1.   Legal and regulatory framework 

• 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

3.    General path to market

• 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
  
   

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

Guideline relevant to ATMP