Table of Contents

Communities", is focussed on development of an information hub for the research and regulatory communities, that facilitates access of these communities to information on the practical steps needed for cell and gene-based therapy development and promotes information exchange within and between these communities. Once developed, this tailored section will create a 'one-stop shop' on where to seek further information and guidance relating to manufacturing guidelines, regulatory requirements, intellectual property rights, market acceptability and ethical matters related to advanced therapies development. WP4 will also promote liaison between cell and gene-based therapy stakeholders and the regulatory agencies.

As part of this development, a key objective of WP4 is to map the European cell and genebased therapies landscapes at multiple levels, encompassing:

(i) Practical steps required for advanced therapies development including: manufacturing guidelines (including analytics/characterisation), legal, regulatory (including preclinical testing strategies) and ethical and socio-economic aspects (including patient attitudes, health economics and market acceptability) (ii) Activity related to cell and gene therapy development including: the academic, clinical and industrial (contract research organisations, biotech, pharma) landscapes, health economists and government agencies.

and to use this information to provide:

(iii) a set of practical guidelines and concise format fact sheets for researchers approaching or engaged with development of new therapies, (iv) an inventory of information and links on where to seek further information and guidance (v) a multi-layered searchable map of the cell and gene-based therapy landscape in Europe, mounted on www.eurogct.org and openly accessible.

Tasks (i) and (ii) above were reported in D4.8, submitted in the first reporting period. D4.1 therefore reports on (iii) and (iv); (v) will be reported in month 48.

Summary

Deliverable 4.1 is a report on the mapping of the European gene-based and cell therapies landscape. This deliverable provides an update to the earlier deliverable, D.4.8 Initial Landscape Mapping, which was submitted in the first reporting period. D4.8 reported the mapping, performed by EuroGCT, of the European landscapes associated with gene and cell therapy related product development pathways including ethical, legal, regulatory and societal issues (ELSI). Related, D4.7 Information collation, also submitted in the first reporting period, detailed our methodology for information collection and curation. The work reported in D4.7 and D4.8 resulted in creation of a development framework for a practical tool entitled "Development pathways for bringing gene and cell therapies from the lab to patients" with the short website name of "Research Pathways" (see D4.8). This tool was organised as a Web tree, into which general information on the development pathways for bringing gene and cell therapies from the lab to patients (hereafter the "Research Pathways Tree") was organised.

The Research Pathways Tree also included the organised information (mapping/inventory of information) of the practical steps required for cell and gene therapy development in Europe as well as links on relevant and existing information and guidance.

The present report, D4.1, therefore moves beyond the initial mapping to focus on implementation of these processes. This has required a combination of actions: Identification of the detailed information required to populate the Research Pathways Tree was described in D4.8; in this reporting period, we have: 1) created original EuroGCT resources around development pathways for bringing gene and cell therapies from the lab to patients, the Research Pathways Tree (see D4.8 Annex 1 for details), 2) co-developed resources through collaboration, 3) selected and signposted to existing high quality resources (based on the methodology detailed in D4.7), and 4) launched an updated 'Research Pathways' database featuring improved navigability and information organisation. In the following sections, we provide the details of each action we have taken, our thought processes and some challenges we have come across.

The outputs are published on the EuroGCT website in the Research Pathways section (www.eurogct.org/research-pathways) as a searchable and filterable database and will continually be updated throughout the course of the project. (See also: D4.2).

Development of an inventory of information and links on information and guidance

This deliverable is built on the initial work reported in D4.8 and further updated and populated with new information collated based on methodology listed in D4.7. In this section, we report the development and expansion processes of our information inventory, as well as the updates on website functions to facilitate user access.

Development of EuroGCT original resources

3.1.1 Ongoing content development for all entries within the 'Research Pathways' tree The Research Pathways Tree is set out using a structure of entries and sub-entries (see D4.8 Annexe 1). In months 18-30, the writing of the full content of entries and sub-entries of the Research Pathways Tree has been implemented, agreed by the core ELSI team, using the sub-entry template shown in D.4.8 Annexe 3. The General Overviews drafts previously written for Research Pathways sub-entries (see D.4.8 Annexes 4.a to 4.i) have been further developed, completed and internally reviewed by the relevant ELSI groups.

Network of Expertise (NoE) resources

The scope of our 'Research Pathways' is vast, as it aims to cover information regarding gene and cell-based therapies broadly: mainly ATMPs, but also other gene and cell therapies that are not ATMPs such as 'Human body elements and medical devices', in accordance with our entry on 'Therapy Classification'. It also aims to cover information on product development, especially on ATMPs, all the way from fundamental research to patient access (lab to patient), their technical and ELSI aspects.

To benefit from additional expertise and research interest on the ELSI aspects of gene and cell therapy, EuroGCT has involved the ELSI Network of Expertise (NoE) members drafting content. The entries drafted by NoE members have been internally reviewed and submitted for comments to the relevant ELSI Working Groups. Once finalised, these written entries will be published on the EuroGCT website.

Work is ongoing both to complete the Research Pathways section, and to inform researchers and regulators on the ongoing evolution of the European Union legislation in the field (e.g. proposal for a regulation on substances of human origin, proposal for a regulation and a directive reforming the pharmaceutical legislation).

Multiple levels

For this deliverable, we have adopted a multiple levels approach in the mapping of the gene and cell therapy landscape. For instance, in terms of legislative and regulatory aspects we focused on the EU law first, but we also link to national laws when it is possible and relevant. Indeed, national competent authorities, mainly in charge of implementing and overseeing the implementation of the EU legislation, can sometimes adopt more stringent measures on a national basis than those required by EU legislation, either in response to local epidemiological risks or considering that a higher level of safety can be ensured with more stringent provisions. This is the case in tissues and cells donor' testing requirements and blood donor' testing requirements.

In terms of legal classification, it is also necessary to encompass national and European levels of regulation to determine the applicable legal framework to gene and cell therapies. The consideration and the articulation of the different levels of regulations is illustrated in the "Human body elements for therapeutics applications" entry (https://www.eurogct.org/research-pathways/therapy-classification/human-body-elementstherapeutic-applications) in the legal classification: for instance, the EU legislation on tissues and cells (directives) applies to the entire development chain of cells or tissues transplants, while it applies to the donation, collection/procurement and testing only regarding the development of advanced therapy medicinal products. Further steps of ATMPs' development depend on the EU pharmaceutical legislation (in particular, the ATMP regulation). As the directives need to be transposed into national laws while regulations have direct effect, the first steps of development of ATMPs are more dependent on national laws (national transpositions of directives and possible more stringent national rules) than further steps of their development that solely depend on European Union law (e.g., centralised marketing authorisation).

Finally, we are covering both binding EU legislation, and non-binding EU guidance and other resources. We are linking to these various levels of resources in terms of being binding or not.

Co-developing resource through collaborations

EuroGCT is part of a collaborative project named 'The Advanced Therapy Medicinal Products Patient and Public Involvement and Engagement Working Group (ATMP Engage)'. This collaboration brings together UK-based stakeholders with an interest in ATMPs to discuss and collaborate on Patient and Public Involvement and Engagement (PPIE) activity. The output of this collaboration is the ATMP Engage PPI Directory (https://www.eurogct.org/ppi-directory). It contains patient and public involvement (PPI) resources for developers of cell and gene therapies, including toolkits, guidelines, advice, templates, and case studies. The resources collated within this directory spans EU and UK and are applicable to users independent of their geographical locations. The ATMP Engage PPI Directory constitutes the Patient and Public Involvement section of our Research Pathways database, and its content will be continuously updated and expanded during the project span.

Signposting to existing resources

External resources

We similarly seek to link to resources produced externally to our partnership. Through our dissemination and networking activities reported in D2.2, we have connected with a number of organisations and projects external to EuroGCT. We have asked these organisations for their expert insight on helping us identify relevant resources produced by them or others. A non-exhaustive list of such resources include: (https://www.eurogct.org/association-british-pharmaceutical-industry-abpi-resources)



External resources through searches

Additional resources are identified and collated by the Information Officer -product development pathway and the Information Officers -Ethics, Legal and Regulatory issues, according to the methodologies reported in D4.7.

Research Pathways Database--updated structure and information organisation

The EuroGCT online research and regulatory community hub, Research Pathways (Figure 1), is built on the initial information published (see deliverable D4.9). New information collated within the current reporting period is vast and mapping it onto the website requires careful planning on the content presentation, both structurally and functionally. Moreover, the nature of the information on product development is structurally complex-it requires cross-linking between sections and also represents interactions and/or parallel development effort between various stakeholders at every stage of development. Simultaneously, this organised information needs to make sense and remain findable by users. This presents a great challenge and a need in web development on features to support this complex information organisation and presentation. Below we report on each of these new features and functions and explains how they support the landscape mapping activity.

Website structure

The IMHT undertook a review of the user experience for the Research Pathways section and have updated the section's original design from a hierarchical structure to a database model. This essentially translates to a flattened website structure for improved searchability and usability-resources that are originally buried at the bottom layer based on the hierarchical structure can now be exposed and becomes findable.

Links to topical sections

Filters and search function

Sorting

Search results

Tagging with taxonomy terms

The key to improved searchability is the thoughtfully designed taxonomies used for tagging.

The taxonomies terms are used for pulling the tagged resource pages when a specific filter is applied. The IMHT has designed the set of taxonomy terms in Patient & Public Involvement and Ethics are added, as they are key topics running alongside the entire product development pathway. Resources specific to a type of therapy are tagged and can be searched for according to its legal classification (ATMPs, Not ATMPs: Human body elements for therapeutic applications, or Not ATMPs: medical devices containing tissues and cells).

Target audience filter refers to whom the resource is written for. Some resources are strictly targeting experts while some may be written in lay language.

Region filter concerns the geo-and political regions the information is effective in. For example, resources on regulations effective only within individual EU Member States will be tagged with the 'EU (National level)' tag, and not the 'EU/EEA tag'. Information on scientific development regardless of geo-or political region, or those indicated within the resource scope will be tagged with the 'Global' tag, examples include: ISSCR Guidelines for Stem Cell Research and Clinical Translation (https://www.eurogct.org/isscr-guidelines-stem-cellresearch-and-clinical-translation), WHO Human Genome Editing (HGE) Registry (https://www.eurogct.org/who-human-genome-editing-hge-registry) and more.

Resource type filter allows users to use the nature of the resource, whether it is a guideline, a database, a webinar, a journal article…etc to help narrow down search results.

Organisation type filter breaks down the type of organisations who produced the resources. For example, EuroGCT's original resources will be tagged as 'Associations / Societies / Networks'.

The Disease of focus filters, although not a primary focus for the Research Pathways section as the main attention is placed on the development process, can still be utilised in several ways. Users can use it to search for information related to the development of medicinal products related to specific types of condition if this information is available. It also provides a future handle to crosslink relevant information with the content that are hosted within the 'Discover' section of our site for the interested non-specialists to follow through.

New search and filter functions

To improve user experience in their searches, we introduced search functions including search by keywords, and checkboxes to apply filters to the taxonomy terms, and implemented the sorting by field and order. Actors and Network section contains our initial mapping of stakeholders in ATMP development in Europe and beyond. This will be further developed and reported in D4.3 which is due in month 48.

Multiple entry points

We have built in multiple entry points to access the same piece of information to facilitate user access, especially for key resources. This feature answers the expectations of various types of users, taking into account their different knowledge and experience, and consequently potential different approaches in looking for relevant information. For example, the ATMP Engage PPI database can be accessed through the links in the topical sections; it can also be accessed through the top menu as well as be searched for directly in the database. EuroGCT's original resources can be accessed through the 'Key Research Pathways' section as well as be searched for in the database. Key resources produced by other organisations can be found in the 'Key Pathway resources' topical section, and also be found directly in the database. We use multiple entry points to highlight the importance of these resources, and for drawing user's attention. It also considers the different knowledge and experience, and thus their possible different approaches in looking for relevant information.

Visual elements and user experience

We have implemented web design to improve visual presentations. We have also developed webpage features to enhance the crosslinking functions on the site, for example, the textboxes used in the Case Study content type (Figure 2) is clickable and links back to relevant search results in the main Research Pathways database.

The information regarding ATMP development is vast, complex and interconnected, and requires custom-designed website features and functions to support its presentation. We have developed features on our website to support this information mapping.

We anticipate the improved searchability and usability will greatly enhance users' experience in searching and navigating within the section, and in turn improve engagement and learning.

Research Pathways Coverage

In this section, we report on the current coverage of the Research Pathways entries published on the Research Pathways database using 'Themes', as 'Theme' is built based on the draft tree reported in D4.8. Table 2 below lists all Theme entries: marked in green are the entries that has the General Overviews published; marked in blue are those with full entries published; marked in pink are those only covered with signposting to external resources; marked in grey is covered by co-developed resources. See Annexe 1 for a complete list and screenshots of published EuroGCT General Overviews and full entries.

Main filter category

Subcategory (1st layer)

Subcategories (2nd layer and beyond) Sub-entries within 'Market access for ATMPs' have all been completed and published on the Research Pathways information hub. Marketing authorisation constitutes the main mandatory step for ATMPs manufactured at the industrial scale to be commercialised in the European Union. These entries collectively provide summarised information in accessible language, signpost to various relevant webpages on the EMA website, and links to external resources, notably EU binding legislation, guidance, and relevant literature. They provide users with easier access to the most relevant and high-quality information, and help them make sense of these various and complementary external resources. The sub-entries in 'Data' is also close to complete. These suites of information fulfil a 'one-stop-shop' for developers as required by the GA and will play a significant role in improving products development.

The curated information currently presents an almost full breadth of coverage for the Research Pathways. Besides the breadth of coverage, we are also working on increasing the depth of Research Pathways contents by publishing more resources written by the EuroGCT consortium. Several entries have been written in full and are under internal review or in the final drafting phase, including:  Clinical trials;  Patentability;  Early interactions with regulators;  Manufacturing Authorisation As the project progresses, we will continue and reinforce our approach to collect information, write, review, and publish the content for each entry of the Research Pathways tree. The involvement of the Network of Expertise members will be continued and strengthened to achieve this objective.

We have started to see uptake by our online audience in several pieces of EuroGCT's original resources. The entries on 'Manufacturing Authorisation', and 'Packaging and labelling' are among the top-accessed pages within WP4. These pages appear in top 20 search results in Google using relevant query terms, and more often, are ranked within top 5 using exact search terms. We have also recorded a significantly longer user retention time for these EuroGCT original resource pages. More details on webpage traffic and online uptake can be found in D2.2 and D2.4. 4 A set of practical guidelines and concise format fact sheets for researchers approaching or engaged with development of new therapies

Complexity in therapy classification

The practical guidelines for gene and cell therapies in development are dependent on their legal classification.

Therapy classification determines the legal mechanisms that govern the regulation of gene and cell therapies and subsequent guidelines to follow, but the classification is a non-trivial task for a therapy in development.

For Research Pathways, we focus on a subset of gene and cell therapies, ATMPs, although other gene and cell therapies that are not ATMPs but are transplants/transfusions or medical devices are also considered in the sub-entry on "therapy classification".

New content type-Case Study

In addition to presenting key information in Research Pathways, another step we took towards tackling the complexity of classification is to develop a new content type-Case Studies. It also aims to achieve Task 3 listed in GA (see page 5, task (iii) of this deliverable). The case studies pages collate existing resources including research articles, review articles, interviews, news articles, EMA authorisation details, HTA appraisals and more related to the development of specific products.

A dedicated case studies topical section (https://www.eurogct.org/case-studies, Figure 3) is set up to host the new content type, and can be accessed through the Research Pathways information hub. It currently contains two case studies for two approved ATMPs: 1) Holoclar, a Tissue Engineered Product (TEP), and 2) Strimvelis, a Gene Therapy Medicinal Product (GTMP). In these two case studies, we collated existing publicly available information about each stage of their development, from early-stage research to approval and beyond, to serve as a guide for the research community to learn about the development process, the keys to success, the challenges and how the developers overcame them. As previously mentioned, the case study content type has specially designed features to implement the necessary complex crosslinking function to connect its various parts to the main Research Pathways database. Therefore, these case studies also serve a second purposethey provide storylines for readers to walk through the resources collated in the Research Pathways database.

We are conscious that ATMPs have unique considerations and complexities at every stage in the development process, from pre-clinical and trial development to licencing and patient access. These considerations and complexities often are product specific. We will try to provide as many product development stories as possible, to help researchers find anchor points and use them as references to facilitate their own development activities.

There are more case studies for additional types of therapies in the pipeline. We are currently in the process of forming a collaboration with a team developing CAR-T therapy in Spain. Through this collaboration, we hope to co-develop a case study on their CAR-T therapy development to report on the key development processes, guidelines to follow, and serves as a learning resource for the researcher and developer community. We are also in the process of co-developing a case study with the developers of Libmeldy, an EMA-approved GTMP.

Besides case studies that span the entire or a large part of the development pathway, we also hope to develop shorter case studies to capture researchers'/developers' practical considerations at specific time points during development. An example is about early classification considerations in developing skin equivalent for healing wounds--different choices of the preparation steps can result in different therapy classification (ATMP or not ATMP; if ATMP, which sub-type) and this in turn determines the requirements that the product must meet, and the relevant procedures leading to commercialisation. These short-format case studies are designed for experience-sharing among the researchers/developers' community. These small lightbulb moments and thoughts happening behind the scenes often are not revealed in research articles but will benefit many if shared with the community.

During the second half of the project, developing more case studies will be one of the main focuses. Contents will be published upon completion and iteratively updated throughout the project span.

Conclusion and future steps

EuroGCT has developed an indexed catalogue of resources and links through the following:

1) created a collection of EuroGCT's original resources for Research Pathways (Annexe 1);

2) collaborated and co-developed the ATMP-Engage Patient and Public Involvement (PPI) Directory; 3) selected and signposted to existing high quality resource; 4) launched an updated 'Research Pathways' database featuring improved navigability, information organisation and presentation. The custom-designed website features and functions supports the mapping of information developed and collated.

This catalogue of resources is mounted on the Research Pathways Information Hub and ensures the researcher and developer community can easily find the high-quality information they need throughout the product development process. It provides a 'one-stop-shop' for these communities and is anticipated to play a significant role in improving product development.

The new case studies topical section (https://www.eurogct.org/case-studies) contributes to tackling the complex issue of therapy classification that determines the legal mechanisms and subsequent guidelines a therapy in development has to follow. Considering each gene and cell therapy have unique considerations and complexities at every stage in the development process, we aim to increase the number and variety of therapy types in our case studies. We have rolled out two case studies on approved ATMPs, and are in the process of developing more content for this section. We are also developing shorter case studies for capturing practical considerations during a specific time point in development.

All of the above outputs are published on EuroGCT's website in the Research Pathways section (www.eurogct.org/research-pathways) as a searchable and filterable database with direct links to topical sections including the newly launched 'Case Studies' section. All contents within will continually be updated to increase the breadth and depth of our information mapping throughout the course of the project.

  Deliverable Report .................................................................................................................................. D4.1 Landscape mapping, report on mapping of European cell and gene therapy landscape at multiple levels .......................................................................................................................................... 1 Introduction ...................................................................................................................................... 2 Summary ......................................................................................................................................... 3 Development of an inventory of information and links on information and guidance ..................... 3.1 Development of EuroGCT original resources ............................................................................... 3.1.1 Ongoing content development for all entries within the 'Research Pathways' tree ........ 3.1.2 Network of Expertise (NoE) resources ............................................................................ 3.1.3 Multiple levels .................................................................................................................. 3.2 Co-developing resource through collaborations ..................................................................... 3.3 Signposting to existing resources ........................................................................................... 3.3.1 EuroGCT Partner's resources ......................................................................................... 3.3.2 External resources .......................................................................................................... 3.3.3 External resources through searches .............................................................................3.4 Research Pathways Database--updated structure and information organisation .................. 3.4.1 Website structure ............................................................................................................ 3.4.2 Tagging with taxonomy terms ....................................................................................... 3.4.3 New search and filter functions ..................................................................................... 3.4.4 Direct access to topical sections ................................................................................... 3.4.5 Multiple entry points ...................................................................................................... 3.4.6 Visual elements and user experience ........................................................................... 3.5 Research Pathways Coverage.............................................................................................. 4 A set of practical guidelines and concise format fact sheets for researchers approaching or engaged with development of new therapies........................................................................................ 4.1 Complexity in therapy classification ...................................................................................... 4.2 New content type-Case Study ............................................................................................ 5 Conclusion and future steps .......................................................................................................... 6 List of Annexes .............................................................................................................................. Annexe 1. Summary of activities and outputs: all published EuroGCT original resources in Research Pathways ...................................................................................................................... List of acronyms ATMP: Advanced Therapy Medicinal Products EuroGCT: The European Consortium for Communicating Gene and Cell Therapy Information IMHT: The EuroGCT Information Management Hub Team, comprised of project staff employed directly by the project, based at the University of Edinburgh (UEDIN) and Aix-Marseille University (AMU) ELSI: Ethical, Legal and Societal Issues EMA: European Medicines Agency EU: European Union GA: Grant Agreement ICH: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use NoE: Gene and Cell Therapy Network of Expertise WP: Work Package D4.1 Landscape mapping, report on mapping of European cell and gene therapy landscape at multiple levels 1 Introduction WP4, entitled "An Information and Engagement Hub for the Research and Regulatory

  3.3.1 EuroGCT Partner's resourcesAn important part of the work of WP4 is to signpost to additional existing resources on gene and cell therapy development relevant to the research and regulatory communities. To achieve this, we ask for consortium partners' input on resources produced by their organisations, or suggestions on information that were useful in their own research and development activities. Resources suggested by this route are then assessed, and promoted through links in the Research Pathways section as appropriate. A few examples of resources collected through this route include:  Resources by ATMP Sweden (https://www.eurogct.org/atmp-sweden-resources)  Resources by CGT Catapult (https://www.eurogct.org/cell-and-gene-therapy-catapult-cgtcatapult-resources)  Resources by ATTC, managed by CGT Catapult (https://www.eurogct.org/advancedtherapies-treatment-centre-attc-resources)  Resources by ECRIN (https://www.eurogct.org/european-clinical-research-infrastructurenetwork-ecrin-resource)

Figure 1 .

 1 Figure 1. Screenshot of the Research Pathways search page (cropped).

  3.4.4 Direct access to topical sections Key Research Pathways section contains the collection of resources developed by EuroGCT WP4. The same set of resources can either be accessed directly through this hierarchicalstructured page, or by filtering/searching within the main database. Key Pathway Resources section contains collated key resources on ATMP development by medicines agencies, and existing complementary work produced by other projects and organisations. Case Studies section contains case studies on ATMP development. We will describe this new section in detail in the next section '4. A set of practical guidelines and concise format fact sheets for researchers approaching or engaged with development of new therapies.' Patient and Public Involvement links to the ATMP Engage Patient and Public Involvement (PPI) Directory, a searchable and filterable directory with PPI resources for developers of cell and gene therapies.

Figure 2 .

 2 Figure 2. Textboxes and features within case study content type enhances the linkage with relevant information in Research Pathways. This screenshot (cropped) is taken from: https://www.eurogct.org/case-study-holoclar.

Figure 3 .

 3 Figure 3. Screenshot of the new Case Studies topical page (https://www.eurogct.org/case-studies).

6

  List of Annexes Annexe 1. Summary of activities and outputs: all published EuroGCT original resources in Research Pathways

  //www.eurogct.org/european-joint-programme-rare-diseases-ejp-rd-resources)  The Association of the British Pharmaceutical Industry (ABPI) Resources

	European Advanced Translational Research Infrastructure in Medicine (EATRIS)
	resources		(https://www.eurogct.org/european-advanced-translational-research-
	infrastructure-medicine-eatris-resources)
	 European	Joint	Programme	on	Rare	Diseases (EJP	RD)	resources
	(https:

Table 1 :

 1

	Main filter	Subcategory (1st layer)	Subcategory (2nd layer)
	category
	Theme	Research and Innovation	Fundamental Research
			Clinical research
			Translational Science
			Funding
			Incentives
			Early interaction with regulators
		Therapy classification	Legal classification
			ATMPs
			Not ATMPs: Human body elements for the
			therapeutic applications
			Not ATMPs: medical devices containing tissues and
			cells
		Manufacturing	Manufacturing Authorisation
			Good Manufacturing Practice
			Investigational medicinal products dossier
			Capability
			Scalability
			Packaging and labelling
		Commercialisation	Market access for ATMPs
			Distribution
			Advertising
			Pharmacovigilance
			Pricing & reimbursement
		Data	Data protection
			Data storage
			Data collection, processing, controlling
			Data sharing / Open Data
			Mission creep / data misuse
		Patient & Public Involvement
		Ethics
	Target	Researchers / developers
	audience	Healthcare providers
		Public / patients
		Regulators
		Industry
		Other
	Region	EU/EEA
		EU (National level)
		UK
		North America
		Global
		Other

Table 1 .

 1 Taxonomy terms used in Research Pathways databaseTheme filter is mainly based on the Research Pathways Tree structure reported in D4.8.

Table 2 .

 2 Theme table to show current coverage of the published Research Pathways content.

	Theme	Research and Innovation	 Fundamental Research
			 Clinical research
			 Clinical trials
			 Translational Science
			 Funding
			 Incentives
			 Intellectual Property rights
				o Patentability
			 Early interaction with regulators
			 Support for (innovative) medicines' development
				o Support	for	innovative	medicines'
				development at the EMA level
			 Support for ATMPs' development
		Therapy classification	 Legal classification
			 ATMPS
			 ATMPs and Orphan medicinal products
			 Not ATMPs: Human body elements for the therapeutic
			applications
			 Not ATMPs: medical devices containing tissues and cells
		Manufacturing	 Manufacturing Authorisation
			 Good Manufacturing Practice
			 Investigational medicinal products dossier
			 Capability
			 Scalability
			 Packaging and labelling
		Commercialisation	 Market access for ATMPs
				Standard Marketing authorization pathway: centralized
				procedure
				o Marketing Authorisation Application file
				Expediting marketing authorisation pathways
				o Conditional MA
				o MA under exceptional circumstances
				o Accelerated Assessment
				o Specificities of the marketing authorisation
				dossier for biosimilars
			 Distribution
			 Advertising
			 Pharmacovigilance
			 Pricing & reimbursement
		Data	 Data protection
			 Data Classification
			 Main Principles
			 Data Protection Authorities
			 Data storage
			 Data collection, processing, controlling
			 Data sharing / Open Data
			 Mission creep / data misuse
		Patient & Public Involvement
		Ethics

https://www.eurogct.org/researchpathways/actors-and-networks

First, colloquial terms for therapies in development are often different from their legal classification. For example, authorised CAR-T cell therapies are considered gene therapy medicinal products (GTMPs) under current European Union legislations as opposed to its wordings 'cell therapies'. Another example is the therapy based on autologous chondrocytes for orthopaedic purposes (first ATMPs authorised in the EU, Chondrocelect, now withdrawn from the market by the marketing authorisation holder for commercial reasons) was generally called "cell therapy" although it was classified as a Tissue Engineered Product and not as a Cell Therapy Medicinal Product by the EMA/CAT.

Second, the classification for a therapy in development is also greatly dependent on the preparation steps. In the case of developing skin equivalents for healing skin wounds, different choices of the preparation steps results in different therapy classification:

 If cells are mechanically separated and sprayed on wound bed to help heal the wound:  this is not an ATMP.  If growing epithelial cells (keratinocytes) from patient or donor's skin to stimulate healing:

 if enzymes are used to separate between epithelium and epidermis:  this therapy is an ATMP;  if individual cells are isolated, and cultured in medium:

 this therapy is a sCTMP;  if combined with sheets, mesh, support scaffold:

 this therapy is a cATMP.  Alternatively, if the donor's dermis structure is used as a scaffold to graft on patient's wound bed, and then spray patient's keratinocyte cells on to this scaffold:  this therapy is a TEP.

As therapy classification is a non-trivial task, EMA has advised that the final classification should be considered on case-by-case basis, and taking into account the scientific recommendation on ATMP classification provided by the EMA's Committee for Advanced Therapies (CAT).

Therefore, it is recommended for developers to contact regulators at the national and/or European levels (including mainly the EMA, national medicines agencies and national reimbursement bodies) as early as possible in order to clarify the regulatory pathway applicable the gene and cell therapy in development and their associated regulatory requirements and incentives.

In response to this need, we have built and presented key information in the Research Pathways entries. EuroGCT's original resources 'Therapy Classification' and its sub-entries within will help increase developers' understanding of therapy classification. Entries within 'Early interactions with regulators' will also help tackle the complexity of classification, as they encourage developers to get in touch with regulators early, and explain what services and procedures are established for supporting their development activities.

EuroGCT Annex 1 to Deliverable D 4.1

Summary of activities and outputs

The General Overviews and the full entries contents of the 'research pathways' tree published within the Research Pathways section of the EuroGCT website are based on the following templates previously developed by the ELSI working group members:

https://www.eurogct.org/research-pathways

Actors and Networks

The 'Actors and Networks' contribution to the mapping of the European landscape related to gene and cell therapy is currently ongoing. This mapping encompasses multiple levels of actors and networks: international, national and regional ones. Some actors and networks have already been identified in the 'research pathways' entries and sub-entries in the 'Stakeholders' and 'Definition' sections and published on the EuroGCT website. The regulatory actors and networks landscape mapping will be regularly completed and updated and published alongside the completion of the entries and sub-entries contents.

The 'Actors and Networks' contents published on the EuroGCT website are the following: