> SECTION 1
AN INTRODUCTION TO ADVANCED THERAPIES REGULATION: BENCH TO BEDSIDE ROADMAP
This section will try to provide students with arguments that will help them translate in regulatory terms the issues related to their particular therapeutic approach. Is it a medicinal product or not? If yes, what kind of product is it? Is it an advanced therapy? Once classified, students should develop the abilities (roadmaps) to bring basic laboratory results to the bedside. The uncertain journey for the clinical translation of promising bench results will be summarised here for cell, gene and tissue engineered products. It will serve as an introductory chapter for subsequent sections that will approach specific issues in a more comprehensive manner.

Table of contents:

1.1 A primer on regulation of cell, tissue and gene therapies in Europe: what is and what is not an Advanced Therapy Medicinal Product (ATMP)?
1.2 An introduction to ATMP development: roadmap from a regulatory perspective

> SECTION 2
HUMAN EMBRYONIC AND ADULT CELLS AND TISSUES. HOMEOSTASIS, DISREGULATION AND DISEASE
This section aims to summarise key knowledge on cell and developmental biology that will be of use for professionals involved in the development of advanced therapy medicinal products. As an introductory module, it is not expected to go into great detail in any of the subheadings. Rather, it should provide the students with some very basic materials to initiate or increase their understanding of human development both in homeostasis and disease, as well as their relationship to basic cell features such as migration, communication, proliferation, differentiation, etc. Importantly, it should provide the students with basic knowledge on cellular aging, oncogenic transformation and cell death that will provide a theoretical basis for several quality control procedures that will appear later in the programme and in the students' professional life.

Table of contents:

2.1 Human cell and tissue diversity.
2.2 Cell migration, communication, adhesion and histogenesis: from the embryo to the adult
2.3 Cell proliferation and differentiation
2.4 Cell progenitors and stem cells. The concept of stem cell niche
2.5 Principles of tissue repair and regeneration
2.6 Aging, senescence and cell death
2.7 Oncogenesis, invasion and metastasis. Cellular hallmarks of cancer initiation and progression

> SECTION 3
CELLS WITH CURRENT AND POTENTIAL CLINICAL APPLICATION
Once the basic cell and tissue biology concepts have been summarised in Section 2, this module will introduce the students to the cell therapy field by means of a historical overview of how cells have been introduced into the clinic. Use of keratinocyte and chondrocyte cultures is now extended practice worldwide. These have been grouped as "committed cells" and the lessons that we learned along the way to their clinical application will be of use to anybody intending to bring another cell type into human patients. A general introduction to stem cells is also expected to be included in this section, alongside an extended description of the decades-long effort concerning HSC characterization and their use in bone marrow transplantation improvement. Finally, pluripotent stem cells will be introduced as well as new approaches to generate tissues in the near future such as iPS cell technology or direct transdifferentiation of somatic cells.

Table of contents:

3.1 Committed cells (chondrocytes, keratinocytes, dendritic cells...)
3.2 Adult stem cells
        I. Mesenchymal stromal cells (MSCs)
       II. Bone marrow derived stem and progenitor cells (HSCs)
      III. Other tissue-specific stem cells (Limbal, Epidermal...)
3.3 Pluripotent stem cells
        I. Human embryonic stem cells (hESCs)
       II. Induced pluripotent stem (iPS) cells
      III. Cell reprogramming and transdifferentiation

 > SECTION 4
METHODS FOR MANUFACTURING OF CELL BASED THERAPIES
This first methodological section will cover all aspects of basic cell culture laboratory. This methodological module is expected to cover cell culture techniques including those related to tissue specific stem cell isolation and analysis. It will provide the student with the theoretical basis to understand cell and tissue culture, with an emphasis on the importance of culture media, equipment, facility design, etc. GMP manufacturing will be covered later in the programme: basic knowledge of cells identity, sterility, virus safety and detection of replicant competent virus will be discussed as the main quality control in cell and gene therapy.

Table of contents:

4.1 Cell and tissue culture basics
4.2 Stem cell isolation, proliferation and differentiation
4.3 Quality control of cell cultures in the basic laboratory
4.4 Good Cell Culture Practice (GCCP)
4.5 Scaling up and bioreactors

> SECTION 5
VIRAL VECTORS AND GENE THERAPY
At this point the student has acquired an understanding of cell biology issues from quite different points of view: basic cell biology, stem cells and their application to cell therapy, and associated methodology for standard cultures. It is therefore appropriate to introduce viruses and their use in gene therapy at this point. This section is expected to summarise important facts concerning virus life cycles that will be of use later when virus vectors are discussed. Rather than introduce virology on a general basis, it is expected that the section will focus on viruses that are being developed into vectors in use in the clinical arena (AAV, AdV, retro and lentiviruses, etc.) both from the theoretical and the methodological point of view. While a general introduction to molecular biology techniques is clearly beyond the scope of this Master, it is clear that all aspects of viral vector production should be touched upon (on a non-GMP basis: this will be dealt with later in the programme). Albeit less comprehensively, this section should also review non-viral gene delivery as well as "advanced concepts" such as gene targeting with custom-designed zinc finger nucleases, exon-skipping, RNAi, transposons and any other genetic modification technique that surpasses the "classical" faulty gene replacement approaches.

Table of contents:

5.1 Viruses and viral vectors
5.2 Non-viral gene delivery
5.3 Methodological aspects of gene therapy
5.4 Advanced concepts in gene therapy
5.5 CAR-T cells
5.6 Manufacturing supply chain: upstream and downstream process in gene therapy

> SECTION 6
TISSUE ENGINEERING FOR CLINICAL APPLICATION
Advanced therapies include tissue-engineered products (TEPs), which are generally composed of cells and biomaterials. Once the methodological aspects of cell culture and gene therapy are well studied, the programme switches its focus to TEPs, looking at these both from a theoretical and methodological standpoint. This module will start with the generalities of tissue engineering, and it is expected to focus more heavily on biomaterials since this is the first time these are introduced during the course. An overview of methodology associated with engineering particular tissues will be presented. Finally, this section will introduce two important issues that are not officially classified as advanced therapies yet which interact closely with them: that is the use of nanotechnology approaches and growth factor delivery in regenerative medicine which will be discussed within the framework of ATMP development.

Table of contents:

6.1 Tissue engineering: concepts, technology and applications
6.2 Biomaterials and nanotechnology
6.3 Tissue engineering models
6.4 Bioengineered organs

> SECTION 7
GOOD MANUFACTURING PRACTICE (GMP) AS APPLIED TO ATMPS
This section is arguably the most important in the programme since it includes many key issues in ATMP development and, thus, it is expected to be lengthy. During this section, we will describe Good Manufacturing Practice (GMP) as applied to ATMPs. While the generic GMP regulations is common knowledge that is easily accessible to anyone, we expect this section to explain it in a very clear manner by making use of specific examples (for example, a cellular product to be injected into the bloodstream)

Table of contents:

7.1 Risk-based approach, personnel, premises, equipment and qualification and documentation
7.2 Starting and raw materials, seed lot and cell bank system, production, validation and quality control
7.3 Qualified person and batch release
7.4 Outsourced activities, quality defects and product recalls
7.5 Environmental control measures for ATMPs containing or consisting of GMOs
7.6 Product reconstitution after batch release
7.7 Automated production of ATMPs

> SECTION 8
QUALITY, MANUFACTURING AND BIOSAFETY ASPECTS IN THE REGULATION OF ADVANCED THERAPY MEDICINAL PRODUCT DEVELOPMENT
Although general biosafety rules were introduced in section 4, this module will now examine biosafety issues related to donor selection, cell and tissue manipulation as considered specifically under transplant and pharmaceutical legislation. ATMP development will now be introduced from the point of view of the different aspects that characterize regulatory guidelines: quality, non-clinical and clinical. This section will first summarise typical quality aspects that should be defined for any ATMP: it is expected to explain full methodology of quality control of cellular products under GMP regulation (not to be confused with previous general quality control procedures for cells produced in a non- regulated environment). While these controls are very much product dependent, there are many that have been described extensively and that will be useful for the student in their professional activity on a daily basis. Although more extensive on cellular products, discussion should also include gene therapy product characterization and TEPs.

Table of contents:

8.1 Biosafety issues related to cell and tissue donation
8.2 Characterization of ATMPs:  potency, identity, purity, stability and comparability
8.3 Current methods in the quality control of ATMPs.
8.4 Environmental monitoring programme
8.5 Genetically modified organisms. Contention levels

> SECTION 9
NON-CLINICAL AND CLINICAL ASPECTS CONCERNING THE REGULATION OF ADVANCED THERAPY MEDICINAL PRODUCT DEVELOPMENT
This section will have to summarise many things and, thus, is expected to introduce ideas for the student to develop further if interested. First, animal models of disease will be introduced, as well as non-clinical protocol design. These two concepts are of great importance since they will impact on product development more than anything else, and therefore all available choices should be carefully considered. Implementation of good laboratory practice (GLP) is a must for these experiments to be considered under pharmaceutical legislation. Although normally done with specialist companies, it is important for the students to understand the issues related to GLP. The section will then move on to describe clinical trial regulation through good clinical practice (GCP) and, finally, the section will introduce investigational medicinal product (IMP) vigilance and pharmacovigilance.

Table of contents:

9.1 An introduction to animal models of human disease. Genetic models
9.2 Good laboratory practice (GLP) implementation
           I.  Requirements regarding organization and personnel
          II.  Quality assurance
         III.  Facilities, equipment, reagents and materials
        IV.  Study documentation, development and reporting
9.3 ATMP non-clinical protocol design
9.4 Clinical trial design
9.5 Clinical trial regulation. Good clinical practice (GCP)
           I.  European GCP regulation
          II.  Clinical trial authorization procedure. Documentation required and their structure
9.6 Risk based approach, risk management, IMP vigilance and pharmacovigilance

> SECTION 10
INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER (IMPD) AND COMMON TECHNICAL DOCUMENT (CTD)
This section will summarise the structure of the investigational medicinal product dossier (IMPD) and the common technical document (CTD). The IMPD will be always required to start a clinical trial. During this section, we will describe it as applied to ATMPs using specific examples not only related to this purpose but also to the difficulties usually encountered by independent researchers.

Table of contents:

10.1 Investigational Medicinal Product Dossier (IMPD)
10.2 Common Technical Document (CTD)

> SECTION 11
CURRENT IMPLICATIONS AND FUTURE PERSPECTIVES IN ATMP DEVELOPMENT
ATMP development is a risky business and the socioeconomic implications must be considered before embarking on it. This module is expected to review different models that are being assayed worldwide for ATMP development. It will provide distinct points of view from academic, biotech and pharmaceutical stakeholders and also from funding bodies, patient associations, etc., providing the student with a general picture of what is needed for a putative therapy to actually reach the market. The current market will be analysed and main company profiles provided, learning both from success stories and major crashes. The section will then review intellectual property and industry right management in advanced therapies adopting a worldwide perspective. Finally, ethical issues related to advanced therapies are expected to be reviewed with an emphasis on the national differences at the European level.

As a final section, the main content is expected to focus on marketed and close to market ATMPs and their development status worldwide. These are the success stories to build upon. Secondly, a comprehensive review on cells, tissues and vectors currently in use in clinical trials as well as a primer on the clinical indications being targeted will be provided. These data are always useful for our own product development and provide cases to support our own products. Finally, some speculation will be provided on next generation ATMPs (iPS? transdifferentiated cells? targeted mutation replacement?) and future perspectives in advanced therapies will be summarised so that the student may foresee alternatives that might impact their product development strategy in the not-so-distant future.

Table of contents:

11.1 Cells, tissues and vectors currently used in clinical trials: indications
11.2 Ethical issues related to advanced therapies
11.3 Intellectual property and industry right management in advanced therapies
11.4 Business model specificities according to product characteristics and worldwide perspective
11.5 Regulatory incentives for ATMP development: quality and non-clinical data certification for SMEs by EMA and orphan drug designation
11.6 Market and future perspectives in advanced therapies