<figure><img src="image_1.png" /></figure>

HAL
open science

# A Booklet of I-BioLex posters

Aurélie Mahalatchimy, Valentin Roby

► To cite this version:

Aurélie Mahalatchimy, Valentin Roby. A Booklet of I-BioLex posters. 2025. halshs-05365079

HAL Id: halshs-05365079

https://shs.hal.science/halshs-05365079v1

Submitted on 14 Nov 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
A booklet
of I-BioLex
posters
I-BioLex "Fragmentation and defragmentation of the law on biomedical innovations" is a research project funded by the French National Agency (ANR-22-CE41-0012-03; PI: A. Mahalatchimy, CNRS-Aix-Marseille University DICE, CERIC, Aix-en-Provence, France) from 1st January 2021 to 30 June 2026.

From 1st January 2021 to 31 October 2025, the I-BioLex members and other colleagues have produced 26 posters that have been presented in International and European congresses in France and abroad. These posters are parts of the analysis conducted on fragmentation (division or segmentation), and defragmentation (gathering together, connecting or 'harmonising') of the European law on Biomedical innovations, regarding biological medicines and their subcategories, Advanced Therapy Medicinal Products and their subcategories, and orphan medicines. They relate to the various topics presented below in the table of contents.

More information on the I-BioLex research project can be found on ELSIBI here

24 October 2025

Authors: Aurélie Mahalatchimy and Valentin Roby
# Table of Contents

## I. Quality aspects/Manufacturing

Comparative quality aspects of gene therapy medicinal products and medicinal products containing genetically modified cells 6

Production Aspects of Advanced Therapy Medicinal Products 8

Quality Control and Batch Release Aspects of Advanced Therapy Medicinal Products 10

What are the quality challenges regarding comparability considerations of advanced therapy medicinal products? 12

Production of ATMPs: What are the specificities for quality aspects? 14

The challenges of Advanced Therapy Medicinal Products manufacturing in the European Union: Strengths and limits of current regulatory tools 16

## II. Clinical aspects

What specificity for the clinical aspects of investigational advanced therapy medicinal products? 20

Specific guidelines requirements for clinical trials with Advanced Therapy Medicinal Products in the European Union 22

## III. Market Access/Hospital Exemption

The Marketing Authorisation of Advanced Therapy Medicinal Products in the European Union 26

Expediting marketing authorization pathways for patients' access to advanced therapies 28

What regulatory pathways for health technologies using both medical devices and T&C in the European Union? 30

ATMPs: exceptional manufacturing returns to the patient's bedside 32

## IV. Health Technology Assessment/ Cost issues

The new European regulation on Health Technology Assessment: what changes for Advanced Therapy Medicinal Products? 36

The European regulation on Health Technology Assessment: balancing European and national levels 38

Contracts for better access to Advanced Therapy Medicinal Products 40

Real access to ATMPs: the cost issue 42
## V. Orphan Medicines

Improving access to innovative medicines: proposals from national authorities to revise the European legislation **46**

The current revision of the orphan medicinal products regulation in the European Union: what is at stake for gene and cell therapy? **48**

## VI. Actors

Which actors to influence the adoption of EU guidelines for Advanced Therapy Medicinal Products? **52**

Comparing actors participating in the adoption process of SoHO and ATMP regulations at the European level **54**

An exploratory analysis on the involvement of European organisations in the field of biomedical innovation **56**

Innovative therapy in European Parliament's positions: a numerical science-based vocabulary analysis **58**

Mapping regulators' early interactions procedures to support innovation **60**

A comparative study of national schemes and services for "early interaction" with Regulators **62**

## VII. Guidance

Mapping the ATMPs Guidance Landscape **66**

## VIII. French policy

Organoids and organs-on-chip in gene and cell therapy: which innovation strategies in France? **70**
# I
Quality aspects/
Manufacturing
# Comparative quality aspects of gene therapy medicinal products and medicinal products containing genetically modified cells

A. MAHALATCHIMY, E. GENNET, V. ANDRIEU, M. FERAUD, V. LACAILLE, J. VÉRAN, F. SABATIER, M. MORRISON, Comparative quality aspects of gene therapy medicinal products and medicinal products containing genetically modified cells, Annual Conference of the European Association of Health Law, Ghent, Belgium, 20-22 April 2022 (POSTER available at https://shs.hal.science/halshs-03779383v1)

## Abstract

The European Medicines Agency has recently revised its guidelines on quality, non-clinical and clinical aspects of Gene Therapy Medicinal Products (GTMPs text) and of medicinal products containing genetically modified cells (GMCMPs text), respectively in 2018 for the former and in 2020 for the latter. The latest revision has been particularly justified by the new developments in genome editing techniques, especially the wide use of the CRISPR-Cas technique, and with T-cells. Gene therapy medicinal product (GTMP) is a legal sub-category of medicines among Advanced Therapy Medicinal Products (ATMPs). However, medicinal product containing genetically modified cells (GMCMP) is not explicitly mentioned as a legal subcategory under EU regulation n°1394/2007 on ATMPs. Nevertheless, both GTMPs and GMCMPs should be considered as ATMPs under European Union Law. On the one hand, quality issues have been raised for all ATMPs regarding the reproducibility of the manufacturing process given the variable character of the starting materials. On the other hand, there is an overlap in the scope of the aforementioned guidelines when medicinal products containing genetically modified cells are to be considered gene therapy medicinal products. What are the similarities and differences between the quality of gene therapy medicinal products and the quality of medicinal products containing genetically modified cells while both are ATMPs? This poster is based on a comparative analysis of the quality sections of the two above-mentioned texts. In a first systematic approach, we identified the similarities and the specificities of texts outline (sub-section titles). Then, we analysed contents through the establishment of 3 types of comparative tables using color codes: common titles, different titles with similar contents, different titles with different contents in order to highlight similarities and specificities regarding the quality requirements between these two kinds of medicinal products when they are intended for use in humans and presented for marketing authorization applications.
<figure><img src="image_3.png" /></figure>

Faculté
de Pharmacie
Aix-Marseille Université

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

AP-AM

<figure><img src="image_8.png" /></figure>

I-BIOLEX

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /></figure>

# COMPARATIVE QUALITY ASPECTS OF GENE THERAPY MEDICINAL PRODUCTS AND MEDICINAL PRODUCTS CONTAINING GENETICALLY MODIFIED CELLS

Aurélie Malathalémy<sup>1</sup>, Eloise GENNET<sup>2</sup>, Véronique ANDRIEU<sup>3</sup>, Marion FERAUD<sup>4</sup>, Victoire LACAILLÉ<sup>4</sup>, Julie VERAN<sup>5</sup>, Florence SABATIER<sup>6</sup>, Michael MORRISON<sup>7</sup>

Interim Report of the French National Group for Scientific Research (CNRS, charge de recherche), Law Faculty, UMR 7319 International, Comparative and Industrial Law (CERIC, CNRS), Aix-Marseille University, Student University, Pus & Days de l'Université, Alain Brozeau, Irène (Bord de l'Orangerie) in Law, Ue, Law Faculty, UMR 7319 DICE CERIC, CNRS, Aix-Marseille University, Joly University, Pau & Papez du Dôme University, An-En-Prisence, France, Senior Researcher in Industrial Pharmacy and Biotechnology Regulation, Faculty of Pharmacy, Aix-Marseille University, Research Unit Microbes Evolution Physiology and Infection (MEPI) in Aix-Marseille University, KIS, Marseille, "Studium is 4 year of pharmaceutical sciences", Aix-Marseille University, CER, "Temperature of the day is the day of the experiment", Center, Marseille, France, Senior Research Fellow in Social Sciences, Centre for Health Law and Emerging Technologies (HeLEx), University of Oxford, Oxford United Kingdom. Acknowledgements: This work has been supported by AMR-funded-BioRxiv project (ANR-20-26-0802-05), LOA 4, Mahatma K. M. Morrison is funded by the Law-Learning Trust through grant to RING-2012-00.

ABBREVIATIONS

ATMPS: Advanced Therapy

Medicinal Products

International Council for

Harm for Pharmaceutical

Integrated ATMP: ALMP

Integrating a medical device

TMMP: Cell Therapy

Medicinal Products

DP: Drug Product

DS: Drug Substance

EMA: European Medicines Agency

GMCMPs: Medicinal

Research Products

GMP: Good Manufacturing

Practice

GTMPS: Gene Therapy

Medicinal Products

International Council for

Harm for Pharmaceutical

Technical Requirements for

Pharmaceuticals for human

Use

DPs: Medicinal Products

TSPs: Tissue Engineered

EMA: European Medicines Agency

TSP: Tissue

EMA: European Medicines Agency

GMP: Spongiform

Recombinant proteins

GMP: Replication Competent

Virus

The European Medicines Agency has recently revised its guidelines on quality, non-clinical and clinical aspects of Gene Therapy Medicinal Products (GTMPs) text) and of medicinal products containing genetically modified cells (GMCMPs) text) respectively in 2018 for the former and in 2020 for the latter. The latest revision has been particularly justified by the new developments in genome editing techniques, especially the use of the CRISPR-Cas technique, and with T-cells. Gene therapy medicinal product (GTMMP) is a legal sub-category of medicines among Advanced Therapy Medicinal Products (ATMPS). However, medicinal product containing genetically modified cells (GMCMP) is not explicitly mentioned as a sub-category under EU regulation n°1394/2007 on ATMMP. Nevertheless, both GTMPs and GMMPs, should be considered as ATMPs, under European Union law. On the one hand, quality issues have been raised for all ATMPS regarding the reproducibility of the manufacturing process given the variable character of the starting materials. On the other hand, there is an overlap in the scope of the aforementioned guidelines when medicinal products containing genetically modified cells are to be considered gene therapy medicinal products.

What are the similarities and differences between the quality of gene therapy medicinal product and the quality of medicinal products containing genetically modified cells while both are ATMPs?

This poster is based on a comparative analysis of the quality sections of the two above-mentioned tests. In a first systematic approach, we identified the similarities and the differences of texts outline (sub- section titles). Then, we analysed contents through the establishment of 3 types of comparative tables using color codes: common titles, different titles with similar contents, different titles with different contents in order to highlight similarities and specifications regarding the quality requirements between these two kinds of medicinal products when they are intended for use in humans and presented for marketing authorization applications.

## Introduction

Gene Therapy MPs

Combined ATMPS

Genetically
modified cells

Cell Therapy MP/
Tissue engineered
MPs

Scope of
analysis

ATMPs

<figure><img src="image_15.png" /></figure>

## Common topics

### Other materials, reagents and excipients

* Various materials covered, either as excipients with a wide meaning, or as "other materials and reagents" in addition to excipients

* References to the European Pharmacopeia, but to different parts of chapter 5

* To consider risk of transmitting agents causing TSE

GTMPS

* Complexed materials considered as excipients or other materials

* Various studies to be conducted for complexing materials, (non-viral, viral and non-conventional) adventitious agents

### Process validation

* Variable numbers of batches needed

* Validation for transport

GTMPS

* Use of sufficient number of consecutive production runs representative of commercial scale manufacturing process

* Reference to ICH Q15

* Potential demonstration of ability of the process to remove or inactivate any helper, hybrid or replication competent viruses generated/used during manufacture or components of the production system

* Highlights on specific cases: use of scaled down experiments, product subjected to hold times, during manufacturing process

* Validation of shipping and reconstitution

### Changes in manufacturing processes

* both changes in product/DP and starting materials/D/S regarding impact of any process change,

* appropriate comparability studies to compare pre- and post-change product

* reference to ICH Q5

* justified choices of criteria/methods use for comparability testing, additional non-clinical clinical studies

GTMPS

* Highlights on complexed nucleic acids

* Specific manufacturing-step concerned & extent of manufacturer's knowledge & experience with process & development data gained to determine impact of any process change.

GMCMPs

* Appropriate comparability studies also to assess the impact of any observed difference on the quality attributes it relates to in the process, safety & efficacy Reference to Q&A or comparability considerations for ATMPs

* Very detailed on comparability studies for changes in manufacturing process of recombinant starting materials, in cell starting material, & in active substance/finished product manufacturing route

### Stability studies

* To be conducted for both types of products:

GTMPS

* Much more detailed

* Reference to ICH Q5 on Stability

* Reference to ICH Q5 on Stability of biotechnological/biological products

* Different types of studies targeted: real time, real time and real time and forced degradation studies are the main ones, accelerated stability studies may be complementary

* To cover: DS, DP, any intermediate product stored during production, vector integrity, biological potency and strength, container-clause system used, and proposed shell-lives and storage conditions

* Specificities emphasised for shelf-life specifications, products formulated with carrier or support materials, in-use stability of DP, impact of transport conditions for DS/DP with short term shelf life

### Manufacturing process

* Implementation of process parameters and control procedures for design & manufacturing process

* Clear definition of drug substance & production guidelines

* Demonstration of absence of RCV based on sensitive assays.

* Covering interdependent/interacting results in quantitative and/or qualitative differences in product/DS quality or impurities presence

* Emphasis on number of passages for cell production (GMCMPs) or between the working stock/cell lot and vector production (GTMPS)

* Implicit (GTMPS) or explicit (GMCMPS) reference to risk-based approach guidelines

* Various manufacturing risks according to type of product, nature/characteristics of the starting materials & level of complexity of manufacturing process

* Purification process to be considered

* Seed/cell bank system to be established & controlled

* Reference to ICHQ5D

GTMPS

* Description distinguishing DS & DP manufacturing process and process

* Emphasis on Cell preparation and culture

* Focus on genetic modification of cells as a manufacturing step affected by a variety of inputs

* Further manufacturing steps (including purification process) other than genetic modification to be considered

* In-process controls very detailed (to be performed at key intermediate stages) and linked to Critical Quality Attributes

* Retention samples should be stored for future analysis

### Quality Controls

GTMPS

* Compliance with ICH guidelines

* Setting of reference batch of vector of assigned potency (with stability profile and relevant storage conditions) to standardise assays where appropriate

* Discussion, justification & comparison of differences between tests proposed for release of commercial batches and those used for clinical development

GMCMPS

GMCMPS

GMCMPS

GMCMPS

GMCMPS

GMCMPS

GMCMPS

GMCMPS

GMCMPS

General information on
GTMPS: Vectors design &
Development Genetics

GTMPs

Specifications of the
DS/DP/Pharmaceutical
development

Reconstitution activities

GMCMPS

## Discussion and Conclusion

### More general approaches for GTMPs than for GMCMPs

* Starting Materials: tests to be conducted depend on product & production process (i.e. genetic manipulation for GMCMPs)

* Manufacturing process: While the GTMPs text distinguishes manufacturing process and process controls of DS and DP, the GMCMPs text focus on cell preparation and culture, and genetic modification as main manufacturing step although further steps are also considered.

* Quality controls: Possibility to use reference batch for GTMPs assays standardization seems not possible for GMCMPS targeting distinct product/process/case

### Changes in the manufacturing process as the topic with most similarities

* The main difference between the two texts is that the GMCMPs text is more detailed than the GTMPs one regarding comparability studies

### Process validation as the topic with most differences

* One of the most significant differences is that "reconstitution" is not part of the manufacturing process to be validated for GMCMPS by opposition to GTMPs. It is only mentioned 3 times in the GTMPs text while it is a dedicated specific section for GMCMPS.

### Link between characterization and release criteria

* It appears there is a close link between characterization and release criteria, but it is explicitly mentioned only in GMCMPS text.

### Specifications highlighted for GTMPs only

* The GTMPs text has sections dedicated to the specifications of DS, DP and pharmaceutical development. However, specifications appear disseminated in the GMCMPS text. Interestingly, the word "specification" appears only 3 times in the GMCMPS text, and 2 times only in the quality part for "release specification" regarding changes in the manufacturing process of recombinant starting material, and characterization.

## Specific topics

Reconstitution activities

GMCMPS

### Questionable cross-references between guidelines

1) Some references to other guidelines appear only in the GTMPs text while they are relevant to GMCMPs

* Regarding Other materials, reagents and excipients: Guidance on Excipients in the Dossier for Application for Marketing Authorisation of a medicinal product, Note for Guidance on minimising the risk of transmitting animal sporeng encephalopathy agents, ICH Q3A(R)1 on Quality of biotechnological products: viral safety evaluation of biotechnology products derived from cell lines of human or animal origin

* Regarding characterization: section 3.4 of Part IV of Annex to Directive 2001/83/EC on Specific requirements for ATMPs containing devices

* Regarding Process validation: ICHQ11 Development and manufacture of drug substances (chemical entities and biotechnological/biological entities)

* Regarding Quality Controls: ICH guidelines in general

* Regarding Stability Studies: ICH QSC Stability testing of biotechnological/biological products

Developers may not be aware of existing
relevant useful guidelines

2) While GMCMPs can be both GTMPs or CTMPs, the GMCMPs text refers more to the guidelines on Cell-based MPs than to the GTMPs text

* Reference to the Cell-based MPs: text & not to GTMPs test regarding characterization, process validation, and stability studies

* Reference to both Cell-based MPs text & GTMPs text regarding manufacturing process

It implies the wrong feeling that GMCMPs will be more often qualified as Cell-based MP. The GMCMPs text has been revised, especially to cover T-Cells, but authorised ATMPs based on T-cells (Vescartas, Kymrich, Tecturus) have been classified as GMPS: more balanced reference to both GTMPs & Cell-based MPs texts would be necessary

3) Some references to other guidelines appear only in the GMCMPS text while they are relevant to GTMPs

* Regarding Process validation:

* Guidelines on GMP for ATMPs

* Regarding Changes in the manufacturing process: O&A on comparability considerations for ATMPs

A later date of adoption
for the O&A on
comparability considerations for
ATMPs

EMA, Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products, 22 March 2018

EMA/LAF/82183/2018

EMA, Guideline on the quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells, 12 November 2017

EMA, ICH Q3A, Development of drug substances (chemical entities and biotechnological/biological entities), November 2012, ECHA/CMVJX/45225/2013

EMA, ICH QC, Quality of Biotechnological Products: Stability testing of biotechnological/biological products, July 1996

CIMM/CH/138/95

EMA, ICH QD, Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates used for Production of biotechnological/biological Products, March 2008, ECHA/CMVJX/297/95

EMA, ICH QE, Step 5: Comparability of biotechnological/biological products, June 2005, ECHA/CMVJX/572/03

EMA, ICH QI, Development of drug substances (chemical entities and biotechnological/biological entities), November 2012, ECHA/CMVJX/45225/2013

EMA, Questions & Answers on comparability considerations for advanced therapy medicinal products (ATMP), 6 December 2013,

EMA/CE/47982/2019

## References

<figure><img src="image_16.png" /></figure>

GHENT - 20-22 APRIL '22
EIGHTH EUROPEAN CONFERENCE ON HEALTH LAW

EQUITY IN HEALTH: THE EUROPEAN CONFERENCE ON HEALTH LAW
# Production Aspects of Advanced Therapy Medicinal Products

J. VÉRAN, F. SABATIER, M. MORRISON, C. LE CORRE, C. S. PEIXOTO, E. GENNET, V. ANDRIEU, A. MAHALATCHIMY, Production Aspects of Advanced Therapy Medicinal Products, Annual Conference of the European Association of Health Law, Ghent, Belgium, 20-22 April 2022 (POSTER available at https://archivesic.ccsd.cnrs.fr/AO-DROIT/halshs-03779408v1)

## Abstract

**Background:** Good Manufacturing Practice (GMP) guidelines established by the European Commission are essential to ensure quality, safety and efficacy of medicinal products. Guidelines are designed to address specific risks of medicinal products and as such, are continuously being adapted. Advanced Therapy Medicinal Products (ATMPs) are medicinal products that have been regulated in the European Union from 2007 to cover the emerging field of genes, tissues or cell-based therapies. Dedicated GMP guidelines for ATMPs are enforceable since 2017. Consequently, GMP guidelines covering manufacture of biological active substances and medicinal products for human use including biological active substances (hereafter "Biologicals") have been revised in June 2018 with the objective to prevent overlapping scope. Research question and methods: Our hypothesis is that the biological nature that commonly characterize ATMPs and biologicals may sustain a large body of similarities in the manufacturing aspects as addressed by the respective guidelines. We aim to comparatively analyze the two following texts : Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, and Manufacture of Biological active substances and Medicinal Products for human use including biological active substances. Focus has been given on manufacturing, i.e. production recommendations including personnel, premises, equipment, documentation, starting and raw materials, seed lot and cell bank systems. In a systematic approach we highlighted similarities and specificities in the text outlines (paragraph and section titles). Then content has been comparatively investigated based on chosen relevant key words found in both texts (production, operation principles, production area, facilities, cross contamination in production, environmental monitoring and specifications, starting and raw materials).
<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /></figure>

# Production Aspects of Advanced Therapy Medicinal Products

Julie Véran<fnref n="1" />, Florence Sabatier², Michael Morrison³, Carla Le Corre⁴, Carlota Santos Peixoto⁵, Eliseo Gennet⁵, Véronique Andrieu⁶, Aurélie Mahalatchimy⁷

Acknowledgements: This work has been supported by ANR-funded i-Biolex project (ANR-20-CE26 0007-01, coord. A. Mahalatchimy). M. Morrison is funded by the Leverhulme Trust through grant no RPG-2017-330

## Introduction

**Background** : Good Manufacturing Practice (GMP) guidelines established by the European Commission are essential to ensure quality, safety and efficacy of medicinal products. Guidelines are designed to address specific risks of medicinal products and as such, are continuously being adapted. Advanced Therapy Medicinal Products (ATMPs) are medicinal products that have been regulated in the European Union from 2007 to cover the emerging field of genes, tissues or cell-based therapies. Dedicated GMP guidelines for ATMPs are enforceable since 2017. Consequently, GMP guidelines covering manufacture of biological active substances and medicinal products for human use including biological active substances (hereafter "Biologicals") have been revised in June 2018 with the objective to prevent overlapping scope.

**Research question and methods:** Our hypothesis is that the biological nature that commonly characterize ATMPs and biologicals may sustain a large body of similarities in the manufacturing aspects as addressed by the respective guidelines. We aim to comparatively analyze the two following texts : Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, and Manufacture of Biological active substances and Medicinal Products for human use including biological active substances. Focus has been given on manufacturing, i.e. production recommendations including personnel, premises, equipment, documentation, starting and raw materials, seed lot and cell bank systems. In a systematic approach we highlighted similarities and specificities in the text outlines (paragraph and section titles). Then content has been comparatively investigated based on chosen relevant key words found in both texts (production, operation principles, production area, facilities, cross contamination in production, environmental monitoring and specifications, starting and raw materials).

## Results

### COMMON TOPICS

#### Premises & Equipments

Constructed to avoid cross-contamination

- Designed in logical order to avoid risk

- Campained manufacturing (separation in place and/or in time)

- Controlled for particulate and microbiological contamination, maintained (air vent filters, positive pressure) and validated frequently by effective control strategy

- Cleaned

- Effective aseptic operations during the process for biological materials that cannot be sterilized

#### General Documentation

- Documentation for all manufacturing process & method

- Exhaustive traceability specially for batch, for starting and raw materials and for all products in contact with cells or tissues

- Traceability records to be for retained for 30 years

#### Operations / Operating Principles

- Process design robustness, minimising variability, enhancing reproducibility to ensure quality and safety of the product

- Definition of critical operational parameters, critical operations

- Product quality reviews required

- Rules for process (entries, disinfected, wasted)

#### Starting and raw materials

Compliance with existing legislation on quality, safety, and traceability of human tissues and cells, especially on donation, procurement and testing

#### Seed lot and cell bank system

- Establishment of seed lots, and cell banks (master and working generation)

- Definition of appropriate specifications and qualification

- Management of a Controlled storage to avoid risk mix up

#### Risk based approach/Quality risk management

#### Personnel

- Qualified

- Trained and retrained

- Prevent and anticipate hazards, control it and apply measures to minimise it

- Based on scientific knowledge and experience

- Quality and safety ensured since the first steps, even for investigational ATMPs.

#### Qualified person and Batch Release/Certification

Functions of the Qualified Person:

- Verification and certification of the batches according to manufacturing/marketing/clinical trial authorization

- Release/certification must be registered and notified if there is a deviation...

### SPECIFIC TOPICS

#### Specific Guidelines for ATMPs

Aseptic
Process &
Environmental
Monitoring

##### General principles

- Manufacturing to be conducted aseptically to limit introduction of contaminants and cross contamination

- Specific aseptic measures detailed for specific kind of manufacturing processes and open or closed operating systems

##### Aseptic processing validation

- Simulated by media fill test /media process test

- Documented as well as the cleaning process

- Environmental monitoring programme to be applied

#### Specific Guidelines for Biologicals

##### Animal sources

- The manufacturer must follow the Transmissible Spongiform Encephalopathy guidelines and have a recorded health program for other agents. Sick animals must be investigated, and everything has to be documented.

- Housing must be separated from production and control areas.

- For each animal species, key criteria have to be defined and recorded. In the case of transgenic animals, traceability must be maintained in their creation.

## Discussion and Conclusion

The ATMPs guidelines is a very detailed text covering the investigational and authorized stages from the raw materials to the final product. Technical measures are very extensively introduced for guidance of manufacturers. By contrast, guidelines on Biologicals is briefer and include more general requests and standards ensuring the quality of the product. A large part of manufacturing recommendations are commonly present in the two texts and in line with the manipulation of raw and starting materials of biological origin that raise common challenges in terms of quality reproducibility, traceability and risk of cross or exogenous contaminations. Main specifics associated to the manufacturing of these two categories of medicinal products, are related to specific aspects addressing the control of contamination risk.

Regarding ATMPs guidelines, a section is dedicated to aseptic measures covering the entire process management. This specificity is justified by the usual lack of terminal sterilization of the product that requires to adopt preventive strategies to limit the introduction of contaminants. Regarding biologicals, specificities address the challenges of using animal sources in the manufacturing process and the associated risk of contamination. These specificities are relevant because a large proportion of biological medicinal products or active substances are issued from living or post-mortem animal sources, while ATMPs are mostly designed based on human materials.

Raw materials of animal origin are poorly addressed in the ATMPs guidelines although this aspect could be of relevance.

## References

European Commission, Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, 22 May 2018.
European Commission, Manufacture of Biological active substances and Medicinal Products for Human Use, 26 June 2018.

<figure><img src="image_22.png" /></figure>

<footnote n="1">¹Responsible of Cell therapy/Advanced Therapy Medicinal Products' production at Marseille Public Hospital (AP-HM), Biotherapies Clinical Investigation Center, Marseille, France. ²Professor of Hematology and Biotherapy, Pharmaceutical Sciences, Faculté, C2Vb INSERM IRD 1263 AIX Marseille University, Director of the cell therapy research centre at Marseille Public Hospital (AP-HM), Marseille, France. ³Senior Research Fellow in Social Sciences, Centre for Health Law and Emerging Technologies (HeLEX), University of Oxford, Oxford, United Kingdom. ⁴Students in 4th year of Pharmaceutical Sciences, Aix Marseille Université, France. ⁵Post-doctoral Researcher in Law, Law Faculty, UMR 7318 International, Comparative and European laws (DICE), CERIC, CNRS, Aix- Marseille University, Toulouse University, Pau & Pays de l'Adour University, Aix-en-Provence, France. ⁶Senior lecturer in Industrial Pharmacy and Pharmaceutical Regulation, Faculty of Pharmacy, Aix-Marseille University, Research Unit Microbes Evolution Physiology and Infection (MEPH) Aix-Marseille Université, IRD, Marseille, France. ⁷Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, chargée de recherche), Law Faculty, UMR 7318 DICE, CERIC, CNRS, Aix Marseille University, Toulouse University, Pau & Pays de l'Adour University, Aix-en-Provence, France.</footnote>
# Quality Control and Batch Release Aspects of Advanced Therapy Medicinal Products

J. VERAN, M. MORRISON, F. SABATIER, L. CHEY, F. MBODJ, E. GENNET, V. ANDRIEU, A. MAHALATCHIMY, Quality Control and Batch Release Aspects of Advanced Therapy Medicinal Products, Annual Conference of the European Association of Health Law, Ghent, Belgium, 20-22 April 2022 (POSTER available at https://shs.hal.science/halshs-03780272v1)

## Abstract

Quality control and batch release raise specific challenges for ensuring quality and complying with regulatory requirements in order to obtain manufacturing and marketing authorizations for Advanced Therapy Medicinal Products (ATMPs). ATMPs are medicinal products based on genes, cells and tissues that have been specifically regulated in the European Union (EU) from 2007. In the guidelines on Good Manufacturing Practices (GMP) specific to ATMPs from the European Commission, specific requirements cover quality control and batch release. They are distinct from the ones that can be found in other guidelines on GMP applicable to other kinds of biological medicinal products. Through a comparative textual analysis of the GMP guidelines for biological medicinal products and ATMPs, this poster will highlight the key areas of similarities and differences. Our analysis mainly focuses on qualification and validation procedures, batch release process, quality defects and product recalls, and automated production of ATMPs. This analysis reveals why we have two different texts and whether they are based on substantial differences regarding quality control and batch release between ATMPs and other types of biological medicinal products.
<figure><img src="image_23.png" /></figure>

Faculté
de Pharmacie
Aix-Marseille Université

<figure><img src="image_24.png" /></figure>

Inserm

C2VN
Conseil d'Etude et de Réalisation

<figure><img src="image_25.png" /></figure>

Conseil d'Etude et de Réalisation

Conseil d'Etude et de Réalisation

Conseil d'Etude et de Réalisation

<figure><img src="image_26.png" /></figure>

<figure><img src="image_27.png" /></figure>

I-BIOLEX

<figure><img src="image_28.png" /></figure>

<figure><img src="image_29.png" /></figure>

<figure><img src="image_30.png" /></figure>

<figure><img src="image_31.png" /></figure>

<figure><img src="image_32.png" /></figure>

Faculté de Droit et de
Science Politique
Aix-Marseille Université

# QUALITY CONTROL AND BATCH RELEASE ASPECTS OF ADVANCED THERAPY MEDICINAL PRODUCTS

Julie VERAN<fnref n="1" />, Michael MORRISON², Florence SABATIER³, Lea CHEY⁴, Fatou MBOJD⁴, Eloise GENNET⁵, Véronique ANDRIEU⁶, Aurélie MAHALATCHIMY⁷

Acknowledgements: This work has been supported by ANR-funded I-Biolex project (ANR-20-CE28-0007-01), coord. A. Mahalatchimy J., M. Morrison's funded by the Leverkusen Trust through grant nr. DPG-2017-330.

## INTRODUCTION

**Background:** Biological medicinal products are products with an active substance produced or extracted from a biological source. Advanced Therapy Medicinal Products (ATMPs) are medicinal products based on genes, cells or bioengineered tissues that have been regulated in the European Union from 2007. Dedicated Good Manufacturing Practice (GMP) guidelines have been established from the European Commission in order to guarantee their quality, efficacy and safety from the development to the marketing authorisation. Consequently, GMP guidelines covering manufacture of biological active substances and medicinal products for human use including biological active substances (hereafter "biologicals") have been revised in June 2018 to prevent overlapping scope. The manufacturing of biologicals and ATMPs has to comply with guidelines that are established by the European Commission.

**Research question:** We hypothesised that due to biological nature of ATMPs, similarities in part of these guidelines related to quality control and batch release aspects could be evidenced in the texts. This analysis will help to understand why two different texts have been elaborated by analyzing whether they are actually based on specific considerations in terms of quality control and batch release arising from the nature of the products and the processes differences between ATMPs and other biological medicinal products.

**Methods:** We conducted a comparative analysis of the following regulatory texts: Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (focuses on front of chapter 10 QUALIFICATION to the end) and Manufacture of Biological active substances and Medicinal Products for Human Use. In a first systematic approach, we identified the similarities and the specificities of texts outline (paragraph and section titles). Then, we analysed contents based on chosen relevant key words that may be diversely used in two texts (control, quality control, strategy of control, certification, release, in process control, quality risk management, analytical techniques/methods, testing etc) in order to highlight similarities and specificities in all aspects related to quality control and batch release.

## RESULTS

### SIMILAR REQUIREMENTS

**Starting and raw materials**

* Compliance with legislations on quality, safety and traceability of human tissues/cells, blood/blood components, and genetically modified cells (donation, procurement and testing)

* Appropriate level of control and requirements

* Possibility to process starting materials before the results of their testing, but release of finished product conditioned by satisfactory results

**Seed lot and call bank system**

To prevent drift of properties during handling and storage:

* Appropriate specifications (number of generations,...)

* Risk of adventitious agents and cross contamination

**Premises and equipment for quality control**

* Apart from production.

* Prevention of mix-ups and cross-contamination during testing.

* Storage space (samples and records)

**Batch certification, release initial and final certification based on:**

* Environmental & analytical testing

* Defined specifications (market authorization, clinical trial authorization)

By qualified person
Management of "out of specifications"

**Retained samples for QC testing**

* "Look-back procedure" attesting for the continued suitability of the biological active substance.

* Re-testing of retained samples from previous collections → "last negative donation"

**In-process control**

* Ensure quality consistency

* Happens at appropriate stages of production.

**Considerations for microbiological risk**
* Level of bioburden or need to be sterile defined in NA and CTA for substances and materials at various stages

* Sterilization process allowing to preserve the activity of materials and exclude the risk of contaminants introduction

* Aseptic process and strategies minimizing the risk of contaminating materials, adapted to environmental monitoring, use of closed system, cleaning, use of antimicrobials or antibiotics without interference

**Hazard identification/quality risk**
* Quality risk management and risk-based approach to minimise variability of biological processes and materials and to reduce/centralize containments.

* Subjects are animals, biological agents, premises, equipment and control operations

**Legend**

<figure><img src="image_33.png" /></figure>

**Primary containment**

* safe & respect products characteristics

* Maintaining quality and prevent spillage.

* Compatibility of labels with ultra-low storage temperatures

**Documentation**

* Specifications, instructions, records/reports

* On the source, origin, distribution chain, methods and controls.

* Traceability records (30 years).

### SPECIFICITIES

**Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (2017)**

**Validation of analytical methods**

**Additional in vitro essays**

* Suitability for the intended purpose

► *purity tests* (or proliferation assays...)

► After batch release as supporting data for process validation

**Cell stocks**

► Obtained from a limited number of passages,

► Do not cover the entire life cycle of the product

► Control and release conditions in accordance with principles of cell banks

**Novel aspects judged by specific challenges of cell-based therapy**

* Complexity of products & processes → limited batch series + variability of the starting materials (especially in autologous setting)

► Flexibility and "risk-based approach" for appropriate measures of quality control

* At the authorized and investigational stages, from the raw material to the final production

**On-going stability program**

► For finished products with shorter shelf-life

► After the marketing authorisation

► Stability of specifications during the shelf-life

**Guidelines on the Manufacturing of Biological active substances and Medicinal Products for Human Use (2018)**

**Quality of starting materials or non human origin**
**Animal sources**

**Controls & Testing using animals**

* 2 types of sources:

► Strictly controlled selection of donor animals.

► Animals used in quality control assays

* Healthy

* Specific pathogen free (SPF)

* Raised in SPF conditions

* Bred in captivity specifically designed for the purpose of the research

* Quality controls and certification aspects: measures emphasizing procurement and quality of starting materials of animal origin, mitigation of a higher risk of low purity and microbiological contamination, and of greater variability of biological analytical methods as it is currently for biologicals.

* Focus on the process, from raw material (principally extracted from animals or donors) to the active substance

## DISCUSSION/CONCLUSION

**Similar spirit of the two texts**

* Based on the crucial role of manufacturing and control processes in determining the quality of such types of medicinal products

* To ensure measures related to the biological origin and the related inherent variability of such medicinal products are adopted regarding the requested standards of quality, a major determinant of safety and efficacy for the patients

**Explicit Rationale for differences in the two texts**

* Substantial specificities due to specific risks, as presented in the scopes and general principles of the texts

* Very detailed text of 90 pages for ATMPs dated of 22/11/2017, and briefer text of 25 pages for biologicals dated of 26/06/2018 that has been revised in order to take into account the new guidelines on ATMPs.

**Questioning the relevance of having two distinct and exclusive texts**

* As ATMPs are a specific category of biologicals, the levels of similarities and differences regarding quality control and batch release is variable, e.g. The "risk-based approach" for ATMPs seems matched to the "risk quality management principles" for biologicals, but the former is more prospective with the idea to anticipate and control current poorly known risks.

* Some specific requirements solely expressed in the ATMPs guidelines may be relevant to other biologicals, e.g., the validation of biological methods used for quality control and testing.

► Large set of similarities in their content on quality control and batch release, based on their common biological nature and related risks in terms of quality of starting human and raw materials, traceability of quality, compatibility of containments, importance of process controls, strategy for initial and final certification and batch release.

► Exclusive Guidelines: It is explicitly stated that the text on biologicals do not apply to ATMPs which are covered by specific guidelines.

* Some specific requirements solely expressed in the text on Biologicals may be relevant to ATMPs: Because ATMPs could also in the future be designed based on xenogenic cells and are prone to necessitate the use of raw materials of animal origin (such as cell culture or extraction reagents etc.). It can be anticipated that details of recommendations on animal sources warrant further considerations in ATMP guidelines as it is currently for biologicals.

The rationale for some style/form differences is unclear: The vocabulary used in the two texts is very different while they have been adopted with a 7 months interval only, and it often refers to the same ideas.

The two texts are presented as exclusive, but they share common aspects.

They share common aspects related to the biological nature of the product.

They could benefit from being formulated in a more similar manner to facilitate full understanding and implementation by stakeholders, especially manufacturers.

<figure><img src="image_34.png" /></figure>

## REFERENCES

* European Commission, Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, 22 May 2018.

* European Commission, Manufacture of Biological active substances and Medicinal Products for Human Use, 26 June 2018.

* Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donator, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, OJ L 102, 7.4.2004, p. 48-58 (and following complementary Directives).

* Directive 2001/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/33/EC, OJ L 31, 8.2.2005, p. 30-40.

* Directive 2005/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of genetically modified micro-organisms (Recast) (text with EAERelative), OJ L 125, 21.5.2009, p. 75-91.

* Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/222/EEC - Commission Declaration, OJ L 106, 17.4.2001, p. 1-39.

<footnote n="1">¹Responsible of Cell Therapy/Advanced Therapy Medicinal Products' production at Marseille Public Hospital (AP-MH). Biotherapies: Clinical Investigation Center, France; ²Senior Research Fellow in Social Sciences, Centre for Health Law and Emerging Technologies (HEXT), University of Oxford, United Kingdom; ³Professor of Hematology and Hematology, Pharmaceutical Sciences Faculty, CIVM INSERM INRA 1263 AX Marseille University, Director of the cell therapy research centre at Marseille Public Hospital (AP-MH), France ⁴ Students in 4th year of Pharmaceutical Sciences, Aix-Marseille University, France; ⁵Post-doctoral Researcher in Law, Law faculty, UMR 7318 International, Comparative and European Law (DICE) CERIS, CNRS, Aix-Marseille University, Toulouse University, Paul & Pays de la Dordure University, Aix-en-Provence, France; ⁶Senior lecturer in Industrial Pharmacy and Pharmaceutical Regulation, Faculty of Pharmacy, Aix-Marseille University, Research Unit Molecular Evolution: Physiology and Infection (EMEDE), French-National Centre for Scientific Research (CNRS, IRD), Law Faculty, UMR 7318 DICE CERIS, CNRS, Aix-Marseille University, Toulouse University, Paul & Pays de la Dordure University, Aix-en-Provence, France</footnote>
# What are the quality challenges regarding comparability considerations of advanced therapy medicinal products?

V. ANDRIEU, E. GENNET, J. VÉRAN, M. MORRISON, F. SABATIER, A. MAHALATCHIMY, What are the quality challenges regarding comparability considerations of advanced therapy medicinal products? Annual Conference of the European Association of Health Law, Ghent, Belgium, 20-22 April 2022 (POSTER available at https://archivesic.ccsd.cnrs.fr/AO-DROIT/halshs-03780293v1)

## Abstract

The question of comparability for Advanced Therapy Medicinal Products (ATMPs) is very often asked during Scientific Advice Meetings at the European Medicines Agency. Indeed, changes to ATMPs manufacturing processes, improvements/changes in equipment, raw materials and critical starting materials, or process scale are frequent in the early stages of development or even after marketing authorization. Quality comparability is the first step in the review of variations procedures of a medicinal product. Indeed, quality information is of major importance with analytical testing, risk-based approach and manufacturing evaluation as it will allow to conclude if non clinical and clinical data on comparability are also needed or not. The text of December 2019 of the Committee for Advanced Therapies (CAT), entitled "Questions and answers, Comparability considerations for Advanced Therapy Medicinal Products" contains the major questions companies can have when a comparison is needed between the pre- and post-change of the manufacturing process of ATMPs. The answers are based on analytical and statistical tools which are needed in frequent experimental changes situations. Generally, this text addresses the issues linked to the demonstration of comparability regarding the quality aspects of ATMPs. Another important text is the ICH Q5E guideline that addresses comparability of biological/biotechnological medicinal products which legally cover ATMPs. However, ATMPs are outside the scope of this guideline, except for the general principles that can be applied to ATMPs. Through of comparative textual analysis of these two texts, this poster will show the complementarity of the information provided, but also the very dynamic impact of the Q&A text targeted on ATMPs in comparison with the large recommendations of the ICH guideline on biotech products.
<figure><img src="image_35.png" /></figure>

Faculté de Pharmacie
Aix-Marseille Université

<figure><img src="image_36.png" /></figure>

Inserm

C2VN
C2VN - Université de Toulouse
Contribution du kaf

<figure><img src="image_37.png" /></figure>

<figure><img src="image_38.png" /></figure>

<figure><img src="image_39.png" /></figure>

I-BIOLEX

<figure><img src="image_40.png" /></figure>

<figure><img src="image_41.png" /></figure>

<figure><img src="image_42.png" /></figure>

<figure><img src="image_43.png" /></figure>

<figure><img src="image_44.png" /></figure>

<figure><img src="image_45.png" /></figure>

Faculté de Droit et de Science Politique
Aix-Marseille Université

# What are the quality challenges regarding comparability considerations of advanced therapy medicinal products?

Véronique Andrieu<fnref n="1" />, Eloïse Gennet², Julie Véran³, Michael Morrison⁴, Florence Sabatier⁵, Aurélie Mahalatchimy⁶

## INTRODUCTION

The question of comparability for Advanced Therapy Medicinal Products (ATMPs) is very often asked during Scientific Advice Meetings at the European Medicines Agency. Indeed, changes to ATMPs manufacturing processes, improvements/changes in equipment, raw materials and critical starting materials, or process scale are frequent in the early stages of development or even after marketing authorization. Quality comparability is the first step in the review of variations procedures of a medicinal product. Indeed, quality information is of major importance with analytical testing, risk-based approach and manufacturing evaluation as it will allow to conclude if non-clinical and clinical data on comparability are also needed or not.

The text of December 2019 of the Committee for Advanced Therapies (CAT), entitled "Questions and answers, Comparability considerations for Advanced Therapy Medicinal Products" contains the major questions companies can have when a comparison is needed between the pre- and post-change of the manufacturing process of ATMPs. The answers are based on analytical and statistical tools which are needed in frequent experimental changes situations. Generally, this text addresses the issues linked to the demonstration of comparability regarding the quality aspects of ATMPs. Another important text is the ICH Q5E guideline that addresses comparability of biological/biotechnological medicinal products. However, ATMPs are outside the scope of this guideline, except for the general principles that can be applied to ATMPs.

Through of comparative textual analysis of these two texts, this poster will show the complementarity of the information provided, but also the very dynamic impact of the Q&A text targeted on ATMPs in comparison with the large recommendations of the ICH guideline on biotech products.

<figure><img src="image_46.png" /><figcaption>ATMPS MANUFACTURE CHANGES during Product Development</figcaption></figure>

Assessing the comparability before/after changes should start with comparison of quality data.

Changes can happen during the development phase or after marketing authorization.

1/ Comparison of quality attributes with analytical testing, based on active substance & finished product properties;

2/ if not satisfactory, comparison of non-clinical & clinical data.

For quality data, comparison integrates all data collected, e.g., routine batch analyses, in-process control, process validation data, characterization or stability.

### Scope

Q&A text: ATMPs, especially cell-based medicinal products
ICHQ5E guideline: proteins, polypeptides, and derivatives, and is recommended for vector-based gene therapy medicinal products.

### Types of data

It is mainly in ICH Q5E that confirmatory nonclinical or clinical studies are appropriate, after comparison of quality data.

### Characterization

By appropriate techniques (described in ICH Q6B) includes determination of physicochemical properties, biological activity, immunochemical properties (if any), purity, impurities, contaminants, and quantity; each "criteria should be considered as a key point in the conduct of the comparability exercise".

ICHQ5E guideline: analytical tests "chosen to define drug substance/drug product specifications alone" and used at release of the product are generally not "considered adequate" to evaluate comparability, & "Modification, elimination, or addition of a test (i.e., in the specification) might be indicated".

Q&A text: "analytical methods used for release testing are the starting point"; "if the used analytical methods differ, it will be difficult to establish a link between the pre- and post-change material" (Q6).

### Stability Studies

ICHQ5E guideline: "Real-time/real temperature stability studies on the product potentially affected by the change" should be initiated for proteins.

Q&A text: full real time stability studies not required to support comparability for stable ATMPs; in-use stability study is only proposed.

WHEN?

HOW?

## COMMON TOPICS

WHAT?

OF WHAT?

"comparability exercise" based on the physico-chemical and biological properties of the product: Analytical methods for release testing can be used; validated methods not necessary.

Even if products are different, comparison method before/after change (in the manufacturing process) is the same.

"A comparability exercise should not only cover evaluation of equivalency of manufactured products but should include also comparison of processes themselves", if relevant.

Knowledge of the manufacture and development data are key words for both texts.

## SPECIFIC TOPICS

The following subjects are only treated in the Q&A text because they are connected to ATMPs.

### Methodology of the comparability exercise:

* Two main approaches are possible for comparability study of ATMPs: "Side-by-side testing of products in the same analytical run", and "Comparison of post-change data to historical data obtained from pre-change process", the latest one is not recommended (Q7).

* "Statistics may provide useful information to support comparability". "Solely meeting specifications is not considered sufficient to conclude on comparability" (Q11).

**Cell-based products:** the comparability exercise can be conducted with healthy donor materials with justification (Q8).

**When a manufacturing site is added** for a marketed product, "a high degree of comparability is expected" with "comparability assessment of the manufacturing process", "equivalence of the analytical methods" and "comparability of the product itself" (Q12).

**A "comparability exercise" is needed for "critical changes in the manufacturing of starting materials for ATMPs having an impact on the manufacturing process of the finished product" (Q13).**

**Regulatory consideration:** a change in the manufacturing process results in a variation procedure of the marketing authorization or an amendment of the clinical trial authorization

**Risk-based approach** should be used to determine an appropriate amount of comparability data and to select a suitable set of relevant critical quality attributes (CQAs).

## DISCUSSION/CONCLUSION

The Q&A is limited to ATMPs whereas the guideline is for Biotechnological/Biological Products.

ICHQ5E coming into operation in 2005 is used as a Reference text for Q&A of 2019.

Nevertheless, only the general principles of ICHQ5E can be applied to ATMPs which are considered to be out of the scope of ICHQ5E due to their characteristics.

The Q&A addresses a number of questions that have been brought to the attention of the EMA by marketing-authorisation holders (MAHs) or European Economic Area competent authorities, on matters related to the quality of medicines. It provides a harmonised position on issues which require clarification, typically during assessment procedures.

The Q&A should be red in conjunction with other guidelines.

The comparability considerations of the ATMPs changes are based on Quality data in the Q&A with a lot of work during the Pharmaceutical Development with the use of modern quality tools; the comparability considerations of the Biotechnological/Biological Products changes are based on quality, non-clinical and clinical data.

The obligations to assess changes based essentially on in vitro studies, as in the Q&A, are extremely important for MAHs, because they thus limit in vivo studies on animals or on patients, which are long, expensive and not necessarily ethical.

<figure><img src="image_47.png" /></figure>

GHENT - 20-22 APRIL '22

EIGHTH EUROPEAN CONFERENCE ON HEALTH LAW

## REFERENCES

European Medicines Agency, Committee for Advanced Therapies (CAT), Questions and answers. Comparability considerations for Advanced Therapy Medicinal Products (ATMP), EMA/CAT/499821/2019, 6 December 2019.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Topic Q5E Comparability of Biotechnological/Biological Products, CPMP/ICH/5721/03, June 2005.

<footnote n="1">¹Senior lecturer in Industrial Pharmacy and Pharmaceutical Regulation, Faculty of Pharmacy, Aix-Marseille University, Research Unit Microbes: Evolution, Physiology and Infection (MEPH) - Aix-Marseille University, IRD, France / Post-doctoral Researcher in Law, Law Faculty, UMR 7118 International, Comparative and European Laws (DICE, CECR), CNRS, Aix-Marseille University, Toulouse University, Pau & Payd de (R)adour University, Aix-en-Provence, France; "Responsable de Cell therapy/Advanced Therapy Medicinal Products" production at Marseille Public Hospital (AP-HM), Biotherapies Clinique Investigation Center, France; ¹Senior Research Fellow in Social Sciences, Centre for Health Law and Emerging Technologies (HLMED), University of Oxford, United Kingdom; "Professor of Toxicology and Biotherapy, Pharmaceutical Sciences Faculty, C2VN, noiz enPVie, 1292 AX, Aix-Marseille University, Director of the cell therapy research centre at Marseille Public Hospital (AP-HM), France; ²Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CRJ), Law Faculty, UMR 7118 DICE, CECR, CNRS, Aix-Marseille University, Toulouse University, Pau & Payd de l'Astur University, Aix-en-Provence, France.</footnote>

<footnote>Acknowledgements This work has been supported by ANR-funded I-Biolex project (ANR-20-CE26-0007-91, contract A, Mahalatchimy), M. Morrison is funded by the Leverhulme Trust through grant no RPC-2017-330.</footnote>
# Production of ATMPs: What are the specificities for quality aspects?

A. MAHALATCHIMY, E. GENNET, M. MORRISON, V. ANDRIEU, J. VÉRAN, F. SABATIER, Production of ATMPs: What are the specificities for quality aspects?, European Society for Gene & Cell Therapy Congress 2022, Edinburgh, the UK, 11-14 October 2022, (POSTER available at https://shs.hal.science/halshs-03901462);

Abstract published in Human Gene Therapy, Volume: 33 Issue 23-24: December 14, 2022, A1-A212. http://doi.org/10.1089/hum.2022.29225.abstracts

## Abstract

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells and tissues that have been specifically regulated in the European Union (EU) from 2007. Their manufacturing (i.e. their production) raises specific challenges for ensuring quality and complying with regulatory requirements in order to obtain manufacturing and marketing authorizations. For this reason, detailed guidelines on Good Manufacturing Practices specific to ATMPs have been adopted by the European Commission, and have been enforceable since 2017. They are distinct from other guidelines on GMP applicable to other kinds of biological medicinal products. Separate GMP guidelines, covering manufacture of biological active substances and medicinal products for human use including biological active substances were revised in June 2018 with the objective of preventing overlaps in scope with the ATMP GMP guidelines. Our hypothesis is that the biological nature that commonly characterizes ATMPs and biologicals may give rise to significant similarities in the manufacturing aspects as addressed by the respective guidelines. Through a comparative textual analysis of the GMP guidelines for biological medicinal products and ATMPs, this poster will highlight the key areas of similarities and differences. This analysis reveals why we have two different texts and whether they are based on substantial differences regarding production between ATMPs and other types of biological medicinal products
<figure><img src="image_48.png" /></figure>

<figure><img src="image_49.png" /></figure>

<figure><img src="image_50.png" /></figure>

<figure><img src="image_51.png" /></figure>

<figure><img src="image_52.png" /></figure>

<figure><img src="image_53.png" /></figure>

# Production of ATMPs:
## What are the specificities for quality aspects?

Aurélie Mahalatchimy<fnref n="1" />, Eloïse Gennet², Michael Morrison³, Véronique Andrieu⁴, Julie Véran⁵, Florence Sabatier⁵

## INTRODUCTION

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells and tissues that have been specifically regulated in the European Union (EU) from 2007. Their manufacturing (i.e. their production) raises specific challenges for ensuring quality and complying with regulatory requirements in order to obtain manufacturing and marketing authorizations. Hence, on top of its **guideline on the manufacturing of Biological active substances and Medicinal Products for Human Use** (26 June 2018, 25 pages revised to consider the new ATMP guidelines), the European Commission also issued **Good Manufacturing Practice specific to Advanced Therapy Medicinal Products** (22 November 2017, very detailed text of 90 pages).

Our hypothesis is that the biological nature that commonly characterizes ATMPs and biologicals may give rise to significant similarities in the manufacturing aspects as addressed by the respective guidelines. Through a comparative textual analysis of the GMP guidelines for biological medicinal products and ATMPs, this poster will highlight the key areas of similarities and differences. This analysis reveals why we have two different texts and whether they are based on substantial differences regarding production between ATMPs and other types of biological medicinal products.

## COMMON TOPICS

Seed lot
and cell
bank
system

Considerations for
microbiological risk

Hazard
identification
/risk-based
approach

Primary
containment

In-process
control

General
documentation

Retained for QC retesting

Qualified staff

Batch certification
& release

Premises and
equipment

Starting and
raw materials

### Main similarities

**Manipulation of raw and starting materials of biological origin** raising common risks and challenges of quality reproducibility and sustainability, traceability and risk of cross or exogenous contaminations (compatibility of containments, importance of process controls, strategy for initial and final certification and batch release)

**Similar spirit of the two texts**

* Crucial role of manufacturing and control processes in determining the quality

* Biological origin and related inherent variability → requested standards of quality

## SPECIFICITIES OF BIOLOGICALS VERSUS ATMPs

<table><thead><tr><th></th><th>ATMPS</th><th>BIOLOGICALS</th></tr></thead><tbody><tr><td>Specific risks</td><td colspan="2">as presented in the scopes and general principles of each text</td></tr><tr><td>Specificities for manufacturing</td><td colspan="2"></td></tr><tr><td>Stages to be considered</td><td>from raw material to final production</td><td>from raw material to active substance</td></tr><tr><td>Appropriate measures of quality control</td><td>Complexity of products & processes, limited batch series, variability of starting materials (especially in autologous setting) & Flexibility and "Risk-based approach"</td><td>Procurement and quality of starting materials of animal origin, mitigation of a higher risk of low purity and microbiological contamination, and of greater variability of biological analytical techniques & "risk quality management principles"</td></tr><tr><td>Especially control of contaminant on risk</td><td>Section dedicated to aseptic measures covering the entire process management. Rationale: Usual lack of terminal sterilization of the product requiring preventive strategies to limit the introduction of contaminants.</td><td>Provisions addressing the use of animal sources in the manufacturing process and associated contamination risk. Rationale: A large proportion of biologicals or active substances are issued from living or post-mortem animal sources versus ATMPs mostly designed based on human materials.</td></tr></tbody></table>

## DISCUSSION & CONCLUSION

Explicitly stated that the text on biologicals does not apply to ATMPs which are covered by specific guidelines, but the two texts share common aspects related to the biological nature of the product: **Relevance of having two distinct and exclusive texts?**

**Some ATMPs specific requirements may be relevant to other biologicals**

e.g., the validation of biological methods used for quality control and testing.

**Variable levels of similarities and differences**

As ATMPs are a specific category of biologicals, e.g., the "risk-based approach" for ATMPs seems matched to the "risk quality management principles" for biologicals, but the former is more prospective with the idea to anticipate and control current poorly known risks.

**Some specific Biologicals requirements may be relevant to ATMPs**

e.g., Raw materials of animal origin are poorly addressed in the ATMPs guidelines although ATMPs could also in the future be designed based on xenogeneic cells and are prone to necessitate the use of raw materials of animal origin (such as cell culture or extraction reagents etc.).

**Unclear rationale for some style/form differences**

Very different vocabulary used in the two texts while they have been adopted with a 7 months interval only, and often refer to the same ideas.

<figure><img src="image_54.png" /></figure>

<figure><img src="image_55.png" /></figure>

<figure><img src="image_56.png" /></figure>

<footnote n="1">¹Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CR), Law Faculty, UMR 7318 DICE CERIC, CNRS, Aix Marseille University, Toulon University, Aix-en-Provence, France; ²Post-doctoral Researcher in Law, Law Faculty, UMR 7318 International, Comparative and European laws (DICE) CERIC, CNRS, Aix- Marseille University, Toulon University, Aix-en-Provence, France; ³Senior Research Fellow in Social Sciences, Centre for Health Law and Emerging Technologies (HeLEX), University of Oxford, United Kingdom; ⁴Senior lecturer in Industrial Pharmacy and Pharmaceutical Regulation, Faculty of Pharmacy, Aix-Marseille University, Research Unit Microbes Evolution Physiology and Infection (MEPHI) Aix-Marseille University, IRD, France; ⁵Responsible of Cell therapy/Advanced Therapy Medicinal Products' production at Marseille Public Hospital (AP-HM), Biotherapies Clinical Investigation Center, France; ⁶Professor of Hematology and Biotherapy, Pharmaceutical Sciences Faculty, C2VN INSERM INRAe 1263 AIX Marseille University, Director of the cell therapy research centre at Marseille Public Hospital (AP-HM), France. Acknowledgements: This work has been supported by ANR-funded I-BioLex project (ANR-20-CE16-0007-01, coord. A. Mahalatchimy). M. Morrison is funded by the Leverhulme Trust through grant no RPG-2017-330.</footnote>
# The challenges of Advanced Therapy Medicinal Products manufacturing in the European Union: Strengths and limits of current regulatory tools

L.-S. GILBERT, A. DELAGE, H.-Y. KUO, A. COUTURIER, A. MAHALATCHIMY, The challenges of Advanced Therapy Medicinal Products manufacturing in the European Union: Strengths and limits of current regulatory tools, European Society for Gene & Cell Therapy Congress 2023, Brussels, Belgium, 24-27 October 2023 (POSTER available at https://shs.hal.science/halshs-04290578v1)

## Abstract

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells and tissues specifically regulated in the European Union (EU) from 2007. Any company wishing to manufacture ATMPs in the EU must hold a manufacturing authorisation issued by the national competent authority of the Member State where they carry out these activities. Ensuring the quality of medicines is a criterion to obtain ATMPs' marketing authorisation issued by the European Commission under the "centralised procedure" after a single application to the European Medicines Agency. All ATMPs marketed in the EU must be produced in accordance with EU quality standards to ensure the quality, safety and efficacy of medicines for the patients: Good Manufacturing Practice (GMP) principles and guidelines dedicated to ATMPs enforceable since 2017, and relevant parts of the European Pharmacopeia provide the main regulatory standards to comply with. The manufacture, meeting the GMP requirements from the raw materials to the final product, is particularly challenging for ATMPs regarding their level of complexity and their specific characteristics, especially the use of substances of human origin as starting materials, and the reproducibility when using live biological samples. The ATMPs' manufacturer has to maintain costly technical specifications capable of guaranteeing the reproducibility of the medicine's composition in accordance with GMP guidelines and the specific requirements of the ATMP marketing authorisation. Regulatory requirements are often seen as obstacles to the development of ATMPs. Nevertheless, they mainly provide a set of solutions to overpass the technical obstacles of ATMPs' manufacturing in order to ensure their quality for the safety of patients. It appears clearly within the various supporting regulatory tools currently available at the European level, which include both guidance documents and procedures for interactions with regulators. This poster will provide an overview of the challenges of ATMPs' manufacturing and link them to the relevant supporting regulatory tools highlighting both their strengths and their limits in the context of ATMPs development for patients.
<figure><img src="image_57.png" /></figure>

Faculté de Droit et de Science Politique
Aix-Marseille Université

<figure><img src="image_58.png" /></figure>

<figure><img src="image_59.png" /></figure>

<figure><img src="image_60.png" /></figure>

<figure><img src="image_61.png" /></figure>

I-BIOLEX

<figure><img src="image_62.png" /></figure>

<figure><img src="image_63.png" /></figure>

# The challenges of Advanced Therapy Medicinal Products manufacturing in the European Union: strengths and limits of current regulatory tools

Luc-Sylvain Gilbert¹, Auxane Delage², Dr. Hsin-Yu Kuo³, Dr. Anna Couturier⁴, Aurélie Mahalatchimy⁵

EuroGCT information Officer on Ethical, Legal & Societal issues (ELSI), Research Engineer in law, Law Faculty, UMR 7318 International, Comparative and European laws (DICE) CERIC, CNRS, AixMarseille Univ, Toulouse Univ, Aix-en-Provence, France; EuroGCT information Officer on ELSI, Research Engineer and PhD student in law, Law Faculty, UMR 7318 DICE CERIC, CNRS, Aix Marseille Univ, Toulouse Univ, Aix-en-Provence, France; EuroGCT information Officer on ATMP Product Development Pathway, Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, UK; EuroGCT Project Manager, Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, UK; EuroGCT Deputy coordinator and WP4 leader, Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CR), Law Faculty, UMR 7318 DICE CERIC, CNRS, Aix Marseille Univ, Toulouse Univ, Aix-en-Provence, France. Acknowledgments: This work has been supported by European Union's Horizon 2020 EuroGCT project (GA No 985241) and by ANR-funded I-Biolex project (ANR-20-CF26-0037-31). Contact: luc.gilbert@univ-cam.fr

## Introduction

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells & tissues specifically regulated in the European Union (EU) from 2007. All ATMPs marketed in the EU must be produced in accordance with EU quality standards to ensure the quality, safety & efficacy of medicines for the patients: Good Manufacturing Practice (GMP) principles & guidelines dedicated to ATMPs enforceable since 2017, & relevant parts of the European Pharmacopeia provide the main regulatory standards to comply with. What are the challenges of ATMPs' manufacturing & what regulatory tools address them?

**Extreme logistical complexity:** collection of patient cells, transportation to manufacturing facility, & supply of the finished ATMP to the patient's healthcare

## Challenges of ATMPs manufacturing

**Validation of the consistency of the ATMP production process:** autologous nature & small sample sizes limiting the number of analytical tests

The use of substances of human origin composed of live cells with a short shelf life from the starting point of procurement of the cellular starting material up to the final product's administration raises complex manufacturing challenges

**Maintaining sterility throughout entire manufacturing process**

**High production & development costs:**

- need for specialised premises, equipment, skilled personnel, rigorous monitoring & quality control system, linked with a relatively long-term return on investment;

- autologous cell therapies +++: need to scale-out & potential need for manufacturing at point-of-care;

- for smaller companies & academic institutions +++: lack of qualified personnel, infrastructure & capital for moving to late phase studies.

**Need for continuous monitoring & controls**

**Complex manufacturing process & regulatory approval timelines:** potential delays in patients' access to ATMPs

**Degree of variability of the finished product:** biological materials &/or complex manipulation steps, especially in autologous setting

**Demonstration of comparability between production processes & batches**

## Regulatory provisions

- **European Commission (EC) GMP guidelines for ATMPs:** EC adapted the GMP requirements for medicinal products to the specific characteristics of ATMPs & their complex manufacturing to issue mandatory guidelines for ATMPs applicable to all type of settings. The guidelines foster a risk-based approach to manufacture & testing of ATMPs, to design the organisational, technical, & structural measures to provide flexibility & ensure a high "pharmaceutical quality system" that safeguards ATMP's quality. These requirements include: Risk-based approach / Personnel / Premises / Equipment / Documentation / Starting & raw materials / Seed lot & cell bank system / Production / Qualification & validation / Qualified person & batch release / Quality control / Outsourced activities / Quality defects & product recalls / Environmental control measures for ATMPs containing or consisting of GMOS / Reconstitution of product after batch release / Automated production of ATMPs

- **European Medicines Agency (EMA)**

- **Quality flowchart on ATMPs (2021)** to help ATMPs developers navigate the most important quality requirements & foster development of ATMPs ensuring quality for the safety of patients;

- **Questions & answers on comparability considerations for ATMPs, 2019**, (EMA/CAT/499821/2019);

- **Questions & answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs, 2021**, (EMA/246400/2021);

- **Guideline on the quality, non-clinical & clinical aspects of gene therapy medicinal products, 2018**, (EMA/CAT/80183/2014);

- **Guideline on quality, non-clinical & clinical requirements for investigational advanced therapy medicinal products in clinical trials, 2019**, (EMA/CAT/852602/2018)

- **Reflection paper on design modifications of gene therapy medicinal products during development, 2011**, (EMA/CAT/GTWP/44236/2009).

- **Council of Europe European Pharmacopoeia:** quality standards & controls.

- **General principles** of ICH Q5E on 'Comparability of biotechnological/biological products subject to changes in their manufacturing process'.

## Interactions with regulators

**Interactions with EMA:** EMA scientific advice & protocol assistance to manufacturers, published common interpretation of EU GMP, & guidance helping manufacturers to navigate the complex regulatory landscape & optimise their ATMPs development & manufacturing processes.

**Innovation Task Force (ITF)**

Forum to foster early dialogue with applicants on innovative aspects in medicines development

**Priority Medicines (PRIME)**

Support for the development of medicines targeting unmet medical need

**Small & medium-sized enterprise (SME) status**

Regulatory & administrative assistance, & fee incentive for micro & SME

**Maintenance of EudraGMDP database** on manufacturing authorisations, GMP & good distribution practices, whose content is provided by national competent authorities

**Interactions with national competent authorities:** any company wishing to manufacture ATMPs in the EU must hold a manufacturing authorisation issued by the national competent authority of the Member State where they carry out these activities.

Provide support & scientific advice to ATMP's manufacturers

Conduct on-site inspections

Are responsible for the official release of the batches by the control authorities

## Conclusion / Discussion

Notwithstanding the regulatory provisions providing a set of solutions to overpass the technical obstacles of ATMPs' manufacturing, some challenges still to be addressed:

- **Due to ATMPs diversity** (from a simple progenitor cell products up to very complex ATMPs), the scientific guidelines might not always be fully applicable to a given medicinal product under development: case by case approach;

- **To avoid regulatory cost burden & imbalance for ATMPs' developers,** needs to update the European Pharmacopoeia in the gene & cell therapy field & clarify the hierarchy between these requirements & the EU provisions;

- **Multiple sites manufacturing issues involved in scaling-out production of autologous ATMPs:** to ensure the quality of the manufacturing process for each manufacturing site involved, mitigating costly transition to GMP & time-consuming confirmatory clinical qualification studies, the 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provisions on decentralised production sites potentially near to the patient. In particular, Article 142 states that by derogation "the manufacturing authorisation shall not be required for [...] the decentralised sites carrying out manufacturing or testing steps under the responsibility of the qualified person of a central site referred to in Article 151(3)";

- **Raw materials of animal origin are poorly addressed in ATMPs guidelines:** ATMPs could also in the future be designed based on xenogeneic cells & are prone to necessitate the use of raw materials of animal origin (cell culture or extraction reagents etc.). It can be anticipated that details of recommendations on animal sources warrant further considerations in ATMP guidelines as it is currently for biologicals.
<figure><img src="image_64.png" /></figure>
II
Clinical aspects
# What specificity for the clinical aspects of investigational advanced therapy medicinal products?

E. GENNET, F. SABATIER, J. VÉRAN, D. A. FATOU, N. MONGALGI, V. ANDRIEU, M. MORRISON, A. MAHALATCHIMY, What specificity for the clinical aspects of investigational advanced therapy medicinal products?, Annual Conference of the European Association of Health Law, Ghent, Belgium, 20-22 April 2022 (POSTER available at https://shs.hal.science/halshs-03780286v1)

## Abstract

While Advanced Therapy Medicinal Products (ATMPs), a European legal classification of medicinal products based on genes, cells and tissues, raise specific quality issues, the latter are particularly acute in the context of clinical trials of ATMPs. In comparison to more traditional medicinal products, ATMPs have been subject to specific regulatory provisions in the European Union (EU) since 2007. In addition, many new guidelines have also been adopted to consider the issues raised by ATMPS. Most importantly for investigational ATMPs, the European Commission has adopted and published Guidelines on Good Clinical Practice specific to ATMPs in 2019. Not only are these guidelines targeting ATMPs, they also have a dedicated section on investigational ATMPs exploring the particular challenges raised when tissues and cells of human origin, are administered to a human trial subject, including when ATMPS incorporate medical devices, or delivered with the aim of reconstituting a given bodily tissue or organ. The aim of this poster is to highlight the specificity of quality requirements of investigational ATMPs by examining the dedicated subsections in the guidelines published by the European Commission and analysing them through the lens of the corresponding scientific literature. On the basis of the identification of the specific requirements regarding the quality of investigational ATMPs, the poster will reveal why they raise specific challenges and why these challenges deserve separate regulation in order to demonstrate quality in clinical trials.
<figure><img src="image_65.png" /></figure>

Faculté de Pharmacie

Aix-Marseille Université

<figure><img src="image_66.png" /></figure>

C2VN INSERM INRAE 2631 Aix-Marseille University, Director of the cell therapy research centre at Marseille Public Hospital (AP-M), France,

<figure><img src="image_67.png" /></figure>

<figure><img src="image_68.png" /></figure>

I-BIOLEX

<figure><img src="image_69.png" /></figure>

<figure><img src="image_70.png" /></figure>

<figure><img src="image_71.png" /></figure>

<figure><img src="image_72.png" /></figure>

<figure><img src="image_73.png" /></figure>

<figure><img src="image_74.png" /></figure>

Faculté de Droit et de Science Politique

Aix-Marseille Université

# What specificity for the clinical aspects of investigational advanced therapy medicinal products?

Elöise Gennet<fnref n="1" />, Florence Sabatier², Julie Véran³, Diack Adja Fatou⁴, Nada Mongalgi⁴, Véronique Andrieu⁵, Michael Morrison⁶, Aurélie Mahalatchimy⁷

Acknowledgments: This work has been supported by ANR-funded I-BIOLEX project (ANR-20-CE25-007-01, co-ord. A. Mahalatchimy), M. Morrison is funded by the Leverkusen Trust through grant no RPG-2017-330.

## BACKGROUND AND AIM

While Advanced Therapy Medicinal Products (ATMPs), a European legal classification of medicinal products based on genes, cells and tissues, raise specific quality issues, the latter are particularly acute in the context of clinical trials and thus cannot be treated as any other medical, notably because of their manufacturing constraints and short shelf-life. In comparison to more traditional medicinal products, ATMPs have been subject to specific regulatory provisions in the European Union (EU) since 2007. In addition, many guidelines have also been adopted to consider the issues raised by ATMPs.

Clinical trials with ATMPs are generally governed by Regulation 536/2014 on clinical trials, which came into effect on 31 January 2022, as well as ICH E6 Guidelines on Good Clinical Practice (GCP). For clinical trials conducted in the EU, it is mandatory to comply with GCP. Most importantly for investigational ATMPs, the European Commission has adopted and published 2019 Guidelines on GCP specific to ATMPs, as required by Article 4 of Regulation (EC) n°1394/2007 on ATMPs. These guidelines are both adapting ICH guidelines to ATMPs characteristics and providing additional measures that have been considered necessary. However, they are not exhaustive as they explain only some specificities of ATMPs and they are complementary to the general rules. Not only are these guidelines targeting ATMPs specifically, they also have a dedicated section on the quality of investigational ATMPs.

The aim of this poster is to highlight the specificity of quality requirements of investigational ATMPs in order to reveal the specific challenges they are addressing and why these challenges deserve separate regulation in order to demonstrate quality in clinical trials.

## METHODOLOGY

The research work has consisted in examining the elements of the 2019 Guidelines from the European Commission that were dedicated to the quality of investigational ATMPs, in order to analyze them through the lens of the corresponding scientific literature.

The first stage of the research has consisted in the study of aforementioned guideline through the analysis of the general structure of the guidelines regarding the challenges covered, and a more detailed analysis of the quality aspects, especially regarding the section on the quality of investigational ATMPs. More specifically, the subsections of the guideline that were relevant to the analysis of specific quality requirements for investigational ATMPs were identified. Then, the main issues at stake for each subsection were formulated and organised by topic.

During the second stage of the research, a literature review was conducted in PudMed and Web of Science, using queries such as ["Investigational Advanced Therapy Medicinal Products"] or ["Advanced Therapy Medicinal Products" AND "Clinical Trials" [Title]]. The research generated 29 results, among which only 4 articles were selected for further content analysis, on the basis of their relevance for the study of specific quality requirements for investigational ATMPs at the EU level of governance.

At the last stage of research, analysis of the literature was compared to the results from the guideline analysis.

## RESULTS

### Main challenges for ATMPs: the design and conduct of clinical trials

Determination and size number of the cohort

Bidirectional traceability system

Benefits/Risks for the Study Population(2)

Tights controls

Scientific and ethical justification of the use of placebo

Short shelf life

Long lasting and irreversible effects

Sensitization and potential compromise of future transplant success

Specific characteristics of the product, treated disease, developmental stage of the population, Vulnerable groups such as children

Invasive procedures required to administer the ATMP or for the collection/extraction of the cells/tissues, Intrinsic variability of the starting materials, Difficulty to identify active cells,

Presence of inactive particles impacting transduction efficiency and potency,

Therapeutic effect linked to engraftment or transduction efficiency,

Dose escalation strategy not necessary or not appropriate,

Novelty and scientific uncertainties linked to the mode of action of ATMPs

End of trial and need for long-term follow-up(1)

Feasibility and ethical aspects of double blinding for the investigators and the subjects

Definition of dose range(2)

Unavailability of active comparators Definition of dose range

Choice of in vivo and in vitro models for non-clinical studies to predict safety profile (1,4)

### Conclusion

Case by case evaluation of the various aspects of the design of the early-phase ATMPs clinical trials and various levels of documentation to be provided for clinical trials authorisation

### Guidelines' specific requirements concerning the quality of experimental ATMPs

#### General considerations

Compliance with the European Commission Guidelines on Good Manufacturing Practice for Advanced Therapy Medicinal Products

#### Starting materials

- Impact of the variability of donor or patient based starting material to define release specifications for cell-based ATMPs (fer autologous product: disease status of the patient)

- Confirmation of compliance with European directives on quality and safety of human tissues and cells, and human blood and blood components for their donation, procurement and testing

- Confirmation of the traceability system's establishment with bidirectional tracking of tissues and cells from donation to administration

#### Storage, transport and handling conditions

- Detailed instructions of the reconstitution process from sponsor to the administration site:

- To specify if the reconstitution requires the use of solvents and/or other materials

- Reconstitution to be described in the Investigators Brochure or in its Annex

- For complex reconstitution process: training to be provided

#### Investigational ATMP Reconstitution before administration

- Detailed conditions from sponsor to investigator (e.g., temperature conditions)

- When short-shelf life: timelines to be clearly documented in trial records

- For handling processes: adequate training of the investigator

#### Medical devices (MD)

- MD integrated within the investigational ATMP (combined ATMP):

- Information on the characteristics, performance and intended use of MD, AND

- Compliance with the relevant MD general safety and performance requirements (Regulation 2017/745), OR justification of the MD suitability for the intended use on the basis of these requirements

- MD used with investigational ATMP (not integrated):

- Cover letter with:

- List of MD to be investigated in the clinical trial

- Statement on the existence of CE-marked for the MD intended use.

- Summary information on characteristics, performance, intended use, and regulatory status of MD

## DISCUSSION AND CONCLUSION

Many different aspects are covered in this guideline. They are **essentials to patients' well-being and product safety**. They permit to **avoid mistakes and minimize risks through the design and the conduct of clinical trials**. As such, they guide medicines' developers in the innovative sector of ATMPs.

ATMPs are innovative and more complicated than traditional or other biological drugs → precise and specific requirements which can raise logistical issues, such as the adaptation needed in terms of equipment and logistics(2).

High risks associated with the manufacturing process and the product → higher expectations for control

Many sources of variability can influence the quality of the investigational ATMPs → they should all be considered and minimized to avoid distorted results(5)

Variability can lead to the discontinuation of the clinical trial although it can also be related to a strategic decision of the sponsor, the poor recruitment of clinical trials' participants or serious adverse events(6).

For phase 1 clinical trials, quality and safety strongly overlap.

**Solution to address the challenges of quality in the context of ATMPs clinical trials: to engage in a pre-clinical trials application meeting with regulatory agencies, such ANSM as it is proposed in France** (4)

## REFERENCES

(1) European Commission, Guideline on Good Clinical Practice specific to Advanced Therapy Medicinal Products, 10 October 2019, CI2019, 7140 final.

(2) Iglesias-Lopez C, Agüiti A, Vallano A, Obach M, Methodological characteristics of clinical trials supporting the marketing authorisation of advanced therapies in the European Union. Front Pharmacol. 2021 Nov 29; 12:773712. doi: 10.3389/fphar.2021.773712.

(3) Jones DR, McIlban JA, MNaughton G, Rajakumarasamy V, Wydenbach K A. Regulatory perspective of clinical trial applications for biological products with particular emphasis on Advanced Therapy Medicinal Products (ATMPs). Br J Clin Pharmacol. 2013 Aug 76(1):203-9. doi: 10.1111/bcp.12057. PMID: 23216470; PMCID: PMCM3731595.

(4) Lucas-Samuel S, Ferry N, Trouin JH. Overview of the Regulatory Oversight implemented by the French Regulatory Authorities for the Clinical Investigation of Gene Therapy and Cell Therapy Products. Adv Exp Med Biol. 2015;871:73-85. doi: 10.1007/978-3-319-18618-4_4. PMID: 26374213.

(5) Hanna E, Fémazat C, Auguier P, Toumi M. Risk of discontinuation of Advanced Therapy Medicinal Products clinical trials. J Mark Access Health Policy. 2016 Aug 24. doi: 10.3402/jmaph.v4.32232. PMID: 27570614; PMCID: PMCM497342.

(6) European Commission, Guidelines of 22 November 2017 on Good Manufacturing Practice for Advanced Therapy Medicinal Products, CI2017 7694.

(7) Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC; OJ L 33, 8.2.2003, p. 30-40. CELEX number: 32002:0098.

(8) Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, OJ L 102, 7.4.2004, p. 48-58. CELEX number: 32004L0023.

<figure><img src="image_75.png" /></figure>

<footnote n="1">¹Post-doctoral Researcher in Law, Law Faculty, UMR 7318 International, Comparative and European laws (DICE) CERIC, CNRS, Aix-Marseille University, Toulon University, Pa & Pays de la Dordure University, Aix-en-Provence, France. ²Professor of Hematology and Biotherapy, Pharmaceutical Sciences Faculty, C2VN INSERM INRAE 2631 Aix-Marseille University, Director of the cell therapy research centre at Marseille Public Hospital (AP-M), France. ³Responsible of Cell Therapy/Advanced Therapy Medicinal Products' production at Marseille Public Hospital (AP-M), Biotherapies Cliniques Investigation Centrale, France. ⁴Students in 4th year of Pharmaceutical Sciences, Aix-Marseille University, France. ⁵Senior acteur in Industrial Pharmacy and Pharmaceutical Regulation, Quality of Pharmacy, Aix-Marseille University, Research Unit Microbiology Evolution Pathology and Infection (MEPH), Aix-Marseille University, IRG, France. ⁶Senior Research Fellow to Social Sciences, Centre for Health Law and Emerging Technological Fields (HELD), University of Oxford, United Kingdom. ⁷Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CRI, Law Faculty, UMR 7313 DICE CERIC, CNRS, Aix-Marseille University, Pa & Pays de la Dordure University, Aix-en-Provence, France.</footnote>
# Specific guidelines requirements for clinical trials with Advanced Therapy Medicinal Products in the European Union

A. MAHALATCHIMY, E. GENNET, M. MORRISON, V. ANDRIEU, J. VÉRAN, F. SABATIER, Specific guidelines requirements for clinical trials with Advanced Therapy Medicinal Products in the European Union, European Society for Gene & Cell Therapy Congress 2022, Edinburgh, the UK, 11-14 October 2022 (POSTER available at https://shs.hal.science/halshs-03901386v1);

Abstract published in Human Gene Therapy, Volume: 33 Issue 23-24: December 14, 2022, A1-A212. http://doi.org/10.1089/hum.2022.29225.abstracts

## Abstract

Advanced Therapy Medicinal Products (ATMPs), a European legal classification of medicinal products based on genes, cells and tissues, raise specific issues in the context of clinical trials. In comparison to more traditional medicinal products, ATMPs have been subject to specific regulatory provisions in the European Union (EU) since Regulation (EC) n1394/2007. Yet for the clinical trials with ATMPs, the general regime laid out in Regulation 536/2014 on clinical trials (which came into effect on 31 January 2022) applies, together with the ICH E6 Guidelines on Good Clinical Practice (GCP). For clinical trials conducted in the EU, compliance with GCP is mandatory. The European Commission has also adopted and published 2019 Guidelines on GCP specific to ATMPs, as required by Article 4 of Regulation (EC) n1394/2007 on ATMPs. These guidelines both adapt the ICH guidelines to ATMPs' characteristics and provide additional measures that have been considered necessary. However, they are not exhaustive as they explain only some specificities of ATMPs and they remain complementary to the general rules. After having analysed these documents, we will highlight the specificity of requirements for investigational ATMPs in order to reveal the specific challenges they are addressing and why these challenges warrant separate regulation in order to obtain clinical trials' authorisation for investigational ATMPs.
<figure><img src="image_76.png" /></figure>

Faculté
de Pharmacie
Aix-Marseille Université

<figure><img src="image_77.png" /></figure>

Inserm

C2VN
Contribution du CNRS

<figure><img src="image_78.png" /></figure>

<figure><img src="image_79.png" /></figure>

AP-HM

<figure><img src="image_80.png" /></figure>

I-BIOLEX

<figure><img src="image_81.png" /></figure>

<figure><img src="image_82.png" /></figure>

<figure><img src="image_83.png" /></figure>

<figure><img src="image_84.png" /></figure>

<figure><img src="image_85.png" /></figure>

Faculté de Droit et de Science Politique
Aix-Marseille Université

# Specific guidelines requirements for clinical trials with Advanced Therapy Medicinal Products in the EU

Aurélie Mahalatchimy<fnref n="1" />, Eloïse Gennet², Michael Morrison³, Véronique Andrieu⁴, Julie Véran⁵, Florence Sabatier⁶

## INTRODUCTION

Advanced Therapy Medicinal Products (ATMPs), a European legal classification of medicinal products based on genes, cells and tissues, raise specific issues in the context of clinical trials (CT). Several normative instruments apply at the European level (see table opposite). The 2019 guidelines from the European Commission on Good Clinical Practice (GCP) both adapt the ICH E6 to ATMPs' characteristics and provide necessary additional measures. However, they are not exhaustive as they explain only some specificities of ATMPs and they remain complementary to the general rules. We will highlight the specific requirements for investigational ATMPs (ATIMPs) to reveal the particular challenges they are addressing and why these challenges warrant separate regulation in order to obtain CT' authorisation for ATIMPs and potentially for further marketing authorisation application (MAA).

### Clinical trials design

1. **Study population**
   **ATMPs characteristics** > Subjects' risks & benefits, interpretable data

2. **Cohorts**
   **Limited manufacturing capacity** > Staggered treatment

3. **Comparators**
   **No active comparator** > Best standard of care, or intra-subject control

4. **Blinding**
   **Double blinding unethical/ unfeasible** > For subjects' where possible; blinded observers if unblinded investigator

5. **Placebo**
   **Invasive procedures** > No more than minimal risk/burden for control groups

6. **Dosing**
   **Identifying active cells; inactive particles with impact; dose variation of cells numbers; complex dosing** > For long-term effects, dose escalation & repeated dosing Or exploratory dose = therapeutic dose

7. **Trial end**
   **Potential need for long-term follow-up** > Clearly defined event marking trial end

### Quality

1. **General considerations**
   **ATMPs characteristics** > Compliance with GMP for ATMPs

2. **Starting materials**
   **Variability** > Compliance with directives on blood and cells/tissues; Traceability system's with bidirectional tracking

3. **Storage, transport & handling conditions**
   **e.g., temperature, short-shelf life** > Timelines in trial records; Investigator's training

4. **Reconstitution before administration**
   **Potentially complex** > use of solvents and/or other materials?; Training

5. **Medical devices (MD)**
   **Combined ATIMP** > MD characteristics, performance and intended use + MD Regulation Compliance OR justification of MD suitability for intended use
   **MD used with ATIMP** > List of investigated MD; statement on CE-marked MD; MD characteristics, performance, intended use, and regulatory status

### Upstream intervention on subjects and administration procedures

1. **General**
   **In autologous setting, deviation from standard clinical practice** >
   * Subjects' risks + impact on product quality and safety;
   * Procedure complexity and novelty > Adapted level of documentation; Training

2. **Traceability**
   * If human origin Cells/tissues > Bidirectional traceability system (anonymous coding); 30 years data keeping; Role and responsibilities of manufacturer, sponsor and investigator & location of traceability records to be documented

3. **Retention of samples**
   **Materials' scarcity** > Autologous ATMPs and certain allogeneic ATMPs: justified not to keep samples; Possible sampling strategy adaptation:

* Short shelf-life > Shorter retention period; Manufacturer to consider conditions for prolonging shelf-life;
   * Samples cannot be kept > Retained label Photographs or copies

### Monitoring

#### Human origin of cells/tissues >

Traceability requirements/long-term follow-up arrangements compliance; For ATMPs, accountability records kept at CT site, possible requirement of adaptation of study requirements' form, records reflecting ATMPs specificities

## ATMPs Guidelines content and potential challenges targeted

### Information in Investigator Brochure and Protocol

**Placebo:** Procedure's risk

**Dosing:** For complex dosing ATMPs, adequate level of understanding & compliance by investigator and those involved in CT

**End of trial:** how follow-up activities will be performed after end of trial

**Product information in IB:**

- product risks;

- previous/ concomitant (or required further treatments) potential impact;

- treatment failure risk;

- emerging issues

**Risk minimization measures:** Where appropriate, measures to protect CT subjects from identified risks:

**Quality:** reconstitution before administration: Description of Reconstitution

**Upstream interventions on subjects and administration procedures:** Detailed instructions, possibly in separate document available at site if attached as Annex

**Long-term follow-up general principles & remote follow-up:**

- Follow-up scheme & after trial follow-up activities;

- Detailed arrangements for remote conduct of follow-up;

- How to ensure collected data quality

<table><thead><tr><td>Text</td><td>General</td><td>ATMPs</td></tr></thead><tbody><tr><td>Level</td><td>Regulation</td><td>Regulation</td></tr><tr><td>Legal</td><td>536/2014 on clinical trials</td><td>1394/2007 on ATMPs</td></tr><tr><td>Regulatory guidelines</td><td>ICH E6 on GCP</td><td>Specific GCP</td></tr></tbody></table>

### Administration of out of specifications products

#### Variability in ATMPs nature >

Exceptionally to avoid immediate significant hazard; manufacturer/ sponsor to provide risks evaluation; records of request kept in manufacturing site; relevant authority to be notified

### Non-clinical studies

**Safety:** Incompatibility between human & animal species > Case by case assessment of non-clinical data

### CT Safe conduct

1. **ATIMP Handling**
   **Infectious biological material** > Handling and disposal detailed instructions
   **Bacterial/viral vector with shedding potential** > Risks and precautionary measures for subject and/or caregivers

**Risks for health care professionals** > Risk minimization measures

2. **Risk minimization measures**
   **e.g. No sterility test result at product release; CT subject risk of cytokine release syndrome** > Mitigation measures; Information to Investigator on measures before treatment

### Long-term follow up

1. **General principles**
   **Safety profile not fully elucidated** > Duration of ATMP biological activity; long term follow-up scheme; Length of observation period; relevance of other product bibliographic data: not required if low risk of delayed adverse events; monitoring of CT subject follow-up in MAA

2. **Remote follow-up**
   **e.g. distance from residence** > Gathering data process; Sponsor responsible for adverse events collection robust system; Writing of each party involved responsibilities; Collected data centralisation & availability for inspection at CT site

3. **Premature end or termination**
   Specificities where CT subjects will and foreseen long-term follow-up

4. **Patient card alerts**
   For CT subjects depending on ATMPs characteristics to inform treating physicians to facilitate medical care in case of emergency & reporting of adverse events

### Protection of CT subjects

#### Uncertainties, novelty... >

**Informed consent:** CT participant information on all risks, e.g., treatment failure, irreversible ATIMP nature...

### Safety reporting

**ATMPs characteristics** > **safety concerns** > Adapted reporting forms & data capture systems; List of safety issues; Sponsor to provide information/training to investigator for adverse events reporting; Foreseen long-term follow-up to include reporting of adverse events

## CONCLUSION

Very useful ATMPs specific guidelines for clinical trials covering many different aspects and all currently identified challenges
Necessary case by case evaluation of the various aspects of ATIMPs clinical trials mainly due to variability of starting materials and specific characteristics of each ATMP. Various levels of justification and documentation to be provided for clinical trials authorization
→ Particularly relevant to engage in a pre-CT application meeting with regulatory agencies, such as the French National Agency (ANSM) as it is proposed in France

**REFERENCES**

European Commission, Guideline on Good Clinical Practice specific to Advanced Therapy Medicinal Products, 10 October 2019, C(2019) 7140 Final

Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004

European Commission, Guidelines of 22 November 2017 on Good Manufacturing on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, OJ L 102, Practice for Advanced Therapy Medicinal Products, C(2017)7694

Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003, 7.4.2004, p. 48-58

<figure><img src="image_86.png" /></figure>

<figure><img src="image_87.png" /></figure>

<footnote n="1">¹Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CR), Law Faculty, UMR 7318 DICE CERIC, CNRS, Aix Marseille Univ., Toulon Univ., Aix-en-Provence, France; ²Post-doctoral Researcher in Law, Law Faculty, UMR 7318 International, Comparative and European laws (DICE) CERIC, CNRS, Aix-Marseille Univ., Toulon Univ., Aix-en-Provence, France; ³Senior Research Fellow in Social Sciences, Centre for Health Law and Emerging Technologies (HeLEX), Oxford Univ., UK; ⁴Senior lecturer in Industrial Pharmacy and Pharmaceutical Regulation, Faculty of Pharmacy, Aix-Marseille Univ., Research Unit Microbes Evolution Physiology and Infection (MEPHI) Aix-Marseille Univ., IRD, France; ⁵Responsible of Cell therapy/Advanced Therapy Medicinal Products' production at Marseille Public Hospital (AP-HM), France; ⁶Professor of Hematology and Biotherapy, Pharmaceutical and Biotechnology, French Medicines Agency, C2VN INSERM INRAe 1263 AIX Marseille Univ., Director of the cell therapy research centre at Marseille Public Hospital (AP-HM), France. Acknowledgements: This work has been supported by ANR-funded I-Biolex project (ANR-20-CE26-0007-01, coord. A. Mahalatchimy). M. Morrison is funded by the Leverhulme Trust through grant no RPG-2017-330.</footnote>
<figure><img src="image_88.png" /></figure>
## III

**Market Access/**
**Hospital Exemption**
# The Marketing Authorisation of Advanced Therapy Medicinal Products in the European Union

A. MAHALATCHIMY, L.-S. GILBERT, A. DELAGE, O. NÈGRE, The Marketing Authorisation of Advanced Therapy Medicinal Products in the European Union, International Society for Cell & Gene Therapy 2023 Paris Annual Meeting, Paris, France, 31 May-3 June 3 2023 (POSTER available at https://shs.hal.science/halshs-04290539v1);

Abstract published in Cytotherapy Volume 25, Issue 6, Supplement, May 2023, Pages S160-S161. https://doi.org/10.1016/S1465-3249(23)00433-4

## Abstract

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells and tissues specifically regulated in the European Union (EU) from the entry into force of Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on ATMPs. Any company wishing to market ATMPs within the EU must hold a Marketing Authorisation (MA) issued by the European Commission under the "centralised procedure", after a single application to the European Medicines Agency (EMA) and its scientific assessment by the Committee for Advanced Therapies. The purpose of the MA is to ensure high quality, safety and efficacy for ATMPs, with a positive risk-benefit balance, to be commercialised. The MA is valid in the EU Member States, Iceland, Norway and Liechtenstein for a five-years period. From the adoption of the EU regulation, 24 ATMPs have been granted a marketing authorisation in the EU and the European Commission decision is pending for another one. There has been a clear increase in approvals from 2018, and most approved ATMPs are gene therapy medicinal products. Almost half of them benefited from expediting pathways or regulatory support schemes for (innovative) medicines to be commercialised in the EU. Nevertheless, MA has been withdrawn or not renewed for 7 of them. This poster will present the European regulatory requirements and pathways for ATMPs to obtain marketing authorisation, and discuss the challenges of their commercialisation.
<figure><img src="image_89.png" /></figure>

<figure><img src="image_90.png" /></figure>

<figure><img src="image_91.png" /></figure>

<figure><img src="image_92.png" /></figure>

<figure><img src="image_93.png" /></figure>

<figure><img src="image_94.png" /></figure>

<figure><img src="image_95.png" /></figure>

# The marketing authorisation of Advanced Therapy Medicinal Products under the regulation of the European Union

Aurélie Mahalatchimy<fnref n="1" />, Luc-Sylvain Gilbert², Auxane Delage³, Olivier Négre⁴

## BACKGROUND & AIM

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells and tissues specifically regulated in the European Union (EU) from the entry into force of Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on ATMPs.

Any company wishing to market ATMPs within the EU must hold a Marketing Authorisation (MA) issued by the European Commission under the "centralised procedure" (CP), after a single application to the European Medicines Agency (EMA) and its scientific assessment involving notably the Committee for Advanced Therapies (CAT). The purpose of the MA is to ensure high quality, safety and efficacy for ATMPs, with a positive risk-benefit balance, to be commercialised.

The CP is the standard procedure to allow MA holders to market ATMPs throughout the EU. The MA shall be refused, suspended or withdrawn if the quality and the safety of the ATMPs is insufficient and if the risk-benefit balance is not favourable. Moreover, expediting MA pathways and regulatory tools have been developed to provide more flexibility and accelerate ATMPs access to the market while other pathways exist for patients to access ATMPs without MA. The latter are alternative to standard CP and possible under strict conditions only.

## STANDARD MA

Expensive and time-consuming process which can delay patients' access to ATMPs although provides a wider market access

CAT opinion

Scientific assessment process

EMA

CHMP
recommendation

Initial assessment and list of question up to 120 days - Clock step 1 - Further assessment and list of outstanding issues by 180 days - Clock step 2 - Further consultations and final recommendation by day 210

European
Commission
decision

MA for 5 years:
binding in all
Member States +
EEA countries

CHMP: Committee for Medicinal Products for Human Use, EEA: European Economic Area

## PROCEDURES AND PROGRAMMES FOR EARLIER ACCESS

### EXPEDITING MARKETING AUTHORISATION PATHWAYS

<table><thead><tr><th></th><th>Accelerated Assessment (AA)</th><th>Conditional MA</th><th>MA under Exceptional Circumstances</th></tr></thead><tbody><tr><th>Basis</th><td>Article 14(9) Reg 726/2004</td><td>Article 14a Reg 726/2004</td><td>Article 14(8) Reg 726/2004</td></tr><tr><th>What</th><td>Assessment time for MA ≤ 150 days</td><td>Less complete data</td><td>Inability to provide comprehensive safety & efficacy data for objective & verifiable reasons</td></tr><tr><th>Why</th><td></td><td>Early access</td><td></td></tr><tr><th>How</th><td>Major interest for public health (unmet medical needs)<br>Standard MA criteria</td><td>Seriously debilitating or life-threatening diseases, emergency situations, orphan drugs, unmet medical needs<br>Standard MA criteria</td><td>Rare condition or collection of full information or data is not possible in the state of scientific knowledge or unethical</td></tr><tr><th>Who</th><td></td><td>MA Applicant to European Medicines Agency</td><td></td></tr><tr><th>When</th><td>Before submission of MA BUT to be discussed earlier via PRIME</td><td>Before submission of MA BUT to be discussed earlier via scientific advice / protocol assistance</td><td></td></tr></tbody></table>

### SPECIFIC REGULATORY SCHEMES

<table><thead><tr><th></th><th>PRIME</th><th>ATMP PILOT for academia & non-profit organisations</th></tr></thead><tbody><tr><th>What</th><td>An enhanced interaction & early dialogue to optimise development plans & speed-up evaluation of promising medicines</td><td>Enhanced regulatory support for up to five selected ATMPs to optimise their development</td></tr><tr><th>Why</th><td>To support medicine development</td><td>To support translation of basic research into medicine</td></tr><tr><th>Criteria</th><td></td><td>Unmet/high medical need</td></tr><tr><th>How</th><td>Fostering early dialogue to improve clinical trials designs</td><td>Guiding through the regulatory process</td></tr><tr><th>Who</th><td>Potential candidate for AA to dedicated person at EMA</td><td>Academic/Non-profit<br>ATMP developers to national competent authority or EMA</td></tr><tr><th>When</th><td>Use of existing routes of approval, especially AA<br>Clinical stages of development<br>(or earlier for academics and SMEs)</td><td>Possible to use existing support scheme (e.g., PRIME)<br>Early stages of development (from best practice principles for manufacturing to planning clinical developments)</td></tr></tbody></table>

SME: Small and Medium Enterprises, PRIME: Priority medicines

### OTHER PATHWAYS FOR PATIENTS' ACCESS TO ATMPS

<table><thead><tr><th></th><th>Compassionate use:<br>Groups of patients</th><th>Compassionate use:<br>Named-patients basis</th><th>ATMP Hospital Exemption</th></tr></thead><tbody><tr><th>Basis</th><td>Article 83 of Regulation 726/2004</td><td>Article 5.1 of Directive 2001/83/EC</td><td>Article 28.2 of Regulation 1394/2007</td></tr><tr><th>What</th><td>Under strict condition for seriously ill groups of patients (life-threatening, long-lasting or seriously debilitating illnesses), Undergoing clinical trials or MAA process</td><td>For a bona fide unsolicited order, with specifications of an authorised healthcare professional, & for use by an individual patient</td><td>ATMP prepared on a non-routine basis, specific quality standards, & used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, to comply with an individual medical prescription</td></tr><tr><th>Why</th><td>To facilitate & improve access to compassionate use programmes</td><td>To fulfil special needs of patients, including without ongoing clinical trials</td><td>To enable patients to receive ATMPs under controlled conditions</td></tr><tr><th>How</th><td>EMA/CHMP recommendations & national rules</td><td>National rules</td><td>National rules but traceability & pharmacovigilance requirements and quality standards equivalent to ATMPs going through the MA pathway</td></tr><tr><th>Who</th><td>National competent authority to EMA & Applicant to National competent authority</td><td>Applicant to National competent authority</td><td>Applicant to National competent authority</td></tr></tbody></table>

## The 25 authorised ATMPs in the EU

<table><thead><tr><th>Name</th><th>Type</th><th>Domain</th><th>MA Year</th><th>MA Type</th><th>Current status</th></tr></thead><tbody><tr><td>Chandra/Collect</td><td>TEP</td><td>Orthopaedic</td><td>2009</td><td>Standard</td><td>Withdrawn, 29-07-2016</td></tr><tr><td>Glybera</td><td>GTMP</td><td>Gastrology</td><td>2012</td><td>Exceptional</td><td>Withdrawn, 28-10-2017</td></tr><tr><td>MACI</td><td>Comb. TEP</td><td>Orthopaedic</td><td>2013</td><td>Standard</td><td>Withdrawn, I-7-20B</td></tr><tr><td>Provence</td><td>CTMP</td><td>Oncology</td><td>2013</td><td>Standard</td><td>Withdrawn, 6-5-2015</td></tr><tr><td>Holoclar</td><td>TEP</td><td>Ophthalmology</td><td>2015</td><td>Conditional</td><td>Positive</td></tr><tr><td>Imhygic</td><td>GTMP</td><td>Oncology</td><td>2016</td><td>Standard</td><td>Positive</td></tr><tr><td>Strimvelis</td><td>GTMP</td><td>Immunology</td><td>2016</td><td>Standard</td><td>Positive</td></tr><tr><td>Zalmoxie</td><td>CTMP</td><td>Graft vs. host</td><td>2016</td><td>Conditional</td><td>Withdrawn, 9-10-2010</td></tr><tr><td>Spharos</td><td>TEP</td><td>Orthopaedic</td><td>2017</td><td>Standard</td><td>Positive</td></tr><tr><td>Alofisel</td><td>TEP</td><td>Gastrology</td><td>2018</td><td>Standard</td><td>Positive</td></tr><tr><td>Yescarta</td><td>GTMP</td><td>Immunocellular cancer</td><td>2018</td><td>Standard (PRIME)</td><td>Positive</td></tr><tr><td>Kymriah</td><td>GTMP</td><td>Immunocellular cancer</td><td>2018</td><td>Standard (PRIME)</td><td>Positive</td></tr><tr><td>Luxturna</td><td>GTMP</td><td>Ophthalmology</td><td>2018</td><td>Standard</td><td>Positive</td></tr><tr><td>Zynteglo</td><td>GTMP</td><td>Beta-Thalassemia</td><td>2019</td><td>Conditional/Accelerated (PRIME)</td><td>Withdrawn, 24-3-2022</td></tr><tr><td>Zoigensmo</td><td>GTMP</td><td>Muscular Atrophy</td><td>2020</td><td>Conditional/Accelerated (PRIME)</td><td>Positive</td></tr><tr><td>Lipemely</td><td>GTMP</td><td>Laukodystrophy, Metachromatic</td><td>2020</td><td>Accelerated</td><td>Positive</td></tr><tr><td>Tecartus</td><td>GTMP</td><td>Lymphoma, Mantle-Cell</td><td>2020</td><td>Conditional/Accelerated (PRIME)</td><td>Positive</td></tr><tr><td>Skysona</td><td>GTMP</td><td>Cerebral adrenia leuka-dystrophy</td><td>2021</td><td>Accelerated (PRIME) reverted to Standard</td><td>Withdrawn, 18-11-2021</td></tr><tr><td>Abecma</td><td>GTMP</td><td>Cancer of plasma cells</td><td>2021</td><td>Conditional/Accelerated (PRIME)</td><td>Positive</td></tr><tr><td>Breyanzi</td><td>GTMP</td><td>Blood cancer</td><td>2022</td><td>Accelerated (PRIME)</td><td>Positive</td></tr><tr><td>Upstaza</td><td>GTMP</td><td>Amino Acid Metabolism, Inborn Errors</td><td>2022</td><td>Exceptional</td><td>Positive</td></tr><tr><td>Carvrykli</td><td>GTMP</td><td>Multiple Myeloma cancer of the bone marrow</td><td>2022</td><td>Conditional (PRIME)</td><td>Positive</td></tr><tr><td>Roctavian</td><td>GTMP</td><td>Haemophilia A</td><td>2022</td><td>Conditional</td><td>Positive</td></tr><tr><td>Ebvalio</td><td>CTMP</td><td>Lymphoplasmolytic Disorders</td><td>2022</td><td>Exceptional (PRIME)</td><td>Positive</td></tr><tr><td>Hemigenix</td><td>GTMP</td><td>Haemophilia B</td><td>2023</td><td>Conditional (PRIME)</td><td>Positive</td></tr></tbody></table>

Latest update - March 2023, TEP: Tissue Engineered Product, GTMP: Gene Therapy Medicinal Product, CTMP: Cell Therapy Medicinal Product, MA: Marketing Authorisation

## RESULTS

* Clear increase in approvals from 2018

* Most approved ATMPs are gene therapy medicinal products

* Half of authorised ATMPs benefited from expediting pathways or regulatory support schemes for innovative medicines

## CONCLUSION

Even if the EU supports and fosters ATMPs' research, development, and access to market with regulatory tools, patients access to effective and affordable ATMP is limited by the high average cost per patient, the withdrawal of authorised ATMPs from MA holder mostly for commercial reasons, and the differences between healthcare systems and reimbursement strategies of the different Member States.

Although the standard procedure and the expediting MA pathways provide the widest commercialisation of ATMPs in Europe, patients' access to ATMPs is dependent on MA granting and on the MA holder strategy to make the product available in Europe. The latter is linked to the agreement(s) on pricing and reimbursement to provide affordable ATMPs as well as an acceptable financial benefit, including return on investment, for the MA holder.

Patients can also access ATMPs, thanks to other pathways, alternative to MA and possible under strict conditions only. However, depending on how these other pathways can be used according to the applicable national heterogeneous rules (e.g., hospital exemption), they could also lead to unfair competition regarding the high requirements for MA granting.

<footnote n="1">¹EuroGCT Deputy coordinator and WP4 leader, Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CR), Law Faculty, UMR 7318 International, Comparative and European laws (DICE), CNRS, Aix Marseille Univ., Toulouse Univ., Aix-en-Provence, France; ²EuroGCT Information Officer on ELSI Research Engineer in law, Law Faculty, UMR 7318 DICE CERIC, CNRS, Aix Marseille Univ., Toulouse Univ., Aix-en-Provence, France; ³BioTherapy Partners Paris, France, EuroGCT Member of The General Committee, Management Group Deputy Coordinator, WP4 Co-Leader, Board Member of the French Society of Cell and Gene Therapy (SFECG), Chief Scientific Officer at Smart Immune, Expert in Cell and Gene Therapy.</footnote>

<footnote>Acknowledgments: This work has been supported by the European Union's Horizon 2020 research and innovation programme (GA No 665241) and by ANR-funded i-Biolex project (ANR-20-CE26-0007-01).</footnote>
# Expediting marketing authorization pathways for patients' access to advanced therapies

V. ROBY, L.-S. GILBERT, V. BRUNEL, A. DELAGE, A. MAHALATCHIMY, Expediting marketing authorization pathways for patients' access to advanced therapies, EAHL 2024, 18-20 September 2024, Warsaw, Poland (POSTER available at https://shs.hal.science/halshs-04842656v1)

## Abstract

Medicinal products based on genes, cells and tissues of human or animal origin are being developed to treat severe diseases that conventional treatments have failed to treat or that have no available and satisfactory treatments, such as rare, genetic, or neurodegenerative diseases.

The risks they raise as innovative and complex medicines but also the therapeutic promises they offer have led to their specific regulation as Advanced Therapy Medicinal Products (ATMPs) in the European Union (EU). Indeed, they are especially submitted to the centralised procedure of Marketing Authorisation (MA) issued by the European Commission. This procedure aims not only to ensure high quality, safety and efficacy for ATMPs with a positive risk-benefit balance to be commercialised, but also a wide access to these medicines for EU patients. Nevertheless, this procedure alone is not always sufficient to allow the commercialisation of ATMPs, and many of them require expediting pathways or regulatory support schemes for innovative medicines to be commercialised. From the adoption of the EU regulation, 25 ATMPs have been granted a MA in the EU. Although there has been a clear increase in approvals from 2018, MA has been withdrawn or not renewed for 7 of them.

Starting from the centralised procedure as the strongest and first legal procedure for the widest and safest patients access to these innovative medicines, this poster will provide an overview of the European MA expediting pathways and of their use, for ATMPs to be accessible, and discuss the challenges of their quick but safe commercialisation.
# The expediting marketing authorisation pathways for patients' access to advanced therapies

Valentin Roby<fnref n="1" />, Luc-Sylvain Gilbert², Valentin Brunel³, Auxane Delage⁴, Aurélie Mahalatchimy⁵

## BACKGROUND & AIM

Medicinal products based on genes, cells and tissues of human or animal origin are being developed to treat severe diseases that conventional treatments have failed to treat or that have no available and satisfactory treatments, such as rare, genetic, or neurodegenerative diseases.

The risks they raise as innovative and complex medicines but also the therapeutic promises they offer have led to their specific regulation as Advanced Therapy Medicinal Products (ATMPs) in the European Union (EU). ATMPs include 4 legal sub-categories: Cell-therapy medicinal products (CTMP), Gene therapy medicinal products (GTMP), Tissue engineered products (TEP) and Combined (Comb.) ATMPs. They are especially submitted to the centralised procedure of Marketing Authorisation (MA) issued by the European Commission. This procedure aims not only to ensure high quality, safety and efficacy for ATMPs with a positive risk-benefit balance to be commercialised, but also a wide access to these medicines for EU patients. To date, 26 ATMPs have been granted a MA in the EU. Nevertheless, this procedure alone is not always sufficient to allow the commercialisation of ATMPs and many of them require expediting pathways or regulatory support schemes for innovative medicines to be commercialised.

What are these expediting pathways and how much have they been used for ATMPs?

## Overview of the 26 authorised ATMPs in the EU

<table><thead><tr><th>Name</th><th>Type</th><th>Domain</th><th>MA Year</th><th>Current status</th></tr></thead><tbody><tr><td>ChondroCelect</td><td>TEP</td><td>Orthopaedic</td><td>2009</td><td>Withdrawn, 29/07/2016</td></tr><tr><td>Glybera</td><td>GTMP</td><td>Gastrology</td><td>2012</td><td>Withdrawn, 28/10/2017</td></tr><tr><td>MACI</td><td>Comb. TEP</td><td>Orthopaedic</td><td>2013</td><td>Withdrawn, 01/07/2018</td></tr><tr><td>Provenge</td><td>CTMP</td><td>Oncology</td><td>2013</td><td>Withdrawn, 06/05/2015</td></tr><tr><td>Holoclar</td><td>TEP</td><td>Ophthalmology</td><td>2015</td><td>Positive</td></tr><tr><td>Imlygic</td><td>GTMP</td><td>Oncology</td><td>2015</td><td>Positive</td></tr><tr><td>Strimvelis</td><td>GTMP</td><td>Immunology</td><td>2016</td><td>Positive</td></tr><tr><td>Zalmaxis</td><td>CTMP</td><td>Graft. vs. host</td><td>2016</td><td>Withdrawn, 09/10/2019</td></tr><tr><td>Spherox</td><td>TEP</td><td>Orthopaedic</td><td>2017</td><td>Positive</td></tr><tr><td>Aloisel</td><td>CTMP</td><td>Gastrology</td><td>2018</td><td>Positive</td></tr><tr><td>Yescarta</td><td>GTMP</td><td>Immunocellular cancer</td><td>2018</td><td>Positive</td></tr><tr><td>Kymriah</td><td>GTMP</td><td>Immunocellular cancer</td><td>2018</td><td>Positive</td></tr><tr><td>Luxturna</td><td>GTMP</td><td>Ophthalmology</td><td>2018</td><td>Positive</td></tr><tr><td>Zynteglo</td><td>GTMP</td><td>Beta-Thalassemia</td><td>2019</td><td>Withdrawn, 24/03/2022</td></tr><tr><td>Zolgensma</td><td>GTMP</td><td>Muscular Atrophy</td><td>2020</td><td>Positive</td></tr><tr><td>Libmeldy</td><td>GTMP</td><td>Metachromatic Leukodystrophy</td><td>2020</td><td>Positive</td></tr><tr><td>Tecartus</td><td>GTMP</td><td>Lymphoma, Mantle-Cell</td><td>2020</td><td>Positive</td></tr><tr><td>Skysona</td><td>GTMP</td><td>Cerebral adreno leuko-dystrophy</td><td>2021</td><td>Withdrawn, 18/11/2021</td></tr><tr><td>Abecma</td><td>GTMP</td><td>Multiple Myeloma cancer of the bone marrow</td><td>2021</td><td>Positive</td></tr><tr><td>Breyanzi</td><td>GTMP</td><td>Blood cancer</td><td>2022</td><td>Positive</td></tr><tr><td>Carvykki</td><td>GTMP</td><td>Multiple Myeloma cancer of the bone marrow</td><td>2022</td><td>Positive</td></tr><tr><td>Upstaza</td><td>GTMP</td><td>Amino Acid Metabolism, Inborn Errors</td><td>2022</td><td>Positive</td></tr><tr><td>Roctavian</td><td>CTMP</td><td>Haemophilia A</td><td>2022</td><td>Positive</td></tr><tr><td>Ebyvallo</td><td>CTMP</td><td>Lymphoprofilerative Disorders</td><td>2022</td><td>Positive</td></tr><tr><td>Hemgenix</td><td>GTMP</td><td>Haemophilia B</td><td>2023</td><td>Positive</td></tr><tr><td>Casgevy</td><td>GTMP</td><td>Beta-Thalassemia and sickle cell disease</td><td>2024</td><td>Positive</td></tr></tbody></table>

<figure><img src="image_96.png" /><figcaption>Fig. 1. Authorised ATMPs by legal sub-categories</figcaption></figure>

<figure><img src="image_97.png" /><figcaption>Fig. 2. Country of ATMPs MA holders</figcaption></figure>

## Expediting pathways

<figure><img src="image_98.png" /></figure>

## Regulatory Support schemes

<figure><img src="image_99.png" /></figure>

## RESULTS

* Clear increase in approvals from 2018 in various medical domains

* Most approved ATMPs are gene therapy medicinal products

* NL, where is established the European Medicines Agency from Brexit, and IE are the countries of most of MA holders among the authorised ATMPs

* Half of authorised ATMPs benefited from expediting pathways or regulatory support schemes for innovative medicines

* BUT MA withdrawn or not renewed for 7 ATMPs out of 26 authorized ATMPs

## DISCUSSION/CONCLUSION

Even if the EU supports and fosters ATMPs' research, development, and access to market with regulatory tools, patients access to effective and affordable ATMP is limited by the high average cost per patient, the withdrawal of authorised ATMPs from MA holder mostly for commercial reasons, and the differences between healthcare systems and reimbursement strategies of the different Member States.

Although the standard procedure and the expediting MA pathways provide the widest commercialisation of ATMPs in Europe, patients' access to ATMPs is dependent on MA granting and on the MA holder strategy to make the product available in Europe. The latter is linked to the agreement(s) on pricing and reimbursement to provide affordable ATMPs as well as an acceptable financial benefit, including return on investment, for the MA holder.

Patients can also access ATMPs, thanks to other pathways, alternative to MA and possible under strict conditions only. However, depending on how these other pathways can be used according to the applicable national heterogenous rules (e.g., hospital exemption), they could also lead to unfair competition regarding the high requirements for MA granting.

<footnote n="1">¹Research Engineer in law, EuroGCT and ²Biolex research projects, Law Faculty, Aix Marseille Univ. CNRS, DICE, CERIC, Aix-en-Provence, France. ²EuroGCT Information Officer on ELSI Research Engineer in law, Law Faculty, Aix Marseille Univ. CNRS, DICE, CERIC, Aix-en-Provence, France. ³Study Engineer at the French National Centre for Scientific Research (IE CNRS), Law Faculty, Aix Marseille Univ. CNRS, DICE, CERIC, Aix-en-Provence, France. ⁴EuroGCT Information Officer on Ethical Legal & Ethical Issues. ⁵EUSIS, Research Engineer and PhD student in law, Law Faculty, Aix Marseille Univ. CNRS, DICE, CERIC, Aix-en-Provence, France. ⁶Research Engineer and PhD student in law, EuroGCT Information Officer on ELSI Law Faculty, Aix Marseille Univ. CNRS, DICE, CERIC, Aix-en-Provence, France. ⁷CNRS Permanent Researcher in law (CR), EuroGCT Deputy coordinator and WF4 leader, H-Biolex PI, Law Faculty, Aix Marseille Univ. CNRS, DICE, CERIC, Aix-en-Provence, France.</footnote>

<footnote>Acknowledgments: This work has been supported by the European Union's Horizon 2020 EuroGCT project (GA No 965241) and by ANR-funded H-Biolex project (ANR-20-CE26-0027-01).</footnote>
# What regulatory pathways for health technologies using both medical devices and T&C in the European Union?

V. ROBY, A. DELAGE, L.-S. GILBERT, A. BOTTACCI, A. MAHALATCHIMY, What regulatory pathways for health technologies using both medical devices and T&C in the European Union?, ESGCT 2025, 7-10 October 2025, Seville, Spain (POSTER available at https://shs.hal.science/halshs-05314492v1)

## Abstract

Medical applications of tissues and cells (T&C), whether from human or animal origin, can be various. While the legal distinction between transplants and Advanced Therapy Medicinal Products (ATMPs) has been widely commented, the legal classification of health technologies based on the association between medical devices (MD) and T&C is poorly explored and known. Yet, from their collection to the patient's administration, they have to follow the appropriate regulatory pathways in accordance with their legal classification. First, the MD and the T&C have to comply with the respectively applicable European legislations: the regulations on MD and on substances of human origin for T&C of human origin. Second, when T&C are substantially manufactured into medicinal products, they would be categorised as biological medicinal products, most of the time as ATMPs. The association between T&C and MD may be external, and MD can be companion diagnostics to a transplant or an ATMP. Parallel regulatory pathways have to be followed by each product. But the association between T&C and medical devices may also be integrative. Depending on what is regulatorily considered as the dominant part in the overall product, the latter can be either a medicine or a MD. On the one hand, if the T&C are the dominant part, the overall product should be a combined ATMP. This is a hybrid sub-category of ATMP that should encompass certain organoids. On the other hand, if the action of the T&C is only ancillary to that of the device, the overall product should be a MD. This latter type of products is not only defined in contrast to medicinal products, they are also following a completely different regulatory pathway to reach the market. While any ATMPs' developer has to go through the centralised procedure to obtain a marketing authorisation (granted by the European Commission after evaluation by the European Medicines Agency), MDs' manufacturers, on the other hand, have to "certify" their products. This requires the involvement of a Notified body - a non-state entity designated by a member state for the assessment of certain MDs - before commercialising MDs based on T&C. And while the European legislation distinguishes between gene therapy, cell therapy, tissue engineering, and combined ATMPs among ATMPs, it divides MDs into classes, depending on their purpose and their risk. Thus, their two distinct regulatory pathways are worst to be known, as each one has its own specific requirements. The distinction criteria between MDs and ATMPs are based on the viability of the tissues or cells, and primary or ancillary action of each part of the overall product. Yet, navigating through the various legal texts regarding definitions and scopes to identify the legal classification and applicable regulatory pathway(s) of health technologies may be challenging, especially as the association between MD and T&C adds another layer of complexity. This poster will clarify and discuss the regulatory pathways applicable to health technologies using T&C of human or animal origin, from the collection of the biological starting materials to the commercialisation of the final health technologies.
# WHAT REGULATORY PATHWAYS FOR HEALTH TECHNOLOGIES USING BOTH MEDICAL DEVICES AND TISSUES AND CELLS IN THE EUROPEAN UNION?

Valentin Roby¹, Auxane Delage², Luc-Sylvain Gilbert³, Adrien Bottacci⁴, Aurélie Mahalatchimy⁵

¹Research Engineer in law, EuroGCT and I-Biolex research projects, Law Faculty, Aix Marseille Univ., CNRS, DICE, CERC, Aix-en-Provence, France; ²EuroGCT Information Officer on Ethical, Legal & Societal issues, Research Engineer and PhD student in law, Law Faculty, Aix Marseille Univ., CNRS, DICE, CERC, Aix-en-Provence, France; ³EuroGCT Information Officer on Ethical, Legal & Societal issues, Research Engineer in law, Law Faculty, Aix Marseille Univ., CNRS, DICE, CERC, Aix-en-Provence, France; ⁴PHD student in law, CNRS, DICE, ADES CERC, Aix-en-Provence, France; ⁵Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, chargee de recherche). Law Faculty, Aix Marseille Univ., CNRS, DICE, CERC, Aix-en-Provence, France; EuroGCT Deputy coordinator and WF4 leader.

**Acknowledgments:** This work has been supported by the European Union's Horizon 2020 research and innovation programme EuroGCT (C-IP85241) and by ANR-funded I-BioLex project (ANR-20-CE26-0007-01).

## Introduction

Medical applications of tissues & cells, whether from human or animal origin, can be various. The legal classification of health technologies based on the association between Medical Devices (MD) or in Vitro Medical Devices (IVMD) and tissues & cells is poorly explored and known. Yet from their collection to the patient administration, they must go through the appropriate regulatory pathways according to their legal classification. Knowing the applicable regulatory pathways is crucial for complying with legal and regulatory requirements and adapting development strategies. This poster clarifies and discusses the regulatory pathways applicable to the associations between MD and tissues & cells, be they of human or animal origin, from the collection of the biological starting materials to the commercialisation of the final health technologies.

## Association of tissues & cells and medical devices

### External association

IVMD / companion diagnostics
Regulation (EU) 2017/746

ATMP
Regulation
(EU) 1394/2007

Transplants
Tissues & cells/
SoHO regulation

Two main distinct regulatory pathways

NB shall consult EMA regarding the associated ATMP or the NCAs regarding transplants or exempted ATMP

Integrative
association

<figure><img src="image_100.png" /></figure>

Tissues and cells
of Animal origin

Combined Products

<figure><img src="image_101.png" /></figure>

Tissues and cells
of Human origin

<figure><img src="image_102.png" /></figure>

<figure><img src="image_103.png" /></figure>

Significantly different from one another, the regulatory pathways to commercialisation of health products combining medical devices and tissues & cells also appear to be complex, involving several cross-references between distinct regulations and cross-linked interventions of their respective actors. If such complexity reflects the EU objective to guarantee health safety for patients to access (new) biomedical technologies, it is also challenging for appropriate regulatory compliance in their development. Nevertheless, three tools have been developed to address this challenge:

* **Dialog and support mechanisms** for developers to interact with regulators at each phase of product development, e.g. possibility to seek advice from NCAs, NBS and/or the EMA.

* **Strengthened Coordination** between Member States' and the European Commission: e.g., Medical Device Coordination Group and SoHO Coordination Board.

* **Guidance documents** are regularly issued and updated on technical, scientific and regulatory aspects: e.g., EMA, Q&A for applicants, marketing authorisation holders of medicinal products and notified bodies with respect to the implementation of the Regulations on medical devices and in vitro diagnostic medical devices (Regulations (EU) 2017/745 and (EU) 2017/746), EMA (3798) (2019 Rev. 5, 30 January 2025) and EMA, Guideline on quality documentation for medicinal products when used with a medical device, EMA/CHMP/GWP/BW/29505/2018, 22 July 2021.

<figure><img src="image_104.png" /></figure>

<figure><img src="image_105.png" /></figure>

* Standard Marketing Authorization Pathway

* Centralized Product for ATMP

* Centralized Marketing Authorization Pathway

* Brand Marketing Authorization for ATMP
# ATMPs: exceptional manufacturing returns to the patient's bedside

J. VÉRAN, J. MAGALON, C. DUMOULIN, S. RABARIMERIARIJAONA, L. AGNELLI, M. VELIER, F. SABATIER, A. MAHALATCHIMY, ATMPs: exceptional manufacturing returns to the patient's bedside, ESGCT 2025, 7-10 October 2025, Seville, Spain (POSTER available at https://shs.hal.science/halshs-05314447v1)

## Abstract

Since the publication of the European Regulation (No. 1394/2007) on Advanced Therapy Medicinal Products (ATMPs) in 2007, innovative therapies based on genes, cells, or tissues have reshaped the pharmaceutical landscape. While offering significant opportunities for economic and medical advances, their complex manufacturing raises specific issues on quality and regulatory issues. Detailed guidelines on Good Manufacturing Practices (GMP) specifically tailored to ATMPs have been adopted by the European Commission and have been enforceable since 2017. They address new technological developments, scientific advances, and more suitable production and distribution pathways. To date, 27 ATMPs have obtained a marketing autorisation in Europe, but most are still at the clinical trial stage although they could provide very promising options for addressing unmet medical needs. Making ATMPs accessible to patients remains challenging due to factors such as high cost, the specialized nature of ATMPs manufacturing including stringent safety and efficacy. Moreover, current healthcare infrastructures often require substantial adaptations to accommodate the logistical demands of these treatments. The Hospital Exemption (HE) is a regulatory provision of the European Regulation, that allows the use of certain ATMPs without formal central marketing authorization provided specific criteria are met: a medical prescription for an individual patient, a use within the same Member State, in a hospital setting under the exclusive responsibility of a medical practitioner, a GMP compliant manufacturing. HE implementation and oversight are regulated at the national level by the competent authority of each EU Member State. It provides a practical solution for bypassing the lengthy centralized authorization and facilitating timely access to innovations stemming from academic research and hospital initiatives. In France, a significant regulatory evolution in the field of ATMPs has been recently introduced by the decree on February 16, 2022, pursuant to French Law No. 2021-1017. It establishes a sub-exemption mechanism within the broader HE framework, specifically designed to address the practical challenges of certain ATMPs derived from autologous cells or tissues and involving no substantial manipulation. It authorizes the preparation, distribution, and administration of ATMPs, within the same medical procedure as the procurement of autologous tissues or cells used in their composition, without requiring a specially authorized manufacturing establishment, providing prior validation by the French National Agency for Medicines Safety (ANSM). By formalizing a legal framework for decentralized, bedside production, the decree aligns regulation with the practical realities of personalized medicine, favors more agile healthcare organization and fasters patient access. We aim to present and discuss the first application of this innovative regulatory framework within the MICROPREP III clinical trial (EudraCT No 2023-507683-40). This trial is designed to evaluate in 180 patients the efficacy of intra-articular injections of autologous microfat, optionally combined with autologous platelet-rich plasma (PRP), as an adjunctive therapy for patients with Knee osteoarthritis. The application of the single-step autologous ATMPs exemption needed to implement new measures and agreements between clinicians and manufacturer to ensure compliance to GMP guidelines and ATMPs quality remaining under the responsibility of the authorized establishment despite delocalization.
# ATMPs: exceptional manufacturing returns to the patient's bedside

J. Véran¹, J. Magalon¹, C. Dumoulin¹, S. Rabarimeriarijaona¹, L. Agnelli³, M. Velier¹, F. Sabatier¹, A. Mahalatchimy²

¹Cell therapy/Advanced Therapy Medicinal Products' Unit, Center for Clinical Investigation in Biotherapy (INSERM CIC 1409), Marseille University Hospital (AP-HM), 13005 Marseille, France
² Law Faculty, Aix Marseille Univ, CNRS, DICE, CERIC, 13628 Aix-en-Provence, France
³ Health Research Department, Marseille Public Hospital (AP-HM), 13005 Marseille, France

Acknowledgments. This work has been supported by the French National grant (Programme Hospitalier de Recherche Clinical 2020) and by ANR-funded I-Biolex project (ANR-20-CE26-0007-01).

## Introduction

Since the European Regulation (No. 1394/2007) on Advanced Therapy Medicinal Products (ATMPs), only 30 ATMPs have obtained a marketing authorization in the European Union as at 30 September 2025, but most are still at the clinical trial stage.

☐ The European Hospital Exemption (HE) allows the use of certain ATMPs at the national level without formal central marketing authorization provided specific criteria are met: a non-routine basis preparation, a medical prescription for an individual patient, a use within the same Member State, in a hospital setting under the exclusive responsibility of a medical practitioner, a GMP compliant manufacturing, and compliance with traceability and pharmacovigilance requirements. It provides a practical solution for facilitating timely access to innovations stemming from national academic research and hospital initiatives.

☐ In France, the decree of February 16, 2022, has established a sub-exemption within the framework of HE, specifically designed to address the practical challenges only for ATMPs derived from autologous cells or tissues and not involving any substantial manipulation. It authorizes the manufacturing, distribution, and administration of these ATMPs, as part of the same medical procedure as the procurement of the autologous tissues or cells used in their composition, without requiring the manufacturing process to take place in a specially approved manufacturing facility (GMP classroom production), subject to prior validation by the French National Agency for Medicines and Health Products Safety (ANSM). By formalizing a legal framework for a so-called "decentralized bedside" production, the decree aligns regulations with the practical realities of personalized medicine, promotes a more agile organization of healthcare, and accelerates access to these ATMPs for patients.

☐ Within this new context, this poster presents the first French implementation of this new decree through the MICROPREP III clinical trial.

<figure><img src="image_106.png" /><figcaption>FIGURE 1: Regulation frame for a national decentralized "bedside" sub-exemption ATMP manufacturing</figcaption></figure>

## New measures for a "decentralized bedside autologous hospital exemption ATMP manufacturing"

<figure><img src="image_107.png" /><figcaption>FIGURE 2: MICROPREP III autologous "bedside" ATMP setup proposal</figcaption></figure>

The First French therapeutic application of this innovative regulatory framework is addressed within the setup of MICROPREP III clinical trial (EudraCT No 2023-507683-40) authorized in May 2024.

☐ It is designed to evaluate in 180 patients the efficacy of intra-articular injections of autologous microfat, optionally combined with autologous platelet-rich plasma (PRP), as an adjunctive therapy for patients with Knee osteoarthritis.

☐ The application of the single-step autologous ATMPs exemption needed to implement new measures and agreements between clinicians and manufacturer to ensure compliance to GMP guidelines and ATMPs quality remaining under the responsibility of the authorized establishment despite delocalization (as mentioned in figure 2). The setup proposal by the national authorized manufacturing establishment consists in:
  ☐ Using directly the operating room for the harvesting-manufacturing-administration of the "single step manufactured autologous ATMP"
  ☐ Training and accrediting the medical staff
  ☐ Centralizing quality controls
  ☐ Centralizing the quality management at the authorized manufacturer level
  ☐ Establishing fluid communication and traceability

## Expectations and Perspectives

☐ Changes to ATMP's remote management rules
  * Responsibilities between the manufacturer and the delegated staff
  * New relationship between the manufacturer and the physician
  * New measures in the quality management system
  ⇒ Formal contract is a mandatory step

☐ Challenges are expected regarding the standardization of protocols, requirement of trained personnel, reproducibility from site to site...

☐ Reduced ATMP's production time should increase patient treatment capacity (see figure 3), and is expected to be more suitable to supply & demand.

☐ More affordable expected cost to the healthcare system for a single batch of autologous ATMP

✓ How will the manufacturer and sponsor manage the risk management plan?

✓ Will other EU countries apply new tools and rules to accelerate decentralized manufacturing at the patient's bedside under the hospital exemption for autologous ATMP, and how?

<figure><img src="image_108.png" /><figcaption>FIGURE 3: Expected ATMP manufacturing time comparison from raw material collection to ATMP batch release between centralized process in GMP classroom (internal data extracted from GMP ATMP batches in Marseille Cell Therapy Unit) and decentralized process in the case of the "bedside" operating room production planned for MICROPREP III clinical trial.</figcaption></figure>
<figure><img src="image_109.png" /></figure>
IV

Health Technology
Assessment/
Cost issues
# The new European regulation on Health Technology Assessment: what changes for Advanced Therapy Medicinal Products?

**B. BARTOS, J. JUËT, F. TABOULET, A. MAHALATCHIMY,** The new European regulation on Health Technology Assessment: what changes for Advanced Therapy Medicinal Products?, European Society for Gene & Cell Therapy Congress 2022, Edinburgh, the UK, 11-14 October 2022 (POSTER available at https://shs.hal.science/halshs-03901269v1); Abstract published in Human Gene Therapy, Volume: 33 Issue 23-24: December 14, 2022, A1-A212. http://doi.org/10.1089/hum.2022.29225.abstracts

## Abstract

The new European regulation (EU) 2021/2282 on Health Technology Assessment (HTA), “a multidisciplinary process that summarises information about the medical, patient and social aspects and the economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased and robust manner”, has been adopted on 15 December 2021. It ensures an efficient use of resources and strengthens the quality of common HTA across the European Union, because until now, the assessment has been realized independently by each Member State. It will thus contribute to the improvement of the availability of health innovative technologies for EU patients that has been widely highlighted by the Council of the European Union and the European Parliament. It mainly establishes a Member State Coordination Group on HTA, a stakeholder network, whom the joint works and exchanges will be facilitated thanks to an IT platform. It also provides rules for joint clinical assessments, joint scientific consultations, horizon scanning for emerging technologies, further voluntary cooperation notably on non-clinical assessments on health technologies, i.e. “a medicinal product, a medical device, or medical and surgical procedures as well as measures for disease prevention, diagnosis or treatment used in healthcare”. The regulation shall apply progressively from 2025 to different types of health technologies, Advanced Therapy Medicinal Products (ATMPs) being the first targeted with cancer medicines. This poster will discuss the expected improvements for patients’ access to ATMPs regarding the forthcoming implementation of this new regulation.
# The new European regulation on Health Technology Assessment: what changes for Advanced Therapy Medicinal Products?

Blanka Bartos<fnref n="1" />, Joséphine Juët², Florence Taboulet³, Aurélie Mahalatchimy⁴

## Health Technology Assessment (HTA)?

> "A multidisciplinary process that summarises information about the medical, patient and social aspects and the economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased and robust manner."

Article 2.5) EU Regulation 2021/2282

<figure><img src="image_110.png" /></figure>

Evidence-based process enabling relative effectiveness assessment of new/ existing technologies

## Health technology?

> "A medicinal product, a medical device or medical and surgical procedures as well as measures for disease prevention, diagnosis or treatment used in healthcare."

Article 3.1) Directive 2011/24/EU

<figure><img src="image_111.png" /></figure>

ATMPs are included

## PAST

- Independent assessments from national HTA bodies

- EUnetHTA (2006-2021): joint action, voluntary cooperation

<figure><img src="image_112.png" /></figure>

BUT

- Redundancy of the evaluation process in the EU

- Misallocation of resources

- Inequitable access to new technologies

## PRESENT (2022)

Rolling implementation plan: preparatory phase

- Setting up the Coordination Group and the Stakeholder Network

- Drafting implementing & delegated acts, and guidance documents

- 2021-23: New EunetHTA (2021)

- 2023-25: Member States remain responsible for drawing conclusions on added value for their health system and taking decisions on pricing & reimbursement. They can give additional multinational or simultaneous national scientific advice on a voluntary basis.

<figure><img src="image_113.png" /></figure>

## FUTURE (from 2025)

Application of Joint Clinical Assessments:

- 2025: ATMPs, cancer drugs

- 2028: orphan drugs

- 2030: all medicines covered by Regulation scope

New HTA process:

- New Coordination Group managing HTA process

- Secretariat provided by the European Commission

- National bodies providing expert views on HTA

- Exchange of information with stakeholder network

<figure><img src="image_114.png" /></figure>

- Increased quality of joint work

- Better allocation of resources: reduced expenses for national bodies and the EU

- Improved accessibility to ATMPs in the EU

<figure><img src="image_115.png" /></figure>

## Remaining challenges:

- Building EU processes from national HTA experiences and feedback from experts

- Training more external expert / organisations on HTA in general, and on EU procedure(s)

- Organising HTA registries, raising awareness, collecting experiences

- Identifying / involving clinicians or patients (organisations' membership list, social networks, European Reference Networks, clinics in Pubmed...)

<figure><img src="image_116.png" /></figure>

<footnote n="1">¹PhD Student in law, CREDIMI, Univ. of Burgundy, Dijon, 27877, France. ²Student in Pharmaceutical Sciences, Univ. of Paul Sabatier-Toulouse 3, Toulouse, 31062, France. ³Professor in Pharmaceutical Law and Health Economics, CERPOP (Center for Epidemiology and Research in PO/Pulation health). UMR 1295 Inserm, Univ of Paul Sabatier-Toulouse 3, Toulouse, 31062, France. ⁴Permanent Researcher in law at the French National Centre for Scientific Research (CNRS), Faculty of Law, UMR 7318 International, Comparative and European law (DICE) CERIC, CNRS. Aix Marseille Univ., Toulon Univ., Pau & Pays de l'Adour Univ., Aix-en-Provence, 13628, France

Acknowledgement: This work has been supported by ANR-funded iBioLex project (ANR-20-CE26-0007-01, coord. A. Mahalatchimy).</footnote>
# The European regulation on Health Technology Assessment: balancing European and national levels

A. MAHALATCHIMY, J. JUËT, B. BARTOS, F. TABOULET, The European regulation on Health Technology Assessment: balancing European and national levels, International Society for Cell & Gene Therapy 2023 Paris Annual Meeting, Paris, France, 31 May-3 June 3 2023 (POSTER available at https://shs.hal.science/halshs-04290552v1);

Abstract published in Cytotherapy Volume 25, Issue 6, Supplement, May 2023, Page S161. https://doi.org/10.1016/S1465-3249(23)00434-6

## Abstract

The European Health Technology Assessment (HTA) regulation was adopted at the end of 2021. HTA is “a multidisciplinary process that summarizes information about the medical, patient and social aspects and the economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased and robust manner”. While HTA has been conducted at national level, the regulation is provided for the harmonization of procedures to avoid redundancy of evaluation processes, misallocation of resources, and inequitable access to new technologies within the European Union (EU). The regulation will be implemented step by step, starting with Advanced Therapy Medicinal Products (medicines based on genes, cells, and tissues) and cancer drugs by 2025. Then it will be implemented for orphan drugs by 2028, and finally, for all medicines by 2030. Although EU Member States remain responsible for drawing conclusions on added value of health technologies for their health system and taking decisions on their pricing & reimbursement, a new coordination group (HTACG) is established at the EU level. The latter will manage the entire HTA process, relying on a Secretariat provided by the European Commission, national bodies providing their expert views on HTA, and a stakeholder network supporting its work. More specifically, the HTACG will coordinate the joint clinical assessments of health technologies and ensure the identification of emerging technologies. It will also carry out joint scientific consultations and facilitate the voluntary cooperation regarding the exchange of scientific information among Member States in the field of HTA. Therefore, this poster will present and discuss the balance established by the new regulation, between European and national activities in the field of HTA, in accordance with the Treaty provisions on the sharing of competences between the European Union and the Member States.
**Contracts for better access to Advanced Therapy
Medicinal Products**

**B. BARTOS**, Contracts for better access to Advanced Therapy Medicinal Products, European Society for Gene & Cell Therapy Congress 2022, Edinburgh, the UK, 11-14 October 2022 (POSTER) Abstract published in Human Gene Therapy, Volume: 33 Issue 23-24: December 14, 2022, A1-A212. http://doi.org/10.1089/hum.2022.29225.abSTRACTS

**Abstract**

The greater part of ATMPs is manufactured in a customized way with high technicity to offer promising health benefits with mostly a one-shot treatment for incurable, often orphan diseases. The scope of use of these therapies is quite narrow and they also raise safety issues for patients. These are some of the reasons why ATMPs are extremely expensive and why they do not fit in the current regulatory and economic framework. If we want as many patients as possible to benefit from these medicines, we need to set a fair price for health insurance systems. On the basis of the Managed Entry Agreements (MEAs), the parties can negotiate on the performance of the product instead of signing a classic contract. The OECD distinguishes between two main types of agreements: financial and performance-based MEAs. Focusing on the latter, this paper will highlight its potential to facilitate access to ATMPs. The "coverage with evidence development (CED) contracts" allow treatment to be temporarily covered by the payer while a study evaluates its performance. Based on the results, coverage can be continued, withdrawn or extended, or prices are adjusted. The "pay-for-results contract" considers the uncertainty of results and organizes a "satisfied or reimbursed" policy. Here, the risk of innovation seems to lie with the laboratory and not with the community. Unfortunately, confidentiality is a barrier to evaluating objectively the strengths and weaknesses of these agreements. Greater transparency and an extended collaboration between States could help them negotiate better with drug laboratories.
<figure><img src="image_117.png" /></figure>

<figure><img src="image_118.png" /></figure>

<figure><img src="image_119.png" /></figure>

<figure><img src="image_120.png" /></figure>

# Contracts for better access to Advanced Therapy Medicinal Products

Blanka BARTOS¹

¹PhD Student in law, CREDIMI, University of Burgundy, Dijon, 27877, France.

**Acknowledgments:** This work has been supported by ANR-funded I-BioLex project (ANR-20-CE26-0007-01, coord. A. Mahalatchimy), by the Labex LipSTIC (ANR-11-LABX-0021), the Region Bourgogne - Franche Comté and the FEDER.

## Advanced Therapy Medicinal Products (ATMPs) Regulation (EC) No. 1394/2007

- Revolutionary treatments for serious diseases

- Target directly the cause

- Often one-shot treatments

- Expensive (1-2 million €)

<figure><img src="image_121.png" /></figure>

Limited patient access

<figure><img src="image_122.png" /></figure>

## Managed Entry Agreements (MEAs) are a possible solution

- 'Risk-sharing agreements / arrangements between a manufacturer and a payer to enable access to a health technology (e.g.: ATMP) subject to specified conditions

- Address uncertainty about the performance of an ATMP or manage ATMP adoption to maximize their effective use or limit their budget impact

- Used mostly for orphan disease treatments as these medicines have high prices and also uncertainties on their long-term efficacy data

Aim of the payers

<figure><img src="image_123.png" /></figure>

Aim of the firms

To provide patient access to new ATMPs quickly and at lower prices after marketing authorization

To sell the highest volume of ATMPs at the highest price

<figure><img src="image_124.png" /></figure>

## PROBLEMS

<figure><img src="image_125.png" /></figure>

## CONSEQUENCES

### High prices of ATMPs:

> several years of development

> high technicity

> highly educated scientists

> small number of patients (mostly with orphan diseases)

> short period of treatment

### Limited affordability for patients and for States

<figure><img src="image_126.png" /></figure>

### High risks:

> medical uncertainty

> low number of patients, the laboratories cannot test the products on enough individuals to receive the market authorisation earlier

### Delayed market entry compared to other medicines

<figure><img src="image_127.png" /></figure>

### Heterogeneous types of ATMPs: do not fit in the current regulatory and economic framework

### Risk-based approach for manufacturers: choosing appropriate measures for each product instead of applying Good Manufacturing Practices → higher responsibility for medicine production

### Lack of transparency between Member States regarding price and efficiency of a new medicine

### Less international cooperation, slower pharmaceutical trade

<figure><img src="image_128.png" /></figure>

### Complex fabrication and logistics of the distribution

<figure><img src="image_129.png" /></figure>

### Geographically inequal, slower and more expensive distribution and fabrication

<figure><img src="image_130.png" /></figure>

Source: Performance-based managed entry agreements for new medicines in OECD countries and EU member states, https://www.oecd.org/fr/sante/systemes-sante/pharma-managed-entry-agreements.htm (last seen: 03/10/2022)

## PRESENT

### DIFFICULTIES of the application of performance-based agreements

<figure><img src="image_131.png" /></figure>

Administrative burden to collect data

<figure><img src="image_132.png" /></figure>

Risk selection: Payment-by-Result - the therapy would be given only to those patients on whom it is 100% successful

<figure><img src="image_133.png" /></figure>

High confidentiality of all parts of the contracts

<figure><img src="image_134.png" /></figure>

Lack of transparency of MEAs' process and content

## FUTURE

### GOOD PRACTICES of performance-based agreements

<figure><img src="image_135.png" /></figure>

Used when benefit of additional evidence on product performance outweighs the cost of negotiating and executing other MEAs

<figure><img src="image_136.png" /></figure>

Appropriate data sources and research designs to address uncertainties

<figure><img src="image_137.png" /></figure>

Transparency assured by governance frameworks to allow payers to act upon additional evidences (e.g. exit or withdrawal the coverage)

<figure><img src="image_138.png" /></figure>

Minimum transparency level of MEAs' content and limited confidentiality
# Real access to ATMPs: the cost issue

A. MAHALATCHIMY, A. DELAGE, L.-S. GILBERT, H.-Y. KUO, V. ROBY, C. CHABANNON, Real access to ATMPs: the cost issue, ESGCT 2024, 22-25 October 2024, Roma, Italy (POSTER available at https://shs.hal.science/halshs-04842702v1)

## Abstract

While industry developed and manufactured Advanced Therapy Medicinal Products (ATMPs) benefit from a centralised marketing authorisation procedure that allows commercialization in all Member States of the European Union (EU), and despite improvement in EU citizen access to ATMPs being stated as one of the two major objectives when the ATMP regulation was released, actual patient access to ATMPs remains one of the most challenging issues to be addressed. Prices of ATMPs are among the highest despite difficulties in proving long term efficacy on significant numbers of patients, although it is fair to acknowledge that cumulative costs of supportive and curative treatments that are administered on repeated occasions may fall in the same ranges. Publicly accessible data show prices that vary from several hundreds of thousands euros to several million euros per treatment, with a continuous trend in increasing prices that has fuelled the concept of "financial toxicity" for those and other categories of treatments. Payment and reimbursement mechanisms as well as decisions on the levels of healthcare expenditures are established at national and possibly in some countries at regional levels by Healthcare Technology Assessment (HTA) agencies and other governmental bodies, with limited possibilities at the European level. Indeed, mainly apart from the Transparency directive and the recently strengthened collaboration in the field of HTA thanks to the adoption of the HTA regulation following the HTA initiatives at the EU level, each Member States is sovereign in determining its health expenses, including to decide on the reimbursement of ATMPs by its National health insurance system. Actual prices paid by public or private payers are not public, and a significant rebate may result from prior and mutual negotiations between drug manufacturers and healthcare providers, the latter receiving reimbursement from health insurers. In addition, specific programs such as the "Early Access" ("Accès précoces") program in France may speed up access to innovative treatments in some countries, thus favouring a category of EU citizens over others. Thus, actual patient access to ATMPs in the European Union is not only limited, but also heterogeneous, highlighting the existing gap between the intentions stated in the ATMP Regulation and other EU documents and the actual achievements; these diverse factors resulting in an unsatisfactory situation where patients in need of lifesaving treatments face a shortage on a day-to-day basis, not because of insufficient manufacturing capacities as is the case for low-cost drugs, but because of insufficient payment capacities. This poster first provides an overview of the known prices of the 26 ATMPs that have so far obtained a marketing authorisation in the EU. It also highlights what is regulated at the EU and at the National levels in this area. Finally, it suggests potential solutions to improve patients' access to ATMPs.
<figure><img src="image_139.png" /></figure>
V
Orphan Medicines
# Improving access to innovative medicines: proposals from national authorities to revise the European legislation

A. MAHALATCHIMY, F. LANSON, B. BARTOS, F. TABOULET, Improving access to innovative medicines: proposals from national authorities to revise the European legislation, European Society for Gene & Cell Therapy Congress 2022, Edinburgh, the UK, 11-14 October 2022 (POSTER available at https://shs.hal.science/halshs-03901248v1); Abstract published in Human Gene Therapy, Volume: 33 Issue 23-24: December 14, 2022, A1-A212. http://doi.org/10.1089/hum.2022.29225 abstracts

## Abstract

Gene and cell therapies are currently considered as the main drivers of innovation in the treatment of genetic diseases and cancer therapies. They offer new hopes to rare disease patients as 80% of rare diseases are of genetic origin in the European Union. Hence, many gene and cell therapies have obtained the orphan medicine status under European regulation (EC) n 141/2000, which provides incentives to promote the development of orphan medicines. The European Union tries to find a balance between the interests of industry, which should be encouraged to invest, patients' access to medicines, and the sustainability of health systems. Nevertheless, the current legal regime needs adaptation. Thus, the European Commission launched two public consultations in 2021: a first one specifically on the revision of the orphan medicines legislation, and then, another one on the revision of the general pharmaceutical legislation. Out of the 303 and 478 answers received, 12 and 30 respectively came from national authorities. On the basis of an analysis of their answers, this poster will discuss the criteria for orphan designation (e.g., the significant benefit which needs clarification and modification), as well as the incentives implemented, and patient access. It will highlight several proposals emphasized by national authorities that might be retained in the future legislations: to reward mainly truly innovative medicines, a transparency obligation on R&D costs before granting incentives to sponsors, or an obligation to launch the medicine in most Member States.
# IMPROVING ACCESS TO INNOVATIVE MEDICINES: PROPOSALS FROM NATIONAL AUTHORITIES TO REVISE THE EUROPEAN LEGISLATION

Aurélie Mahalatchimy[1], Florence Lanson[2], Blanka Bartos[3], Florence Taboulet[4]

[1] Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, research fellow), Law Faculty, UMR 7318 International, Comparative and European law (DICE) CERIC, CNRS, Aix-Marseille University, Toulon University, Pau & Pays de l'Adour University, Aix-en-Provence, 13628, France. ; [2] CERPOP (Center for Epidemiology and Research in POPulation health), UMR 1295 Inserm, University of Paul Sabatier- Toulouse 3, Toulouse, 31062, France. ; [3] PhD Student in law, CREDIMI, University of Burgundy, Dijon, 27877, France. ; [4] Professor in Pharmaceutical Law and Health Economics, CERPOP, UMR 1295 Inserm, University of Paul Sabatier- Toulouse 3, Toulouse, 31062, France. Acknowledgement: This work has been supported by ANR-funded I-Biolex project (ANR-20-CE26-0007-01, coord. A. Mahalatchimy).

80% of rare diseases are of genetic origin in the EU

= Many advanced therapies have obtained the orphan medicine status under

European regulation (EC) n° 141/2000 of 16 December 1999 on orphan medicinal products

Provides orphan designation and incentives (market exclusivity for 10 years)

Needs to be revised. Why?

Public consultations on revision of European legislation

* Ensure the relevance of incentives granted to industry (to avoid abuses)

* Reward risk-taking and innovation more

* Improve equitable patient access in the EU

<table><thead><tr><td>Orphan medicines legislation</td><td>General pharmaceutical legislation</td></tr></thead><tbody><tr><td>7 May - 30 July 2021</td><td>28 Sept. - 21 Dec. 2021</td></tr><tr><td>303 answers including 12 public authorities from 9 Member States*</td><td>478 answers including 31 public authorities from 15 Member States**</td></tr></tbody></table>

*AT, DE, DK, ES, FI, FR, HU, NL, SE ; **AT, BE, CZ, DE, DK, EE, ES, FI, FR, HU, IS, MT, NL, PT, SE

## MAIN PROPOSALS FROM NATIONAL AUTHORITIES

On the criteria for orphan designation

<figure><img src="image_140.png" /></figure>

On the incentives granted to sponsors

Prevalence : < 5 in 10,000 persons in the EU

○ To be adjusted to avoid "salami slicing" (segmenting therapeutic indications)

○ To be taken into account with the severity of the disease (level of unmet medical need - UMN)

Significant benefit : no EU satisfactory method of diagnosis, prevention or treatment, or drug significant benefit

○ To be clarified and graduated

○ Proportionate to the level of UMN (e.g. variable duration of market exclusivity)

○ Focused on neglected therapeutic areas

○ Conditional to certain obligations

■ Be transparent on R&D costs and actual prices

■ Launch in all or most Member States

■ UMN re-evaluated after commercialization

○ Use experiences developed from covid-19 crisis

■ Joint procurement

■ Flexibility in clinical trials conduct

## DISCUSSION AND CONCLUSION

* Many isolated proposals : difficult to identify a consensus among the authorities

* Request of better cooperation between all agencies and more EMA support

* BUT emphasis on respecting the EU and Member States competences sharing

> Orphan single status transformed into a mosaic of statuses

<figure><img src="image_141.png" /></figure>

Complexities : how to quantify ? which indicators ?

> Future EU considerations of national authorities proposals and answers from other respondents ?

Objectives to be balanced

Innovation
support

EU
legislation

Health systems
sustainability

Patient access
to medicines
# The current revision of the orphan medicinal products regulation in the European Union: what is at stake for gene and cell therapy?

A. MAHALATCHIMY, E. GENNET, The current revision of the orphan medicinal products regulation in the European Union: what is at stake for gene and cell therapy?, European Society for Gene & Cell Therapy Congress 2022, Edinburgh, the UK, 11-14 October 2022 (POSTER available at https://shs.hal.science/halshs-03901429v1); Abstract published in Human Gene Therapy, Volume: 33 Issue 23-24: December 14, 2022, A1-A212. http://doi.org/10.1089/hum.2022.29225.abstracts

## Abstract

In the European Union, gene and cell therapy medicinal products are mainly regulated by the specific legal framework applicable to Advanced Therapy Medicinal Products (ATMPs): regulation (EC) n°1394/2007. Yet most ATMPs that have been authorised for marketing in the European Union are also classified as orphan medicinal products. The latter are regulated by a different but also specific legal instrument : Regulation (EC) n°141/2000, which aims to promote the development of innovative medicines for orphan diseases thanks to a set of incentives for investigators. However, after twenty years of implementation, results are still unsatisfactory for several reasons. One of these reasons is that the market of orphan medicinal products had “started to look more similar to ‘standard’ medicines” than innovative medicines like ATMPs. Moreover, it has also been observed that even when marketed, orphan medicinal products fail in being equally accessible to patients in the different Member States. The European Commission has started a long and thorough revision process of the pharmaceutical legislation in order to give a new impulse to the development of, and access to, truly innovative orphan medicinal products, which may have a positive impact for patients as well as for investigators working on gene and cell therapies. In this poster, we will discuss what aspects of the revision of the regulation on orphan medicinal products may have an impact on the development of gene and cell therapy in the European Union.
<figure><img src="image_142.png" /></figure>

<figure><img src="image_143.png" /></figure>

<figure><img src="image_144.png" /></figure>

# The current revision of the orphan medicines regulation in the EU: what is at stake for gene and cell therapy?

## Aurélie Mahalatchimy<fnref n="1" /> and Éloïse Gennet²

## REGULATORY CONTEXT

In the European Union, gene and cell therapy medicinal products are mainly regulated by the specific legal framework applicable to Advanced Therapy Medicinal Products (ATMPs) Regulation n°1394/2007; but also possibly by the Orphan Medicines (OMPs) Regulation n°141/2000.

OMPs
Regulation
141/2000

→ Most OMPs so far are also OMPs (74%)

→ Many OMPs used to be innovative

ATMPs
Regulation
1394/2007

## CHALLENGES AND ACTION PLAN

After 20 years of OMPs Regulation's implementation, results remain unsatisfactory. OMPs & ATMPs still fail in being equally accessible to patients in all Member States: e.g. their price and reimbursement level may vary between countries, or they are not even commercialized in others. Plus, OMPs look increasingly similar to standard medicines rather than innovative medicines like ATMPs (personalised and genetic medicine allow to isolate sublevels of one same condition for product to be qualified as OMP and benefit from incentives).

**Fields of EU legislative action:**

Adoption of Regulation 2021/2282 on Health Technology Assessment

Upcoming revision of the general pharma legislation

Revision of the specific regulation on OMPs

<figure><img src="image_145.png" /></figure>

## CURRENT INCENTIVES

EU Law, especially Regulation 141/2000 and Regulation 1394/2007, aims to incentivize the development and marketing of OMPs and ATMPs to palliate acute scientific and financial difficulties that these medicines represent.

### Incentives for OMPs

### Incentives for ATMPs (except hospital exemption)

Research funding for instance the E-RARE project, the European Joint Programme on Rare Diseases

<figure><img src="image_146.png" /></figure>

Research funding for instance with the Joint undertaking on Innovative Medicines Initiative

Free scientific assistance from the European Medicines Agency and its Committee on Orphan Medicinal Products (COMP)

<figure><img src="image_147.png" /></figure>

Fee reduction on scientific assistance from the European Medicines Agency and its Committee on Advanced Therapies (CAT)

Partially or totally reduced administrative fees for the marketing authorisation application process

/%

Partially reduced administrative fees for the marketing authorisation application process

Mandatory centralized procedure for marketing authorization, valid in all EU Member States

<figure><img src="image_148.png" /></figure>

Mandatory centralized procedure for marketing authorization, valid in all EU Member States

Ten-year commercial exclusivity

<figure><img src="image_149.png" /></figure>

## POTENTIAL REGULATORY EVOLUTIONS

The European Commission has issued reports and conducted several public consultations from which potential solutions have emerged in order to enhance the promotion of innovative/advanced therapy orphan medicinal products:

Modification of the current definition of OMPs (including such criteria as low occurrence and lack of available treatment) to include a supplementary criterion of innovativeness

Support and incentives conditional to timely placing on the market after authorization has been obtained

Introduce a new type of incentive such as a priority or expedited review from EMA and EC for products targeting unmet medical needs

Introduce new types of incentives for unmet medical needs such as transferable/tradable vouchers extending IP/regulatory exclusivities of products on the market

<figure><img src="image_150.png" /></figure>

Provide longer periods of data and market protection in areas of unmet medical need OR ON THE CONTRARY Reduce data and market protection periods to allow earlier patients access for generics and biosimilars

Provide additional early scientific support and faster review for medicines for unmet medical needs

Public listing of priority therapeutic areas of high unmet medical need to support product development by providing incentives

Better coordination of internal procedures and decision-making timelines within EMA, especially between CAT and COMP

<figure><img src="image_151.png" /></figure>

Require transparent reporting from companies about their R&D costs and public funding as a condition to obtain certain incentives

<figure><img src="image_152.png" /></figure>

### Some proposed new incentives are challenging:

**Priority review:** already tight timelines pressuring regulators

<figure><img src="image_153.png" /></figure>

**Tradable exclusivity vouchers:** hindered timely access to market for generics and biosimilars for the most expensive products; unfair for patients by delaying lower prices of more used medicines; increased healthcare systems expenditures; increased uncertainty and litigation regarding IP/regulatory exclusivities

<figure><img src="image_154.png" /></figure>

## CONCLUSION

Nevertheless, the revision of OMP regulation has the potential to provide solutions to address unmet medical needs of rare disease patients and greatly enhance innovation, and as such to be beneficial for ATMPs development:

<figure><img src="image_155.png" /></figure>

Focus on unmet medical needs that should be defined dynamically, ie taking into account the evolving scientific and medical context, in a multi-stakeholder setting;

<figure><img src="image_156.png" /></figure>

Dedicated public funding and financial incentives to promote research on unmet medical needs and neglected illnesses, health conditions, and populations;

<figure><img src="image_157.png" /></figure>

To introduce a corrective mechanism to prevent unaffordable prices or excessive return on investment: e.g. developer to justify the proposed price would be particularly relevant for high manufacturing costs of ATMPs.

The proposal for a new pharmaceutical legislation, including the revision of the OMP regulation, should be published by the European Commission by the end of 2022. The Council of the EU and the European Parliament will then try to reach an agreement and adopt a (usually amended) legislative act.

<figure><img src="image_158.png" /></figure>

## REFERENCES

Regulation 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, OJ L 18, 12.1.2000, p. 1-5
Regulation 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation No 726/2004, OJ L 324, 10.12.2007, p. 121-137
European Commission, Joint evaluation of Regulation (EC) No 1501/2006 and

Regulation No 141/2000, Brussels, 11.8.2020, SWD (2020) 363 final
European Parliament resolution of 2 March 2017 on EU options for improving access to medicines (2016/2057)(INI)
European Commission, "R&D diseases: A major unmet medical need", 2017.
European Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions, European Commission, Revision of the EU general pharmaceutical legislation - Pharmaceutical strategy for Europe, COM/2020/761 final

European Parliament resolution of 24 November 2021 on a pharmaceutical strategy for Europe (2021/2013(INI))
European Commission, Revision of the Union legislation on medicines for children and rare diseases - Public consultation factual summary report, 4 November 2021.
Public consultation factual summary report, 10 February 2022.

<footnote n="1">¹Permanent Researcher in law at the French National Centre for Scientific Research (CNRS, CR), Law Faculty, UMR 7318 DICE CERIC, CNRS, Aix Marseille University, Toulon University, Aix-en-Provence, France; ²Post-doctoral Researcher in Law, Law Faculty, UMR 7318 International, Comparative and European laws (DICE) CERIC, CNRS, Aix-Marseille University, Toulon University, Aix-en-Provence, France.

**Acknowledgement** This work has been supported by ANR-funded I-Biolex project (ANR-20-CE26-0007-01, coord. A. Mahalatchimy).</footnote>
<figure><img src="image_159.png" /></figure>
VI
Actors
# Which actors to influence the adoption of EU guidelines for Advanced Therapy Medicinal Products?

A. MAHALATCHIMY, V. BRUNEL, Which actors to influence the adoption of EU guidelines for Advanced Therapy Medicinal Products? International Society for Cell & Gene Therapy 2023 Paris Annual Meeting, Paris, France, 31 May-3 June 3 2023 (POSTER available at https://shs.hal.science/halshs-04290558v1); Abstract published in Cytotherapy Volume 25, Issue 6, Supplement, May 2023, Page S161. https://doi.org/10.1016/S1465-3249(23)00435-8

## Abstract

Genes, cells, and tissues based medicinal products are specifically regulated as Advanced Therapy Medicinal Products (ATMPs) within the European Union (EU) from the adoption of Regulation (EC) n°1394/2007 on ATMPs. Beyond legislative requirements, the complexity and scientific technicity of these medicines, as well as the necessary flexibility to take into account the evolutions and the scientific and regulatory experience gained has led to the development of an important amount of guidelines in the field. These guidelines have mainly been adopted by the European Medicines Agency (EMA), the European regulatory agency especially in charge of the scientific assessment of medicines to be commercialized in the EU. Some of them have also been adopted by the European Commission which grants the final marketing authorization for medicines to enter the EU market. The adoption of EU guidelines involves a public consultation procedure to gather comments from stakeholders and interested parties. Our poster aims at mapping these different actors, and their potential changes over time, to allow for a realistic and concrete portrait of all stakeholders and interested parties involved in the field of ATMPs regarding their European regulation through guidelines. The identification of EU scientific guidelines applicable to ATMPs, and of the actors involved in the consultation process has led to the establishment of a database with over 200 organizations corresponding to fourteen guidelines for which dates of production range from 2008 to 2022. The organizations have been classified by type (Business, Academia, National bodies, etc.), country, and theme of the drafts of guidelines they commented on. This poster especially highlights and discusses which organizations have influenced the adoption of EU scientific guidelines on ATMPs; some of them commenting almost all guidelines in the field while others considered only certain guidelines. Findings concern both the number and quality of stakeholders with the aim to understand over time, what types of organizations from which country have been the most active in answering to guidelines' consultations, who were the major or more prolific respondents, and what themes were more often commented.