharmaceutical market

The current size of the market for therapeutic radionuclides (in terms of volume) is much smaller than the market
for diagnostic radionuclides. Factors of 100 have been reported, meaning that the market for therapeutic
radionuclides is 100 times smaller than that of diagnostic radionuclides. 92 As an example, in the Netherlands
roughly 1% (3,800) of all radionuclide procedures in nuclear medicine (370,000) are therapeutic.93
The therapeutic market is younger and less established than the diagnostic market, showing more growth than
the diagnostic market.94 In terms of revenue, an expected annual growth of 5-8% has been reported for the
therapeutic market.95 Much larger growth numbers are expected when PSMA-617 will receive marketing

92 PWC (2018). PALLAS/LightHouse Review. Extract of final report.
93 L.P. Roobol, C.E.N.M. Rosenbaum and I.R. de Waard (2020). Leveringszekerheid voor medische radionucliden – aanvullingen 2020. RIVM.

See: https://www.rivm.nl/bibliotheek/rapporten/2020-0153.pdf
94 L.P. Roobol and I.R. de Waard (2019). Marktontwikkeling en leveringszekerheid voor medische radionucliden. RIVM. See:

https://www.rivm.nl/bibliotheek/rapporten/2019-0101.pdf.
95 Ibid.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

approval – depending on the outcomes of the currently ongoing VISION clinical trial. Two distinct interviewees
suggest that in ten years’ time the market for radionuclides will have grown, and the share of therapeutic
radionuclides (in terms of expenditures) will outnumber the share of diagnostic radionuclides in this market. The
demand for diagnostic radionuclides will not decrease, but the demand for therapeutic radionuclides will be
significantly higher. This will also depend on successful outcomes of ongoing clinical trials (e.g. for [177Lu]Lu-PSMA
-617).
The market for therapeutic radionuclides is much more volatile with new products that entered the market in
the last five years (e.g. Lutathera®) and that are on the brink of entering (e.g. [177Lu]Lu-PSMA). Several new
therapeutic radiopharmaceuticals are used compassionately or being tested in clinical trials. 96 Due to the timecomplexity of the product and supply and regulations regarding both pharmaceuticals as well as radiation
protection, these products take more time to bring to the market and are associated with higher risks.
In 10 years’ time the interest in radionuclide therapies has increased. Although a small market, radionuclide
therapies caught the interest of big pharmaceutical companies. BAYER, Novartis and AstraZeneca have been
taking over (or have been partnering with) smaller radiopharmaceutical companies and their product pipelines
in recent years. Through these mechanisms they are entering the market of therapeutic radiopharmaceuticals.
Expectations for the development of these markets are at the basis of these decisions of non-specialised big
pharmaceutical companies.
Europe is traditionally the hotspot for medical radionuclides, with several research reactors producing a large
part of the world’s demand for medical radionuclides (especially diagnostics). The US and Canada rely more on
foreign sources than Europe does, especially for the diagnostic 99Mo/99mTc, and have been supporting
(innovative) local initiatives to produce medical radionuclides. North American entrants, such as SHINE and Bruce
Power, supplying also 177Lu, are in part a result of these efforts and politics. Such new entrants can change the
dynamics of the market and the position of European players into this market. New initiatives still have to prove
their promises, and some are focusing on specific radionuclides (due to technical limitations), leaving the supply
side of some radionuclides unaffected – at least in the short term.

5.2

Expected development of demand in Europe

5.2.1

Therapeutic radionuclides

Experts in nuclear medicine, clinical practitioners and producers of therapeutic radionuclides across Europe have
been surveyed to understand their expectation for the development of demand for specific radionuclides in the
next 10 years. Their response is displayed in Figure 19.
Most surveyed experts believe that the demand for 177Lu, 225Ac, 227Th and 166Ho will increase in the next ten
years. In terms of our study, increase means a growth of demand between 1-15% in 10 years’ time. The growth
of 166Ho is also signalled by the acquisition of Quirem Medical by the Japanese Terumo mid-2020, after clinical
trails showed the safety and efficacy of 166Ho-microspheres for treatment in liver cancer. 97
Many respondents believe that for 177Lu and 225Ac demand will strongly increase, even well beyond 15% growth
in 10 years’ time. Indeed, 177Lu is considered the workhorse for nuclear medicine in the next decades.
Interviewees support these projections for 177Lu, which are also confirmed by other studies: reporting even

96 See Appendix A.
97 Quirem Medical (2020). Terumo acquires Quirem medical to enhance its interventional oncology field. See:

https://www.quirem.com/terumo-acquires-quirem-medical-to-enhance-its-interventional-oncology-field/

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

growths of 7% or more per annum (which would almost double current demand in 10 years’ time). 98 For 225Ac
similar demand growth expectations of 5-8% per annum have been reported.99 However, interviewees express
different views regarding 225Ac, with some being more sceptical, noting its long half-life, strong radiotoxicity with
four α-particles in its decay chain (potentially causing side effects of the treatment) and current severe supply
issues requiring significant investments to be solved. Similar notions have been made for 227Th, with an even
longer half-life, one additional α-particle in its decay chain and currently limited supply – although better scalable
than 225Ac. Both 225Ac and 227Th are subject of clinical studies100 and still need to be proven effective for
application in targeted alpha therapy – which is quite novel, with 223Ra being the only radionuclide for alpha
therapy on the market. Respondents in the survey are however mostly positive regarding the clinical potential
of targeted alpha therapy.
Most surveyed experts believe that the demand for 90Y, 131I and 169Er will remain stable in the next 10 years.
Both 90Y and 131I are currently widely applied in clinics across Europe. Some experts expect a decrease of the use
of these radionuclides in the next 10 years, while roughly a similar number of experts expect an increase,
suggesting that the number of centres performing treatments is currently the limiting factor. Experts indicate
that in the treatment of primary liver cancer or liver metastases, 166Ho-microspheres is an alternative for 90Ymicrospheres, with the advantage that 166Ho can also be used for imaging. For the treatment of synovitis, 186Er
and 90Y have been mentioned as alternatives for 169Er. However, for 131I several clinical trials are in phases 2/3 in
the US, labelling 131I to novel conjugates (CLR131/PDC), for the treatment of multiple myeloma and lymphoma
(Cellectar Biosciences)101, and antibodies (Iomab-B/BC8), for the treatment of leukaemia and lymphoma
(Actinium Pharmaceuticals)102. If these products enter the market, demand for 131I may indeed increase.
Most surveyed experts expect a decrease in demand for 89Sr, 32P and 153Sm, while many experts also foresee a
decrease of demand for 188Re in the next 10 years. More than one third of responding experts even expect a
strong decrease of demand for 89Sr and 32P. Therapy with 89Sr is phased out, as well as its production, because
alternative shorter-lived radiopharmaceutical therapies are preferred over the use of 89Sr, e.g. [153Sm]SmEDTMP, [188Re]Re-EDTMP and [223Ra]RaCl2, and [177Lu]Lu-PSMA will likely be used for its main indication prostate
cancer. For 153Sm the argument was given that impurities/low specific activity of this radionuclide, and the lack
of new applications beyond [153Sm]Sm-EDTMP , will potentially lead to decreased use. The first therapeutic
radionuclide on the market was 32P in 1936, but currently it has limited applications. Still, these trends can be
influenced by innovations: novel radiopharmaceuticals that are tested, such as [188Re]Re-HER2-Sd, could change
demand trends when outcomes of clinical trials are positive.
The expectation on the development of demand for 223Ra is ambiguous: roughly an equal amount or
respondents assess a decrease, stable and increase demand in 10 years’ time. Some respondents list the positive
aspects of alpha therapy and its replacement of other therapies as a reason for growing demand. Several other
respondents indicate that the demand for [223Ra]RaCl2 will be reduced once PSMA pharmaceuticals (esp.
[177Lu]Lu-PSMA) are authorised on the market and because of side effects of 223Ra.

98 L.P. Roobol and I.R. de Waard (2019). Marktontwikkeling en leveringszekerheid voor medische radionucliden. RIVM. See:

https://www.rivm.nl/bibliotheek/rapporten/2019-0101.pdf.
99 Ibid.
100 Phase 1 clinical trials, which indicates still long-term development before entering the market. Our clinical trial analysis in appendix B.1

has excluded such Phase 1 trials because of their uncertain trajectories and long-term development.
101 Celectar Biosciences website: https://www.cellectar.com/product-pipeline/clr-131
102 Actinium Pharmaceuticals website (2021): https://www.actiniumpharma.com/product-pipeline/iomab-b

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Figure 19 Expected demand development of therapeutic radionuclides according to experts

Source: Technopolis Group, survey among experts

5.2.2

Therapeutic radiopharmaceuticals

The market for therapeutic radionuclides has strongly developed in the last few decades. The introduction of
Lutathera® ([177Lu]Lu-DOTATATE) and Xofigo® ([223Ra]RaCl2) to the market in respectively 2017103 and 2013104 has
further driven developments in the market and in R&D. It has also increased the interest of pharmaceutical
companies into the market of radiopharmaceuticals, leading to investments by Bayer and Novartis. Several
clinical trials are ongoing of which those on [177Lu]Lu-PSMA (for the treatment of prostate cancer) are far
developed and considered very promising by experts. New products are therefore expected to enter the market
in the next 5-10 years.
These developments show that the market is developing but quite volatile. A new success product on this market
can change the market characteristics significantly (market size, investments, dominance of players, number of
players etc.) and could further boost R&D as well as the use of radionuclide therapies in clinical practice. The
uptake of these products in clinical practice is also determined by investments and knowledge of these products
in hospitals (e.g. prescriptions by oncologists, facilities for nuclear medicine) as well as the supply capacity.
The characteristics of the market for radionuclide therapy makes it hard to foresee how this market is developing
in the next 10 years. We therefore relied on expert assessments, mainly from the medical field, across Europe.
Through our survey we asked experts to share their expectations for the development of demand for therapeutic
radiopharmaceuticals. Their response is displayed in Figure 20.

103 See: https://www.ema.europa.eu/en/medicines/human/EPAR/lutathera
104 See: https://www.ema.europa.eu/en/medicines/human/EPAR/xofigo

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Figure 20 Expected demand development of therapeutic radiopharmaceuticals according to experts

Source: Technopolis Group, survey among experts

Most surveyed experts expect a strong increase in the demand/use of PSMA105 based radiopharmaceuticals for
prostate cancer therapy, specifically [177Lu]Lu-PSMA and [225Ac]Ac-PSMA, and to a lesser extent [227Th]Th-PSMA.
An effective radionuclide therapy for prostate cancer has indeed strong potential for increased demand/use as
prostate cancer is the most frequent diagnosed cancer among men in Europe, resulting in 10% of total cancer
deaths in the EU.106 As European populations are ageing the incidence of prostate cancer is likely to increase. So
far, experts are positive of the results obtained with the use of PSMA based radiopharmaceuticals.
Most respondents expect an increase or even strong increase of several targeted alpha therapies, including
225
Ac and 227Th pharmaceuticals. The only exception is [223Ra]RaCl2, where responses are ambiguous.

105 PSMA = Prostate-Specific Membrane Antigen
106 See: https://ec.europa.eu/jrc/en/publication/epidemiology-prostate-cancer-europe

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Respondents name alpha therapies as promising, although availability of 225Ac and 225Th may be an issue.
Although not addressed in the survey, several experts mention 212Pb as a promising candidate for targeted alpha
therapy, that is currently being studied and in early development by Orano Med 107.
In general, for 177Lu-based radiopharmaceuticals an increase in demand/use is expected by most experts.
Respondents name the positive experiences with [177Lu]Lu-DOTATATE, which is currently the only accessible
therapy for NETs, and the fact that 177Lu is widely available and easy to handle. Furthermore, more hospitals are
expected to prepare 177Lu pharmaceuticals in-house. [177Lu]Lu-PSMA is also considered very promising, being
most developed of all PSMA-radiopharmaceuticals, and expected to be entering the market in short term.
Competing PSMA-radiopharmaceuticals are being less available in terms of supply and less far in clinical
development.
A majority of surveyed experts also believe that we will see an in increase in the demand/use of 166Homicrospheres. Expectations for the latter are based on its multimodality purpose: apart from being a therapy for
liver tumours, it is also imageable in SPECT and MRI (due to magnetic properties). The latter makes 166Homicrospheres more favourable for demand growth than 90Y-microspheres – for which most respondents expect
stable demand.
On the other hand, most surveyed experts expect a decrease in the demand/use of [89Sr]SrCl2, [153Sm]SmEDTMP, [188Re]Re-HEDP and 32P-sodium-phosphate. These radiopharmaceuticals are currently less used, not
much in development and being replaced by more favourable alternatives (e.g., shorter half-lives, fewer side
effects).

5.3

Developments in the therapeutic radiopharmaceutical market

5.3.1

Drivers

First and foremost, the market for therapeutic radionuclides is driven by the promise of growth in demand.
The outcomes of the survey reflect a shared belief among healthcare professionals, as well as among large
pharmaceutical companies, that the importance of several radionuclides (177Lu and 225Ac, followed by 227Th,
166
Ho) will increase. This belief is strengthened by R&D activities: good clinical results in the past decades and an
ongoing portfolio of clinical trials using radionuclides. The expected approval of PSMA-617-based therapies by
the European Medicines Agency will be a further boost for radiopharmaceuticals. Positive results of the [177Lu]LuPSMA clinical trial (VISION) will likely drive increased investments of new radiopharmaceuticals, negative results
may cause a set-back in investments.
Not only the quantity of demanded treatments is driving the market, also the expected higher margins for
therapeutical radionuclides increases the interest of producers. This holds especially when compared to
radionuclides for diagnostics. The prices of commercially available radiopharmaceuticals reflect the expected
return by market players for risks taken. As we will elaborate below, this is countered by some consumers’ and
national medicine authorities’ opinion on fairness.
All in all, the market for therapeutic radiopharmaceuticals is still young, volatile, and uncertain: there is room for
new entrants and subsequent acquisitions, market positions are still to be found, and the overall lack of
coordination among European member states allows for risks and associated rewards.

107 All candidate 212Pb radiopharmaceuticals are currently in Phase 1 or pre-clinical phases of development. See:

https://www.oranomed.com/en/pipeline

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5.3.2

Challenges: production, regulation, market asymmetries, and political decisions

Whereas the drivers seem to push the business case in a favourable direction, there remain many uncertainties
and hence risks for the further development of the radiopharmaceutical market.
Competition with non-radioactive drugs and/or treatments acting on the same disease
Therapeutic radiopharmaceuticals, with the only exception of 131I for thyroid cancer and hyperthyroidism, are
employed in clinical settings where multiple drugs are used. In reality the competition with drugs that can be
directly managed by the treating physician has an influence, on top of the other issues mentioned below, on the
willingness to invest in this field from pharmaceutical companies.
Production capacity
Like with diagnostic radionuclides, the production capacity for therapeutic radionuclides remains limited to a
relatively small set of ageing production facilities and infrastructures both within and outside Europe. Currently,
production capacity seems adequate for meeting demand, but overall projected growth cannot be sustained.
Within Europe, most research reactors are planned to be decommissioned this decade. The follow-up is largely
uncertain and often focussed on a limited set of radionuclides. Although replacement of BR2 and HFR are
planned, no final decision has been taken. No replacements for MARIA and LVR-15 are planned, further
weakening production capacity within Europe.
All in all, Europe remains dependent on the US and Russia for the enrichment of several stable isotopes for targets
used in the production of therapeutic radionuclides, such as 177Lu NCA, which currently is one of radionuclides
with the largest growth potential. In addition, Europe relies on the US and Russia for research reactor fuel (highassay low-enriched uranium – HALEU), which is obtained from Russia or from down-blending US highly-enriched
uranium stocks. A recent ESA-report108 highlights the risk that foreign supply of HALEU cannot be guaranteed
beyond 2030-2040, impacting medical radionuclide production.
While reactors constitute proven technology, several alternative routes for production are being tested and/or
only recently proven viable (SMART/Lighthouse and SHINE). These alternatives weaken the business case for
private or even public reactors providing medical radionuclides: they provide an innovative, but hardly proven
option that requires time to scale up to global demand.
New European production capacity for therapeutic radionuclides is needed to sustain Europe’s position in this
market and to meet expected demand, especially for 177Lu. This requires significant investments in infrastructure
in the next few years.
Regulatory barriers
In the global context, there are fewer barriers for producing radionuclides in the US and Russia as compared to
the European Union. In the EU, legislative frameworks for handling radionuclides and radioactive waste are not
consistent among countries or even within countries (e.g. in Germany this is a state (Länder) rather than a federal
issue).
Furthermore, regulation for pharmaceuticals and radiation protection do not always align, delaying the
development and market entry of new radiopharmaceuticals.
Market asymmetries

108 Euratom Supply Agency (2019). Securing the European Supply of 19.75% enriched Uranium Fuel. A revised Assessment. May 2019. See:

https://ec.europa.eu/euratom/docs/ESA_HALEU_report_2019.pdf

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

The market for radiopharmaceuticals is largely intransparent and maintains information asymmetries among
players. Such conditions can lead to market failure: mismatches of supply and demand. The lack of information
makes it extremely difficult to coordinate supply and to tackle supply issues timely. This makes it difficult to
gather market information for policy decisions, such as investments in new irradiation facilities, the appointment
of reactor time or supply to specific parties.
Political decisions
The special character of nuclear technology and the associated infrastructures puts radiopharmaceuticals (for
therapy) in a realm that is in essence one of political decisions.
As indicated above, there is no framework or coordination mechanism to prioritise production of certain
radionuclides over others to avoid shortages or to address medical/societal needs. In our interviews, the decision
logic in the supply chain was characterised as “first come, first serve” and long-term relationship driven.
The long-term security of supply requires timely investment discussions and discussions regarding new capacity
at European level. Building new capacity or even extending current capacity takes five to ten years and requires
significant investments that will not be fully carried by commercial investors.
As currently the market does not want to bear the costs and risks of major investments – given the case of the
Pallas reactor – a coordinated European view on the need, importance and conditions for future capacity for
therapeutic radionuclides is needed.

5.3.3

Matching supply and (expected) demand is difficult under current situation

Matching supply and demand in an intransparent, volatile market is difficult. Due to the short shelf lives of
their products, pharmaceutical companies wish to control their supply chain, making long-term agreements with
radionuclide suppliers, enrichers and target producers. They also tend to protect supply for their product and
limit access to their suppliers and the market of other, competing businesses. Lack of transparency is then
beneficial and sustained.
Under such conditions, it is not likely that on a system level supply and demand for therapeutic radionuclides
will be optimally met. A resilient and sustainable supply first of all requires more openness in terms of
information, to which this report is contributing. There is little quantitative information available on this fairly
novel and small therapeutic market. There is no international coordination of supply (European and beyond) and
countries do not (consistently) record information on the use of therapeutic radionuclides (providing insight in
current demand on system/market level instead of product level). Also, there are no frameworks for radionuclide
suppliers to prioritise production capacity to match supply/demand other than client relations/contracts and
price. Therefore, international coordination similar to that for 99Mo/99mTc is advisable.

5.3.4

Adequacy and resilience of the supply chain cannot be maintained

The current European supply chain for radiopharmaceuticals that are currently used in clinical practice seems
to be adequate, but fragile. Sometimes supply shortages occur, but these occur not often for most therapeutic
radionuclides. However, this is likely not sustained in the medium to long-term (10+ years) due to the following:
•

The overall demand for radiopharmaceuticals is expected to grow in the next decades, with especially a
strong increase in demand for 177Lu.

•

At the same time existing irradiation facilities (reactors) in Europe are planned for decommissioning in the
next decades. Replacement is only foreseen for some of these reactors and the replacement plans are
shrouded in unclarity. Some of the reactors only focus on specific radionuclides. Therefore, uncertainty
remains on several levels: whether/when planned capacity is truly built in Europe, which/how much
radionuclides they can/will produce, and whether they will meet proclaimed expectations.

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•

Enrichment of targets for some of the most promising therapeutic radionuclides (for which strong demand
growth is expected), relies on old facilities in Russia that need replacement in the coming decades.

•

Europe has limited capacities for the enrichment of stable isotopes for the production of therapeutic
radionuclides.

Additionally, the development of several new radiopharmaceuticals is hindered by insufficient current supply
of radionuclides, requiring the development of new industrial processes and the uptake by producers once
radiopharmaceuticals pass clinical trials and market authorisation. Here some foreign dependencies exist (mainly
US) that need to be overcome. Once demand increases, it is likely that these problems can be absorbed by the
market. Coordination of supply capacity, as is done for 99Mo/99mTc, is relevant to organise.

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6

Policy recommendations

Based on the findings from this study, there are clear opportunities for action at EU level. In this chapter we
present the main policy recommendations along the main topics of this report.

6.1

Recommendations on monitoring demand

In order to be able to better monitor the market for therapeutic radionuclides, official (annual) data collection
on the use of radiopharmaceuticals has to be improved. Data collection should be at the level of
radiopharmaceuticals in terms of number of treatments as well as activity used (at time of administration). This
needs to be organised first and foremost at national level in a standardised way – the standard is to be agreed
upon at European level. This report has shown good examples of data gathering in e.g. Belgium, Czech Republic
and Sweden. However, coordination of such efforts lies with the European Commission. Eurostat could be tasked
with this data collection in collaboration with national statistical offices, but this would require a mandate from
EU Member States and is thus a matter to discuss with the EU Council.
The European Commission should consider supporting (translational) research, innovation and training in
novel radionuclide therapies and pharmaceuticals to accelerate innovation and translation of knowledge to
clinical practice. Given the European cancer incidence (and the development thereof), the demand expectations
and the promises of this fairly novel targeted therapy, public interest for better healthcare in the field of oncology
could be served through such research, innovation and training actions. Activities in this field should be aligned
with the new Horizon Europe Mission against cancer.109

6.2

Recommendations on securing future supply

Concerted and timely action at European level is required to secure sufficient irradiation capacity for
therapeutic radionuclides in Europe for the future. This urges for a more active role at European level, including
a vision on the need, importance, role of governments, and conditions/requirements for (future) irradiation (and
processing) capacity for medical radionuclides in Europe. Current plans for new facilities to replace or add to
current irradiation capacity for therapeutic radionuclides are uncertain in terms of realisation date, state of
innovation, start of operations, the therapeutic radionuclides produced, and production volumes. To reduce
these uncertainties information sharing (monitoring), coordinated planning, and identifying and removing
barriers for new build (incl. public/private investments) are essential now to secure the public interest of a
secured supply of therapeutic radionuclides in the future.
Europe relies for enrichment of some important target materials (stable isotopes, such as 176Yb) on Russia, and
for the supply of (enriched) research reactor fuel (LEU) on Russia and the US. As both supply chains are associated
with risks, either due to old foreign facilities, reducing stockpiles or possible political instabilities, a political
decision should be made on whether Europe wants to be self-sufficient for these products to secure the
(therapeutic) radionuclide supply chain (for the future). Being self-sufficient would require (co)investments in
enrichment facilities, and perhaps innovation in enrichment technology, in Europe.
The European Commission should consider supporting applied research and innovation to strengthen the
future supply chain for therapeutic radionuclides. This can be best implemented in the form of a public-private
partnership (e.g. in the shape of an Institutionalised European Partnership)110 between the European
Commission, Member States, industry and research organisations, as changes to or innovation in the supply chain
require collaborative involvement and investments. It should focus on applied research (at high Technology

109 See: https://ec.europa.eu/info/horizon-europe/missions-horizon-europe/cancer_en
110 See https://ec.europa.eu/info/horizon-europe/european-partnerships-horizon-europe_en

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Readiness Levels) and innovation regarding irradiation concepts, processing methods, enrichment of stable
isotopes and accelerator-based production of radionuclides (such as with the European Spallation Source). It is
advisable to keep several technology options open rather than “choosing” a preferred technology.

6.3

Recommendations on the factors influencing demand and supply

Given the volatility and future expectations of the therapeutic radiopharmaceutical market, and the concerns
regarding future supply, similar international mechanisms as for the security of supply 99Mo/99mTc should be
developed. Such efforts should be undertaken with industry to make this market more transparent. Historically,
both the OECD-NEA High-level Group on the Security of Supply of Medical Radioisotopes (HLG-MR) and the
European Observatory on the Supply of Medical Radioisotopes focus on the main diagnostic radionuclide. As this
is still the most used radionuclide this makes sense, but more information-sharing regarding supply capacities,
new builds, demand expectations and outages for key therapeutic radionuclides is important to secure supply
for these medicines. For starters, the focus should be on 131I (the most used therapeutic radionuclide and the
one with most reported supply disruptions) and 177Lu (the therapeutic radionuclide that is expected to grow most
and has substantial concerns for future supply). This could be incorporated in existing mechanisms, such as the
European Observatory, with involvement of the industry.

6.4

Recommendations on regulation, reimbursement, finance and guidelines

Differences in prices for radiopharmaceuticals between European Members States exists, that cannot be fully
explained by inherent regional differences such as in transport. Negotiations with suppliers are considered a
significant factor in price differences between hospitals, regions or countries, depending on the level at which
prices and contractual conditions are negotiated. In discussion with Member States, the European Commission
could explore the possibilities for and desirability of EU-level negotiations on price and contractual conditions,
opening up possibilities to also negotiate supply issues, such as guaranteed levels of production,
(co)investment in supply infrastructure and fallback capacity. Lessons from the centralised procurement and
negotiation for COVID-19 vaccines could be of use here.
In Europe legislative frameworks for handling radionuclides and radioactive waste is not consistent among (or
even within) Member States. In addition, regulations for pharmaceuticals and radiation protection do not always
align, delaying the development and market entry of new radiopharmaceuticals. It is recommended to review
current EU and national legislative frameworks that deal with transport, waste, use and R&D of
radiopharmaceuticals to identify opportunities for harmonisation and removing regulatory barriers, whilst
safeguarding high levels of safety and security.
Heath Technology Assessment (HTAs) inform decision-making in order to promote an equitable, efficient, and
high-quality health system. Thus, they are highly relevant in national reimbursement decisions for new, especially
expensive, medicines and treatments. HTAs are generalisable and adaptable to specific national contexts (e.g.
specific healthcare systems) and therefore the European Network for Health Technology Assessment (EUnetHTA)
was established to help Member States collaborate on Joint Assessments and share HTA resources. However,
EUnetHTA does not include radiopharmaceuticals in their assessment list. It is therefore recommended to
include radiopharmaceuticals within EUnetHTA activities to facilitate HTA-based reimbursement decisions for
radiopharmaceuticals at Member States. This will be of particular help to Member States’ healthcare bodies
that lack capacity to conduct HTAs.

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Reimbursement models
Financing healthcare in Europe
Medicines must be approved for use by gaining marketing authorisation before they can be used for the patient
population. In the context of the EU marketing authorisation may occur through a centrally based procedure via
the European Medicines Agency, or a. The traditional process by which medicines are reimbursed in Europe may
follow a number of different routes. A key stakeholder in this process is the European Medicines Agency (EMA).
Although healthcare coverage in Europe is varied between member states, two main types are observed: social
health insurance systems (SHI) and national health services (NHS).111 In SHI systems health risks of the population
are pooled through insurance contributions by, for example, the workforce and their employers. Thus, revenues
to cover the costs of healthcare are sourced from earnings-based contributions to funds and further subsidised
by the national governments. SHI systems also vary themselves where subsets of the population may be covered
by different funds through different means, such as by region or employment type, for example.
By contrast NHS type healthcare systems gather money to cover the costs of healthcare through general taxation.
There are typical differences between SHI and NHS type healthcare delivery. SHI systems are more likely to
contract healthcare providers to deliver healthcare to patients, thus setting up a competitive contract-based
environment. Those member states with competitive and non-competitive SHI systems are shown in Table 10.
Table 10 European member state healthcare systems
Country
NHS/SHI
Single (S) or
Multi payer
(M)

Competitive SHI

Proportion of population covered by
public health insurance

Austria

SHI

M

No

100%

Belgium

SHI

M

Yes

99%

Bulgaria

SHI

S

No

88.2% (2013)

Croatia

SHI

S

No

100%

Cyprus

NHS

S

Not applicable

83% (2013)

Czechia

SHI

M

Yes

100%

Denmark

NHS

S

Not applicable

100%

Estonia

SHI

S

No

94%

Finland

NHS

S

Not applicable

100%

France

SHI

M

No

100%

Germany

SHI

M

Yes

88.9% (public) 10.9% (private)

Greece

Mixed SHI/NHS

S

No

86% (2015)

Hungary

SHI

S

n/a

95%

Ireland

NHS

S

Not applicable

100%

Italy

NHS

S

Not applicable

100%

111 The management of health systems in the EU Member States - The role of local and regional authorities, 2012. See:

https://cor.europa.eu/en/engage/studies/Documents/health-systems/health-systems-en.pdf

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Country

NHS/SHI

Single (S) or
Multi payer
(M)

Competitive SHI

Proportion of population covered by
public health insurance

Latvia

NHS

S

Not applicable

100%

Lithuania

SHI

S

No

100%

Luxembourg

SHI

M

No

96%

Malta

NHS

S

Not applicable

100%

Netherlands

SHI

M

Yes

100%

Norway

NHS

S

Not applicable

100%

Poland

SHI

S

No

91%

Portugal

NHS

S

Not applicable

100%

Romania

SHI

S

No

86%

Serbia

SHI

S

No

100%

Slovakia

SHI

M

Yes

94%

Slovenia

SHI

S

No

100%

Spain

NHS

S

Not applicable

99.1% (public) 0.8% (private)c

Sweden

NHS

S

Not applicable

100%

Switzerland

SHI

M

Yes

100%

United Kingdom

NHS

S

Not applicable

100%

Adapted from WHO

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Table 11

Reimbursement models used in EU member states for radiotherapy

Country

Budget
Per hospital

Austria

Yes

Belgium

Yes

Bundled payment
Per
department

Per disease

Per
treatment

Fee for
service
Per day

Yes

Bulgaria

Yes

Czechia

Yes

Denmark

Yes

Yes

Estonia
Finland

Yes
Yes

Yes

France

Yes

Germany

Yes

Greece

Yes (private)

Hungary

Yes

Ireland

Yes

Italy

Yes (public)

Yes

Yes (private)

Lithuania
Luxemburg

Yes
Yes

Yes

Netherlands
Poland

Yes
Yes

Yes

Portugal

Romania

Yes (in
patient)

Spain
UK

Yes
(inpatient)

Yes

Yes

Yes
(outpatient)
Yes
(outpatient)

Yes

Yes (Scotland and
Wales)

Yes (England)

Source: Lievens et al. (2020)

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Methodological notes and caveats
In order to fill in the lack of information concerning the use of radionuclides for therapy, we have taken a mixed
method approach to gather as much reliable information as possible. This appendix describes methodological
approaches, caveats and sources of information.

Analysis of radionuclide therapy clinical trials
To establish the prominence of radionuclides, we analysed a database of global clinical trials. The analysis only
includes treatment trials of Phase 1/2 and higher, and which started between 1 April 2010 and 31 March 2020
were included in the analysis. As such, a total of 244 trials were included in the analysis. However, data for all
variables were not available for each trial.
Figure 21 Count of radionuclide therapy clinical trials by isotope and start year
30
Y-90

Number of clinical trials

25

Sm-153
Re-188

20

Re-186
15

Ra-223
Lu-177

10

In-111
I-131

5

I-123
0
2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

Ho-166

2020

Ga-67

Start year
Based on data from ClinicalTrials.Gov (2020)
Table 12
Start Year

225Ac

Clinical trials per radionuclide over years 2010-2020
2010

2011

2012

2013

2014

2015

2016

2017

1

213Bi

1

2020

Grand
Total

1

2

1

3

1

1

67Cu

1

67Ga

123I

2019

1

211At

166Ho

2018

1

1
1

1
2

1

1

71

1

1

2

1

7

1

2

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

131I

3

5

6

3

5

2

2

3

4

8

4

1

1

3

3

4

4

4

3

6

9

7

5

49

2

4

8

9

5

4

7

4

4

48

111In

177Lu

1

223Ra

1

2020

Grand
Total

Start Year

41

1

7

186Re

1

1

2

1

5

188Re

1

1

2

1

5

153Sm

1

1

90Y

10

10

13

5

6

5

6

7

2

4

2

70

Grand Total

15

22

29

20

25

24

17

26

26

26

14

244

Based on data from ClinicalTrials.Gov (2020)
90

Y, 177Lu, 223Ra and 131I account for the most clinical trials in the last 10 years. The total number of radionuclide
therapy clinical trials has not changed greatly year on year except for a dip in 2016.
Out of the 234 clinical trials for which location of the trial sites was available, over half had at least one trial site
in the USA. 90Y and 223Ra accounted for the most clinical trials in the US (58%, 69 out of 120). Interestingly, 166Ho
radionuclide therapy clinical trials have been solely conducted in the Netherlands. Overall, 90Y, 223Ra and 177Lu
are the isotopes that feature most prominently in clinical trials in most countries.
It should be noted that although 227Th is listed in other parts of this report, it was not found in the clinical trials
analysis as most these trials are in early stages.112
Table 13

Distribution of radionuclide therapy clinical trials by country

Country

166Ho

131I

111In

177Lu

223Ra

186Re

188Re

90Y

TOTAL

United States

0

23

4

20

27

2

2

42

120

France

0

5

3

8

9

0

0

11

36

Netherlands

7

1

2

8

5

1

1

5

30

Canada

0

4

1

7

8

1

1

6

28

Italy

0

2

1

7

9

0

0

7

26

112 See: https://clinicaltrials.gov/ct2/results?cond=&term=Thorium&cntry=&state=&city=&dist=

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Spain

0

3

1

3

12

0

0

7

26

Belgium

0

3

1

6

6

0

0

9

25

United Kingdom

0

3

1

4

8

0

0

5

21

Germany

0

3

0

2

8

0

0

5

18

Australia

0

3

1

7

3

0

0

2

16

South Korea

0

6

0

1

6

0

0

3

16

China

0

6

0

2

1

1

1

4

15

Israel

0

1

1

1

8

0

0

2

13

Austria

0

2

1

4

2

0

0

3

12

Poland

0

2

0

3

5

0

0

2

12

Total

7

67

17

83

117

5

5

113

414

Note: only countries with 10 or more clinical trials and radionuclides with 5 or more clinical trials are shown. Based on data
from ClinicalTrials.Gov (2020)

Just under half (47%, 115 out of 244) of the radionuclide therapy clinical trials were Phase 2 trials. Consequently,
Phase 2 trials accounted for the highest number of clinical trials for most isotopes.
Figure 22 Count of radionuclide therapy clinical trials by isotope and phase
80

Number of clinical trials

70
60
Phase 4
50

Phase 3

40

Phase 2|Phase 3
Phase 2

30

Phase 1|Phase 2

20

Not Applicable

10
0
Ho-166 I-131 In-111 Lu-177 Ra-223 Re-186 Re-188 Y-90

Note: isotopes with fewer than 5 trials are not shown. Based on data from ClinicalTrials.Gov (2020)

The therapeutic interventions being tested in clinical trials were largely drugs (45%, 109 out of 244 trials) or drugs
in combination with a biological, device, diagnostic, procedure, radiation or other intervention (32%, 77 out of
244), followed by devices (10%, 24 out of 244). A large number of the 90Y trials (33%, 23 out of 70) concerned
devices or devices in combination with a drug.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Figure 23 Count of radionuclide therapy clinical trials by isotope and intervention type
60

Number of clinical trials

50

Radiation
Drug|Radiation

40

Drug|Pr ocedure
Drug|Other|Radiation

30

Drug|Other
Drug

20

Device|Drug
Device

10

Biological
0
Ho-166

I-131

In-111

Lu-177

Ra-223

Re-186

Re-188

Y-90

Note: isotopes and interventions with fewer than 5 trials are not shown. Based on data from ClinicalTrials.Gov (2020)

In terms of indications, almost all 90Y trials (67 out of 70) were looking at cancer treatments with more than onethird (39%, 27 out of 70) focussing on liver cancers. All 177Lu, 223Ra and 131I trials were related to cancer with over
half 177Lu trials (57%, 28 out of 49) concerning neuroendocrine tumours, almost two-thirds of 223Ra trials (71%,
34 out of 48) concerning prostate cancer treatment and just under half of 131I trials (41%, 17 out of 41) concerning
thyroid cancers.

Methodology to calculate current demand
From national statistical data
National statistical data was collected from interviews or e-mail exchange with key national contacts from
national public health agencies and national nuclear medicine societies. Data requested included:
•

number of procedures per radiopharmaceutical and indication

•

number of patients per radiopharmaceutical and indication

•

total annual activity administered per radiopharmaceutical and indication

Availability of data was highly variable from country to country. Country-level data on total annual activity
administered per radiopharmaceutical and indication was preferred. However, few countries collect data at this
level, Sweden, Belgium and Czechia being three of the best examples. Failing the availability of activity data, the
annual number of procedures or patients per radiopharmaceutical and indication were multiplied with the
prescribed activity per procedure.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Assumptions:
•

Activity – This number was derived primarily from EANM guidelines. Where guidelines provided a range for
the optimal activity, we assumed that the mid-point of the range was the activity given. For example, EANM
guidelines suggest113 “optimal” activity of 1-5 GBq for [131I]-NaI thyroid remnant ablation of adults, in this
case 3GBq was be used for further calculation. Where activity was described in terms of MBq or Gbq per
kilogram (kg) of bodyweight, activity per procedure was calculated assuming typical bodyweights of
70.8kg114 and 30kg115 for adults and children respectively. Where EANM guidelines were not available,
country-specific guidelines were used and where these were also not available a brief literature search was
conducted to determine typical activity amounts.

•

Where only data on numbers of patients were available, guidelines were used to determine the number of
procedures per patient.

•

Radionuclide level – In some instances, the data regarding the number of annual procedures were supplied
at the radionuclide level rather than the radiopharmaceutical level. Hence, procedures could not be matched
to indication.
From survey data

Survey participants were invited to fill out the total number of procedures administered in their organisation by
radiopharmaceutical and indication. For each country, the average number of procedures administered per
indication per radiotherapy centre was then calculated. This number was then multiplied by a) the typical activity
per procedure (as outlined in the previous section) and b) the total number of radionuclide therapy centres in a
given country.
Assumptions:
The main assumptions were as follows.
•

Radionuclide therapy centres – Our calculations assume that in a given country, all radionuclide therapy
centres offer the same services and administer the same number of procedures. This is of course unlikely to
be the case, particularly in countries with many radionuclide therapy centres. Moreover, it was not possible
to find a reliable figure for radionuclide therapy centres for all countries. In such cases, we had to rely on
figures provided in interview responses or from published literature. The latter includes centres offering
external radiotherapy as well. Thus, current demand estimates needs to be treated with caution.

•

Representativeness of responses: We assume that the survey responses received are representative i.e. our
responses cover the different sizes of and therapies delivered in radionuclide therapy centres, and
consequently averages are a good overall representation of procedures being delivered. This is especially a
concern for estimations for countries where survey participation was low: the calculation may be based on
responses from very few participants, much lower than the actual number of national radionuclide therapy
centres. In these instances, there is a danger that estimates of demand are very skewed.

Validation of acquired information and calculated data
The information in this study is obtained from several sources. Most is collected bottom-up from experts
participating in our survey, interviews or responding to our country factsheets. This information is used in
calculations, such as explained in Appendix B.2.

113 See: https://eanm.org/publications/guidelines/gl_radio_ther_259_883.pdf
114 See: https://bmcpublichealth.biomedcentral.com/articles/10.1186/1471-2458-12-439/tables/3
115 Technopolis’ estimate

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Based on our calculations and the information collected, we have completed the country factsheets and asked
for validation at various national contacts. These included national authorities and national nuclear medicine
associations (see Appendix B.4). For each country we have approached several contacts and – when needed –
reminded them of our validation request. Not all contacts responded, resulting in some country data not being
validated, which is indicated.
For most countries we received a validation response. Respondents sometimes provided additional information
or alternative figures when data were considered incorrect. In most cases respondents indicated that – although
no other data available – figures are in line with their expectation or understanding of the nuclear medicine
practice in their country. Only for one country the respondent indicated that figures are not correct, but no
alternative data could be provided.
Country factsheets were updated based on new information received or comments made. The final country
factsheets are presented in Appendix C. The information in these country factsheets have been used throughout
the report and for our calculations.
In January 2021, a workshop was held in which over 40 experts participated and the main results of the study
were presented. The goal of the workshop was to validate these main results and to test the study's
recommendations. During the workshop some comments were made regarding the data presented. These
comments were followed-up and resulted in additional and improved data for two countries. The data,
calculations and factsheets were adapted accordingly.
An additional round of validation was undertaken by contacting the main suppliers of therapeutic
radiopharmaceuticals in Europe. They were provided with our data and calculations on national and European
level for their products, requesting validation of those figures (and, if possible due to the commercially sensitive
nature of this information, providing alternative internal data). When requested a call was set up to explain our
request. One reminder was sent when no response was received. In the end, three responses were received with
data at a high aggregate level. For one country this led to alterations to data, factsheet and calculations.
Information received from distinct suppliers of 177Lu radiopharmaceuticals showed that for 177Lu-antibodies our
figures were in line with their estimates, [177Lu]Lu-PSMA was said to be underestimated with 20-30% and
[177Lu]Lu-DOTATATE seems overestimated. For the overestimation, a crude estimated figure for the number of
patients treated across Europe was provided, indicating that our calculations are in the same order of magnitude
and certainly less than a factor 2.5 off. Strong conclusions regarding validity of our figures could not be drawn
based on the provided level of detail, also considering that these medicines are in some countries produced inhospital.
Overall, we conclude that most of the data presented in this report is validated to the study team’s best efforts.
When not validated, this is explicitly indicated. The data in this report presents the best publicly available
information at the time of publishing. Calculated data (mainly those for the use of radionuclides and
radiopharmaceuticals) are indicative figures but provide the best insights available to the study team.

Involved stakeholders and experts in interviews, workshop and national data
requests
As part of the data collection and validation of our findings, we have interacted extensively with individual
stakeholders and experts in the wider field of therapeutic radionuclides. We have approached many
knowledgeable individuals and organisations (stakeholders) across Europe throughout our study, but not all
responded to our (repeated) requests or were able to cooperate. Here we provide information on the
characteristics of those that did respond and cooperated, providing us with information that was used in this

76

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study. These stakeholders and experts either participated in an interview, provided information on their country
or their business’ products, participated in our workshop or validated our findings.
In this study we have consulted/involved 84 stakeholders and/or experts across Europe, distributed over 25
European countries, in our data collection – meaning that they provided us with insights in any of our data
collection methods (excl. the survey). Of these, 52 provided information on their country or organisation in an
online interview or via e-mail (e.g. in the country fact sheets or for validation). In total 41 stakeholders and/or
experts (also) participated in the workshop that was organised to present and validate the main findings and
recommendations of the study. In Table 14 and Table 15 we provide statistics on the number of stakeholders
and experts involved.
Table 14

Type of organisations involved in or consulted for data collection (excl. survey)

Type of organisation

Number of stakeholders/experts

National nuclear medicine association

19

National authority

19

Supplier

14

European authority

14

Nuclear medicine professional/expert

10

Research consultancy

4

International organisation

2

European nuclear medicine association

2

Total

84

Source: Technopolis Group
Table 15

Number of stakeholders per country involved in or consulted for data collection through interview, e-mail or
workshop.

Country

Number of stakeholders/experts involved in data collection
Unique total

Involved via interview or e-mail

Involved in workshop

Belgium

5

4

Bulgaria

1

Croatia

2

1

Cyprus

1

1

Czech Republic

2

2

1
1

77

1

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Country

Number of stakeholders/experts involved in data collection
Unique total

Involved via interview or e-mail

Involved in workshop

Denmark

1

1

Estonia

1

1

1

France

5

1

4

Germany

6

5

1

Greece

2

2

Hungary

1

1

Ireland

2

2

Italy

2

1

Malta

1

1

Netherlands

12

9

Norway

2

2

Poland

3

3

Portugal

3

1

3

Romania

1

1

1

Slovakia

1

Slovenia

1

1

Spain

2

2

Sweden

1

1

Switzerland

4

4

United
Kingdom

1

1

European
Commission

14

International

7

1

1

5

1

1

14

4

78

5

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Country

Number of stakeholders/experts involved in data collection
Unique total

Total

Involved via interview or e-mail
84

Involved in workshop
52

41

Source: Technopolis Group

Delphi survey respondents
Taking a bottom-up approach to gather more detailed information on Member States as well as the European
Union in general, we sent out a Delphi survey to experts in the field of nuclear medicine. The survey took place
in two rounds during the summer of 2020. The first round was deployed to 800+ named individuals, which yielded
a response rate of ~16% (125). With the help of EANM, DGN and several other national nuclear medicine
societies, as well as several professional LinkedIn groups, a wide invitation was sent out, which yielded 69
responses, a fraction of a percent of the targeted population. In total, 194 full responses were received in the
first round – including from non-EU countries Norway, USA, Israel, Switzerland, and even Kazakhstan. Round two
was only sent to the 175 EU-respondents of the first round and yielded a 48% response rate with 84 full
responses.
Figure 24 shows the responses per EU member state. At a national level, the response rate was not very high
except for the first 7 countries (NL, IT, PT, BE DE, IE, UK). In terms of representativity, the responses for these
countries seem sufficient. Also, in smaller member states, such as Luxembourg, Estonia and Cyprus, we have
reached a representative sample of respondents (as was indicated by some of our contacts). Nevertheless, at the
European level, this group of respondents provides a sufficient sample of professionals to represent larger
developments in supply and demand.

79

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Figure 24 Survey respondents per member state (per round)

Note: only respondents to round 1 were invited to round 2

In terms of the profession of the respondents, Figure 25 shows the main respondents were medical doctors
(predominantly nuclear medicine), with as sizeable group of pharmacists, researchers, and physicists.

80

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Figure 25 Profession of respondents (per round)

Most of the respondents were active in the application or patient delivery (see Figure 26), however there were
quite some respondents from other parts of the supply chain. It needs to be noted that respondents were
allowed to select several supply chain positions.
Figure 26 Activity in the supply chain (per round)

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Country factsheets
The following appendices present the country factsheets that have been filled based on the available information
in our survey, and (where relevant) interviews, email exchanges, and other sources of information.
Note that the provided information differs per country. In the overview below we provide insight in the
completeness of the information and the robustness per section of the factsheet.
Completeness is our assessment of the amount of information we received from our sources, taking into
consideration that different sources may have complemented each other. This is indicated with the colour: dark
green is more complete information from several sources, light green indicates some sources, and light red
indicates no sources or no information available.
Robustness relates to the types of sources used to gather the information. Letters indicate sources and in case
more than one source is mentioned, this allowed for triangulation of the data. D=official (statistical) data;
I=interviews and email exchanges; S=survey; L=supporting literature; C=database of clinical trials (own analysis).
Whereas this information is based on the different data gathering methods at our disposal, we have encountered
both positive support from national representatives as well as what could be called “fatigue” at being asked the
same questions again (note that both HERCA and UNSCEAR had recently deployed surveys with similar
questions). All communication explicitly mentioned the openness of the report, which we believe should be a
positive incentive to most respondents involved.

Country

1 - RP used

2 - emerging
RP

4 - prices

5 - medical
guidelines

6 - future

7 - supply

8 - access

Austria

S

C

S

S

S

S

L

Belgium

DS

C

D

DS

DS

S

IS

DI

Bulgaria

IS

C

IS

S

IS

S

S

I

Croatia

IS

C

SL

S

S

S

S

I

Cyprus

IS

C

IS

D

S

S

IS

s

Czechia

DI

DI

DI

DIL

D

I

I

IL

Denmark

ID

C

I

S

Estonia

SI

Finland

S

France

3 - therapies

SI

I

I

S

I

I

C

S

S

S

S

L

L

SI

C

S

L

D

S

Germany

IS

C

S

S

S

S

S

DS

Greece

S

C

L

IS

IS

S

IS

L

Hungary

S

C

IS

S

S

S

S

L

Ireland

IS

I

IS

I

IS

I

IL

Italy

IS

C

S

S

S

S

IL

Latvia

S

C

S

Lithuania

S

Luxembourg

S

C

S

S

L

SL

S

82

L

S
S

S

S
S

L

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Malta
Netherlands

DIS

C

DL

IS

ISL

S

IS

DI

Poland

IS

C

IS

IL

D

S

I

I

Portugal

IS

C

IS

S

S

S

S

I

Romania

S

C

IS

I

I

S

L

Slovakia

DI

C

I

I

I

S

Slovenia

DS

C

DL

IS

I

I

I

DI

Spain

S

C

S

ISL

I

IS

IS

IL

Sweden

DI

C

D

I

I

I

I

UK

IS

IC

I

DI

I

I

IL

I

DIL

Austria – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 153Sm, 169Er, 177Lu, 186Re, 223Ra, 225Ac, 90Y
The above listed RNs have been indicated in the survey.

2.

Emerging radionuclides / radiopharmaceuticals

Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

177Lu-OPS201, Satoreotide tetraxetan

Neuroendocrine Tumours

Ipsen: Study to Evaluate the
Safety and Preliminary Efficacy of
177Lu-OPS201 in NETs

Neuroendocrine Tumours

ITM Solucin GmbH: Efficacy and
Safety of 177Lu-edotreotide PRRT
in GEP-NET Patients

Non-Hodgkin Lymphoma,
Follicular Lymphoma

Nordic Nanovector: A Phase I/II
Study of Betalutin® for Treatment
of Relapsed Non-Hodgkin
Lymphoma

Neoplasms

AAA: [177Lu]-NeoB in Patients
With Advanced Solid Tumours
and With [68Ga]-NeoB Lesion
Uptake

(Phase 1/2)
177Lu-edotreotide PRRT, Everolimu,

Amino-Acid Solution
(Phase 3)
177Lu-lilitomab (Betalutin®)

(Phase 1/2)

177Lu / 68Ga

[177Lu]-NeoB|[68Ga]-NeoB
(Phase 1/2)

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

3.

Therapies and procedures

According to the 2008 UNSCEAR Global Survey of Medical Radiation Usage and Exposure, 6250 therapeutic
treatments in nuclear medicine are performed in Austria.
Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of data

Average dose
per
procedure
(MBq)

National
annual
demand
(GBq)

90Y

90Y-colloids used in radiation

360

Survey

203

73

synovectomy
90Y

[90Y]Y-ibritumomab-tiuxetan used in
b-cell lymphoma and non-hodgkin
lymphoma (EMA authorised)

2

Survey

1000

2

90Y

90Y-resin microspheres used in intra-

2

Survey

3000

6

arterial treatments in the liver
131I

[131I]I-mIBG (IOBENGUANE) used in
adult neuroendocrine tumours (EMA
authorised)

5

Survey

7450

37

131I

[131I]I-mIBG (IOBENGUANE) used in
neuroblastoma (EMA authorised)

14

Survey

7450

104

131I

[131I]-NaI used in benign thyroid
diseases

1366

Survey

500

683

131I

[131I]-NaI used in thyroid cancer
therapy for adults

697

Survey

5500

3834

131I

[131I]-NaI used in thyroid cancer
therapy for children and young adults

119

Survey

1942

231

131I

[131I]-NaI used in thyroid remnant
ablation of adults

1540

Survey

3000

4620

131I

[131I]-NaI used in thyroid remnant
ablation of children and young adults

189

Survey

1942

367

177Lu

177Lu-antibodies used in non-hodgkin

7

Survey

1062

7

lymphoma
177Lu

[177Lu]Lu-DOTATATE used in
gastroenteropancreatic
neuroendocrine tumours (EMA
authorised)

756

Survey

6475

4895

177Lu

[177Lu]Lu-PSMA used in therapy of
castration resistant prostate cancer
and pc-metastases

1232

Survey

7400

9117

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of data

Average dose
per
procedure
(MBq)

National
annual
demand
(GBq)

223Ra

[223Ra]RaCl2 used in bone metastases
(EMA authorised)

237

Survey

3,85

1

153Sm

[153Sm]Sm-EDTMP used in bone
metastases (EMA authorised)

21

Survey

3133

66

169Er

169Er-colloids used in radiation

1050

Survey

25

26

36

Survey

111

4

synovectomy
186Re

186Re-colloids used in radiation

synovectomy

4.

Prices and reimbursement

Radio-pharmaceutical

Price (€)

Other information / reflection on distributors

[131I]-NaI

€41-€400 per GBq (from survey)

From survey: Curium Pharma/THP and GE

[131I]I-mIBG
[223Ra]RaCl2

From survey: GE and Polatom
€4300-€4400 (from survey)

From survey: BAYER

[90Y]Y-ibritumomab-tiuxetan

From survey: Curium Pharma/THP and IBA

90Y-resin microspheres

From survey: IBA/ Curium Pharma

186Re

From survey: Curium Pharma/THP and IBA

169Er

From survey: Curium Pharma/THP

90Y-colloids

From survey: Curium Pharma/THP and IBA

[177Lu]Lu-PSMA

From survey: FZ Sibersdorf/BSM and ITG

177Lu-colloids

From survey: ITG

153Sm

From survey: Curium Pharma/THP

5.

Medical guidelines

According to the survey responses Austria uses both European and national clinical guidelines for all relevant
radiopharmaceuticals.

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6.

Future demand

Radionuclide

Growth / Number of Patients Expected to receive
therapy in future

Source of data

177Lu-peptides

Respondent believes RP will strongly increase
(+15%) in 10 years

Survey

177Lu-antibodies

Respondent believes RP will strongly increase
(+15%) in 10 years

Survey

[225Ac]Ac-PSMA

Respondent believes RP will strongly increase
(+15%) in 10 years

Survey

166Ho-microspheres

Respondent believes RP will strongly increase
(+15%) in 10 years

Survey

[177Lu]Lu-PSMA

Respondent believes RP will strongly increase
(+15%) in 10 years

Survey

[223Ra]RaCl2

Respondent believes RP will strongly decrease (15%) in 10 years

Survey

[153Sm]Sm-EDTMP

Respondent believes RP will strongly decrease (15%) in 10 years

Survey

The expected strong decrease of the demand for [223Ra]RaCl2 is due to replacement of the radiopharmaceutical
with either [177Lu]Lu-PSMA or [225Ac]Ac-PSMA as soon as these radiopharmaceuticals receive market
authorisation and their use described in clinical guidelines. For 177Lu, a strong increase is expected for labelled
antibodies and peptides once they enter the clinic or receive marketing authorisation.
7.

Supply situation

In Austria supply issues only happened rarely (1-2 times in five years) for [131I]-NaI, which had to a great extent
impact on patients. The supply issue was caused by technical issues during external production. No other supply
issues have been reported in the survey.

8.

Patient access to radionuclide therapy (e.g. regional differences)

•

Number of radiopharmacies:
Unknown, but likely similar to number of radionuclide therapy practicing centres.

•

Number of radionuclide therapy practicing centres:
According to Gleisner (2017) Austria has 7 (inpatient) practicing centres for radionuclide therapy in 20152016.

9.

Sources of information / References

[1] Both surveys (N = 4 in Round 1 and N = 1 in Round 2) of this study (2020)

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[2] Gleisner, K. S., Spezi, E., Solny, P., et al. (2017). Variations in the practice of molecular radiotherapy and
implementation of dosimetry: results from a European survey. EJNMMI physics, 4(1), 28.
[3] ClinicalTrials.Gov database (2020)

Belgium – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 90Y, 131I, 153Sm, 166Ho, 177Lu, 186Re, 223Ra, 213Bi
Radionuclides in bold have been listed by FANC and were confirmed by the survey. Underlined RNs have been
indicated in the survey, but are likely only rare RNs in experimental use.

2.

Emerging radionuclides / radiopharmaceuticals

[177Lu]Lu-DOTATATE is currently only supplied under magistral preparation as it is not officially registered yet.
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

177Lu-3BP-227 (also

Pancreatic Ductal Adenocarcinoma,
Colorectal Cancer, Gastric Cancer,
Squamous Cell Carcinoma of the
Head and Neck, Bone Cancer,
Metastatic Tumours

Ipsen: Study to Evaluate the Safety and
Activity (Including Distribution) of 177Lu3BP-227 in Subjects With Solid Tumours
Expressing Neurotensin Receptor Type
1.

Gastroenteropancreatic
Neuroendocrine Tumours,
Neuroendocrine Tumours

Jules Bordet Institute: 177Lutetiumoctreotate Treatment Prediction Using
Multimodality Imaging in Refractory
NETs

Prostate Cancer

Endocyte: Study of [177Lu]Lu-PSMA-617
In Metastatic Castrate-Resistant
Prostate Cancer

Carcinoid Tumour of the Small
Bowel, Neuroendocrine Tumour

AAA: A Study Comparing Treatment
With 177Lu-DOTA0-Tyr3-Octreotate to
Octreotide LAR in Patients With
Inoperable, Progressive, Somatostatin
Receptor Positive Midgut Carcinoid
Tumours

Non-Hodgkin Lymphoma, Follicular
Lymphoma

Nordic Nanovector: A Phase I/II Study of
Betalutin® for Treatment of Relapsed
Non-Hodgkin Lymphoma

Intrahepatic Cholangiocarcinoma

Sirtex Medical: SIRT Followed by CISGEM Chemotherapy Versus CIS-GEM
Chemotherapy Alone as 1st Line
Treatment of Patients With
Unresectable Intrahepatic
Cholangiocarcinoma

called 177LuIPN01087)
(Phase 1/2)
[177Lu]Lu-DOTATATE
(Phase 3)

[177Lu]Lu-PSMA
(Phase 3)
[177Lu]Lu-DOTATATE
(Phase 3)

177Lu-lilitomab

(Betalutin®)
(Phase 1/2)
90Y

90Y SIRT +

chemotherapy
(Phase 2/3)

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Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

90Y / 131I

131I/90Y

Hepatocellular Carcinoma (HCC)

Ghent University Hospital: Transarterial
RAdioembolisation Versus
ChemoEmbolization for the Treatment
of Hepatocellular Carcinoma

Prostate Cancer

European Organisation for Research and
Treatment of Cancer – EORTC:
Comparing Enzalutamide vs. a
Combination of Ra223 and Enzalutamide
in Asymptomatic or Mildly Symptomatic
Castration Resistant Prostate Cancer
Patients Metastatic to Bone.

Carcinoma, Non-Small-Cell Lung,
Non-small Cell Lung Cancer

BAYER: An Open-label, Multicenter,
Phase 1/2 Study of Radium-223
Dichloride in Combination With
Pembrolizumab in Participants With
Stage IV Non-small Cell Lung Cancer

radioembolisation +
TACE-DEB) (Phase 2)

223Ra

223Ra, Enzalutamide

(Phase 3)

[223Ra]RaCl2,
Pembrolizumab
(Phase 1/2)

3.

Therapies and procedures

Radiopharmaceutical

Number of Patients receiving
therapy per year

Number of procedures

Activity
(2019)

Source
of data

[131I]-NaI

2729

2729

4204.49 GBq

FANC

[131I]I-mIBG

19

19

45.56 GBq

FANC

90Y-Cl (precursor for

-

-

10.63 GBq

FANC

90Y-colloid (citrate)

28

28

7606.81 GBq

FANC

90Y-microspheres

251

251

1426.95 GBq

FANC

[177Lu]Lu-PSMA

25 (calculated: 2 injections
per patient)

50 (calculated from average
patient dose of 7400 MBq)

371.37 GBq

FANC

[177Lu]Lu-DOTATATE

25 (calculated: 4 injections
per patient)

100 (calculated from average
patient dose of 6475 MBq)

651.24 GBq

FANC

[153Sm]Sm-EDTMP

-

11

27.45 GBq

FANC

166Ho-microspheres

-

-

5.2 GBq

FANC

186Re-sulphide

-

2 (calculated from average
patient dose of 111 MBq)

208 MBq

FANC

per year (2018)

[90Y]Y-ibritumomabtiuxetan)

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Radiopharmaceutical

Number of Patients receiving
therapy per year

Number of procedures

[223Ra]RaCl2

250

1498

4.

per year (2018)

Activity
(2019)

Source
of data

26.52 GBq

FANC

Prices and reimbursement

Information on prices, producers and reimbursement in Belgium is monthly updated and published on the
website of the national health insurance institute of Belgium: https://www.riziv.fgov.be/nl/themas/kostterugbetaling/door-ziekenfonds/geneesmiddelgezondheidsproduct/terugbetalen/radiopharma/Paginas/vergoedbare-radiofarmaceutische-referentielijstenreferentiebestanden.aspx
Radiopharmaceutical

Price (€)

Type of
procedure

Total budget
spent per
year

Calculation
method

Other information /
reflection on
distributors

[131I]-NaI

€166-€960
(depending on
supplier and
activity)

Capsule

€453k€2.62M

No. of
procedures x
price

Producers: CIS BIO
International
(CAPSION),
Mallinckrodt/ Curium
Pharma (CAPSULE T),
GE Healthcare
(THERACAP®)

€3060-€7242
(depending on
activity)

Injection

No. of
procedures x
price

Producer: CIS BIO
International

€2290

Precursor

[131I]I-mIBG

90Y-Cl (precursor for

(calculated
estimate)

€58k-€138k
(calculated
estimate)
-

[90Y]Y-ibritumomabtiuxetan)

Producer: CIS BIO
International
Additional
reimbursement
condition:
Reimbursable for the
radiolabeling of
ibritumomabtiuxetan,
for the treatment, in
third line or later, of
adult patients with
rituximab relapsed or
refractory CD20+
follicular B-cell nonHodgkin's lymphoma
(NHL) stage III and IV.
Ibritumomabtiuxetan is
reimbursable only once
in patient’s life time.

[90Y]Y-ibritumomabtiuxetan (Zevalin®)

€8255

Injection

-

89

Producer: SPECTRUM
Pharmaceuticals BV

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Radiopharmaceutical

Price (€)

Type of
procedure

Total budget
spent per
year

Calculation
method

Other information /
reflection on
distributors
Same additional
reimbursement
condition as 90Y-Cl (this
RPs precursor)

90Y-colloid (citrate)

90Y-microspheres

€264-€437
(depending on
activity)

Injection

€7.39k€12.2k
(calculated
estimate)

€12.000 €15.000
(depending
onsupplier,
independent
on activity)

€3.01M€3.77M
(calculated
estimate)

[177Lu]Lu-PSMA

-

Injection

-

[177Lu]Lu-DOTATATE

Costs about
€4.000 to
produce inhouse,
commercial
price is
expected to
be around
€12.000

Injection

€400k€1.20M

[153Sm]Sm-EDTMP
(samarium
lexidronaat,
QUARDAMET®)

€1300

Injection

166Ho-microspheres

€15000

(calculated
estimate)

€14.3k
(calculated
estimate)

Microspheres

No. of
procedures x
price

Producer: CIS BIO
International

No. of
procedures x
price

Producers: SIRTEX
Medical Europe,
BIOCOMPATIBLES UK
Ltd

Not reimbursed
No. of
procedures x
price

Not reimbursed, but
request has been
submitted to add to list
of reimbursable RPs.
Until then, only
produced in-house by
some hospitals using
177Lu from ITG.

No. of
procedures x
price

Supplier: CIS BIO
International

-

Supplier: TERUMO
Europe NV

-

Not reimbursed

(Quirem spheres®)
186Re-sulphide

-

[223Ra]RaCl2
(Xofigo®)

€4400 (per
injection)

Injection

€6.59M
(calculated
estimate)

No. of units
administered
(no. of injections)
x price

Producer: BAYER
Additional
reimbursement
conditions:
a) Reimbursable for the
treatment of adult
patients with
metastatic castrationresistant prostate
cancer (mCRPC),
symptomatic bone

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Radiopharmaceutical

Price (€)

Type of
procedure

Total budget
spent per
year

Calculation
method

Other information /
reflection on
distributors
metastases and no
known visceral
metastases, in
progression after at
least two prior lines of
systemic therapy for
mCRPC (other than
LHRH analogues), or
ineligible for any
available systemic
mCRPC treatment
b) maximum 6 vials
reimbursable per
patient (max 1 vial
every 4 weeks). Per
administration
maximum 1 vial is
reimbursable, if needed
the second vial is
delivered for free by
the company.

5.

Medical guidelines

In Belgium the EANM guidelines and SNMMI guidelines are used. There are several advices from the Belgian
Higher Health Council (advisory body of the Federal Public Service Health) which can be found on the FANC
website (https://fanc.fgov.be/nl/studies-en-projecten):
•

https://fanc.fgov.be/system/files/aanbeveling_inzake_therapie_door_middel_van_radionucliden_onder_n
iet-ingekapselde_vorm.pdf

•

https://fanc.fgov.be/system/files/radionuclide_therapy_for_symptomatic_prostate_cancer_in_castrationresistant_prostate_cancer_patients_with_raci.pdf

•

https://fanc.fgov.be/system/files/peptide_receptor_radionuclide_therapy.pdf

•

https://fanc.fgov.be/system/files/advies_betreffende_de_problematiek_van_de_crematie_van_overleden
_dragers_van_radioactieve_bronnen.pdf

6.

Future demand

90

Y microspheres currently used are expected to be in-part replaced by 166Ho microspheres, as these are magnetic
and therefore can be traced in MRI scanners.
[177Lu]Lu-DOTATATE is expected to be used a lot in the future, depending on approval for use on several
indications. Use requires however significant infrastructural investments by hospitals (see supply situation),
which may spread growth over several years.

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Radionuclide

Growth / Number of Patients
Expected to receive therapy in future

Source of
data

[177Lu]Lu-PSMA

80% of respondents believes RP will strongly increase (>15%), while 20%
believes RP will increase (1-15%) in 10 years

Survey
(N=5)

[177Lu]Lu-DOTATATE

60% of respondents believes RP will strongly increase (>15%), while 40%
believes RP will increase (1-15%) in 10 years

Survey
(N=5)

[225Ac]Ac-PSMA

67% of respondents believes RP will strongly increase (>15%), while 33%
believes RP will increase (1-15%) in 10 years

Survey
(N=3)

177Lu-antibodies

67% of respondents believes RP will strongly increase (>15%), while 33%
believes RP will increase (1-15%) in 10 years

Survey
(N=3)

177Lu-peptides

67% of respondents believes RP will strongly increase (>15%), while 33%
believes RP will increase (1-15%) in 10 years

Survey
(N=3)

166Ho-microspheres

(HoMS)

50% of respondents believes RP will strongly increase (>15%), while 50%
believes RP will increase (1-15%) in 10 years

Survey
(N=2)

32P-sodium-

Respondent believes RP will decrease (-1% - -15%) in 10 years

Survey
(N=1)

227Th-conjugate

Respondent believes RP will strongly increase (>15%) in 10 years

Survey
(N=1)

227Th-antibody

Respondent believes RP will increase (1-15%) in 10 years

Survey
(N=1)

[89Sr]SrCl2

Respondent believes RP will decrease (-1% - -15%) in 10 years

Survey
(N=1)

[153Sm]Sm-EDTMP

67% of respondents believe RP will decrease (-1% - -15%), while 33% believes
RP will remain stable in 10 years

Survey
(N=3)

[223Ra]RaCl2

50% of respondents believe RP will remain stable, while 50% believes RP will
decrease (-1% - -15%) in 10 years

Survey
(N=4)

phosphate

7.

Supply situation

In Belgium supply issues only happened rarely (1-2 times in five years) for [131I]-NaI, which had to a small extent
impact on patients. The supply issue was caused by reactor issues during external production of the radionuclide.
No other supply issues have been reported in the survey.
[177Lu]Lu-DOTATATE is currently produced in-house in some centres in Belgium, using supply of 177Lu by ITG. Only
these hospitals use this RP, roughly 2 treatments/week fulfilling current demand (each patient will receive 4
treatments with 2-3 months interval). Requires special beds and infrastructure: 24h stay is needed and urine and
faeces need to be collected and disposed as radioactive waste. Some hospitals are investing in this infrastructure
so that they can use this RP once it is licenced for the treatment of multiple cancers. This determines future
demand.

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SCK-Mol and IRE are collaborating to produce 225Ac with linear accelerators. They are currently investing to
produce this RN for world supply. This is an alpha emitter that is expected to be growing in clinical use over 10
years.

8.

Patient access to radionuclide therapy (e.g. regional differences)

In Belgium hospitals work in hubs and spokes, with central hospitals performing most RN therapy, while
peripheral hospitals refer their patients to these hospitals. This results in a good access and coverage of RN
therapy across the country.
•

Number of radiopharmacies:
Unknown, but likely similar to number of radionuclide therapy practicing centres.

•

Number of radionuclide therapy practicing centres:
According to the Belgian competent authority FANC, 136 centres are performing any form of radionuclide
therapy in Belgium. Roughly 7 of these centres perform a wider scala of (more complex) RN therapies.

9.

Sources of information / References

[1] Information based on interview (2020) with Dr. Patrick Flamen (chair of BELNUC workgroup regarding
development of therapeutic radionuclides) from the Jules Bordet Institute of the Université Libre de Bruxelles
(ULB).
[2] Information based on extensive national data provided by FANC, resulting from communications with Annie
Vanderlinck from FANC (2020)
[3] Information based on public data from RIZIV (2020), the Belgian institute for health and disability insurance,
see:
https://www.riziv.fgov.be/nl/themas/kost-terugbetaling/door-ziekenfonds/geneesmiddelgezondheidsproduct/terugbetalen/radiopharma/Paginas/vergoedbare-radiofarmaceutische-referentielijstenreferentiebestanden.aspx
[4] Both surveys (N = 11 in Round 1 and N = 5 in Round 2) of this study (2020)
[5] Gleisner, K. S., Spezi, E., Solny, P., et al. (2017). Variations in the practice of molecular radiotherapy and
implementation of dosimetry: results from a European survey. EJNMMI physics, 4(1), 28.
[6] ClinicalTrials.Gov database (2020)

Bulgaria – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 223Ra, 153Sm
Radiopharmaceuticals in compassionate use: none reported

2.

Emerging radionuclides/radiopharmaceuticals

Radiopharmaceuticals in experimental use (clinical trials): none reported in Technopolis clinical trials analysis

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3.

Therapies and procedures

Radiopharmaceutical

Indication
and type of procedure

Number of
procedures

Source of
data

Activity per
procedure
(MBq)

Total annual
activity
(MBq)

per year
[131I]-NaI

Benign thyroid diseases

2000

Survey

500

1,000,000

[223Ra]RaCl2

Bone metastases

30

Survey

3.8

114

153Sm

Bone metastases

n/a

n/a

n/a

n/a

4.

Prices and reimbursement

Information based on survey
Radiopharmaceutical

Price per patient dose in € [mean (min,
max)]

Number of procedures

131I

325 (200, 450)

2000

€650,000

[223Ra]RaCl2

5,000, (5,000, 5,000)

30

€150,000

5.

per year

Total budget spent per
year

Medical guidelines

National and organisational guidelines are used [1], [2]

6.

Future demand

Radionuclide

Growth / Number of Patients

Source of data

Expected to receive therapy in future
[153Sm]Sm-EDTMP

100% of Bulgarian respondents expect there to be a weak decrease (-1% to
-15%) in demand

[1]

177Lu-peptides

100% of Bulgarian respondents expect there to be a weak increase (+1% to
+15%) in demand

[1]

[177Lu]Lu-PSMA

100% of Bulgarian respondents expect there to be a weak increase (+1% to
+15%) in demand

[1]

[223Ra]RaCl2

100% of Bulgarian respondents expect there to be a strong decrease (<15%) in demand

[1]

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Radionuclide

Growth / Number of Patients

Source of data

Expected to receive therapy in future
[89Sr]SrCl2

100% of Bulgarian respondents expect there to be a strong decrease (<15%) in demand

[1]

7.

Supply situation

•

[131I]-NaI - 100% of relevant respondents suggested that [131I]-NaI had been shortage sometimes (3-4 times)
over the last 5 years. These shortages were reported to have happened due to procurement issues.

8.

Patient access to radionuclide therapy (e.g. regional differences)

•

Number of radiotherapy practicing centres:
There are 10 radiotherapy practicing centres in Bulgaria [2]

9.

Other information

Radiopharmaceuticals are imported to Bulgaria as there are no small-scale facilities for preparation of
radiopharmaceuticals for therapeutic purposes.

10. Sources of information / References
[1] Technopolis survey (N = 2)
[2] E-mail exchange with Professor Valeria Hadzhiyska, Head of Clinic of Nuclear medicine, University Hospital
Alexandrovska

Croatia – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 177Lu, 223Ra, 90Y
Radiopharmaceuticals in compassionate use: none reported

2.

Emerging radionuclides / radiopharmaceuticals

Radiopharmaceuticals in experimental use (clinical trials):
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

177Lu-antibodies

Relapsed Non-Hodgkin Lymphoma

Yes - Phase I/II

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3.

Therapies and procedures

According to the 2008 UNSCEAR Global Survey of Medical Radiation Usage and Exposure, 1274 therapeutic
treatments in nuclear medicine are performed in Croatia, however, our current estimates place this number
much higher.
Radiopharmaceutical

Indication and type
of procedure

Estimates
number of
annual
procedures

Source of
data

Average
activity per
procedure

Activity
(MBq)

[131I]-NaI

Benign thyroid
diseases

4176

Survey

500

2,088,000

[131I]-NaI

Thyroid remnant
ablation of adults

2940

Survey

3000

8,820,000

[131I]-NaI

Thyroid cancer
therapy for adults

1320

Survey

5550

7,326,000

[223Ra]RaCl2

Bone metastases

72

Survey

3.8

274

[131I]-NaI

Thyroid remnant
ablation of children
and young adults

408

Survey

1942

792,540

[131I]-NaI

Thyroid cancer
therapy for children
and young adults

138

Survey

1942

268,065

[131I]I-mIBG (IOBENGUANE)

Neuroendocrine
tumours

42

Survey

7450

312,900

[131I]I-mIBG (IOBENGUANE)

Neuroblastoma

102

Survey

7450

759,900

[90Y]Y-ibritumomab-tiuxetan

B-cell lymphoma
and non-hodgkin
lymphoma

6

Survey

1000

6,000

177Lu-antibodies

Non-hodgkin
lymphoma

6

Survey

1062

6,372

4.

Prices and reimbursement

Information based on survey
Radiopharmaceutical

Price per patient dose in € mean (min, max)

[131I]-NaI

100 (50, 150)

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Radiopharmaceutical

Price per patient dose in € mean (min, max)

[131I]I-mIBG (IOBENGUANE)

1976 (1976, 1976)

[223Ra]RaCl2

4300 (4300, 4300)

5.

Medical guidelines

Croatia uses both European (e.g. the EANM) and national medical guidelines for radiotherapy according to survey
respondents.

6.

Future demand

Radionuclide

Growth / Number of Patients

Source
of data

Expected to receive therapy in future
[225Ac]Ac-PSMA

75% of Croatian respondents expect there to be a weak increase (+1 to +15%) in demand.
Another 25% expect there to be strong increase in demand (> +15%)

[1]

[177Lu]LuDOTATATE

100% of Croatian respondents expect there to be a weak increase (+1 to +15%) in
demand.

[1]

177Lu-peptides

75% of Croatian respondents expect there to be a weak increase (+1 to +15%) in demand.

[1]

[177Lu]Lu-PSMA

100% of Croatian respondents expect there to be a weak increase (+1 to +15%) in
demand.

[1]

7.

Supply situation

No significant issues have been reported

8.

Patient access to radionuclide therapy

Number of radiotherapy practicing centres: 12 [2]

9.

Sources of information / References

[1] Technopolis survey (N = 4)
[2] E-mail exchange with Zdravka Tečić, Head of Radiological and Nuclear Safety, Ministry of the Interior Civil
Protection Department and Boris Ilijas Head of Environment and Radioactive Waste Unit

Cyprus – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: I131I, 153Sm, 177Lu, 223Ra, 225Ac
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Radiopharmaceuticals in compassionate use: 153Sm

2.

Emerging radionuclides / radiopharmaceuticals

Radiopharmaceuticals in experimental use (clinical trials):
Clinical trials analysis suggested that Cyprus is not involved with any radionuclides or radiopharmaceuticals in
clinical trials

3.

Therapies and procedures

Radiopharmaceutical

Indication and type of
procedure

Number of
procedures
per year

Source of
data

Average
dose per
procedure
(MBq)

Activity (MBq)

[223Ra]RaCl2 (Xofigo®)

Bone metastases

27

National
statistics

3.8

103

131-NaI

Thyroid remnant ablation
(adults)

110116

National
statistics

3,000

330,000

131-NaI

Thyroid remnant ablation
(young adults and
children)

110

National
statistics

327.5

36,020

4.

Prices and reimbursement

Radiopharmaceutical

Price (€)

Number of annual
procedures

Total budget spent
per year

[131I]-NaI

€160-€320 per patient dose

210

€33,600 - €67,200

[131I]I-mIBG

€253/vial

n/a

-

[223Ra]RaCl2

€5000 per patient dose

27

€135,000

5.

Medical guidelines

Information from survey

116 Data did not specify distribution of treatments between adults, young adults and children, so a 50/50 split was assumed

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Radiopharmaceutical

Indication

Guideline making
organisation

Title of/link to guideline

131I

Thyroid remnant ablation
(adults, young adults and
children)

EANM

Guidelines for radioiodine therapy of
differentiated thyroid cancer

[223Ra]RaCl2

Bone metastases

EANM

EANM guideline for radionuclide therapy
with radium-223 of metastatic
castration-resistant prostate cancer

6.

Future demand

Radionuclide

Growth / Number of Patients Expected to receive therapy in future

Source of data

[131I]-NaI

Estimates range between stable an and strong increase (>15%)

[3]

[131I]I-mIBG

Decrease (-1% to -15%

[3]

[177Lu]LuDOTATATE

Increase (+1% to +15%)

[3]

177Lu-peptides

Increase (+1% to +15%)

[3]

[177Lu]Lu-PSMA

Increase (+1% to +15%)

[3]

[225Ac]Ac-PSMA

Increase (+1% to +15%)

[3]

[223Ra]RaCl2

Stay stable or increase (+1% to +15%)

[3]

[153Sm]Sm-EDTMP

Decrease (-1% to -15%

[3]

7.

Supply situation

Cyprus have had several issues due to problems with connected flights to Cyprus. Radionuclides have arrived late
or not at all [1].
Shortages or supply disruption has been reported in Cyprus over the last 5 years for [3]:
•

[131I]-NaI - Reported as being due to transportation issues where flights did not arrive, or flight activity limit
was reached. This was reported as occurring between 1-2 times and more than 4 times). These shortages
were reported to have had to some extent, and in one case to a great extent had a disruptive effect on the
treatment of patients.

•

[177Lu]Lu-PSMA - Reported as being due to transportation issues where flights did not arrive, or flight activity
limit was reached. This was reported as occurring between 1-2 times. These shortages have had a disruptive
effect on the treatment of patients to a small extent.

•

[177Lu]Lu-DOTATATE - Reported as being due to transportation issues where flights did not arrive, or flight
activity limit was reached and also due to production stopping due to COVID-19. This was reported as
occurring between 1-2 times. These shortages have had a disruptive effect on the treatment of patients to
some extent.
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•

[223Ra]RaCl2 - Reported as being due to transportation issues and logistics issues. This was reported as
occurring between 1-2 times. These shortages have had a disruptive effect on the treatment of patients to
a small extent.

One survey respondent suggested that in order to help these issues of shortages specific to Cyprus that “flight
companies should have a process to monitor in advance the activity limits booked for the specific flight and let
the involved people know in advance to make other transport arrangements”.

8.

Patient access to radionuclide therapy (e.g. regional differences)

•

Number of radiotherapy practicing centres:
7 +2 hospitals with therapy rooms, Therapy in 2+2 Hospitals [1]

9.

Other information

Cyprus do not produce any radiopharmaceuticals. They have reported one request for compassionate use of Sm153.

10. Sources of information / References
[1] Email exchange with Demetris Sakkas, Radiation Inspection and Control Service, Cyprus
[2] Nicosia Hospital price data
[3] Technopolis survey (survey respondents N = 3)

Czech Republic – validated
1.

Radiopharmaceuticals currently in use [1]

Radionuclides in use: 131I, 90Y, 153Sm, 89Sr, 223Ra, 186Re,169Er, 177Lu
Radiopharmaceuticals in compassionate use: While allowed, not really used

2.

Emerging radionuclides

Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

225Ac

PSMA-PRRT

mCRPC

N/A

227Th

N/A

N/A

N/A

149Tb

N/A

N/A

N/A

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3.

Therapies and procedures

Information based on data supplied by Czech Society of Nuclear Medicine (CSNM) for 2018 (data selected from
comprehensive statistics of State institute for Drug Control and the Institute of Health Information and Statistics
of the Czech Republic)
Radiopharmaceutical

Number of
Patients

Indication
and type of procedure

Source of
data

Receiving
therapy per
year

Number of
procedures
per year

National
annual
demand
(GBq)

89Sr Metastron®

Bone painful metastases

96

CSNM

96

12.8

[153Sm]Sm-EDTMP

Bone painful metastases

32

CSNM

34

53.5

223Ra

CR prostate cancer

60

CSNM

335

0.0013

90Y-colloid

Synoviorthesis

385

CSNM

390

93.2

186Re-colloid

Synoviorthesis

39

CSNM

39

3.4

169Er-colloid

Synoviorthesis

25

CSNM

25

0.24

131I

Hyperthyroidism

199

CSNM

199

4859

[131I]I-mIBG

Thyroid carcinoma

1093

CSNM

1292

123.2

[131I]I-mIBG

Pheochromocytoma,
neuroblastoma

CSNM

16

[90Y]Y-ibritumomab

Lymphoma

1

CSNM

2

2

177Lu-oxodotreotid

Neuroendocrine Tumours
(NET G1 and G2) and
Neuroendocrine
Carcinomas

30-45

CSNM

120-180

1000
(estimate
from
incidence
data)

(Lutathera®)

4.

Prices and reimbursement

In 2015, the equivalent of €75.4 million (based on 2014 purchasing power parity) was spent on radiotherapy i.e.
a per capita expenditure of €7.2. Radiotherapy accounted for 0.37% of the total healthcare spending and 8.5%
of total cancer care expenditure (Lievens et al. (2020)).
Radiopharmaceutical

Price (€)

Total budget spent
per year (€, 2018)

Calculation
method

89Sr Metastron®

13.28/MBq

169 984.00

Price x no. of MBq
used

101

Other information /
reflection on distributors

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

[153Sm]Sm-EDTMP

0.5/MBq

26 750.00

As above

223Ra

4824.30
/injection

1 616 140.50

As above

90Y-colloid

1.07/MBq

99 724.00

As above

186Re-colloid

2.72/MBq

9 248.00

As above

169Er-colloid

6.67/MBq

1 600.80

As above

131I

0.067/MBq

325 553.00

As above

[131I]I-mIBG

0.44/MBq

54 208.00

As above

[90Y]Y-ibritumomab

19533.34
/injection

39 066.68

Price x no. of
procedures

177Lu-oxodotreotide

22320.12
/injection

3 348 018.00

Price x no. of avg
estimated
procedures

(Lutathera®)

Total

5.

5 690 292.98

Medical guidelines

Radionuclide therapies are covered by
a) EANM guidelines
b) National standards for Clinical Audits in Nuclear Medicine117
c) Summaries of Product characteristics (manufacturer documents)
Radiopharmaceutical

Indication

Guideline making organisation

89Sr Metastron®

Bone painful metastases

European

[153Sm]Sm-EDTMP

Bone painful metastases

European

223Ra

CR prostate cancer

European

90Y-colloid

Synoviorthesis

European

186Re-colloid

Synoviorthesis

European

117 In Czech at http://www.mzcr.cz/Legislativa/dokumenty/vestnik-c2/2016_11347_3442_11.html

102

registered by State
institute for Drug Control
and reimbursed by Health
Insurance Companies since
2020

Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radiopharmaceutical

Indication

Guideline making organisation

169Er-colloid

Synoviorthesis

European

131I

Hyperthyroidism

European

[131I]I-mIBG

Thyroid carcinoma

European

[131I]I-mIBG

Pheochromocytoma,
neuroblastoma

European

[90Y]Y-ibritumomab

Lymphoma

European

177Lu- oxodotreotide

Neuroendocrine Tumours
and Carcinomas

European

Radionuclide

Indication

Number of Patients
expected to receive
therapy in future

Procedures and dosage

Source
of data

177Lu

metastatic castrationresistant prostate cancer
(mCRPC)

200-400/year

3 doses of 6
GBq/patient

CSNM

225Ac (as 177Lu

mCRPC

200-400/year

3 doses of 7
MBq/patient

CSNM

6.

Future demand

alternative)

Radiopharmaceutical

Number of Patients Expected to receive therapy in future

Source of data

[177Lu]Lu-PSMA

Strong increase or increase expected by majority of respondents

Survey(n=4)

[225Ac]Ac-PSMA

Strong increase expected by half of all respondents

Survey(n=4)

[177Lu]Lu-DOTATATE

Strong increase or increase expected by majority of respondents

Survey(n=4)

177Lu-peptides

Increase expected by half of all respondents

Survey(n=4)

177Lu-antibodies

Increase expected by half of all respondents

Survey(n=4)

90Y-colloids

Stable expected by half of all respondents; Increase by a minority

Survey(n=4)

90Y-glass microspheres

Stable expected by half of all respondents

Survey(n=4)

[153Sm]Sm-EDTMP

Stable expected by majority of respondents

Survey(n=4)

131-mIBG

Stable expected by half of all respondents

Survey(n=4)

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Radiopharmaceutical

Number of Patients Expected to receive therapy in future

Source of data

131-NaI

Stable expected by half of all respondents; Increase by a minority

Survey(n=4)

169Er-colloids

Stable expected by majority of respondents

Survey(n=4)

7.

Supply situation

Only registered radionuclides may be imported for human use with the exception of commercial clinical trials
[1]. Transportation of these radiopharmaceuticals is without any problem.
There is no production of radiotherapeutic pharmaceuticals in the Czech Republic [1]. So called all “in-house”
production of diagnostic or therapeutic radiopharmaceuticals (at Universities etc.) is strictly prohibited in the
Czech Republic. Therefore, in clinical practice (except clinical trials) only the use of radiopharmaceuticals
authorised by State Institute for Drug Control is permitted – process of registration copies usually previous EMA
registration or other international European registration. Exceptional cases are transient (2 years) permissions
to use F-choline in patients with hyperparathyroidism and imaging of hypoxia using F-MISO.
Therapeutic PRRT radiopharmaceuticals are not commercially produced in the Czech Republic. Currently there is
no official information on the upcoming marketing authorisation of the PRRT product manufactured in the Czech
Republic.

8.

Patient access to radionuclide therapy

According to Gleisner et al. (2017), there are 4.4 radiotherapy centres per million inhabitants, 47 in total [3].
Among these, according to the CSNM, there are 6 Inpatient radionuclide therapy practicing centres and 4
outpatient radionuclide therapy practicing departments [1]

9. Sources of information / References
[1] Email exchange with Dr Pavel Koranda, Czech Society of Nuclear Medicine (CSNM)
[2] Email exchange with Mr Petr Papírník, State Office for Nuclear Safety, Czech Republic
[3] Gleisner, K. S., Spezi, E., Solny, P., et al. (2017). Variations in the practice of molecular radiotherapy and
implementation of dosimetry: results from a European survey. EJNMMI physics, 4(1), 28.
[4] Lievens, Y., Borras, J. M., & Grau, C. (2020). Provision and use of radiotherapy in Europe. Molecular Oncology.
[5] Technopolis survey (N = 4)

Denmark – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 90Y, 131I, 177Lu, 223Ra
Radiopharmaceutical

Trade Name

Supplier/Distributor

177Lu oxodotreotide

Lutathera®

Advanced Accelerator Application

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Radiopharmaceutical

Trade Name

Supplier/Distributor

223Ra dichloride

Xofigo®

Bayer Pharma AG

153Sm-ethylenediaminetetramethylene

Quadramet®

Cis Bio International Oris Ind.

90Y compounds

Ytracis®

Cis Bio International Oris Ind.

131I sodium iodide

Sodium iodide (I131) capsules
T

Curium Netherlands B.V.

Other therapeutic radiopharmaceuticals

Yttriga®

Eckert & Ziegler

[131I]-iobenguane

(131-I)Metaiodobenzylguanidine therap.
GE Health.

GE Healthcare Buchler GmbH .

[131I]-sodium-iodide

Sodium Iodide (131I) Injection
GE Healthcare Limited

GE Healthcare Buchler GmbH .

[131I]-sodium iodide

Theracap®

GE Healthcare Buchler GmbH .

Other therapeutic radiopharmaceuticals

EndolucinBeta®

ITG Isotope Technologies Garchin

131I sodium iodide

Moniyot-131 Capsule T

Monrol Europe S.R.L.

131I sodium iodide

Moniyot-131 Oral Solution

Monrol Europe S.R.L.

90Y Ibritumomab tiuxetan

Zevalin®

Schering AG

phosphonic acid

2.

Medical guidelines

Overall, EANM guidelines are used with a few local guidelines. Source: [1]

3.

Future demand

Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of data

[131I]-NaI

Respondent expects increase in the next 10 years

Survey (n=1)

177Lu-peptides

Respondent expects increase in the next 10 years

Survey (n=1)

4.

Patient access to radionuclide therapy (e.g. regional differences)

•

Number of radiotherapy practicing centres:
5 large centres (benign and malign) and 9 small centres (benign). Source: [1]

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5.

Sources of information / References

[1] Information received from Dr. Peter Hovind, Danish Society of Clinical Physiology and Nuclear Medicine
[2] Technopolis survey (N = 1)

Estonia – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 32P, 223Ra, 186Re, 169Er,153Sm, 89, 90Y, 177Lu
Radiopharmaceuticals in compassionate use: [177Lu]Lu-DOTATATE

2.

Therapies and procedures

Radiopharmaceutical

Indication and type of procedure

Number of Patients
Receiving therapy per
year

Source of data

131I, 131-MIBG

Differentiated thyroid cancer
(adults)

137 (2019)

Estonian Nuclear Medicine
Society

131I, 131-MIBG

Differentiated thyroid cancer
(children)

137 (2019)

Estonian Nuclear Medicine
Society

131I

Benign thyroid disease

363 (2019)

Estonian Nuclear Medicine
Society

223Ra-dichloride

Bone lesions in prostate cancer

95 (2019)

Estonian Nuclear Medicine
Society

[177Lu]Lu-PSMA

Prostate cancer

31 (2019)

Estonian Nuclear Medicine
Society

90Y-colloid

Radiosynovectomy

6 (2019)

Estonian Nuclear Medicine
Society

186Re-colloid

Radiosynovectomy

1 (2019)

Estonian Nuclear Medicine
Society

(Xofigo®)

Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of data

Average dose
per
procedure
(MBq)

National
annual
demand
(GBq)

90Y

90Y-colloids used in radiation

11

Survey

203

2

synovectomy

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Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of data

Average dose
per
procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]I-mIBG (IOBENGUANE) used in
adult neuroendocrine tumours (EMA
authorised)

2

Survey

7450

15

131I

[131I]I-mIBG (IOBENGUANE) used in
neuroblastoma (EMA authorised)

2

Survey

7450

15

131I

[131I]-NaI used in benign thyroid
diseases

660

Survey

500

330

131I

[131I]-NaI used in thyroid cancer
therapy for adults

143

Survey

5500

787

131I

[131I]-NaI used in thyroid cancer
therapy for children and young adults

12

Survey

1942

23

131I

[131I]-NaI used in thyroid remnant
ablation of adults

308

Survey

3000

923

131I

[131I]-NaI used in thyroid remnant
ablation of children and young adults

9

Survey

1942

17

177Lu

[177Lu]Lu-DOTATATE used in
gastroenteropancreatic
neuroendocrine tumours (EMA
authorised)

3

Survey

6475

19

177Lu

[177Lu]Lu-PSMA used in therapy of
castration resistant prostate cancer
and pc-metastases

45

Survey

7400

333

223Ra

[223Ra]RaCl2 used in bone metastases
(EMA authorised)

108

Survey

3.85

0.4

32P

32P-sodium-phosphate used in

3

Survey

185

1

myeloproliferative disease
89Sr

[89Sr]SrCl2 used in bone metastases
(EMA authorised)

6

Survey

150

1

153Sm

[153Sm]Sm-EDTMP used in bone
metastases (EMA authorised)

6

Survey

3133

19

186Re

186Re-colloids used in radiation

2

Survey

111

0.2

synovectomy

3.

Prices and reimbursement

107

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Source: [1]
Radiopharmaceutical

Price (€)

Type of procedure

Supplier/Distributor

All reimbursement sums; price per
procedure
[131I]-NaI

1066 EUR

treatment of Thyroid cancer
with131I

Curium; GE

[131I]-NaI

588 EUR

treatment of Thyrotoxicosis
with 131I

Curium; GE

[131I]I-mIBG

7355 EUR

treatment of NET with
[131I]I-mIBG

153 Sm-EDTMP

1959 EUR

palliative treatment of bone
metastasis with [153Sm]SmEDTMP

CisBio, Curium Pharma

89Sr -chloride

1643 EUR

palliative treatment of bone
metastasis with 89Sr chloride

GE; Polatom

223Ra-dichloride

27 EUR + radiopharmaceutical 4803
EUR (limited to 1st, 2nd, 3rd and 6th
dose, each)

treatment of bone
metastasis with 223Radichloride

Bayer

169Er

3404 EUR (reimbursement for one
procedure, which can include the
treatment of several joints at one
time)

radiosynovectomy with
169Er for small joints

90Y

938 EUR (per procedure per joint)

radiosynovectomy with 90Y
for medium and large joints

186Re

938 EUR (per procedure per joint)

radiosynovectomy with
169Er for medium and large
joints

[177Lu]Lu-PSMA-ligand

currently no reimbursement,
however the hospital may perform
treatment without reimbursement

treatment of prostate
cancer with [177Lu]Lu-PSMAligand

[177Lu]Lu-DOTATATE

-

-

4.

CisBio, Curium Pharma

AAA Novartis

Medical guidelines

Mainly EANM/SNMMI guidelines are used. Institutional guidelines in Estonian are in place. Thyroid cancer
treatments are also covered by ATA (American Thyroid Association)/ETA (European Thyroid Association)
guidelines, bone pain palliation by ESMO (European Society for Medical Oncology) and NCCN guidelines (National
Comprehensive Cancer Network).

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5.

Future demand

Radiopharmaceutical

Demand expectation

Source of data

[177Lu]Lu-DOTATATE

Strong increase (more than +15%)

Survey

[177Lu]Lu-PSMA

Strong increase (more than +15%)

Survey

[89Sr]SrCl2

Strong decrease (more than -15%)

Survey

6.

Supply situation

As radiopharmacies with only operational level 2 are in operation in the country, all therapeutic
radiopharmaceuticals are imported. [1]

7.

Patient access to radionuclide therapy (e.g. regional differences)

There are three hospitals in the country that practice nuclear medicine, incl. therapy with radionuclides. All of
them have a radiopharmacy with operational level 2 (according to IAEA classification). There are two hospitals in
the country that practice external beam radiotherapy and HDR therapy. And finally, there is one hospital that
uses brachytherapy in ophthalmology. [1]

8.

Sources of information / References

[1] Information received from Dr. Sergej Nazarenko, Estonian Nuclear Medicine Society
[2] Survey responses (N = 3), Technopolis Group

Finland – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: [131I]-NaI, [177Lu]Lu-DOTATATE, 90Y-glass microspheres, [131I]I-mIBG, 186Re-colloids. [1]

2.

Therapies and procedures

Radiopharmaceutical

Indication

Number of procedures

Activity
(GBq)

Source of
data

and type of procedure

per year

[131I]-NaI

benign thyroid diseases

155

77

[1]

[131I]-NaI

thyroid remnant ablation of
adults

99

297

[1]

[131I]-NaI

thyroid remnant ablation of
children and young adults

3

6

[1]

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Activity
(GBq)

Source of
data

3

17

[1]

thyroid cancer therapy for
children and young adults

8

15

[1]

[131I]I-mIBG

neuroblastoma

2

11

[1]

[131I]I-mIBG (IOBENGUANE)

adult neuroendocrine tumours

2

11

[1]

[177Lu]Lu-PSMA

therapy of castration resistant
prostate cancer and pcmetastases

30

222

[1]

32P-sodium-phosphate

myeloproliferative disease

29

5

[1]

[223Ra]RaCl2

bone metastases

20

74

[1]

Radiopharmaceutical

Indication

Number of procedures

and type of procedure

per year

[131I]-NaI

thyroid cancer therapy for
adults

[131I]-NaI

3.

Prices and reimbursement

Radiopharmaceutical

Price (€) per patient dose

[131I]-NaI

360

[223Ra]RaCl2

5000

90Y-resin microspheres

12000

90Y-colloids

1200

4.

Medical guidelines

Radiopharmaceutical

Guideline making organisation

[131I]-NaI

Both European and national clinical guidelines

[131I]I-mIBG

European clinical guidelines (e.g. from the EANM)

5.

Future demand

Radiopharmaceutical

Growth expected in future

Source of data

[177Lu]Lu-DOTATATE

Up to 15%

[1]

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Radiopharmaceutical

Growth expected in future

Source of data

177Lu-peptides

More than 15%

[1]

90Y-resin microspheres

Up to 15%

[1]

6.

Patient access to radionuclide therapy (e.g. regional differences)

In Finland there are five university hospitals with full nuclear medicine services, all of which are equipped with
PET/CT. One of the leading European radiopharmaceutical companies, MAP Medical Technologies Oy, has three
production sites in Finland, so the access to the radiopharmaceuticals is good in spite of long distances within
the country. There is nuclear medicine activity in approximately 40 laboratories in Finland. The cyclotron facilities
for radiopharmaceutical production are located in Turku and Helsinki. Nuclear medicine research has been active
throughout the years in Finland, but it has been focusing to Turku, Kuopio and Helsinki. [2]

7.

Sources of information / References

[1] Technopolis Survey data (N = 6)
[2] Kairemo K. (2012). Nuclear medicine in Finland. World journal of nuclear medicine, 11(3), 101–102.
https://doi.org/10.4103/1450-1147.103406

France – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 89Sr, 90Y, 131I, 153Sm, 166Ho, 169Er, 177Lu, 186Re, 223Ra
Radiopharmaceuticals in compassionate use: not used

2.

Emerging radionuclides / radiopharmaceuticals

Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

Betalutin®

Non-Hodgkin Lymphoma, Follicular
Lymphoma

No

90Y

90Y-Epratuzumab

Acute Lymphoblastic Leukemia

Yes – Phase I/II

166Ho

166Ho-microspheres

intra-arterial treatment in the liver

Don’t know

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3.

Therapies and procedures

Radiopharmaceutical

Indication and type of
procedure

Average
number of
procedures
per year
nationally

Source of
data

Average dose
per
procedure
(MBq)

National
annual
demand
(GBq)

[131I]I-mIBG
(IOBENGUANE)

adult neuroendocrine tumours

15

[5]

7450

114

[131I]I-mIBG

neuroblastoma

15

[5]

7450

114

[131I]-NaI

benign thyroid diseases

3925

[5]

500

1963

[131I]-NaI

thyroid cancer (adults)

1840

[5]

5550

10120

[131I]-NaI

thyroid cancer (children and
young adults)

230

[5]

1942.5

447

[131I]-NaI

thyroid remnant ablation
(adults)

3688

[5]

3000

11063

[131I]-NaI

thyroid remnant ablation
(children and young adults)

383

[5]

1942.5

744

[153Sm]Sm-EDTMP

bone metastases

130

[5]

3133

408

169Er-colloids

radiation synovectomy

161

[5]

25

4

[177Lu]Lu-DOTATATE

gastroenteropancreatic
neuroendocrine tumours

1100

[1]

6475

7123

[177Lu]Lu-PSMA

castration resistant prostate
cancer and metastases

690

[5]

7400

5106

186Re-colloids

radiation synovectomy

161

[5]

111

18

[223Ra]RaCl2

bone metastases

101

[4]

3.85

0.384

90Y-colloids

radiation synovectomy

276

[5]

203.5

56

90Y-glass

intra-arterial treatment (liver)

196

[4]

11500

2254

intra-arterial treatment (liver)

230

[4]

3000

690

b-cell lymphoma and nonhodgkin lymphoma

61

[5]

1000

61

microspheres
90Y-resin

microspheres
[90Y]Y-ibritumomabtiuxetan

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According to a survey conducted in 2017, about 14 000 patients annually receive radiotherapy. About half of
these (6 580) are treated as outpatients for hyperthyroidism, synoviorthesis (treated with synovectomy) etc. [4]

4.

Prices and reimbursement

In 2015, the equivalent of €921 million (based on 2014 purchasing power parity) was spent on radiotherapy i.e.
a per capita expenditure of €13.9. Radiotherapy accounted for 0.39% of the total healthcare spending and 6.9%
of total cancer care expenditure (Lievens et al. (2020)).

Radiopharmaceutical

Price (€, mean) per treatment

Other information / reflection on distributors

169Er-colloids

430.50

[5,6]

[131I]-NaI

80.00

[5,6]

[153Sm]Sm-EDTMP

1321.50

[5, 6]

186Re-colloids

443.00

[5,6]

[223Ra]RaCl2

3575.00

[5,6]

90Y-colloids

296.00

[5, 6]

5.

Medical guidelines

Radiopharmaceutical

Indication

Guideline making organisation

Source of data

[131I]-NaI

Thyroid conditions

National

[6]

[153Sm]Sm-EDTMP

bone metastases

National

[6]

[223Ra]RaCl2

bone metastases

National

[6]

90Y-colloids

radiation synovectomy

European and National

[6]

All other radiopharmaceuticals are covered under EANM guidelines.

6.

Future demand

Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of
data

177Lu-peptides

Strong increase for majority of respondents

[6], n=3

[177Lu]Lu-PSMA

Strong increase for majority of respondents

[6], n=3

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Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of
data

[177Lu]Lu-DOTATATE

Increase for majority of respondents

[6], n=3

177Lu-antibodies

Increase for all respondents

[6], n=3

[223Ra]RaCl2

Decrease for majority of respondents

[6], n=3

169Er-colloids

Increase for all respondents

[6], n=3

[131I]I-mIBG

Unclear

[6], n=3

[131I]-NaI

Stable for majority of respondents

[6], n=3

90Y-colloids

Decrease for majority of respondents

[6], n=3

90Y-glass and resin

Unclear

[6], n=3

[90Y]Y-ibritumomab-tiuxetan

Decrease for all respondents

[6], n=3

186Re-colloids

Decrease for all respondents

[6], n=3

[153Sm]Sm-EDTMP

Decrease for majority of respondents

[6], n=3

microspheres

7.

Supply situation

Shortages were reported rarely (1–2 times for [131I]-NaI, [153Sm]Sm-EDTMP and [223Ra]RaCl2) or sometimes (3-4
times) for 90Y-colloids by one individual [6]. This was caused by external production issues and affected patients
to a small ([131I]-NaI, [153Sm]Sm-EDTMP ) or some extent ([223Ra]RaCl2, 90Y-colloids).

8.

Patient access to radionuclide therapy (e.g. regional differences)

0.9 radiotherapy centres per million inhabitants (based on Gleisner et al. (2017))
In France, radiopharmacies are directly included in NM departments. They are mandatory in public hospitals but
not in private hospitals
According to the 2017 ASN survey, about 46 nuclear medicine departments that carry out internal radiation
therapy procedures. [4]

9.

Other information

The production capacity of 177 Lu has (and could) to increase to meet the clinical demand [6]. Moreover, if high
efficacy is confirmed for [177Lu]Lu-PSMA in prostate cancer, the number of patients treated will be much higher
[6].

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10. Sources of information / References
[1] Email and interview exchange with IRSN – Institute for Radiological Protection and Nuclear Safety
[2] Gleisner, K. S., Spezi, E., Solny, P., Gabina, P. M., Cicone, F., Stokke, C., ... & Tipping, J. (2017). Variations in the
practice of molecular radiotherapy and implementation of dosimetry: results from a European survey. EJNMMI
physics, 4(1), 28.
[3] Lievens, Y., Borras, J. M., & Grau, C. (2020). Provision and use of radiotherapy in Europe. Molecular Oncology
[4] Autorité de sûreté nucléaire (2019) Médecine nucléaire en France: État du parc, des moyens humains et des
activités en 2017. Available at: https://www.asn.fr/Professionnels/Activites-medicales/Medecinenucleaire/Bilan-des-inspections-en-medecine-nucleaire/Medecine-nucleaire-en-France-Etat-du-parc-desmoyens-humains-et-des-activites-en-2017
[5] Technopolis survey Round 1, N = 22 respondents
[6] Technopolis survey Round 2, N = 3 respondents

Germany – not validated
Please note: the German Society of Nuclear Medicine (DGN) has carefully examined the country factsheet for
Germany. It strongly recommends that the data must not be used to determine the radionuclide use for therapy
in Germany. In its assessment, the data presented in no way reflects the real need for therapeutic radionuclides
and are not representative (i.e. based on a survey including only 8 centres).
The research team acknowledges this caveat and refers to this in the report.

1.

Radiopharmaceuticals currently in use

Radionuclides in use: 32P, 67Cu, 89Sr, 90Y, 131I, 153Sm, 166Ho, 169Er, 177Lu, 186Re, 188Re, 211At, 213Bi, 223Ra, 225Ac, 227Th
Clinics/centres try to expand compassionate use if legislation is very strict. The compassionate use route is used
relatively much in Germany: some centres have done more than 1000 PSMA treatments.[2]

2.

Emerging radionuclides

Radionuclide

Radiopharmaceutical

227Th

[227Th]Th-HER2 antibody

177Lu

[177Lu]Lu-DOTA0-Tyr3Octreotate

Inoperable, Progressive, Somatostatin Receptor
Positive Midgut Carcinoid Tumours

Y

177Lu

177Lu-edotreotide PRRT

GEP-Net patients

Y

Transarterial Radioembolisation in Uveal Melanoma
Liver Metastasis

Y

Advanced Stage Intrahepatic Biliary Tract Cancer

Y

90Y

90Y

Y-90 SIRT

Indication

In clinical
trials?
N/A [3]

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Radionuclide

Radiopharmaceutical

Indication

In clinical
trials?

90Y

TheraSphere®

Inoperable Liver Cancer

Y

90Y

TheraSphere®

Metastatic Colorectal Cancer

Y

131I

Lenvatinib (E7080)

Differentiated Thyroid Cancer

Y

223Ra

Radium-223 Dichloride

Castration-resistant Prostate Cancer Metastatic to the
Bone

Y

223Ra

Radium-223 Dichloride

Castration-Resistant (Hormone-Refractory) Prostate
Cancer Patients With Bone Metastases

Y

223Ra

Radium-223 Dichloride

Bone Predominant HER2 (Human Epidermal Growth
Factor Receptor 2) Negative Hormone Receptor
Positive Metastatic Breast Cancer

Y

223Ra

Radium-223 Dichloride

Stage IV Non-small Cell Lung Cancer With Bone
Metastases

Y

3.

Therapies and procedures

Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of
data

Average
dose per
procedure
(MBq)

National
annual
demand
(GBq)

90Y

90Y-colloids used in radiation

995

Survey

203

202

77

Survey

11500

880

synovectomy
90Y

90Y-glass microspheres used in intra-

arterial treatments in the liver
90Y

[90Y]Y-ibritumomab-tiuxetan used in
b-cell lymphoma and non-hodgkin
lymphoma (EMA authorised)

64

Survey

1000

64

90Y

90Y-resin microspheres used in

1403

Survey

3000

4209

intra-arterial treatments in the liver
131I

[131I]I-mIBG (IOBENGUANE) used in
adult neuroendocrine tumours
(EMA authorised)

77

Survey

7450

574

131I

[131I]I-mIBG (IOBENGUANE) used in
neuroblastoma (EMA authorised)

38

Survey

7450

283

131I

[131I]-NaI used in benign thyroid
diseases

9435

Survey

500

4718

131I

[131I]-NaI used in thyroid cancer
therapy for adults

510

Survey

5500

2805

131I

[131I]-NaI used in thyroid cancer
therapy for children and young
adults

38

Survey

1942

74

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Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of
data

Average
dose per
procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]-NaI used in thyroid remnant
ablation of adults

4845

Survey

3000

14535

131I

[131I]-NaI used in thyroid remnant
ablation of children and young
adults

102

Survey

1942

198

177Lu

177Lu-antibodies used in non-

13

Survey

1062

14

Hodgkin’s lymphoma
177Lu

[177Lu]Lu-DOTATATE used in
gastroenteropancreatic
neuroendocrine tumours (EMA
authorised)

4718

Survey

6475

30549

177Lu

[177Lu]Lu-PSMA used in therapy of
castration resistant prostate cancer
and pc-metastases

3570

Survey

7400

26418

223Ra

[223Ra]RaCl2 used in bone
metastases (EMA authorised)

230

Survey

3,85

0.9

225Ac

[225Ac]Ac-PSMA used in metastatic
castration resistant prostate cancer

1658

Survey

8

13,3

153Sm

[153Sm]Sm-EDTMP used in bone
metastases (EMA authorised)

163

Survey

3133

511

169Er

169Er-colloids used in radiation

1875

Survey

25

47

1063

Survey

111

118

25

Survey

3079

77

synovectomy
186Re

186Re-colloids used in radiation

synovectomy
188Re

4.

[188Re]Re-HEDP used in painful
bone metastases

Prices and reimbursement

Radiopharmaceutical

Price (€)

Other information / reflection on distributors

[131I]-NaI

300-1800

Survey

[131I]I-mIBG

1700

Survey

177Lu-antibodies

1800-2600

Survey

177Lu-peptides

2600-3500

Survey

[177Lu]Lu-PSMA

2600-3500

Survey

[177Lu]Lu-DOTATATE

24000-26000

Survey

[223Ra]RaCl2

6500

Survey

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Radiopharmaceutical

Price (€)

Other information / reflection on distributors

153Sm-EDTP

600-1500

Survey

[90Y]Y-ibritumomab-tiuxetan

2500-17000

Survey

90Y-resin microspheres

12500

Survey

90Y-glass microspheres

12000-13000

Survey

90Y-colloids

300-600

Survey

5.

Medical guidelines

Radiopharmaceutical

Guideline making organisation

90Y-colloids

Both European and national

[90Y]Y-ibritumomab-tiuxetan

Both European and national

[131I]I-mIBG (IOBENGUANE)

Both European and national

[131I]-NaI

Both European and national

[153Sm]Sm-EDTMP

European

169Er-colloids

National

[177Lu]Lu-DOTATATE

Both European and national

177Lu-peptides

Both European and national

[177Lu]Lu-PSMA

Both European and national

186Re-colloids

Both European and national

[223Ra]RaCl2

Both European and national

6.

Future demand

Radionuclide

Number of Patients Expected to receive therapy in future

Source of data

[177Lu]Lu-PSMA

Strong increase expected by large majority of respondents

Survey

[225Ac]Ac-PSMA

Strong increase expected by large majority of respondents

Survey

[177Lu]Lu-DOTATATE

Strong increase expected by majority of respondents

Survey

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Radionuclide

Number of Patients Expected to receive therapy in future

Source of data

177Lu-peptides

Strong increase expected by majority of respondents

Survey

177Lu-antibodies

Strong increase expected by majority of respondents

Survey

32P-sodium-phosphate

Decrease expected by majority of respondents

Survey

[89Sr]SrCl2

Decrease expected by majority of respondents

Survey

[153Sm]Sm-EDTMP

Decrease expected by majority of respondents

Survey

7.

Supply situation

Survey respondents indicate there are often shortages in 212Pb, less so in 131I and 186Re. They indicate that
shortages in 131I may have some effects on patients. However, most respondents indicate that supply is not a
large problem. The commonly used reactor produced radionuclides are generally available. The deficit is in novel
radionuclides. Shortages are sometimes related to reactor maintenance, which could be solved with better
information and coordination. One respondent suggests the regulations regarding the production process are
overly complicated. [4]

8.

Patient access to radionuclide therapy (e.g. regional differences)

There are 102 centres offering therapy (in 2020). [1] The following graph shows the number of therapeutic
centres in Germany from 2009-2015, showing a slight decline in centres, and a more significant decline in number
of beds, cases and patient-days. [4]

Source: [4]

9.

Other information

Germany has a federal system: states handle permits, which means there are different offices for radiology and
radioisotopes. Also, there are different surveillance authorities in different states.
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10. Sources of information / References
[1] Interview with Bernd Krause, German Society of Nuclear Medicine (DGN)
[2] Interview with Sabine Klingele, Bundesamt für Strahlenschutz (BfS - German Federal Office for Radiation
Protection)
[3] Technopolis survey (N = 8)
[4] Dirk Hellwig; Jörg Marienhagen; Karin Menhart; Jirka Grosse, Nuklearmkedizin in Deutschland,
Nuklearmedizin, 2, 2017

Greece – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 89Sr, 90Y, 131I, 153Sm, 169Er, 177Lu, 186Re, 188Re, 223Ra
Radiopharmaceuticals in compassionate use: compassionate use is generally not possible in Greece. However,
the use of [177Lu]Lu-PSMA is allowed for only very specific patients, as this RP is not yet commercially licensed in
Greece.

2.

Therapies and procedures

According to the 2008 UNSCEAR Global Survey of Medical Radiation Usage and Exposure, 1315 therapeutic
treatments in nuclear medicine are performed in Greece.
Radionuclide

Indication and type of
procedure

Average number of
procedures per
year nationally

Source of
data

Average dose
per procedure
(MBq)

National annual
demand (GBq)

90Y

90Y-colloids used in

975

Survey

203

198

15

Survey

11500

173

465

Survey

3000

1395

radiation synovectomy
90Y

90Y-glass microspheres used

in intra-arterial treatments
in the liver
90Y

90Y-resin microspheres used

in intra-arterial treatments
in the liver
131I

[131I]I-mIBG (IOBENGUANE)
used in adult
neuroendocrine tumours
(EMA authorised)

12

Survey

7450

89

131I

[131I]I-mIBG (IOBENGUANE)
used in neuroblastoma
(EMA authorised)

9

Survey

7450

67

131I

[131I]-NaI used in benign
thyroid diseases

1050

Survey

500

525

131I

[131I]-NaI used in thyroid
cancer therapy for adults

2175

Survey

5500

11963

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Radionuclide

Indication and type of
procedure

Average number of
procedures per
year nationally

Source of
data

Average dose
per procedure
(MBq)

National annual
demand (GBq)

131I

[131I]-NaI used in thyroid
cancer therapy for children
and young adults

150

Survey

1942

291

131I

[131I]-NaI used in thyroid
remnant ablation of adults

4050

Survey

3000

12150

131I

[131I]-NaI used in thyroid
remnant ablation of
children and young adults

525

Survey

1942

1020

177Lu

177Lu-antibodies used in

18

Survey

1062

19

non-Hodgkin’s lymphoma
177Lu

[177Lu]Lu-DOTATATE used in
gastroenteropancreatic
neuroendocrine tumours
(EMA authorised)

36

Survey

6475

233

177Lu

177Lu-peptides (other than

15

Survey

?

?

somatostatin analogues and
PSMA)
177Lu

[177Lu]Lu-PSMA used in
therapy of castration
resistant prostate cancer
and pc-metastases

15

Survey

7400

111

223Ra

[223Ra]RaCl2 used in bone
metastases (EMA
authorised)

330

Survey

3,85

1

89Sr

[89Sr]SrCl2 used in bone
metastases (EMA
authorised)

6

Survey

150

1

153Sm

[153Sm]Sm-EDTMP used in
bone metastases (EMA
authorised)

24

Survey

3133

75

169Er

169Er-colloids used in

30

Survey

25

1

30

Survey

111

3

33

Survey

3079

102

radiation synovectomy
186Re

186Re-colloids used in

radiation synovectomy
188Re

3.

[188Re]Re-HEDP used in
painful bone metastases

Prices and reimbursement

Greece has a public healthcare insurance which reimburses low-cost radiopharmaceuticals and therapies, e.g.
for 131I RPs. For high-costs radiopharmaceuticals and therapies patients need to receive permission for
reimbursement. These expensive treatments are not officially (or generally) reimbursed and require permission
to make exemptions.
Interviewees indicated that the price of (many) RPs in Greece is higher than in some (neighbouring) countries.
Prices can be five times higher, which is not likely explained by transport costs when it concerns neighbouring

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countries. Another issue is the fact that in-house prepared medicine cannot be reimbursed, while costs are
significantly lower (roughly factor 3 for [177Lu]Lu-DOTATATE). This is mainly an issue for patients.
Radiopharmaceutical

Price (€)

Other information / reflection on distributors

90Y-resin microspheres

From survey: Mediray

90Y-colloids

€650 (estimate from survey)

From survey: Curium

223RaCl

€4000 (estimate from survey)

From survey: Bayer

[131I]-NaI

€120-€200 (from survey)

From survey: Polatom

[153Sm]Sm-EDTMP

€3800 (from survey)

From survey: Curium

4.

Medical guidelines

Greece has no national guidelines but uses the EANM guidelines.

5.

Future demand

Radionuclide

Growth / Number of Patients Expected to receive therapy in
future

Source of data

[225Ac]Ac-PSMA

Respondents believe RP will strongly increase (>15%)

Survey (N=2)

[177Lu]Lu-PSMA

Respondents believe RP will strongly increase (>15%)

Survey (N=2)

[177Lu]Lu-DOTATATE

50% of respondents believes RP will strongly increase (>15%),
while 50% believes RP will increase (1-15%) in 10 years

Survey (N=2)

223RaCl

50% of respondents believes RP will strongly increase (>15%),
while 50% believes RP will increase (1-15%) in 10 years

Survey (N=2)

177Lu-peptides

50% of respondents believes RP will strongly increase (>15%),
while 50% believes RP will increase (1-15%) in 10 years

Survey (N=2)

[153Sm]Sm-EDTMP

Respondent believes RP will increase (1-15%) in 10 years

Survey (N=2)

[188Re]Re-HEDP

Respondent believes RP will increase (1-15%) in 10 years

Survey (N=2)

90Y-glass microspheres

Respondent believes RP will increase (1-15%) in 10 years

Survey (N=2)

90Y-colloids

Respondent believes RP will remain stable in 10 years

Survey (N=2)

90Y-resin microspheres

Respondent believes RP will increase (1-15%) in 10 years

Survey (N=2)

177Lu-antibodies

Respondent believes RP will increase (1-15%) in 10 years

Survey (N=2)

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The expected increases for [225Ac]Ac-PSMA and [177Lu]Lu-PSMA is due to the current success stories for prostate
cancer therapy with PSMA radiopharmaceuticals. In addition, some hospitals have started to produce 177Lu
radiopharmaceuticals in-house.

6.

Supply situation

In Greece quite some supply issues have been reported in the survey.
•

Often (>4 times in five years) shortages have occurred for 169Er-colloids, 186Re-colloids, 90Y-colloids, all had
to a great extent impact on patients. These supply issues were caused during external production.

•

Sometimes (3-4 times in five years) shortages have occurred for [153Sm]Sm-EDTMP , which had to some
extent impact on patients. The supply issue was caused during external production.

•

Rarely (1-2 times in five years) shortages gave occurred for [131I]-NaI and [223Ra]RaCl2, which had resp. to
some extent and to a small extent impact on patients. The supply issue for [131I]-NaI was caused due to
transport, while the cause for [223Ra]RaCl2 is unknown.

Radiopharmaceuticals and radionuclides used in radionuclide therapy are imported. Greece has no RP or RN
production facilities, only for diagnostics or industrial applications. However, one hospital in Greece is currently
in the process acquiring a license for producing [177Lu]Lu-DOTATATE in-house. All equipment is already available
and licensing is expected soon.
The supply from abroad has been quite stable, without any significant disruptions for radionuclide therapy (these
were only for diagnostics).

7.

Patient access to radionuclide therapy (e.g. regional differences)

Number of radiopharmacies is unknown, but likely similar to number of radionuclide therapy practicing centres.
There are many centres in Greece who apply radionuclide therapy, especially for 131I radiopharmaceuticals.
According to Gleisner (2017) there were 33 radionuclide therapy practicing centres in 2015-2016 in Greece.
Interviewees estimate this number a bit lower, with 10-15 centres using 131I RPs and 3 centres using radionuclide
microspheres and 177Lu RPs.

8.

Sources of information / References

[1] Information based on interview (2020) with Dr. Prassopoulos (former delegate of the Hellenic Society of
Nuclear Medicine and Molecular Imaging to the EANM) and Dr. Ntalianis (medical physicist), both working at the
Hygeia Hospital.
[2] Technopolis survey (N = 5)

Hungary – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 32P, 90Y, 131I, 153Sm, 166Ho, 177Lu, 186Re, 223Ra

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2.

Emerging radionuclides

Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

Betalutin®

Relapsed Non-Hodgkin Lymphoma

Y

3.

Therapies and procedures

Radiopharmaceutical

Indication and type of
procedure

Number of
procedures per
year

Source of
data

Average
dose per
procedure
(MBq)

National
annual
demand
(GBq)

90Y-colloids

radiosynovectomy

approx. 500

Estimation
based on
national
statistics

200

86.5

90Y resin

SIRT of primary and
secondary hepatic
malignancies

4

National
statistics

2500

10

[90Y]Y-ibritumomab
tiuxetan

relapsed/refractory CD20+
follicular non-Hodgkin
lymphoma

2

National
statistics

1500

3

131I

benign thyroid diseases

1366

National
statistics

500

683

131I

thyroid cancer

697

National
statistics

2500

1743

[131I]I-mIBG
(Iobenguane)

metastatic neuro-crest
tumours
(pheochromocytomas and
paragangliomas)

5

National
statistics

3700

18.5

166Ho-colloids

radiosynovectomy

75

National
statistics

600

45

223Ra-dichloride

metastatic castrationresistant prostate cancer
(mCRPC)

237

National
statistics

3.85

2

[153Sm]Sm-EDTMP

palliative treatment of
multiple painful
osteosclerotic bone
metastases

36

National
statistics

2500

9

186Re-colloids

radiosynovectomy

approx.120

Estimation
based on
national
statistics

100

12

microspheres

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Source: Szilvasi, based on national data

All of these therapies were reimbursed (with negligible few exceptions) by the National Health Insurance Fund.
The calculated “average” costs of each radiopharmaceuticals are included in the total reimbursement of the
given type of (inpatient or outpatient) treatment (except 223Ra-dichlorid). The number of therapeutic procedures
may sometimes limited by the underestimated cost of treatment.
Due to the high cost of 223Ra-dichloride – compared to other therapeutic radiopharmaceuticals currently used in
Hungary – it has a “special” financing procedure. Its real cost is separately reimbursed from a special budget of
the National Health Insurance Fund after approval of the given patient’s treatment by a medical committee of
the Fund [1].
Some patients (estimated 30-35 per year) are treated with [177Lu]Lu-DOTATATE abroad (e.g. in Basel), even
financed by the National Health Insurance Fund [1].

4.

Medical guidelines

For all radiopharmaceuticals, the European (EANM) guidelines are followed.
For radiosynovectomy using 166Ho-colloid the Hungarian guideline is an adaptation of the European one.
Radiopharmaceutical

Guideline making organisation

90Y-colloids

European

[131I]I-mIBG (IOBENGUANE)

European

[131I]-NaI

European

[153Sm]Sm-EDTMP

European

186Re-colloids

European

[223Ra]RaCl2

European

5.

Future demand

Remark: medical demand is high, but reimbursement is limited(1).
Radionuclide

Number of Patients Expected to receive
therapy in future

Source of data

[177Lu]Lu-PSMA

Strong increase expected by large
majority of respondents

Survey

[225Ac]Ac-PSMA

Strong increase expected by large
majority of respondents

Survey (although in validation this was
deemed too high – suggest “increase’)

[177Lu]Lu-DOTATATE

Strong increase expected by majority of
respondents

Survey

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Radionuclide

Number of Patients Expected to receive
therapy in future

Source of data

177Lu-peptides

Strong increase expected by majority of
respondents

Survey (although in validation this was
deemed too high – suggest “increase’)

[227Th]Th-PSMA antibody

Increase expected by majority of
respondents

Survey

32P-sodium-phosphate

Strong decrease expected by majority of
respondents

Survey

[90Y]Y-ibritumomab-tiuxetan

Strong decrease expected by majority of
respondents

Survey

[89Sr]SrCl2

Decrease expected by majority of
respondents

Survey (validation suggests: never used)

90Y-glass microspheres

Decrease expected by majority of
respondents

Survey (validation suggests: never used)

Decrease expected by majority of
respondents

Survey

227Th-conjugate

90Y-colloids

[153Sm]Sm-EDTMP

6.

Supply situation

One respondent indicates there are often shortages of 90Y-colloids, whereas others indicate sometimes shortages
in 131I (mIBG and NaI), 186Re-colloids, [153Sm]Sm-EDTMP , which may to some extent impact patients (131I and
153
Sm). These shortages lie in external production, no further explanation is given. [2]

7.

Patient access to radionuclide therapy (e.g. regional differences)

With 13 centres [3], Hungary has 1.3 centres per million inhabitants.

8.

Sources of information / References

[1] Istvan Szilvasi, President, National College of Nuclear Medicine
[2] Technopolis survey (N=4)
[3] Gleisner et al. 2017

Ireland – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 90Y, 131I, 177Lu, 186Re, 223Ra, 153Sm, 169Er, 32P [1, 3]

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Radiopharmaceuticals in compassionate use: [177Lu]Lu-PSMA-617 (in discussion); Lutathera® i.e. [177Lu]LuDOTATATE (planned use in one hospital)

2.

Emerging radionuclides / radiopharmaceuticals

Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

Betalutin®

Lymphoma

Yes

3.

Therapies and procedures

Radionuclide

Indication and type of procedure

Average number
of procedures
per year
nationally

Source of
data

Average
activity per
procedure
(MBq)

National
annual
demand (GBq)

223Ra

[223Ra]RaCl2 used in bone
metastases

310

[1, 3]

3.85

1

131I

[131I]-NaI used in benign thyroid
diseases

336

[1, 3]

500

168

131I

[131I]-NaI used in thyroid remnant
ablation of adults

69

[1, 3]

3000

240

131I

[131I]-NaI used in thyroid remnant
ablation of children and young
adults

2

[1, 3]

1942

4

131I

[131I]-NaI used in thyroid cancer
therapy for adults

171

[1, 3]

5500

1110

131I

[131I]-NaI used in thyroid cancer
therapy for children and young
adults

2

[1, 3]

1942

4

186Re

186Re-colloids used in radiation

2

[1, 3]

111

0.22

55

[1, 3]

203.5

11

31

[1, 3]

11500

414

34

[3]

3000

102

synovectomy
90Y

90Y-colloids used in radiation

synovectomy
90Y

90Y-glass microspheres

(TheraSpheres®) used in intraarterial treatments in the liver
90Y

90Y-resin microspheres used in

intra-arterial treatments in the
liver (90Y-SIRT)

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Radionuclide

Indication and type of procedure

Average number
of procedures
per year
nationally

Source of
data

Average
activity per
procedure
(MBq)

National
annual
demand (GBq)

169Er

169Er-colloids used in radiation

2

[3]

25

0.05

2

[3]

1062

2

2

[3]

450

1

2

[3]

3133

6

synovectomy
177Lu

177Lu-antibodies used in non-

Hodgkin lymphoma
32P

32P-sodium-phosphate used in

bone metastases
153Sm

4.

[153Sm]Sm-EDTMP used in bone
metastases

Prices and reimbursement

Radiopharmaceutical

Price (€)

Other information / reflection on distributors

223Ra

Not available

Bayer [3]

177Lu

Not available

Business plan for reimbursement created [1]

5.

Medical guidelines

Radiopharmaceutical

Indication

Guideline making
organisation

Title of/link to guideline

223Ra

castration-resistant
metastatic prostate
cancer (mCRPC)

National Cancer
Control Program

https://www.hse.ie/eng/services/list/5/canc
er/profinfo/chemoprotocols/genitourinary/
257-radium-223-therapy1.pdf

All other radiopharmaceuticals are covered under EANM guidelines.

6.

Future demand

Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of data

177Lu PSMA

Significant demand increase

[1]

[225Ac]Ac-PSMA

Increase for majority of respondents

[4]

[131I]I-mIBG

Stable for majority of respondents

[4]

[131I]-NaI

Stable for majority of respondents

[4]

90Y-glass microspheres

Stable for majority of respondents

[4]

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Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of data

90Y-colloids

Stable for majority of respondents

[4]

[90Y]Y-ibritumomabtiuxetan

Stable for majority of respondents

[4]

177Lu-peptides

Strong increase for majority of respondents

[4]

7.

Supply situation

No local production of any therapeutic isotope.
Brexit has potential implications for supply of radionuclides. This has been discussed at length at EU level and
with industry. Plans are adequate.

8.

Patient access to radionuclide therapy (e.g. regional differences)

2.8 radiotherapy centres per million inhabitants [2]
•

One independent Radiopharmacy Company, M2i: https://www.m2i.ie/

•

21 Radiopharmacies in teaching hospitals, general hospitals and private hospitals. [1] These are not for
therapeutic radioligand production.

•

Number of radionuclide therapy practicing centres: 12 [1]

9.

Other information

There is very poor awareness about radionuclide therapy in regulatory authorities despite interactions over 10
years.

10. Sources of information / References
[1] Email exchange with Dr Martin O’Connell and Ronan Killeen, Irish Nuclear Medicine Association
[2] Gleisner, K. S., Spezi, E., Solny, P., et al. (2017). Variations in the practice of molecular radiotherapy and
implementation of dosimetry: results from a European survey. EJNMMI physics, 4(1), 28.
[3] Technopolis survey (Round 1), N = 14
[4] Technopolis survey (Round 2), N = 5

Italy – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 166Ho, 177Lu, 169Er, 188Re, 223Ra, 89Sr, 90Y,

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2.

Emerging radionuclides / radiopharmaceuticals

Radiopharmaceuticals in experimental use (clinical trials):
Radio-nuclide

Radio-pharmaceutical

Indication

In clinical trials?

177Lu

[177Lu]Lu-DOTATATE

Neuroendocrine Tumours

Yes – Phase II

177Lu

[177Lu]Lu-PSMA

Castration Resistant Prostate Cancer
(CRPC)

Yes – Phase II

177Lu

177Lu-edotreotide PRRT

Neuroendocrine Tumours

Yes – Phase III

177Lu

177Lu-edotreotide PRRT

Neuroendocrine Tumours

Yes – Phase II

177Lu

177Lu-antibodies

Non-Hodgkin Lymphoma

Yes – Phase I and Phase II

90Y

90Y- resin microspheres

Intrahepatic Cholangiocarcinoma

Yes – Phase II and Phase III

3.

Therapies and procedures

Radiopharmaceutical

Indication
and type of procedure

Number of
procedures

Data source

Average
activity per
procedure(M
Bq)

Activity (GBq)

24

Survey

7450

176

41

Survey

7450

303

per year
[131I]I-mIBG
(IOBENGUANE)

Adult neuroendocrine
tumours

[131I]I-mIBG
(IOBENGUANE)

Neuroblastoma

[131I]-NaI

Benign thyroid diseases

1646

Survey

500

8223

[131I]-NaI

Thyroid cancer therapy
for adults

2704

Survey

5500

15009

[131I]-NaI

Thyroid cancer therapy
for children and young
adults

135

Survey

1942.5

262

[131I]-NaI

Thyroid remnant
ablation of adults

1982

Survey

3000

5946

[131I]-NaI

Thyroid remnant
ablation of children and
young adults

96

Survey

1942.5

187

Bone metastases

17

Survey

3133

54

[153Sm]Sm-EDTMP

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Radiopharmaceutical

Indication
and type of procedure

Number of
procedures

Data source

Average
activity per
procedure(M
Bq)

Activity (GBq)

per year
166Ho-microspheres

Intra-arterial treatment
in the liver

6

Survey

1890

12

177Lu-antibodies

Non-hodgkin lymphoma

21

Survey

1062

23

[177Lu]Lu-DOTATATE

Gastroenteropancreatic
neuroendocrine
tumours

3525

Survey

6475

22824

[177Lu]Lu-PSMA

Prostate cancer and pcmetastases

647

Survey

7400

4789

[223Ra]RaCl2

Bone metastases

1361

Survey

3.8

5

[89Sr]SrCl2

Bone metastases

19

Survey

150

3

90Y-colloids

Radiation synovectomy

11

Survey

203.5

2

90Y-glass

microspheres

Intra-arterial
treatments in the liver

257

Survey

11500

2957

[90Y]Y-ibritumomabtiuxetan

b-cell lymphoma and
non-hodgkin lymphoma

9

Survey

1000

9

90Y-resin

Intra-arterial
treatments in the liver

255

Survey

3000

765

microspheres

4.

Prices and reimbursement

Radio-pharmaceutical

Price per patient treatment
in € (mean (min, max)) [1]

Type of procedure

Total budget
spent per year

[131I]-NaI

157.5 (65, 250)

Benign thyroid diseases

€259,245

[131I]-NaI

157.5 (65, 250)

Thyroid cancer therapy for adults

€425,880

[131I]-NaI

157.5 (65, 250)

Thyroid cancer therapy for children and
young adults

€21,262.5

[131I]-NaI

157.5 (65, 250)

Thyroid remnant ablation of adults

€312,165

[131I]-NaI

157.5 (65, 250)

Thyroid remnant ablation of children and
young adults

€21,262.5

[131I]I-mIBG
(IOBENGUANE)

750 (700, 800)

Adult neuroendocrine tumours

€18,000

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Radio-pharmaceutical

Price per patient treatment
in € (mean (min, max)) [1]

Type of procedure

Total budget
spent per year

[177Lu]Lu-PSMA (not
licensed)

20,000 (20,000, 20,000)

Neuroblastoma

€12,940,000

[177Lu]Lu-DOTATATE

17500 (15000, 20000)

Gastroenteropancreatic neuroendocrine
tumours

€61,687,500

[223Ra]RaCl2

2,870 (2,500, 3,240)

Bone metastases

€3,906,070

[90Y]Y-ibritumomabtiuxetan

15,000 (10,000, 20,000)

b-cell lymphoma and non-Hodgkin
lymphoma

€135,000

90Y-resin microspheres

1,000 (1,000, 1,000)

Intra-arterial treatments in the liver

€255,000

90Y-glass microspheres

1,000 (1,000, 1,000)

Intra-arterial treatments in the liver

€257,000

5.

Medical guidelines

Italy uses both European (e.g. the EANM) and national medical guidelines for radiotherapy according to survey
respondents [1]

6.

Future demand

Radionuclide

Growth in the next 10 years

Source of data

[177Lu]Lu-PSMA

61.5% of Italian respondents expect there to be a strong increase (>15%) in
demand. Another 30.8% expect there to be weak increase in demand (+1 to
+15%)

[1]

[225Ac]Ac-PSMA

46.2% of Italian respondents expect there to be a strong increase (>15%) in
demand. Another 30.8% expect there to be weak increase in demand (+1 to
+15%)

[1]

[177Lu]LuDOTATATE

53.9% of Italian respondents expect there to be a weak increase (+1 to +15%) in
demand. Another 23.1% expect there to be strong increase in demand (> +15%)

[1]

177Lu-peptides

69.2% of Italian respondents expect there to be a weak increase (+1 to +15%) in
demand. Another 23.1% expected there to be strong increase in demand (>
+15%)

[1]

[89Sr]SrCl2

38.5% of Italian respondents expect there to be a strong decrease (<-15%) in
demand. Another 15.4% expect there to be weaker decrease in demand (-15%
to -1%)

[1]

[153Sm]Sm-EDTMP

38.5% of Italian respondents expect there to be a strong decrease (<-15%) in
demand. Another 23.1% expect there to be weaker decrease in demand (-15%
to -1%)

[1]

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Radionuclide

Growth in the next 10 years

Source of data

[90Y]Yibritumomabtiuxetan

30.8% of Italian respondents expect there to be a weak decrease in demand (15% to -1%. Another 23.1% of respondents expect there to be a strong decrease
(<-15%) in demand.

[1]

7.

Supply situation

Italy have had few reported issues with supply of radionuclides. However, shortages or supply disruption have
been reported in Italy over the last 5 years for [3]:
•

[223Ra]RaCl2 - 50% of relevant respondents suggested that [223Ra]RaCl2 had been shortage rarely (1-2 times)
over the last 5 years. A variety of reasons were suggested for these shortages occurring: during external
production, during transport and during procurement. These shortages were reported to have had a small
disruptive effect on the treatment of patients.

•

177

8.

Patient access to radionuclide therapy (e.g. regional differences)

Lu-antibodies - 50% of relevant respondents suggested that 177Lu-antibodies had been shortage rarely (12 times) over the last 5 years. These shortages were reported to have happened during transport.

There are an estimated 0.50 radionuclide therapy centres per million inhabitants in Italy. This has been calculated
from:
•

There being 30 radiotherapy centres in Italy [2]

•

The Italian population being 60,462,000 in 2020 (United Nations Population Division)118

It has been reported that regional governance structures can create differences in reimbursement fees. For
example, in the Lombardia region healthcare services are reimbursed much less than healthcare services in the
Romania region. However, these differences in reimbursement do not affect patient access [2]
There are 4 to 5 radiopharmacies in Italy equipped for radionuclide therapy (academic studies) [2].

9.

Other information

Italy was reported to have had a radiotherapy expenditure of 508 million euros in 2016, this was 0.36% of total
health care expenditure [4].

10. Sources of information / References
[1] Technopolis survey (survey respondents N = 24)
[2] Interview with Professor Giovanni Paganelli, Director at School of Specialisation in Nuclear Medicine
University of Ferrara
[3] Gleisner et al. (2017)

118 See: https://population.un.org/wpp/Download/Standard/Population/

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[4] Lievens et al. (2020)

Latvia – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 90Y, 131I, 223Ra

2.

Therapies and procedures

Radionuclide

Indication and type of procedure

Average
number of
procedures per
year nationally

Source of
data

Average
dose per
procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]I-mIBG (IOBENGUANE) used in
neuroblastoma (EMA authorised)

1

Survey

7450

7

131I

[131I]I-mIBG (IOBENGUANE) used in adult
neuroendocrine tumours (EMA authorised)

2

Survey

7450

15

131I

[131I]-NaI used in benign thyroid diseases

250

Survey

500

125

131I

[131I]-NaI used in thyroid cancer therapy for
adults

60

Survey

5550

333

131I

[131I]-NaI used in thyroid cancer therapy for
children and young adults

15

Survey

1942

29

131I

[131I]-NaI used in thyroid remnant ablation
of adults

160

Survey

3000

480

131I

[131I]-NaI used in thyroid remnant ablation
of children and young adults

15

Survey

1942

29

223Ra

[223Ra]RaCl2 used in bone metastases (EMA
authorised)

1

Survey

3.85

0

3.

Patient access to radionuclide therapy

Number of radiotherapy practicing centres: 1 centre (based on survey data).

4.

Sources of information / References

[1] Technopolis survey (N = 1)
[2] Gleisner et al. (2017)

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Lithuania – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 90Y, 131I, 166Ho, 223Ra
Radiopharmaceuticals in compassionate use: N/A

2.

Therapies and procedures

Radionuclide

Indication and type of
procedure

Average number of
procedures per
year nationally

Source of
data

Average dose
per procedure
(MBq)

National annual
demand (GBq)

131I

[131I]-NaI used in benign
thyroid diseases

500

Survey
(n=2)

500

250.00

131I

[131I]-NaI used in thyroid
remnant ablation of adults

1

Survey
(n=2)

3000

3.00

223Ra

[223Ra]RaCl2 used in bone
metastases

38

Survey
(n=2)

3.85

0.15

3.

Prices and reimbursement

In 2016, the equivalent of €9.7 million (based on 2014 purchasing power parity) was spent on radiotherapy i.e. a
per capita expenditure of €3.3. Radiotherapy accounted for 0.24% of the total healthcare spending and 4.3% of
total cancer care expenditure (Lievens et al. (2020)).
Radiopharmaceutical

Reflection on distributors

[131I]-NaI

GE, Polatom/Elins

[223Ra]RaCl2

Bayer

4.

Future demand

Radiopharmaceutical

Number of Patients Expected to receive therapy in future

Source of data

[131I]I-mIBG

Strong increase expected by respondent

Survey (n=1)

[131I]-NaI

Strong increase expected by respondent

Survey (n=1)

[177Lu]Lu-DOTATATE

Strong increase expected by respondent

Survey (n=1)

[223Ra]RaCl2

Increase expected by respondent

Survey (n=1)

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5.

Patient access to radionuclide therapy

Number of radionuclide therapy practicing centres: two

6.

Sources of information / References

[1] Lievens, Y., Borras, J. M., & Grau, C. (2020). Provision and use of radiotherapy in Europe. Molecular Oncology.
[2] Survey data (Round 1), N = 2
[3] Survey data (Round 2), N = 1

Luxembourg – not validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 32P, 90Y, 131I, 153Sm, 169Er, 186Re, 211At, 213Bi, 223Ra, 225Ac, 227Th

2.

Emerging radionuclides

Trials with 177Lu and 225Ac are reported by one respondent.

3.

Therapies and procedures

Radiopharmaceutical

90Y

Indication and type of procedure

Average number
of procedures per
year nationally

Source
of data

Average
activity per
procedure
(MBq)

National
annual
demand
(GBq)

90Y-glass microspheres used in

1

Survey

11500

12

10

Survey

3000

30

intra-arterial treatments in the
liver
90Y-resin microspheres used in

90Y

intra-arterial treatments in the
liver
1

Survey

7450

7

131I

[131I]I-mIBG (IOBENGUANE) used
in neuroblastoma (EMA
authorised)
[131I]-NaI used in benign thyroid
diseases

110

Survey

500

55

131I

[131I]-NaI used in thyroid cancer
therapy for adults

35

Survey

5550

194

131I

3

Survey

1942

6

131I

[131I]-NaI used in thyroid cancer
therapy for children and young
adults

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Radiopharmaceutical

Indication and type of procedure

Average number
of procedures per
year nationally

Source
of data

Average
activity per
procedure
(MBq)

National
annual
demand
(GBq)

[131I]-NaI used in thyroid remnant
ablation of adults

180

Survey

3000

540

131I

2

Survey

1942

4

131I

[131I]-NaI used in thyroid remnant
ablation of children and young
adults
[223Ra]RaCl2 used in bone
metastases (EMA authorised)

31

Survey

3.85

0.12

223Ra

[153Sm]Sm-EDTMP used in bone
metastases (EMA authorised)

12

Survey

3133

38

153Sm

169Er-colloids used in radiation

1

Survey

25

0.02

2

Survey

111

0.22

169Er

synovectomy
186Re-colloids used in radiation

186Re

4.

synovectomy

Prices and reimbursement

Radiopharmaceutical

Price (€)

Other information

[131I]-NaI

100-300

estimate

[223Ra]RaCl2

4400

153Sm-EDTP

700-1000

estimate

90Y-resin microspheres

3000-5000

estimate

5.

Medical guidelines

Radiopharmaceutical

Guideline making organisation

[131I]-NaI

Both European and national

[153Sm]Sm-EDTMP

National

[223Ra]RaCl2

Both European and national

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6.

Future demand

Radionuclide

Number of Patients Expected to receive therapy in future

Source of data

[225Ac]Ac-PSMA

Strong increase expected by respondents

Survey

Strong increase expected by majority of respondents

Survey

Increase expected by majority of respondents

Survey

Increase expected by majority of respondents

Survey

Increase expected by majority of respondents

Survey

32P-sodium-phosphate

Strong decrease expected by majority of respondents

Survey

[223Ra]RaCl2

Strong decrease expected by majority of respondents

Survey

[90Y]Y-ibritumomabtiuxetan

Strong decrease expected by majority of respondents

Survey

[153Sm]Sm-EDTMP

Strong decrease expected by majority of respondents

Survey

[89Sr]SrCl2

Decrease expected by majority of respondents

Survey

90Y-glass microspheres

Decrease expected by majority of respondents

Survey

[225Ac]Ac-Lintuzumab
177Lu-peptides
177Lu-antibodies

[227Th]Th-PSMA
227Th-conjugate

166Ho-microspheres

(HoMS)
90Y-glass microspheres
90Y-resin microspheres

90Y-colloids

7.

Supply situation

Only sometimes shortages in 131I occur, which may have some impact on patients. Reasons are given as
production issues and/or nuclear reactor issues. [1]

8.

Patient access to radionuclide therapy (e.g. regional differences)

With 3 centres, Luxembourg has 4.8 centres per million inhabitants. [2]

9.

Sources of information / References

[1] Technopolis survey (N = 3)
[2] Gleisner et al. (2017)

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Malta – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 90Y
Radiopharmaceuticals in compassionate use: N/A

2.

Emerging radionuclides / radiopharmaceuticals

Radiopharmaceuticals in experimental use (clinical trials): None found according to clinicaltrials.gov.
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

N/A

3.

Therapies and procedures

Radiopharmaceutical

Indication
type
procedure

[131I]-NaI

Number of
Patients
Receiving
therapy per
year

Number
of
procedures per
year

Activity

Thyroid Ca

52

52

211.84
GBq

[131I]-NaI

Thyrotoxicosis

45

45

16.65 GBq

90

SIRT

3

3

6.52GBq

4.

Y-microspheres

and
of

Source of
data

Prices and reimbursement

NM therapy procedures are all performed at the main general hospital of the island. The campus encompasses
Mater Dei Hospital and the Sir Anthony Mamo Oncology Centre. The health care model in Malta (public) is similar
to the UK model i.e. free at the point of use, funded through taxes. No departmental re-imbursement procedures
are in place.

5.

Medical guidelines

Guidelines generally followed are those issued by EANM and SNMMI.

6.

Future demand

In May 2020, 68Ga PSMA and DOTATATE PET imaging was started.
The next step that would follow would be 177Lu therapy (both PSMA and DOTATATE) though there are no plans
for this in the immediate future.
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7.

Supply situation

2020 has been fraught with logistical problems for all radiopharmecuticals due to a heavily curtailed flight
schedule. Being an island, all radiopharmaceuticals are imported via commercial flights. Freight costs have also
increased substantially since the start of the COVID pandemic though this has not resulted in any curtailing of
services.

8.

Patient access to radionuclide therapy (e.g. regional differences)

Number of radiotherapy practicing centres: 1, as country has only one hospital

9.

Other information

N/A

10. Sources of information / Reference
Email correspondence with Anthony Samuel, Consultant Nuclear Medicine Physician, Mater Dei Hospital

Netherlands – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 32P, 89Sr, 90Y, 103Pd, 125I, 131I, 152Eu, 154Eu, 153Sm, 166Ho, 169Er, 177Lu, 186Re, 188Re, 213Bi, 223Ra,
225
Ac, 227Ac, 227Th
Based on NVS report from 2017, but underlined RNs have not been mentioned in other sources – likely only
incidental use – while those in bold have been confirmed by this study’s survey.

Radiopharmaceuticals in compassionate use:
Only “magistral preparation” is allowed in certain cases and in clinical trials. Due to high price, it is allowed to
produce [177Lu]Lu-DOTATATE in-house. [225Ac]Ac-PSMA is prepared in-house as well for clinical trials.

2.

Emerging radionuclides (RNs) / radiopharmaceuticals (RPs)

Based on an analysis of registered clinical trials (Clinicaltrials.gov), several emerging RNs are studied in the
Netherlands: 177Lu, 90Y, 223Ra, 188Re. Some of these are already used in clinic as different RP or for different
indications. In interviews we understood that 225Ac (PSMA for prostate cancer, phase 1), 227Th and 212Pb are also
studied, but no details have been found on Dutch involvement.
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

[177Lu]Lu-DOTATATE

Neuroendocrine Tumours,
Liver Metastases

Utrecht University: Intraarterial [177Lu]Lu-DOTATATE
for Treatment of Patients
With Neuro-endocrine
Tumour Liver Metastases

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Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu-3BP-227 (also called 177Lu-

(Phase 1/2)

Pancreatic Ductal
Adenocarcinoma, Colorectal
Cancer, Gastric Cancer,
Squamous Cell Carcinoma of
the Head and Neck, Bone
Cancer, Metastatic Tumours

Ipsen: Study to Evaluate the
Safety and Activity
(Including Distribution) of
177Lu-3BP-227 in Subjects
With Solid Tumours
Expressing Neurotensin
Receptor Type 1.

[177Lu]Lu-PSMA

Prostate Cancer

Endocyte: Study of
[177Lu]Lu-PSMA-617 In
Metastatic CastrateResistant Prostate Cancer

Neuroendocrine Tumours

ITM Solucin GmbH: Efficacy
and Safety of 177Luedotreotide PRRT in GEPNET Patients

Non-Hodgkin Lymphoma,
Follicular Lymphoma

Nordic Nanovector: A Phase
I/II Study of Betalutin® for
Treatment of Relapsed NonHodgkin Lymphoma

Intrahepatic
Cholangiocarcinoma

Sirtex Medical: SIRT
Followed by CIS-GEM
Chemotherapy Versus CISGEM Chemotherapy Alone
as 1st Line Treatment of
Patients With Unresectable
Intrahepatic
Cholangiocarcinoma

Prostate Cancer

Memorial Sloan Kettering
Cancer Center: A Study to
Test Radium-223 With
Docetaxel in Patients With
Prostate Cancer

Prostate Cancer Metastatic
to Bone, Prostate Cancer

VU University Medical
Center: Rhenium-188-HEDP
vs. Radium-223-chloride in
Patients With Advanced
Prostate Cancer Refractory
to Hormonal Therapy

IPN01087)

(Phase 3)

177Lu-edotreotide PRRT,

Everolimu, Amino-Acid Solution
(Phase 3)
177Lu-lilitomab (Betalutin®)

(Phase 1/2)

90Y

90Y SIRT + chemotherapy

(Phase 2/3)

223Ra

Docetaxel 75 mg/m2, Docetaxel
60 mg/m2, Radium-223
(Phase 3)

223Ra / 188Re

[223Ra]RaCl2, [188Re]Re-HEDP
(Phase 3)

3.

Therapies and procedures

According to the 2008 UNSCEAR Global Survey of Medical Radiation Usage and Exposure, 5000 therapeutic
treatments in nuclear medicine are performed in the Netherlands.
Information based on analysis of national insurance codes for specific treatments, not always retraceable to
specific RPs, but some to RNs. Analysis provided by RIVM, based on 2017 data.

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Radionuclide

Average number of
procedures per year
nationally

Source of data

Average dose per
procedure (MBq)

National annual
demand (GBq)

90Y

25

Health Authority

-

121*

131I

1394

Health Authority

-

3934*

166Ho

50

Health Authority

1890

95

177Lu

900

Health Authority

-

5855*

223Ra

1021

DBC, 2017

3.85

4

32P

15

DBC, 2017

185

3

89Sr

44

Survey

150

7

153Sm

6

Survey

3133

19

*Spread of procedures across different indications based on proportions indicated from survey data

4.

Prices and reimbursement

In this study’s survey we have received estimates for the price of RPs. Full data was not available or not possible
to disclose.
Radiopharmaceutical

Price (€)

[131I]-NaI

Est. 50-200 per patient
dose

177Lu-peptides

Est. 1000-1500 per
patient dose

[177Lu]Lu-PSMA

Est. 1000-1500 per
patient dose

[177Lu]Lu-DOTATATE

Est. 1000-1500 per
patient dose

32P-sodium-phosphate

Est. 1000-1500 per
patient dose

(Na332PO4)
[223Ra]RaCl2

Est. 1500-2500 per
patient dose

Est. Total budget spent
per year

Calculation method

1.5M-2.5M

Est. Price x no. Procedures/year
(DBC data)

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5.

Medical guidelines

Based on interviews and link to national guidelines. National guidelines are all based on European guidelines
(EANM) or international guidelines (SNMMI). National medical guidelines are used, which have been developed
by the Dutch Society for Nuclear Medicine (NVNG) and can be found online at:
https://richtlijnendatabase.nl/richtlijn/nucleaire_geneeskunde/part_ii_-_radionuclide_therapy.html
This study’s survey suggests that in practice national and European clinical guidelines are used, some even use
only European guidelines.
Radiopharmaceutical

Indication

Guideline making
organisation

Link to
guideline

[131I]-NaI

Graves’ hyperthyroidism

NVNG

Link

[131I]-NaI

Non-toxic goitre-reduction

NVNG

Link

[131I]-NaI

Toxic adenoma

NVNG

Link

[131I]-NaI

Toxic multinodular goitre

NVNG

Link

[131I]-NaI

Thyroid Carcinoma

NVNG

89Sr Chloride (Metastron®)

Pain reduction skeletal metastasis

NVNG

Link

153Sm Lexidronam

Pain reduction in (osteoblastic) skeletal
metastases

NVNG

Link

(Quadramet ®)
188Re HEDP Etidronate

Pain reduction skeletal metastasis

NVNG

Link

[223Ra]RaCl2 (Xofigo ®)

pain relief in symptomatic bone
metastases due to castration-resistant
prostate cancer

NVNG

Link

90Y Ibritumomab tiuxetan

Treatment of follicular non-Hodgkin’s
lymphoma

NVNG

Link

(Zevalin®)
90Y radioembolisation

Treatment of hepatic malignancies

NVNG

Link

32P

Treatment Polycythaemia vera and
Essential T hrombocythaemia

NVNG

Link

[177Lu]Lu-DOTATATE
(octreotate)

Treatment of advanced and
metastasized neuroendocrine tumours
(NET)

NVNG

Link

(microspheres)

(and neuroblastoma or medullary
thyroid carcinoma)

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6.

Future demand

Base on this study’s survey we have some indication on the expected growth in future demand in the
Netherlands. These concern expectations, we have listed the majority response.
Radionuclide

Growth / Number of Patients Expected to receive
therapy in future

Source of data

[177Lu]Lu-PSMA

Strong increase (>15%)

Survey

[225Ac]Ac-PSMA

Increase (+1-15%)

Survey

166Ho-microspheres (HoMS)

Increase (+1-15%)

Survey

166Ho-microspheres

Increase (+1-15%)

Survey

[177Lu]Lu-DOTATATE

Increase (+1-15%)

Survey

[223Ra]RaCl2

Increase (+1-15%)

Survey

177Lu-antibodies

Increase (+1-15%)

Survey

[153Sm]Sm-EDTMP

Increase (+1-15%)

Survey

169Er-colloids

Decrease (-1-15%)

Survey

177Lu-peptides

Increase (+1-15%)

Survey

[89Sr]SrCl2

Strong decrease (<-15%)/ Decrease (-1-15%)

Survey

90Y-colloids

Increase (+1-15%)

Survey

90Y-glass microspheres

Increase (+1-15%)

Survey

188Re

Decrease (-1-15%)

Survey

[188Re]Re-HEDP

Decrease (-1-15%)

Survey

7.

Supply situation

In the Netherlands shortages in the supply of RPs is generally not a big problem, but supply issues have been
mentioned for [131I]I-mIBG and [131I]-NaI. In the survey respondents answered often or sometimes for these RPs,
meaning that the supply was disrupted at least more than three times in the past five years. Also, for 166Homicrospheres, sometimes shortages have been experienced (3-4 times/5 years). The impact of these disruptions
has a great impact on patients, especially disruptions for 177Lu and 166Ho have. The origin of these disruptions is
all with external production, so reside at the side of the supplier/producer. The causes have been linked to
reactor downtime, so is already caused at the stage of RN production.

8.

Patient access to radionuclide therapy (e.g. regional differences)

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Patients across the country have good access to radionuclide therapy. Hospitals have different specialisations
and facilities, but patients can go to other hospital for specific therapies.
2017 data on reimbursement (non-specific aggregation level for radiotherapy), suggest that 18 centres have been
practicing radionuclide therapy in the Netherlands. The main providers of radionuclide therapy are the 7
Academic hospitals in the Netherlands. Largest capacity is 6 therapy beds in special radionuclide therapy facility
of Erasmus MC.

9.

Sources of information / References

[1] Interviews (2020) with RIVM, ErasmusMC and NRG.
[2] Data provided by RIVM and NVNG through e-mail exchange.
[3] Technopolis surveys (2020) (N = 25 in Round 1 and N = 8 in Round 2)
[4] Data from national insurance (DBC)

Poland – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 153Sm, 89Sr, 223Ra, 90Y, 169Er, 186Re, 131I, 177Lu [1, 3, 5]

2.

Emerging radionuclides

Radiopharmaceuticals in experimental use (clinical trials): [1,5]
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

225Ac

[225Ac]Ac-PSMA

Prostate cancer

Yes

225Ac

[225Ac]Ac-DOTA-SP

glioblastoma

Yes

211At

PSMA, DOTATATE

Cancer

No

3.

Therapies and procedures

Radionuclide

Radiopharmaceutical

Number of doses
in 2019

Average dose
(MBq)

Total
Activity

Source
of data

(GBq)
153Sm

[153Sm]Sm-EDTMP

112

3133

351

[6]

89Sr

[89Sr]SrCl2

60

150

9

[6]

90Y

90Y-colloids*

664

203.5

135

[6]

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Radionuclide

Radiopharmaceutical

Number of doses
in 2019

Average dose
(MBq)

Total
Activity

Source
of data

(GBq)
90Y

90Y-glass spheres

53

90Y
177Lu

DOTATATE (30% 90Y/177Lu and
70% 177Lu)

350

6475

2266

131I

[131I]-NaI

22097

(5500 for
12%; 500 for
88%)

24439

131I

[131I]I-mIBG

45

7450

335

[6]

223Ra

[223Ra]RaCl2

714

3.85

3

[6]

186Re

186Re-colloids*

210

111

23

[6]

169Er

169Er-colloids

101

25

3

[6]

[6]
[6]

[6]

*vial could be divided Re-colloids 4-6, Y-colloids to 4-8 patients so number of procedures could be higher

4.

Prices and reimbursement

In 2016, the equivalent of €328.2 million (based on purchasing power parity) was spent on radiotherapy i.e. a
per capita expenditure of €8.6. Radiotherapy accounted for 0.67% of the total healthcare spending and 10.8% of
total cancer care expenditure [2].
The prices of individual reimbursed radionuclides/radiopharmaceuticals are not publicly available. Radionuclide
therapies are typically reimbursed under the general regulation of National Health Fund and separate pricing is
not available. Below is a list of estimated prices (excluding transportation costs) provided by the national supplier
- The National Centre For Nuclear Research – POLATOM.
Radiopharmaceutical

Price (€ per MBq)

IODOPOL® - Sodium iodide (131I) for therapy

1.00

Gelatin capsules 131I

20.00

Strontium (89Sr) chloride for injection

3.73

Quadramet® [153Sm]Sm-EDTMP

0.55

Colloidal erbium citrate (169Er) (Radiosynovectomy)

15.00

Colloidal Rhenium sulphide (186Re) (Radiosynovectomy)

12.00

Colloidal Yttrium (90Y) citrate (Radiosynovectomy)

8.00

146

Other information /
reflection on distributors

Manufactured and
distributed by the
National Centre for
Nuclear Research –
POLATOM

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5.

Medical guidelines

Radiopharmaceutical

Indication

Guideline making
organisation

Title of/link to guideline

131I

Hyperthyroidism (in Graves’ disease)

National and European
recommendation

131I

Hyperthyroidism (goitre)

131I

Struma neutralis

Published in Journal of
Laws of the Ministry of
Health of 2014, item 82
(based on national and
European guidelines [6])

131I

Hyperthyroidism in children I-131

89Sr

Bone metastases (pain therapy)

153Sm

Bone metastases (pain therapy)

223Ra

Bone metastases (pain therapy)

186Re

Bone metastases (pain therapy)

90Y

Joint diseases

186Re

Joint diseases

169Er

Joint diseases

90Y

Lymphoma (radioimmunotherapy)

90Y

Primary/metastases of liver cancers

131I

Thyroid cancer

131I

Treatment with [131I]I-mIBG

90Y, 177Lu

Neuroendocrine tumours

All other radiopharmaceuticals and indications are covered under EANM guidelines.

6.

Future demand

Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of data

[131I]I-mIBG

Stable for majority of respondents

[4]

[131I]-NaI

Stable for majority of respondents

[4]

[153Sm]Sm-EDTMP

Stable for majority of respondents

[4]

169Er-colloids

Stable for majority of respondents

[4]

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Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of data

[177Lu]Lu-DOTATATE

Increase or strong increase for vast majority of respondents

[4]

177Lu-peptides

Increase for vast majority of respondents

[4]

[177Lu]Lu-PSMA

Strong increase for majority of respondents

[4]

186Re-colloids

Stable for majority of respondents

[4]

[223Ra]RaCl2

Increase for majority of respondents

[4]

Increase or strong increase for vast majority of respondents (NOTE:
currently in clinical trials)

[4]

[225Ac]Ac-PSMA
[89Sr]SrCl2

Decrease for majority of respondents

[4]

7.

Supply situation [1]

POLATOM is the manufacturer and distributor of isotopes used in medicine, science, industry and environmental
protection in Poland. The construction of a large cyclotron at POLATOM for the production of
radiopharmaceuticals is currently underway. Currently, production of certain radiopharmaceuticals is carried out
as follows:
•

LUTAPOL® or Lutetium (177Lu) chloride [radiopharmaceutical precursor] is produced from Lutetium enriched
with 176Lu isotope which is irradiated with neutrons in a nuclear reactor

•

MIBG and sodium iodide (131I) is produced in a nuclear reactor from tellurium oxide irradiated with neutrons
in the reactor or from uranium fission products

•

Strontium (89Sr) chloride is produced in the nuclear reactor

•

ITRAPOL® - Yttrium (90Y) chloride [radiopharmaceutical precursor] is produced from the decay of Strontium90

8.

Patient access to radionuclide therapy

1.2 centres per million inhabitants
•

There are 45 practicing radionuclide therapy centres (according to the National Centre for Radiation
Protection in Health, Poland). [1]

9.

Sources of information / References

[1] Email exchange with Mr Dariusz Kluszczyński, Director of the National Centre for Radiation Protection in
Health, Poland
[2] Lievens, Y., Borras, J. M., & Grau, C. (2020). Provision and use of radiotherapy in Europe. Molecular Oncology.
[3] Technopolis survey (Round 1), N = 11
[4] Technopolis survey (Round 2), N = 5
[5] Email exchange with Dr Rafał Czepczyński, Polish Society of Nuclear Medicine
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[6] Email exchange with Dr Jolanta Kunikowska, Polish Society of Nuclear Medicine

Portugal – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use [1]: 131I, 166Ho, 177Lu, 223Ra, 90Y, 32P, 89Sr, (but 32P and 89Sr is exceptional - roughly one patient
every 5 years).
Radiopharmaceuticals in compassionate use: [177Lu]Lu-DOTATATE (Lutathera®) to treat neuroendocrine tumours
[2]

2.

Emerging radionuclides / radiopharmaceuticals

Radiopharmaceuticals in experimental use [2][3]:
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

[177Lu]Lu-DOTATATE

Neuroendocrine
tumours

NETTER-P and NETTER-2 trials to evaluate
paediatric use and long term safety.
Under pharmaco-economic evaluation by
INFARMED for adult use.

3.

Therapies and procedures

Radiopharmaceutical

Indication
and type of procedure

Number of
procedures per year
(in all Nuclear
Medicine
Departments)

Average activity
per procedure
Total activity (GBq) (in
(MBq)
all Nuclear Medicine
Departments)

Source
[4]

[131I]I-mIBG
(IOBENGUANE)

Adult neuroendocrine tumours

6

[131I]I-mIBG
(IOBENGUANE)

Neuroblastoma

2

[131I]-NaI

Benign thyroid diseases

855

[131I]-NaI

Thyroid cancer therapy for adults

201

[131I]-NaI

Thyroid cancer therapy for children
9
and young adults

[131I]-NaI

Thyroid remnant ablation of adults 721

[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]

149

[4]
[5]

Source

7400

7400

464

5541

4812

1425

[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]

44

15

385

1114

44

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Radiopharmaceutical

Indication
and type of procedure

Number of
procedures per year
(in all Nuclear
Medicine
Departments)

Average activity
per procedure
Total activity (GBq) (in
(MBq)
all Nuclear Medicine
Departments)

Source

[131I]-NaI

Thyroid remnant ablation of
children and young adults

166Ho-microspheres

Intra-arterial treatment in the liver 9

[177Lu]Lu-DOTATATE

Gastroenteropancreatic
neuroendocrine tumours

40

[223Ra]RaCl2

Bone metastases

98

90Y-colloids

Radiation synovectomy

1

90Y-glass

Intra-arterial treatments in the
liver

18

Intra-arterial treatments in the
liver

25

microspheres
90Y-resin

microspheres

4.

[4]

18

[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]

Source

1457

1833

7400

3,9

185

1757

1001

[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]
[4]
[5]

23

30

296

<1

<1

11

44

Prices and reimbursement

Information based on survey
Radio-pharmaceutical

Price in € (mean, (min max))

Total budget
spent per
year

Calculation
method

Other information
/ reflection on
distributors

[131I]-NaI

242.50 (85, 400)

-

-

-

[177Lu]Lu-DOTATATE

22,500 (20,000, 25,000)

-

-

-

[223Ra]RaCl2

4,300 (4,300, 4,300)

-

-

-

90Y-glass microspheres

12,500 (10,000, 15,000)

-

-

-

5.

Medical guidelines

Portuguese survey respondents only reported using European clinical guidelines

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6.

Future demand

Radionuclide

Growth / Number of Patients

Source of data

Expected to receive therapy in future
177Lu-peptides

42.9% of Portuguese respondents expect there to be a strong increase (>15%)
in demand. Another 28.6% expect there to be weak increase in demand (+1 to
+15%)

[1]

[177Lu]LuDOTATATE

28.6% of Portuguese respondents expect there to be a strong increase (>15%)
in demand. Another 28.6% expect there to be weak increase in demand (+1 to
+15%)

[1]

[177Lu]Lu-PSMA

42.9% of Portuguese respondents expect there to be a weak increase(+1 to
+15%) in demand. Another 28.6% expect there to be strong increase in
demand (>15%)

[1]

[225Ac]Ac-PSMA

28.6% of Portuguese respondents expect there to be a weak increase(+1 to
+15%) in demand. Another 14.3% expect there to be strong increase in
demand (>15%)

[1]

[153Sm]SmEDTMP

28.6% of Portuguese respondents expect there to be a strong decrease (<15%) in demand. Another 14.3% expect there to be weaker decrease in
demand (-15% to -1%)

[1]

[89Sr]SrCl2

42.9% of Portuguese respondents expect there to be a strong decrease (<15%) in demand

[1]

7.

Supply situation

•

[131I]-NaI – 16.7% of relevant respondents suggested that [131I]-NaI had been in shortage often (>4 times)
over the last 5 years whilst 50% of relevant respondents suggested that [131I]-NaI had been shortage rarely
(1-2 times) over the last 5 years. A variety of reasons were suggested for these shortages occurring: during
external production and during transport. These shortages were reported to have had a disruptive effect to
some extent on the treatment of patients.

•

[131I]I-mIBG (IOBENGUANE) - Relevant respondents suggested that [131I]-NaI had been in shortage often (>4
times) over the last 5 years. It was suggested that the reason for these shortages occurring was due to
external production. These shortages were reported to have had a large disruptive effect on the treatment
of patients.

8.

Patient access to radionuclide therapy (e.g. regional differences)

There are 34 Nuclear Medicine Departments in Portugal. All are authorised to give therapy, however, only 7 of
have the facilities to do inpatient procedures [2]. Twelve have a significant number of therapeutic procedures
and the other twenty-two have only a residual therapeutic activity. There is a strong concentration of Nuclear
Medicine Departments in the 3 main Portuguese cities (Lisbon, Porto and Coimbra), where 26 of the 34
departments are located. The remaining 8 departments are located in other high population density areas.

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9.

Other information

Lutathera® is imported from Spain, Iodine based radionuclides from France, Radium from the US and Yttrium
from The Netherlands.

10. Sources of information / References
[1] Technopolis survey (survey respondents N = 14)
[2] Interview with Dr Gracinda Costa, Portuguese Nuclear Medicine Society - SPMN
[3] Technopolis clinical trials analysis
[4] SPMN survey to the twelve Nuclear Medicine Departments that are more representative in the therapeutic
area (survey respondents N = 8)
[5] SPMN estimation based on reliable historical data (N = 26)

Romania – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 89Sr, 90Y, 131I, 153Sm, 177Lu, 188Re

2.

Emerging radionuclides

Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

131I

Lenvatinib (E7080)

Differentiated Thyroid Cancer

Y

3.

Therapies and procedures

Radiopharmaceutical

Indication and
type of
procedure

Number of
procedures per
year

Source of
data

Average dose per
procedure (MBq)

National annual
demand (GBq)

131I, e.g. [131I]-

Thyroid cancer

2600

[2]

4000

1040

Thyrotop

With regard to the remaining radiopharmaceuticals, we only know that they are used in Romania, but not in
what amount – no data was provided in the survey.

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4.

Prices and reimbursement

Radiopharmaceutical

Price (€)

Total budget spent per year

Calculation
method

131I

>520€

If the patient is not insured, the payment goes up from 2500
RON (520 EURO), depending on the associated procedures
performed and the days of hospitalisation.

Patients x price =
€ 1.352 million

5.

Medical guidelines

Radiopharmaceutical

Indication

Recommended dosage

Guideline
making
organisation

Title of/link to
guideline

131I

thyroid
malignancies,
hyperthyroidism

Patients with hyperthyroidism receive doses between 10-20 mCi,
on average 15 mCi. Usually, a
single administration is sufficient.

EANM, ATA,
NCCN

National Guide to the
diagnosis and
treatment of
differentiated thyroid
cancer derived from
follicular epithelium
(2010)

Patients with thyroid cancer receive doses of 30-50 mCi for the
low-risk category, 100 mCi for the
other categories, > 100 mCi for
patients with metastases.

National Guide to the
diagnosis and
treatment of clinical
hyperthyroidism
EANM guidelines on I131 therapy of
Differentiated Thyroid
Cancer (2008)
ATA Guidelines for
Diagnosis and
Management of
Hyperthyroidism and
other causes of
Thyrotoxicosis (2016)
ATA Management
Guidelines for Adult
Patients with Thyroid
Nodules and
Differentiated Thyroid
Cancer (2015)
NCCN Clinical Practice
Guidelines in
Oncology 2019

Note: EANM = European Association for Nuclear Medicine, ATA = American Thyroid Association, NCCN = National
Comprehensive Cancer Network (USA)

6.

Future demand

The Romanian survey respondents did not provide any data on future demand.

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7.

Patient access to radionuclide therapy (e.g. regional differences)

5 hospitals: two private and three public [2]. This would mean access of 0.3 centres per million inhabitants.
8.

Sources of information / References

[1] Survey respondents (N = 4)
[2] Email exchange with Olga Girjoaba, National Institute of Public Health
[3] IAEA DIRAC (Directory of radiotherapy centres)

Slovakia – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 223Ra, 177Lu, 89Sr, 90Y

2.

Therapies and procedures

Information based on data received from the national contact point:
Radiopharmaceutical

Indication and type of
procedure

Number of Patients receiving therapy per year
(dose)

Source of
data

131I-Nal

thyroid cancer

656 (1.1-4.1 GBq)

[1]

131I-Nal

adjuvant therapy/therapy
of metastatic diseases

307 (3.7-7.4 GBq)

[1]

131I-Nal

orbitopathy

41 patients (2.4-3.7 GBq)

[1]

131I-Nal

thyreotoxicosis

135 patients, about 10% of them need second
therapy (185-925 MBq)

[1]

circa 180 applications

[1]

223Ra

Information based on data received from Technopolis survey:
Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of
data

Average
dose per
procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]-NaI used in benign thyroid
diseases

1133

Survey

500

567

131I

[131I]-NaI used in thyroid cancer
therapy for adults

4095

Survey

5500

22523

131I

[131I]-NaI used in thyroid cancer
therapy for children and young
adults

98

Survey

1942

190

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Radionuclide

Indication and type of procedure

Average
number of
procedures
per year
nationally

Source of
data

Average
dose per
procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]-NaI used in thyroid remnant
ablation of adults

1095

Survey

3000

3285

131I

[131I]-NaI used in thyroid remnant
ablation of children and young adults

38

Survey

1942

74

177Lu

[177Lu]Lu-PSMA used in therapy of
castration resistant prostate cancer
and pc-metastases

135

Survey

7400

999

223Ra

[223Ra]RaCl2 used in bone metastases
(EMA authorised)

1058

Survey

3.85

4

89Sr

[89Sr]SrCl2 used in bone metastases
(EMA authorised)

8

Survey

150

1

153Sm

[153Sm]Sm-EDTMP used in bone
metastases (EMA authorised)

8

Survey

3133

25

3.

Prices and reimbursement

Radionuclides and radiopharmaceuticals for therapy are bought from qualified and certified distributors: 131I - GE
(company MGP) prices as in EU, 223Ra– Bayer, prices as in EU, 177Lu – in-house preparing. Source: [1]

4.

Medical guidelines

Overall, EANM guidelines are used.

5.

Future demand

Radionuclide

Number of Patients expected to receive therapy in future

Source of data

[177Lu]Lu-DOTATATE

Strong increase (more than +15%)

Survey data

177Lu-peptides

Strong increase (more than +15%)

Survey data

[177Lu]Lu-PSMA

Strong increase (more than +15%)

Survey data

6.

Supply situation

According to data from national contacts, 89Sr stopped after Brexit.

7.

Patient access to radionuclide therapy (e.g. regional differences)

Reported problems with insurance for the radionuclide therapy: diagnosis-related groups (DRG) system in place
leading to very low price for inpatient therapy. If expensive radiopharmaceuticals (such as [177Lu]Lu-PSMA) are

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needed, patients have to be treated on outpatient basis. In some patients with neuroendocrine tumour this can
be risky, at the moment they are treated abroad. Source: [1]
•

Number of radiotherapy practicing centres:
There are 3 centres for therapy (12, 10, 10 beds) in Slovakia, according to our data request [1]. However,
national statistics mention 15 centres for nuclear medicine in the country. [3]

8.

Sources of information / References

[1] Information received from Dr Pavol Povinec
[2] Technopolis survey data (N = 3)
[3] Cinnost_nuklearnej_mediciny_klinickej_a_radiacnej_onkologie_v_SR_2018c
[4] Gleisner et al. (2017)

Slovenia – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 177Lu, 90Y, 223Ra, 186Re, 64Cu
Radionuclides in bold have been listed by URSJV and were confirmed by the survey. Underlined RNs have been
indicated in the survey but are likely only rare RNs in experimental use.

2.

Therapies and procedures

According to the 2008 UNSCEAR Global Survey of Medical Radiation Usage and Exposure, 1360 therapeutic
treatments in nuclear medicine are performed in Slovenia. More recent (2019) and specific data is obtained from
the URSJV and provided in the table below.
Radiopharmaceutical

Number of Patients

Number of procedures

Activity

Source of data

Receiving therapy per
year

per year

131I

700 (average 2017-2019

700 (average 2017-2019)

1027.4 GBq

URSJV, 2019

177Lu

17 (average 2017-2019)

17 (average 2017-2019)

111.5 GBq

URSJV, 2019

90Y

2 (average 2017-2019

2 (average 2017-2019)

12.0 GBq

URSJV, 2019

223Ra

31 (average 2017-2019)

186 (average 2017-2019)

1.4 GBq

URSJV, 2019

186Re

3 (average 2017-2019

3 (average 2017-2019)

<1 GBq

URSJV, 2019

3.

Prices and reimbursement

Radiopharmaceuticals are fully reimbursed in Slovenia from the “Public Insurance Budget”. Some proce data
have been obtained from this Public Insuramce Budget on the radiopharmaceuticals listed below, obtained from

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the Slovenian Government. These concern the highest prices that have been paid. Based on these max prices a
total max budget spent per year has been calculated using the numbers on procedures and total annual activity.
No information was obtained on distributors/producers in Slovenia.

Radiopharmaceutical

Price (€, highest)

Total budget spent
per year (€, max)

Calculation method

Other information
/ reflection on
distributors

[131I]-NaI

273.47

37,968-

(Average activity per year
(in MBq) /7400 MBq) x
price

POLATOM, 37-7400
MBq

75,936
[90Y]Y-ibritumomabtiuxetan

10,334.27

20,669

Average number of
procedures per year x
price

Zevalin® 1,6
mg/mL, [90Y]Yibritumomab
tiuxetan

[223Ra]RaCl2

4,434.27

824.774

Average number of
procedures per year x
price

Xofigo® 1,000
kBq/mL

177Lu (precursor)

31,509.50

63,019

(Average activity per year
/ 40GBq/ML)

2 mL
EndolucinBeta®
40GBq/mL

59,054.50

59,055

(Average activity per year
/ 40GBq/ML)

10 mL
EndolucinBeta®
40GBq/mL

4.

Medical guidelines

In Slovenia guidelines and protocols are based on EANM guidelines.

5.

Future demand

In Slovenia the demand of 177Lu is growing quickly: from 6 patients in 2017, through 15 patients in 2018 to 30
patients in 2019. No other demand information for Slovenia was obtained in the survey or interviews.

6.

Supply situation

No isotopes are produced within Slovenia. Radionuclides and radiopharmaceuticals are imported without any
serious supply issues in the last years. No additional information was obtained in the survey regarding shortages.

7.

Patient access to radionuclide therapy (e.g. regional differences)

•

Number of radiopharmacies:
Slovenia has six radiopharmacies related to radionuclide therapy, located at the six centres that practice
radionuclide therapy.

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•

Number of radionuclide therapy practicing centres:
Slovenia has six centres practicing radionuclide therapy: KNM, OI, UKC Maribor, SB Celje, SB Slovenj Gradec
and SB Izola.

8.

Sources of information / References

[1] Information based on written interview/e-mail exchange (2020) with Dr. Damijan Skrk from the Slovenian
Radiation Protection Administration.
[2] The Slovenian Radiation Protection Administration (URSJV) (2019), Razširjeno poročilo o varstvu pred
ionizirajočimi sevanji in jedrski varnosti v Republiki Sloveniji leta 2018, section 2.2.7.2.
[3] Technopolis survey (N = 1)

Spain – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 32P, 89Sr, 90Y, 131I, 153Sm, 166Ho, 169Er, 177Lu, 186Re, 188Re, 223Ra

2.

Emerging radionuclides

Radionuclide

Radiopharmaceutical

Indication

In clinical
trials?

177Lu

[177Lu]Lu-DOTA0-Tyr3Octreotate

Inoperable, Progressive, Somatostatin Receptor
Positive Midgut Carcinoid Tumours

Y

177Lu

[177Lu]Lu-edotreotide PRRT

GEP-Net patients

Y

177Lu

Betalutin®

Relapsed Non-Hodgkin Lymphoma

Y

90Y

90Y SIRT

Unresectable Intrahepatic Cholangiocarcinoma

Y

Transarterial Radioembolisation in Uveal Melanoma
Liver Metastasis

Y

90Y

90Y

90Y SIRT

Advanced Stage Intrahepatic Biliary Tract Cancer

Y

90Y

TheraSphere®

Inoperable Liver Cancer

Y

90Y

TheraSphere®

Metastatic Colorectal Cancer

Y

90Y

Nivolumab After SIRT

HCC

Y

131I

131I-omburtamab

Neuroblastoma Central Nervous
System/Leptomeningeal Metastases

Y

131I

Lenvatinib (E7080)

Differentiated Thyroid Cancer

Y

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Radionuclide

Radiopharmaceutical

Indication

In clinical
trials?

223Ra

Radium-223 Dichloride

Castration-resistant Prostate Cancer Metastatic to
the Bone

Y

223Ra

Radium-223 Dichloride

Castration-Resistant (Hormone-Refractory) Prostate
Cancer Patients With Bone Metastases

Y

223Ra

Radium-223 Dichloride

Bone Predominant HER2 (Human Epidermal Growth
Factor Receptor 2) Negative Hormone Receptor
Positive Metastatic Breast Cancer

Y

223Ra

Radium-223 Dichloride

Stage IV Non-small Cell Lung Cancer With Bone
Metastases

Y

223Ra

Radium-223 Dichloride

Asymptomatic Patients With mCRPC

Y

223Ra

Radium-223 Dichloride

Cancer of the Prostate

Y

3.

Therapies and procedures

Radiopharmaceutical

Indication and type of
procedure

Average number
of procedures
per year
nationally

Source
of data

Average
activity per
procedure
(MBq)

National
annual
demand
(GBq)

90Y

90Y-colloids used in radiation

600

Survey

203

122

372

Survey

11500

4278

synovectomy
90Y

90Y-glass microspheres used in

intra-arterial treatments in the
liver
90Y

[90Y]Y-ibritumomab-tiuxetan
used in b-cell lymphoma and
non-hodgkin lymphoma (EMA
authorised)

84

Survey

1000

84

90Y

90Y-resin microspheres used in

540

Survey

3000

1620

intra-arterial treatments in the
liver
131I

[131I]I-mIBG (IOBENGUANE)
used in adult neuroendocrine
tumours (EMA authorised)

60

Survey

7450

447

131I

[131I]I-mIBG (IOBENGUANE)
used in neuroblastoma (EMA
authorised)

96

Survey

7450

715

131I

[131I]-NaI used in benign thyroid
diseases

5484

Survey

500

2742

131I

[131I]-NaI used in thyroid cancer
therapy for adults

3540

Survey

5550

19647

131I

[131I]-NaI used in thyroid cancer
therapy for children and young
adults

1056

Survey

1942

2051

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Radiopharmaceutical

Indication and type of
procedure

Average number
of procedures
per year
nationally

Source
of data

Average
activity per
procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]-NaI used in thyroid
remnant ablation of adults

3084

Survey

3000

9252

131I

[131I]-NaI used in thyroid
remnant ablation of children
and young adults

396

Survey

1942

769

166Ho

166Ho-microspheres used in

168

Survey

1890

318

intra-arterial treatment in the
liver (EMA authorised)
177Lu

[177Lu]Lu-DOTATATE used in
gastroenteropancreatic
neuroendocrine tumours (EMA
authorised)

336

Survey

6475

2176

223Ra

[223Ra]RaCl2 used in bone
metastases (EMA authorised)

240

Survey

3.85

1

32P

32P-sodium-phosphate

12

Survey

185

2

(Na332PO4) used in
myeloproliferative disease
89Sr

[89Sr]SrCl2 used in bone
metastases (EMA authorised)

24

Survey

150

4

153Sm

[153Sm]Sm-EDTMP used in bone
metastases (EMA authorised)

72

Survey

3133

226

169Er

169Er-colloids used in radiation

84

Survey

25

2

132

Survey

111

15

24

Survey

452

11

24

Survey

3079

74

synovectomy
186Re

186Re-colloids used in radiation

synovectomy
188Re

188Re used in non-melanoma

skin cancer
188Re

4.

[188Re]Re-HEDP used in painful
bone metastases

Prices and reimbursement

In Spain, radiopharmaceuticals related medical procedures are classified as procedures “for hospital use”. For
this category of procedures/products, the National Health System (NHS) funds 100% of cost as long as it is applied
in a hospital/centre within the NHS (not in a private centre/hospital).[1]
There is a National Commission in charge of pricing policy to assess the price of the radiopharmaceutical.[1]
Radionuclides are reimbursed at the price defined by the AEMPS (Spanish agency of Drugs and sanitary
products).[2]
Radiopharmaceutical

Price (€)

Other information / reflection on distributors

[131I]-NaI

93-587

Survey

[131I]I-mIBG

1031-3712

Survey

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Radiopharmaceutical

Price (€)

Other information / reflection on distributors

[177Lu]Lu-DOTATATE

13478

Survey

[223Ra]RaCl2

4596

Survey

153Sm-EDTP

1716

Survey

186Re-colloids

514-1249

Survey

[89Sr]SrCl2

1800-1900

Survey

[90Y]Y-ibritumomab-tiuxetan

13518

Survey

90Y-resin microspheres

8500-8600

Survey

90Y-glass microspheres

8500-8600

Survey

90Y-colloids

353-637

Survey

5.

Medical guidelines

Radiopharmaceutical

Indication

Guideline making organisation

131I

American Thyroid Association

177Lu

ENETS guidelines

223Ra

Prostate Cancer

90Y

6.

European Urological Guideline for Prostate Cancer and NCCN
Hepatocellular carcinoma guidelines and many digestive cancer
guidelines for SIRT

Future demand

The most important advance in the near future could be the use of [177Lu]Lu-PSMA and the most products with
alpha emitter agents [2]
Radionuclide

Number of Patients

Source of data

Expected to receive therapy in future
[177Lu]Lu-DOTATATE

Strong increase expected by majority of respondents

Survey

[177Lu]Lu-PSMA

Increase to strong increase expected by large majority of
respondents

Survey

166Ho-microspheres

Increase expected by majority of respondents

Survey

177Lu-peptides

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Radionuclide

Number of Patients

Source of data

Expected to receive therapy in future
32P-sodium-phosphate

Strong decrease expected by majority of respondents

Survey

Decrease expected by majority of respondents

Survey

(Na332PO4)
[89Sr]SrCl2

7.

Supply situation

The therapeutic products are manufactured outside Spain, with the exception of 177Lu.[2] According to one
interviewee, at this moment the supply is appropriate, even in a landscape with increased demand.[2] However,
survey respondents report shortages with 131I (mIBG and NaI), which they believe impacts patients to a certain
extent. The shortages occur during external production and transport. To increase supply, licences would have
to be increased (in the case of 131I). [4]

8.

Patient access to radionuclide therapy (e.g. regional differences)

Spain has approximately 60 centres (including public and private practice). The majority have radiopharmacies,
however some rely on external radiopharmacies. [2]

9.

Sources of information / References

[1] Correspondence with Yolanda Agra Varela, Ministry of Health, 22 April 2020
[2] Correspondence with Juan Antonio Vallejo (Hospital Universitarior Reina Sofía), 31 March 2020
[3] Gleisner et al. (2017)
[4] Technopolis survey (N = 6)

Sweden – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 131I, 90Y, 223Ra, 153Sm, 32P, 177Lu

2.

Emerging radionuclides / radiopharmaceuticals

Radiopharmaceuticals in experimental use (clinical trials):
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

[177Lu]Lu-PSMA

Metastatic
CastrateResistant
Prostate Cancer

Yes – Phase III

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Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

[177Lu]Lu-DOTATATE

Relapsed NonHodgkin
Lymphoma

Yes - Phase I and Phase II

225Ac

[225Ac]Ac-PSMA

Men With Cancer
of the Prostate

Yes - Phase III

3.

Therapies and procedures

According to the 2008 UNSCEAR Global Survey of Medical Radiation Usage and Exposure, 3496 therapeutic
treatments in nuclear medicine are performed in Sweden. More recent data is presented below:
Radiopharmaceutical

Indication
and type of procedure

Number of
Patients

Number of
procedures

Receiving
therapy per
year

per year

Activity
(MBq)

Source of data

[131I]-NaI

Hyperthyroidism

n/a

1,502

660,880

SSM

[131I]-NaI

Thyroid cancer

n/a

476

1,642,200

SSM

90Y-colloids

Radiosynovectomy

n/a

1

209

SSM

[223Ra]RaCl2

Palliation of bone
metastases

n/a

1,466

6,597

[153Sm]Sm-EDTMP
(Quadramet® )

Palliation of bone
metastases

n/a

6

17,016

SSM

SSM

32P–sodium-

SSM

phosphate
(Na332PO4)

Polycytemia vera

n/a

50

9,200

[131I]I-mIBG
(IOBENGUANE)

Neuroendocrine tumours

n/a

7

93,100

[177Lu]Lu-DOTA-NOC
(Octreotid)

Neuroendocrine tumours

n/a

444

3,210,120

90Y- microspheres

Liver tumours

n/a

4

4,500

4.

SSM

SSM

SSM

Prices and reimbursement

No price information was available.
5.

Medical guidelines

There are no official Swedish national guidelines issued by authorities. There are however national care
programmes issued by the care providers in which radionuclide therapy can be recommended with guidelines

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on how to perform the treatments. In some cases, international guidelines, such as the EANM guidelines will be
used [1].

6.

Future demand

No survey information was reported on future demand for radionuclides in Sweden. However, an interviewee
suggested that there has been a trend in Sweden towards more complex treatments with individualised
treatment planning by using dosimetry based on SPECT-imaging. These developments add more demand on the
radiotherapy sessions in terms of time as several SPECT CT sessions are needed to calculate dosimetry [1].

7.

Supply situation

No issues have been raised regarding supply of radionuclides in Sweden. Radiopharmaceuticals are imported
from other countries as ready to use capsules or injectable solutions. These countries include the Netherlands,
Poland and Germany [1].

8.

Patient access to radionuclide therapy (e.g. regional differences)

All radiotherapy is performed by public health care givers in 21 different regions at 23 different hospitals. There
are more hospitals concentrated in Stockholm than other regions [2].

9.

Sources of information / References

There were no complete responses from Sweden from the Technopolis survey
[1] Interview conducted in April 2020 with Lars Idestrom, Inspector at the Swedish Radiation Safety Authority
(also known as the Strålsäkerhetsmyndigheten or SSM)
[2] SSM also provide public information on annual radiotherapy statistics in Sweden

UK – validated
1.

Radiopharmaceuticals currently in use

Radionuclides in use: 90Y, 131I, 177Lu, 223Ra
Radiopharmaceuticals in compassionate use: may be used to fund Lu-177 PSMA in Scotland and Wales but
unlikely in England and Wales but some privately funded treatment may occur

2.

Emerging radionuclides / radiopharmaceuticals

Radiopharmaceuticals in experimental use (clinical trials):
Radionuclide

Radiopharmaceutical

Indication

In clinical trials?

177Lu

[177Lu]Lu-DOTATOC

rarer neuroendocrine tumours
such as phaeochromocytoma

Used as part of research
trials suspended for

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Radionuclide

Radiopharmaceutical

Indication

In clinical trials?
about 6 months
restarting soon

177Lu

[177Lu]Lu-PSMA

Prostate cancer

Trial completed awaiting
product authorisation
and re-imbursement
before roll-out

225Ac

[225Ac]Ac-PSMA

Prostate cancer

Not yet in clinical trials

32P

32P-silicon

Pancreatic cancer

Trails completed and
now authorised awaiting
decision on
reimbursement

3.

Therapies and procedures

According to the 2008 UNSCEAR Global Survey of Medical Radiation Usage and Exposure, 14500 therapeutic
treatments in nuclear medicine are performed in the United Kingdom.
However, there is no central register of number of patients receiving radionuclide therapy or procedures. A new
register for Lu-177 DOTATATE therapy has started and will be adapted for Lu-177 PSMA. The register is
administered by the BNMS. In the meanwhile, a cross-section review of radionuclide usage was performed in
July/August 2020.
Radionuclide

Indication and type of
procedure

Average number of
procedures per year
nationally

Source of
data

Average dose
per procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]-NaI used in benign
thyroid diseases

5623

[3]

500

2811

131I

[131I]-NaI used in thyroid
remnant ablation of adults

3931

[3]

3000

11794

131I

[131I]-NaI used in thyroid
remnant ablation of children
and young adults

155

[3]

1942.5

302

131I

[131I]-NaI used in thyroid
cancer therapy for adults

1015

[3]

5500

5632

131I

[131I]-NaI used in thyroid
cancer therapy for children
and young adults

64

[3]

1942.5

124

131I

[131I]I-mIBG used in
neuroblastoma

101

[3], BNMS

7450

749

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Radionuclide

Indication and type of
procedure

Average number of
procedures per year
nationally

Source of
data

Average dose
per procedure
(MBq)

National
annual
demand
(GBq)

131I

[131I]I-mIBG used in adult
neuroendocrine tumours

357

[3], BNMS

7450

2656

177Lu

177Lu-antibodies used in non-

64

[3]

1062

68

hodgkin lymphoma
177Lu

[177Lu]Lu-PSMA used in
therapy of castration resistant
prostate cancer and pcmetastases

1189

[3]

7400

8795

177Lu

[177Lu]Lu-DOTATATE used in
gastroenteropancreatic
neuroendocrine tumours
(PRRT)

3438

[3], BNMS

6475

22259

166Ho

166Ho-microspheres used in

18

[3]

1890

35

73

[3]

185

14

intra-arterial treatment in the
liver
32P

32P-sodium-phosphate used in

myeloproliferative disease
223Ra

[223Ra]RaCl2 used in bone
metastases

7077

[3]

3.85

27

186Re

186Re-colloids used in radiation

82

[3]

111

9

synovectomy
90Y

[90Y]Y-ibritumomab-tiuxetan
used in b-cell lymphoma and
non-hodgkin lymphoma

9

[3]

1000

9

90Y

90Y-resin microspheres used in

777

[3]

3000

2331

722

[3]

11500

8306

329

[3], BNMS

203.5

67

intra-arterial treatments in the
liver
90Y

90Y-glass microspheres used in

intra-arterial treatments in the
liver
90Y

90Y-colloids used in radiation

synovectomy

4.

Prices and reimbursement

The table below is based on data from the Technopolis survey [4]

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Other information / reflection on
distributors

Radiopharmaceutical

Mean Price (€ per procedure)

[223Ra]RaCl2

1948.00

[177Lu]Lu-PSMA

14439.00

Price will increase after authorisation is
obtained

[131I]-NaI

178.50

According to BSNM, price is ~£500

[131I]I-mIBG

4652.00

According to BSNM, price is ~£500

90Y-resin microspheres

8853.00

90Y-glass microspheres

8853.00

5.

Medical guidelines

The National Institute of Health Excellence (NICE) publishes guidelines for radiotherapy in England. These allow
for re-imbursement in England and may be adopted by the other UK nations as well.
For therapies not covered by NICE guidelines, the guidelines of the European Association of Nuclear Medicine
are recommended.
Radio-pharmaceutical

Indication

Guideline making
organisation

Title of/link to guideline

131I

benign thyroid
disease

NICE

https://www.nice.org.uk/guidance/ng145/docume
nts/evidence-review-12

223Ra

Prostate cancer
with bone
metastases

NICE

https://www.nice.org.uk/guidance/ta412/resource
s/radium223-dichloride-for-treatinghormonerelapsed-prostate-cancer-with-bonemetastases-pdf-82604599866565

177Lu DOTATATE

neuroendocrine
tumours

NICE

https://www.nice.org.uk/guidance/ta539/docume
nts/committee-papers

90Y (SIRT)

Liver cancer (HCC)
and metastases

NICE

https://www.nice.org.uk/guidance/ipg460/chapter
/2-The-procedure

6.

Future demand

According to the BSNM, future demand will depend on funding and training. At present only about 50% of the
eligible UK population receives radionuclide therapies they could benefit from as there is a lack of trained staff
and ignorance among oncologists.
Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of data

[131I]-NaI

Stable for majority of respondents

[4]

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Radiopharmaceutical

Number of Patients expected to receive therapy in future

Source of data

Increase and strong increase for majority of respondents; will
depend on results of clinical trials

[4]

166Ho-microspheres

[177Lu]Lu-PSMA (or [225Ac]AcPSMA in 5-10 years)

Strong increase for vast majority of respondents; this will take 10
years to achieve due to capacity issues

[4], BSNM

90Y-glass microspheres

Stable for majority of respondents

[4]

90Y-resin microspheres

Stable for majority of respondents

[4]

223Ra

Growth expected until Lu-PSMA is authorised and reimbursed

BSNM

[177Lu]Lu-DOTATATE
(Lutathera®)

Growth expected to a plateau in about 5 years

BSNM

7.

Supply situation

No radionuclide product used in the UK is made in the UK. They are mainly shipped from the EU, with some
products being shipped directly from the US. Brexit has the potential to cause major change to supply chains –
in the event of no EU-UK trade deal, radionuclide supply may have to come directly from the US and South Africa.

8.

Patient access to radionuclide therapy (e.g. regional differences)

1 radiotherapy centres per million inhabitants (based on Gleisner et al. (2017))
Inhabitants in London, South East England, Manchester and Liverpool are offered a full range of services with
highly trained staff. Elsewhere availability of services varies depending on the regional infrastructure and
capacity. For instance, all the UK centres give 131I for thyroid disease. The BSNM believes there are about 30
centres giving 223Ra, 20 doing PRRT, and 10 doing SIRT in the UK. [131I]I-mIBG is given in about 6 centres including
2 that treat children, while synovectomy is available in about 10 centres.
Regional differences seem to have a bigger impact on access to Lutathera® than other radiopharmaceuticals
according to the BSNM. It also reports that almost no patient is eligible to receive SIRT in the UK.
•

Number of radiopharmacies:
There are about 30 radiopharmacies in England, 3 in Scotland, 2 in Northern Ireland and 3 in Wales run by
the relevant National Health Service. Almost all of these are involved in providing some radionuclide therapy
products even if just dispensing I-131. There are about 7 private radiopharmacies in the UK, but these only
provide imaging products

•

Number of radiotherapy practicing centres:
The actual number of NHS hospitals providing radionuclide therapies is unknown. However, data from the
British Institute of Radiology (2009) suggests that there are about 50 such centres in England including 2
which specialise in treating children. In Scotland, Wales and Northern Ireland, there are 5, 2 and 2 centres
respectively. In England there are 5 private centres giving a range of radionuclide therapies. All these centres
are in or near London and most of their patients come from outside the UK.

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9.

Sources of information / References

[1] Email exchange and interview with Dr John Buscombe, British Nuclear Medicine Society (BNMS)
[2] Gleisner, K. S., Spezi, E., Solny, P., et al. (2017). Variations in the practice of molecular radiotherapy and
implementation of dosimetry: results from a European survey. EJNMMI physics, 4(1), 28.
[3] Technopolis survey (Round 1), N = 24
[4] Technopolis survey (Round 2), N = 4

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Glossary
Abbreviation

Full description

IAEA

International Atomic Energy Agency

EANM

European Association for Nuclear Medicine

Bq

Becquerel, unit of activity (disintegrations per second) (GBq = Giga Bq, MBq = Mega Bq)

CA

Carrier added

DCP

Decentralised procedure

DOE

Department of Energy (USA)

EC

European Commission

ECIS

European Cancer Information System

EEA

European Economic Area

EMA

European Medicines Agency

EU

European Union

ESA

Euratom Supply Agency

ESS

European Spallation Source

HTA

Health Technology Assessment

JRC

Joint Research Centre

HALEU

High-assay low-enriched uranium

HLG-MR

High-level Group on the Security of Supply of Medical Radioisotopes

LEU

Low Enriched Uranium

LET

Linear energy transfer

MRI

Magnetic Resonance Imaging

MRP

Mutual recognition procedure

NCA

Non-carrier added

NET

Neuro endocrine tumour

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

Abbreviation

Full description

NHS

National Health Service

OECD-NEA

Organisation for Economic Cooperation and Development – Nuclear Energy Agency

PET

Positron emission tomography, a nuclear medicine imaging technique

PSMA

Prostate-specific membrane antigen, also known as PSMA617

RN

Radionuclide

RP

Radiopharmaceutical

RRDB

Research reactor database

SAMIRA

Strategic Agenda for Medical, Industrial and Research Applications of radionuclides

SHI

Social health insurance system

SPECT

Single-photon emission computed tomography, a nuclear medicine imaging technique

TOA

Time of administration

TRL

Technology Readiness Level

Notations for radionuclides and radiopharmaceuticals
Note that throughout the report the conventions for the notation of radiopharmaceuticals and radionuclides as
promoted by the EANM119 is followed as much as possible. In figures (for better readability) and sources (using
different convention) notations may vary. For example, the notation [177Lu]Lu-DOTATATE refers to the identical
radiopharmaceutical (i.e. Lutathera®) in the 177Lu-DOTATATE notation. Similarly, [223Ra]RaCl2 denotes the same
radiopharmaceutical (i.e. Xofigo®) as 223RaCl2 or 223RaCl2 (as seen in some figures). For radionuclides similar
differences between notations exist, where (for example) 90Y is identical to 90Y and Y-90 (or Yttrium-90), albeit
different notations are used.

This notation is summarised in: EANM (2019). Let’s be precise! Available at: https://www.eanm.org/contenteanm/uploads/2019/12/EANM_GUIDANCE-_TRACER_NOMENCLATURE-1.pdf.
119

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

View of the EANM
The European Association of Nuclear Medicine has been supportive in promoting participation of and providing
access to their members for the data collection and validation exercise performed in this study. Given the lack of
accessible official data, their support has been important for the best-available insights provided in this report.
The EANM has been granted to opportunity to provide their view on the outcomes of this study. Therefore, their
unedited commentary letter in the box below presents the sole view of the EANM Board and not the view of the
authors nor the European Commission.

Comment by the European Association of Nuclear Medicine (EANM) on Study on sustainable and resilient
supply of medical radioisotopes in the EU THERAPEUTIC RADIONUCLIDES
As prime umbrella organization for nuclear medicine, molecular and hybrid imaging in Europe, the EANM
highly appreciates the focus that is given to the sustainability of supply of radionuclides for therapeutic
purposes as examined in the SMER 2 project, based upon the learnings of SMER 1 for diagnostic radionuclides.
The EANM supports the general message given in the executive summary of the project, outlining the trends
of current and future use of radionuclides. The general recommendations drawn will surely be a good basis
for further decisions taken and actions put forward by the European Commission. Having said that, the devil
is in the details i.e. data. While the general recommendations reflect the view of the EANM, the survey data
as presented in Appendix B of this report needs to be put into perspective. Further, the methodological
drawbacks of the survey at hand shall not stay unaddressed.
Firstly, the overall number of responses is considered to be very low, hence not representative and therefore
also not suited to calculate demand of activities or number of procedures. Calculations as included in the
report are considered to be unrealistic and are most certainly not reflecting the true demand.
Secondly, the report puts currently used and registered radiopharmaceuticals (e.g. [131I]NaI, [131I]mIBG, 90Ylabeled colloids, [177Lu]Lu-DOTATATE) onto the same level as radiopharmaceuticals there are not registered
and only used in clinical trials or experimental therapies (e.g. 177Lu-labeled antibodies; PSMA-ligands labeled
with 177Lu, 225Ac, , and 227Th; 227Th –labeled conjugates). As a consequence of this clinical situation, the future
demand of the two distinctively different types of radiopharmaceuticals should have been addressed and
described separately in the report.
For the specific case of [177Lu]Lu –PSMA-ligands, EANM supports the conclusion that demand will be increasing
significantly in the near future compared to other radiopharmaceuticals. The authors very briefly investigate
the main problem with the supply of 177Lu which is the lack of sufficient target material for the irradiation
process which is key when it comes to significantly increasing its production. Naturally, also other phases of
the production and supply chain are important, but the availability of target materials in required quality and
quantity seems to be the most important and pressing issue.
In summary, EANM is appreciative of the SMER 2 initiative and supports the statements of the main executive
summary. The general parts of the report may surely serve as basis for further discussions and deeper
evaluation but the European Commission shall stay away from taking actions based on the data presented in
Appendix B, as this is not reliable and far from complete. A more reliable source of information could be the
national health systems of the EU Member States, who, as a paymaster, should have the most reliable data.
In other countries, national radiation protection authorities or producers and distributors could be addressed.

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About EANM
The European Association of Nuclear Medicine (EANM) is the largest organisation dedicated to nuclear
medicine in Europe. In this role, it has become the umbrella organisation which represents the whole sector
towards the European Institutions and other international institutions.
The EANM’s vision is to optimise and advance science and education in nuclear medicine for the benefit of
public health and humanity within the concept of personalised healthcare.
The goal of the EANM is to be a platform for the dissemination and discussion of the latest results in the field
of nuclear medicine including multimodality imaging and related subjects. It fosters and co-ordinates the
mutual exchange of knowledge relating to the diagnosis, treatment and prevention of diseases through the
use of unsealed radioactive substances and the properties of stable nuclides in medicine.
The EANM is a professional non-profit medical association, incorporated in Vienna/Austria. The EANM
membership comprises physicians, scientists, technologists as well as other persons working in nuclear
medicine or related fields. Currently, the EANM represents more than 9,000 specialists from 41 different
countries within Europe and serves the interests of a community that goes far beyond these numbers and any
geographical boundaries.

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

List of tables
Table 1

Overview of radionuclides included in the study ______________________________________________ 11

Table 2

EU incidence of cancers occurring in therapeutic areas for radiopharmaceuticals in 2010 _____________ 18

Table 3

Reimbursement models used in European healthcare settings ___________________________________ 24

Table 4

Level of radiopharmaceutical guidelines used by country _______________________________________ 27

Table 5

Average prices of radiopharmaceuticals per patient dose in Europe ______________________________ 30

Table 6

Radionuclides, their properties and production routes _________________________________________ 34

Table 7

Suppliers of radionuclides and radiopharmaceuticals in Europe __________________________________ 40

Table 8

Reported supply causes of supply issues per radionuclide ______________________________________ 52

Table 9

Overview of identified critical issues and foreign dependencies per radionuclide ____________________ 53

Table 10

European member state healthcare systems _________________________________________________ 68

Table 11

Reimbursement models used in EU member states for radiotherapy ______________________________ 70

Table 12

Clinical trials per radionuclide over years 2010-2020 ___________________________________________ 71

Table 13

Distribution of radionuclide therapy clinical trials by country ____________________________________ 72

Table 14

Type of organisations involved in or consulted for data collection (excl. survey) _____________________ 77

Table 15

Number of stakeholders per country involved in or consulted for data collection through interview, email or workshop. ______________________________________________________________________ 77

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Study on sustainable and resilient supply of medical radioisotopes in the EU: Therapeutic Radionuclides

List of figures
Figure 1

Types of radionuclides and their characteristics _______________________________________________ 10

Figure 2

Current demand for radionuclides (1000 GBq activity) across Europe _____________________________ 14

Figure 3

Current demand for radionuclides (GBq activity) across Europe __________________________________ 14

Figure 4

Current demand for radiopharmaceuticals (1000 GBq activity) across Europe ______________________ 15

Figure 5

Current demand for radiopharmaceuticals (GBq activity) across Europe ___________________________ 15

Figure 6

Current demand for radiopharmaceuticals (1000 annual procedures) across Europe _________________ 16

Figure 7

Current demand for radiopharmaceuticals (annual procedures) across Europe _____________________ 16

Figure 8

Number of annual radionuclide therapy procedures by country and radionuclide (excluding 131I) _______ 17

Figure 9

Reported prices of radiopharmaceuticals per patient dose across Europe – high end _________________ 28

Figure 10

Reported prices of radiopharmaceuticals per patient dose across Europe – low end _________________ 29

Figure 11

Supply chain for therapeutic radiopharmaceuticals ____________________________________________ 32

Figure 12

Therapeutic radionuclides produced by research reactors across the globe ________________________ 37

Figure 13

Therapeutic radionuclides produced by cyclotrons across the globe ______________________________ 38

Figure 14

Radionuclides produced by current research reactors in Europe _________________________________ 45

Figure 15

Timelines of current and planned infrastructures for radionuclide production in the EU ______________ 46

Figure 16

Supply chain shortages or long-term production disruptions in the last five years ___________________ 50

Figure 17

Impact of supply disruptions on the treatment of patients ______________________________________ 51

Figure 18

Position in supply chain where supply issues originate _________________________________________ 52

Figure 19

Expected demand development of therapeutic radionuclides according to experts __________________ 60

Figure 20

Expected demand development of therapeutic radiopharmaceuticals according to experts ___________ 61

Figure 21

Count of radionuclide therapy clinical trials by isotope and start year _____________________________ 71

Figure 22

Count of radionuclide therapy clinical trials by isotope and phase ________________________________ 73

Figure 23

Count of radionuclide therapy clinical trials by isotope and intervention type _______________________ 74

Figure 24

Survey respondents per member state (per round) ____________________________________________ 80

Figure 25

Profession of respondents (per round) ______________________________________________________ 81

Figure 26

Activity in the supply chain (per round) _____________________________________________________ 81

175

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