This article aims to organize current information on the commercialization of advanced therapy medicinal products (ATMPs) and provides a brief overview of requirements for registration and descriptions of essential data elements leading to marketing authorization (MA) to serve as a practical approach for bringing the state-of-the-art research in ATMPs to clinical application.

ATMPs are classified as nucleic acid-based product (Gene Therapy Medicinal Product, GTMP), cell-based product (Somatic Cell Therapy Medicinal Product, SCTMP), and tissue-based (Tissue Engineered Product, TEP). It should be noted that ATMPs, GTMP in particular, are also classified as genetic modifying organism (GMO) either in the framework of deliberate release or contained use, which require environmental risk assessment (ERA) before filing a clinical trial application and/or initiating study. In addition, the pharmacology of ATMPs is characterized by distinct biological features with respect to their starting materials and specific constructs which call for special attention in trial design and pre-clinical and clinical measurement. 

1.   Legal and regulatory framework 

In the EU, the legal and regulatory framework for human medicines promotes unified scientific and technical standards to ensure public health protection and the quality, safety and efficacy of investigational medicinal products (IMPs) for human use.¹ It requires a marketing authorization by experienced authorities before being placed on the market.A medicinal product for humans may be authorized either by the European Commission through the centralized procedure or by national competent authorities through a mutually recognized, decentralized or national procedure^1-2 in the case of marketing authorization of ATMPs. It is a concerted effort between the EMA and national competent authority and other relevant government agencies at the national level of the member state involved in approval of clinical trial application (CTA) and GMO assessment.

A series of legislations have been developed over the past few decades, and they are evolving with the progressive harmonization of requirements for marketing authorization to be granted along with post-marketing monitoring and other implementations.¹ A legal and regulatory framework has been put into place to govern the product development for ATMPs. The legal and regulatory framework is hierarchical and is organized in three levels:

• Legislation
  All EU legislation including regulations and directives in the area of medicinal products for human use is compiled in Volume 1 of "The Rules Governing Medicinal Products in the European Union."
  
  The requirements and procedures for marketing authorization, as well as the rules for monitoring authorized products, are primarily stipulated in Directive 2001/83/EC and in Regulation (EC) No 726/2004.  The Table 1 of Appendix lists relevant legislations in regulation and directive.¹
   

• Explanation and guideline
  To facilitate the interpretation of the legislation and its uniform application across the EU, a series of guidelines of regulatory procedures and scientific requirements have been developed. A detailed explanation of the marketing authorization procedures and other regulatory guidance is contained in volume 2of "The Rules Governing Medicinal Products in the European Union"  (Notice to Applicants).  (https://ec.europa.eu/health/documents/eudralex/vol-2_en)  The Table 2 of Appendix lists relevant legislations in guidance.
   

• Scientific and procedural advice
  In general, product or development specific advices can be classified into two categories, namely scientific and procedural. Specific feedback related to a product under development can be obtained through interactions with the regulatory authorities. In fact, competent authorities also suggest it would be helpful for clinical development through a structured process of exchanges of information and conversations in planning stage. Thereby, the competent authorities encourage and welcome early communications and interactions during the product life cycle for scientific and procedural advice with respect to product specific issues and questions. 

2.     Regulatory requirements

EU legislation provides for common rules for conducting clinical trials to test the safety and efficacy of medicines under controlled conditions in the EU. Various rules have also been adopted to address the particularities of certain types of medicinal products and the promotion of research in areas of ATMPs as intended use for rare disease, pediatric patients. The ATMPs cover three types of medicines for human use including somatic cell medicine, gene therapy medicine, and tissue-engineering medicine which is a technical, not mechanistic, scheme in classification.¹

The authorization of the ATMPs builds on comprehensive data requirements from structured and stepwise evaluations of quality, safety and efficacy, to ensure that innovative medicinal products under development for human use are of acceptable quality with a favorable benefit-risk profile that can change the natural history of intended human diseases. ¹

1)   Quality evaluation

When applying for marketing authorization, companies must provide evidence demonstrating that the product is of sound quality. This is assessed in accordance with criteria set out in EU legislation (Annex 1 of Directive 2001/83/EC and guidelines (EudraLex Volume 3).¹

The quality evaluations are carried out based on a set of rules and good practice guidelines that provide safeguards against deviation from product specifications and inappropriate production and distribution practices, including source materials and testing and release criteria. Further guidance on quality is provided in EudraLex - Volume 4, and the key elements are shown in Table 2.

2)   Safety and efficacy evaluation

The safety and efficacy of medicines are evaluated through a series of clinical studies in phases. For investigational medicines, sponsors are required to demonstrate safety and efficacy through experimental data and by providing agreeable interpretations of the clinical trials.^1-3

Safety and efficacy continue to be monitored after marketing authorization through pharmacovigilance activities and in reviews of the benefit-risk data in a larger patient population.¹

3.    General path to market

The data on the safety and efficacy of investigational ATMPs will be assessed by the competent authorities before a product receives marketing authorization. For centrally authorized products of ATMPs, the assessment is carried out by the Commission of Advanced Therapies (CAT) of the European Medicines Agency (EMA) even though the approval of the clinical trial application (CTA of ATMPs) is the responsibility of the national competent authority (NCA) of a member state. The Committee for Medicinal Products for Human Use (CHMP) falls under the EMA and is responsible for reviewing IMPs for human use. This committee works closely with CAT on MAA of ATMP as a higher authority for ensuring the quality evaluation of MAA of ATMP. 

https://ec.europa.eu/health/authorisation-procedures-centralised_en. Some critical questions should be addressed before preparing a clinical development plan (Table 1)².

• Classification and certification
  
  Classification is carried out by the EMA, which makes recommendations with EC in 60 days. ATMPs are a product category with substantially modified starting materials of DNA, cells and tissues and their mode of action is attributable to the substantial modifications from production on an industrial scale. It may be helpful for certain ATMPs, especially in the SCTMPs area. It will offer ascertainment on the regulatory path and necessary guidance for both documentation and data sets as needed for a MAA.
  https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-therapy-classification

• Quality, non-clinical and clinical study
  
  The ATMPs are usually characterized by different starting materials with distinctive biological features. Different strategies and designs for quality characterization, non-clinical study and early phases of clinical study for ATMPs may need to be adopted which are different from that of traditional IMPs. The evaluation parameters are also different, which require different methodology in measurement and timeframe to follow-up for outcome.^3-5https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy_en.pdf

•  Marketing authorization application (MAA)
  CAT is one of the seven committees in EMA which oversees the review process for MAA of ATMPs. It makes recommendations to CHMP regarding MA. If CHMP concurs with CAT, it generates a favorable opinion to EC, which grants the MA. It usually takes 277 procedural days from MAA to final decision. 

4.   Other important considerations

• GMOs
  
  ATMPs are also regulated under the current GMO regulations either in the framework of deliberate release (Directive 2001/18/EC) or contained use (Directive 2009/41/EC) which requires environmental and health risk assessment before or in parallel to the clinical trial application. The directives being implemented in the member states are varied in practice with significant procedural differences. For deliberate release, formal consent is always required before activity may start and only higher classes of risk categories pre-approval. In general, ATMPs may likely be subject to contained use with the understanding that there is no intention to release the IMPs, and the activities in clinical trials are not expected to release the IMPs into the environment. In addition, Directive 2001/18/EC focuses on the deliberate release of genetically modified plants and agricultural products, not IMPs.
  
  On the operational level, it must follow the specific requirements of risk assessment with respect to deliberate release or contained use in each member state. Shedding and transmission studies should be carried out accordingly, as the basis for determining the environmental risk and effects on human health. The EMA provides guidelines for conducting the risk assessment and lists specific scientific requirements for the exercise. (https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-environmental-risk-assessments-medicinal-products-consisting-containing-genetically_en.pdf and https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-scientific-requirements-environmental-risk-assessment-gene-therapy-medicinal_en.pdf).
  
  While the review of ATMPs is a centralized procedure by CAT of EMA, however, CTA and GMO assessment typically occurred independently at the national level. Central to the GMO assessment is environment risk analysis, using either a framework of contained use or deliberate release. The contained use is defined by the risk class of the GMOs and protective barriers are designed to limit the unexpected exposure of the potentially infective agents and harmful effects. The deliberate release is, in contrast, in consideration of less restrictive measures to protect or limit the public from exposure in the general environment.⁴ 
  
  The methodology for risk assessment is similar for the contained use and the deliberate release; including steps of hazard identification, characterization, exposure assessment and risk assessment. The requirements for the data and information regarding the IMPs and the environment may be of greater burden in performing the risk analysis to the sponsor for deliberate release, since the containment procedures are less stringent.
   

• Orphan medicinal product
  If a target disorder of unmet medical needs with prevalence of less than 5 per 10,000 population, an ATMP may be qualified as orphan medicinal product.² 
   

• Pediatric study plan
  A Pediatric Investigational Plan (PIP) is required if ATMPs are indicated for affected children before the completion of the Phase 1 study for the ATMPs, which is intended for pediatric patients.²
  
   

Dave Li MD, PhD, KCR Trial Execution Consulting

References

1. European Commission: Legal framework governing medicinal products for human use in the EU https://ec.europa.eu/health/human-use/legal-framework_en
2.  Detela G and Lodge A, EU Regulatory Pathways for ATMPs: Standard, Accelerated and Adaptive Pathways to Marketing Authorisation. Mol Ther Methods Clin Dev. 2019 Jan 29;13:205-232.
3. Salmikangas P and Schuessler-Lenz M et al.  Marketing Regulatory Oversight of Advanced Therapy Medicinal Products (ATMPs) in Europe: The EMA/CAT Perspective. Adv Exp Med Biol. 2015; 871:103-30. doi: 10.1007/978-3-319-18618-4_6.
4. Renner M and Anliker B et al. Regulation for Gene and Cell Therapy Medicinal Products in Europe In S. Terai, T. Suda (eds.), Gene Therapy and Cell Therapy Through the Liver,© Springer Japan 2016 105
5. EMA/CAT/852602/2018 Committee for Advanced Therapies (CAT) 31 January 2019 Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials (Draft) https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy_en.pdf

Appendix

European Legislations Relevant to ATMP

Directive 90/385/EEC 20 June 1990 On the approximation of the laws of the Member States relating to active implantable medicalCombined ATMPs

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:31990L0385&from=EN

Directive 93/42/EEC 14 June 1993 Concerning medical devicesCombined ATMPs

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:01993L0042-20071011&qid=1541092964363&from=EN

Regulation (EC) No 141/2000

16 December 1999 On orphan medicinal productshttps://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02000R0141-20090807&qid=1541091199884&from=EN

Regulation (EC) No 847/2000 7 April 2000 Laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’

https://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2000:103:0005:0008:en:PDF

Directive 2001/18/EC 12 March 2001     On the deliberate release into the environment of genetically modified organisms and repealing

Council Directive 90/220/EEC     Deliberate release of GMOs

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0018-20180329&from=EN

Directive 2001/20/EC 4 April 2001 On the approximation of the laws, regulations and administrative provisions of the Member Statesrelating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use Conducing randomized clinical trials and GCP

https://ec.europa.eu/health/human-use/clinical-trials/directive_en

Directive 2001/83/EC6 November 2001 On the Community code relating to medicinal products for human use The general requirement to document the quality, non-clinical and clinical development

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0083-20121116&from=IT

Directive 2002/98/EC27 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         Human blood and blood components

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2002_98/dir_2002_98_en.pdf

Directive 2003/63/EC 25 June 2003 Amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use To regulate ATMPs as a new category including gene and cell therapy productshttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2003_63/dir_2003_63_en.pdf

Directive 2003/94/EC8 October 2003 Laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use GMP https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32003L0094&qid=1541089722176&from=EN

Directive 2004/33/EC 22 March 2004 Implementing Directive 2002/98/EC of the European Parliament and of the Council as regards certain technical requirements for blood and blood components        Blood and blood components

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:091:0025:0039:EN:PDF

Directive 2004/23/EC 31March 2004 On setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells For the donation, procurement and testing of the human tissues or cells that will become the starting materials of the ATMPs

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:102:0048:0058:en:PDF

Regulation 726/2004/EC31 March 2004 Laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency  ERA requirements

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol1/reg_2004_726/reg_2004_726_en.pdf

Directive 2005/28/EC8 April 2005 Laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization of the manufacturing or importation of such productsGCP

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2005_28/dir_2005_28_en.pdf

Directive 2005/61/EC30 September 2005Implementing Directive 2002/98/EC of the European Parliament and of the Council as regards traceability requirements and notification of serious adverse reactions and events Legislation concerning traceability and pharmacovigilance follow-up

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/commission-directive-2005/61/ec-30-september-2005-implementing-directive-2002/98/ec-european-parliament-council-regards-traceability-requirements-notification-serious-adverse_en.pdf

Directive 2005/62/EC30 September 2005 Implementing Directive 2002/98/EC of the European Parliament and of the Council as regards Community standards and specifications relating to a quality system for blood establishments

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/commission-directive-2005/62/ec-30-september-2005-implementing-directive-2002/98/ec-european-parliament-council-regards-community-standards-specifications-relating-quality-system_en.pdf

Regulation (EC) No 190/20062 February 2006 Fixing the maximum reduction in the duty on maize imported in connection with the invitation to tender issued in Regulation (EC) No 2093/2005

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32006R0190&from=EN

Directive 2006/17/EC8 February 2006 Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:038:0040:0052:EN:PDF

Directive 2006/86/EC24 October 2006  Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells.

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:294:0032:0050:EN:PDF

Regulation (EC) No 1901/200612 December 2006 On medicinal products for pediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004

https://publications.europa.eu/en/publication-detail/-/publication/f02fd0de-82a9-42d8-9cd1-723176bb5ce0/language-en

Regulation (EC) No 1902/200620 December 2006 Amending Regulation 1901/2006 on medicinal products for pediatric use (Text with EEA relevance)

https://tukija.fi/documents/1481661/5113082/1902amendment.pdf/fac4060b-1f13-4fec-8cb7-ce8babbfad3a/1902amendment.pdf.pdf

Regulation (EC) No 1394/200713 November 2007 On advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004To reg ulate three classes of ATMPs as gene, cell and tissue-engineered products

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2007_1394/reg_2007_1394_en.pdf

Regulation (EC) No 1234/200824 November 2008 Concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2008_1234_cons_2012-11-02/reg_2008_1234_cons_2012-11-02_en.pdf

Directive 2009/41/EC6 May 2009 On the contained use of genetically modified micro-organisms

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:125:0075:0097:EN:PDF

Directive 2009/53/EC 18 June 2009 Amending Directive 2001/82/EC and Directive 2001/83/EC, as regards variations to the terms of marketing authorizations for medicinal products

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2009_53/dir_2009_53_en.pdf

Directive 2009/84/E  28 July 2009 Amending Directive 98/8/EC of the European Parliament and of the Council to include sulfuryl fluoride as an active substance in Annex I thereto

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:197:0067:0069:EN:PDF

Directive 2009/120/EC14 September 2009 Amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products - Technical requirements for ATMPs which are reviewed by the centralized procedure by Committee for Advanced Therapy (CAT);

-           Risk-based approach (RBA)

-           GTMPs are genetically modified, SCTMPs and TEPs are not.

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2009_120/dir_2009_120_en.pdf

Regulation (EU) No 1235/201015 December 2010 Amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency and Regulation(EC) No 1394/2007on advanced therapy medicinal products

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:348:0001:0016:EN:PDF

Directive 2011/38/EU 11 April 2011 Amending Annex V to Directive 2004/33/EC with regards to maximum pH values for platelets concentrates at the end of the shelf life

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32011L0038&from=en

Directive 2011/62/EU 8 June 2011 Amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:174:0074:0087:EN:PDF

Directive 2012/26/EU 25 October 2012  Amending Directive 2001/83/EC as regards pharmacovigilance        https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:299:0001:0004:EN:PDF

Regulation (EU) No 1027/201225 October 2012 Amending Regulation (EC) No 726/2004 as regards pharmacovigilance

https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:316:0038:0040:EN:PDF

Directive 2012/39/EU26 November 2012 Amending Directive 2006/17/EC as regards certain technical requirements for the testing of human tissues and cells

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32012L0039&from=EN

Regulation (EU) No. 536/2014 16 April 2014 On clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC   GCP

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

Directive 2014/110/EU17 December 2014 Amending Directive 2004/33/EC as regards temporary deferral criteria for donors of allogeneic blood donations

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32014L0110&from=EN

Directive (EU) 2016/121425 July 2016  Amending Directive 2005/62/EC as regards quality system standards and specifications for blood establishments          

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016L1214&from=EN

Regulation (EU) 2017/745 5 April 2017  On medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC    

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745&from=EN

Regulation (EU) 2018/781 29 May 2018Amending Regulation (EC) No 847/2000 as regards the definition of the concept ‘similar medicinal product’

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32018R0781&from=EN

Guideline relevant to ATMP 

CHMP/BWP/2458/03 26 May 2005 Guideline on development and manufacture of lentiviral vectors

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-development-manufacture-lentiviral-vectors_en.pdf

CHMP/EWP/83561/2005 27 July 2006 Guideline on clinical trials in small populations On orphan drug trial

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-trials-small-populations_en.pdf

EMEA/CHMP/SWP/4447/00 corr 21 01 June 2006Guideline on the environmental risk assessment of medicinalproducts for human use

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-environmental-risk-assessment-medicinal-products-human-use-first-version_en.pdf

EMEA/273974/2005 16 November 2006 Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors           

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-testing-inadvertent-germline-transmission-gene-transfer-vectors_en.pdf

EMEA/CHMP/BWP/473191/2006 – Corr 11 December 2006  Guideline on environmental risk assessments for medicinal products consisting of, or containing genetically modified organisms (GMOs) GMO

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-environmental-risk-assessments-medicinal-products-consisting-containing-genetically_en.pdf

EMEA/CHMP/SWP/28367/07 19 July 2007 Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with investigational medicinal products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-mitigate-risks-first-human-clinical-trials-investigational-medicinal_en.pdf

EMEA/CHMP/410869/2006 21 May 2008 Guideline on human cell-based medicinal products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-human-cell-based-medicinal-products_en.pdf

EMEA/CHMP/GTWP/125459/2006 30 May 2008 Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-studies-required-first-clinical-use-gene-therapy-medicinal-products_en.pdf

EMEA/CHMP/GTWP/125491/2006 30 May 2008 Guideline on scientific requirements for the environmental risk assessment of gene therapy medicinal products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-scientific-requirements-environmental-risk-assessment-gene-therapy-medicinal-products_en.pdf

EMEA/CHMP/BWP/398498/2005 24 July 2008Guideline on virus safety evaluation of biotechnological Investigational medicinal products 

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-virus-safety-evaluation-biotechnological-investigational-medicinal-products_en.pdf

EC ENTR/F/2/SF/dn D (2009) 35810 03/12/2009 detailed guidelines on good clinical practice specific to advanced therapy medicinalProducts

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2009_11_03_guideline.pdf

EMEA/CHMP/GTWP/60436/2007 22 October 2009Guideline on follow-up of patients administered with gene therapy medicinal products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-follow-patients-administered-gene-therapy-medicinal-products_en.pdf

EMEA/CHMP/CPWP/83508/2009 22 October 2009Guideline on xenogeneic cell-based medicinal products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-xenogeneic-cell-based-medicinal-products_en.pdf

EMA/CHMP/BWP/706271/2010 21 July 2011 Guideline on plasma-derived medicinal products

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-plasma-derived-medicinal-products_en.pdf

EMA/CAT/CPWP/686637/2011 Committee for Advanced Therapies (CAT) 11 February 2013 Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products      

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-risk-based-approach-according-annex-i-part-iv-directive-2001/83/ec-applied-advanced-therapy-medicinal-products_en.pdf

EMA/CHMP/BWP/271475/2006 rev.1 Committee for medicinal products for human use (CHMP) 21 July 2016 Guideline on potency testing of cell-based immunotherapy medicinal products for the treatment of cancer

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-potency-testing-cell-based-immunotherapy-medicinal-products-treatment-cancer-revision-1_en.pdf

EUROPEAN COMMISSION Guidelines of 22.11.2017 C (2017) 7694 final 22 November 2017 Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf

EMA/CAT/216556/2017 Inspections, Human Medicines, Pharmacovigilance and Committees Division 3 July 2017 Development of non-substantially manipulated cell-based atmps1: flexibility introduced via the application of the risk-based approach            

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/development-non-substantially-manipulated-cell-based-advanced-therapy-medicinal-products-flexibility_en.pdf

EMEA/149995/2008 rev.1 Committee for Medicinal Products for Human Use (CHMP)

25 January 2018 Guideline on safety and efficacy follow-up and risk  Management of Advanced Therapy Medicinal Products 

(Draft)https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-safety-efficacy-follow-risk-management-advanced-therapy-medicinal-products-revision_en.pdf

EMA/CAT/80183/2014 Committee for Advanced Therapies (CAT)

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

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-clinical-aspects-gene-therapy-medicinal-products_en.pdf

EMA/CAT/GTWP/671639/2008 Rev. 1 2 Committee for Advanced Therapies (CAT)

26 July 2018Guideline on quality, non-clinical and clinical aspects of 4 medicinal products containing genetically modified cells    

https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clinical-aspects-medicinal-products-containing-genetically_en.pdf

EMA/CAT/852602/2018 Committee for Advanced Therapies (CAT)

31 January 2019 Guideline on quality, non-clinical and clinical requirements. For investigational advanced therapy medicinal products

In clinical trials (Draft)          https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy_en.pdf