While ATMPs are classified as biologics by the FDA and EMA, they face additional regulatory hurdles compared to more established biologics like monoclonal antibodies (mAbs). For example, ATMPs require specialized manufacturing processes that are often individualized for each patient. This raises significant challenges for developers in demonstrating the scalability, quality, consistency, and efficacy of ATMPs. These advanced therapies also present several safety considerations that can further complicate regulatory approval. This includes risks of contamination, immunogenicity, tumorigenicity, off-target genetic effects, and high patient-to-patient variability. To account for these unique complexities of ATMP development, regulatory authorities have developed specific pathways for their approval and regulation. The main EU and US regulatory pathways for ATMPs are shown in Figure 3, and a more detailed overview can be found in supplementary Tables 1 and 2.

The Committee for Advanced Therapies (CAT) is a multi-disciplinary body within the EMA that plays a central role in the regulation of ATMPs in Europe, offering scientific guidance and contributing to the assessment of market authorization applications (MAAs). The overarching legislative framework for ATMPs is set out in Regulation (EC) No 1394/2007, which builds on and amends Directive 2001/83/EC and Regulation (EC) No 726/2004. Additional detail is provided in Commission Directive 2009/120/EC (amending Directive 2001/83/EC), outlining the scientific and technical requirements for gene-therapy medicinal products, somatic cell-therapy medicinal products, and tissue-engineered medicinal products.  

In addition to this core legislation, developers must comply with the Cell and Tissue Directive 2004/23/EC (and subsequent modifications) – which will soon become Substances of Human Origin Regulation (SoHO-R) – when using human-derived materials, such as tissues and cells, as source material. Introduced in 2024, SoHO-R establishes a unified regulatory framework in the EU to ensure the quality and safety of substances of human origin. By 2027, this framework will repeal the Cell and Tissue Directive (2004/23/EC) and the Blood and Blood derivatives Directive (2002/98/EC). Hence, cell-based ATMP developers must fulfil this legislation concerning the procurement of cell-based material, including donation, collection, and testing.  

Furthermore, for ATMPs that involve genetically modified organisms (GMOs), there are two separate legal pathways required – the Content Use Directive (2009/41/EC) and the Deliberate Release Directive (2001/18/EC). As EU Directives are implemented at a national level, the application of this GMO legislation varies between different Member States. In these cases, developers must submit a GMO authorization request to the competent authority at a national level during development. Additionally, an environmental risk assessment (ERA) in the MAA Module 1 must be submitted at the time of registration for the market. However, the European Commission is striving to harmonize this GMO regulatory approval process, proposing a single CTA framework for ATMPs and other medicines containing GMOs, to be managed centrally in CTIS (Clinical Trial Information System).  

As for all drugs in the EU, a clinical trial application (CTA) must be submitted and approved by the relevant national authorities and ethics committees before each clinical trial can begin. The CTA must include detailed information on the product's quality, non-clinical, clinical controls, and data. These controls are outlined in the EMA’s recent ‘Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials’, released in January 2025.  

Following successful clinical trials, a marketing authorization application (MAA) is submitted to the EMA, with health technology assessment (HTA) procedures conducted almost in parallel. ‘Regulation (EU) 2021/2282’ in force as of January 2025 is aiding a more structured and collaborative approach for HTA. This regulation introduces joint clinical assessments starting from certain medical products, including ATMPs, to be conducted centrally to avoid multiple EU/EEA countries independently evaluating the same data. The introduction of this regulation aims to improve the efficiency, transparency, and consistency of HTA processes across the EU. 

To further support the development of innovative ATMPs, the EMA offers a portfolio of programs. This includes the Priority Medicines (PRIME) scheme, designed to expedite the development and review of therapies that address conditions with an unmet medical need. Through PRIME, developers receive early and enhanced advice from the EMA and may be eligible for accelerated MAA assessment. The EMA also offers the Innovation Task Force (ITF) briefing meetings, which provide an opportunity to engage in early dialogue with the EMA on innovative medicines. These meetings address regulatory, technical, and scientific concerns arising from innovative medicines, technologies, and methodologies. Taking place earlier in the development process than scientific advice, they facilitate informal exchanges of information and guidance. The EMA also offers a Pilot Program to support academic and non-profit organizations developing ATMPs. In addition to this, the EMA has the Qualification of Novel Methodologies for medicine development process, which offers scientific advice to support the qualification of innovative development methods for their specified intended use in pharmaceutical research and development.  

Pharmaceutical companies with large medicinal product portfolios can apply to attend informal meetings with the EMA, called Portfolio and Technology meetings. These meetings can: identify any issues impacting the progress of product portfolios and assist successful development; capture innovative and disruptive technologies; and anticipate the scientific and regulatory expertise needed to assess future applications. 

Last but not least, the EMA proposes the orphan designation program that incentivizes the development of treatments for rare diseases. This program offers several benefits, such as protocol assistance, post-authorization market exclusivity, and reduced fees, depending on the sponsor’s status and service needs. In some cases, orphan-designated ATMPs that have completed development but haven’t yet been authorized may be made available to patients under compassionate use programs.  

The Center for Biologics Evaluation and Review (CBER), a division of the FDA, is responsible for the regulation and approval of Cellular and Gene Therapy Products. In the US, the term ATMPs is not used, and the FDA generally classifies them as either cell and gene therapies, or human cells, tissues, and cellular and tissue-based products (HCT/Ps). CBER regulates these therapies under the authority of the Public Health Service Act (PHSA), in addition to the Federal Food, Drug, and Cosmetic Act (FD&C Act), and specific sections of the US Code of Federal Regulations (CFR), particularly Title 21.  

As with all drugs in the US, Investigational New Drug (IND) submission is required for Cellular and Gene Therapy Products prior to clinical testing. Following successful clinical trials, the biologics license application (BLA) pathway is required for market approval. The FDA has established several regulatory programs that can expedite the development and review of Cellular and Gene Therapy Products for serious medical conditions:  

• Fast Track – Designed for therapies to treat serious conditions with an unmet medical need.
• Breakthrough Therapy – For treatments that could substantially improve patient outcomes over available therapies, based on preliminary clinical evidence.
• Regenerative Medicine Advanced Therapy (RMAT) Designation – For the faster approval of regenerative medicines, including Cellular and Gene Therapy Products, intended to treat serious conditions with unmet medical needs.
• Accelerated Approval – For drugs treating serious conditions with an unmet medical need, with approval based on a surrogate endpoint (a marker that predicts clinical benefit), allowing for faster approval. 
• Priority Review – Speeds up the review process for products that have the potential to improve the treatment, diagnosis, or prevention of serious medical conditions. 

In Europe, the evaluation of an initial CTA submitted through the Clinical Trials Information System (CTIS) as per Clinical Trial Regulation (CTR) 536/2014/EC generally takes up to 60 procedural days. However, for ATMPs, this timeline could be extended if deemed necessary by the regulatory authorities. This period includes validation, assessment, and the decision on whether the clinical trial is fit to be performed in the specified EU Member States and EEA (European Economic Area) countries. However, this 60-day timeline may also be extended if a Member State Concerned (MSC) issues Requests for Information (RFIs) during validation or assessment phases.⁴ Specifically, the timeline can be extended by up to 15 days for validation RFIs and up to 31 days for assessment RFIs. Regarding market authorization, the EMA conducts a standard review within a maximum of 210 procedural days, excluding two clock stops for applicants to address questions. These clock stops can extend the timeline by several months. For applicants granted accelerated approval, the review period can be reduced to 150 days, excluding clock stops.⁵ 

In contrast, in the US, the FDA reviews an initial IND application within 30 days of receipt. Providing the FDA doesn’t impose a clinical hold within this period, sponsors can proceed with the clinical trial. However, for any unresolved safety concerns or deficiencies, the FDA may place the trial on clinical hold until these issues are addressed. The FDA's standard review timeline for a Biologics License Application (BLA) is 10 months from the filing date. For applications granted Priority Review designation, the FDA aims to complete the review process within 6 months from the filing period.⁵ 

When developing an ATMP, planning your regulatory strategy should start as early as possible. This should build on a thorough understanding of the mechanism of action, therapeutic indication, and target population, in addition to strong preclinical data to support the safety and efficacy of the therapy. At this stage, understanding the regulatory frameworks specific to the ATMP and using these to develop a robust regulatory strategy will enable a smoother journey to CTA/IND approval and market authorization. This will reduce the risks of costly and time-consuming delays, improving patient access. 

There are several considerations that should be made when planning your regulatory strategy. This includes early R&D considerations, such as countries of intended use, ATMP classification, clinical trial requirements, controls for raw materials and starting materials, and keeping up with regulatory updates.  

One of the first considerations when building your regulatory strategy should be the type of product in development, as this can largely influence the regulatory pathways required. The FDA mainly categorizes these products into Cellular and Gene Therapy Medicinal Products, or HCT/Ps (with minimal manipulation) (Figure 2). However, within Europe, ATMPs fall within four categories: ‘Gene Therapy Medicinal Products’, ‘Somatic Cell Therapy Medicinal Products’, ‘Tissue-Engineering Products’, and ‘Combined ATMPs’, as outlined in Regulation (EC) No 1394/2007, and Part IV of Annex I to Directive 2001/83/EC (Figure 2). The key questions for classification in the EU are: (1) what is the product is made of; (2) what is its scope of use. In particular for cell-based products, it is important to define if the cells are substantially manipulated or not and if they’re intended for “non-homologous” use. 

Some ATMPs also contain medical devices, such as scaffolds for drug delivery. ATMPs that contain one or more medical devices as an “integral part” of the product are classified as ‘combined ATMPs’ in the US. In contrast, ATMPs in Europe that are co-packaged with medical devices, or administered with a separately marketed device, should comply with several additional regulatory frameworks associated with medical devices, including Annex I of the Medical Devices Regulation (MDR), and Regulation 2017/745. Further details on the EMA’s regulation of combined ATMPs can be found in their updated guidelines on investigational ATMPs.  

In the USA, for most combination products, a single IND/marketing application is used for the entire product, with the application pathway corresponding with the designated lead review center for the product. For combination Cellular and Gene Therapy Products, the lead review center may be CBER OTP (Office for Therapeutic Products), with draft guidance for devices intended to deliver drugs and biological products. Although the FDA usually encourages a single application for a combination product, data and information for each constituent part should be included, as if they were separate applications. Any other regulatory frameworks specific to your product also need to be considered, including environmental risk assessments for GMOs, and regulations for the use of human-derived materials.  

Finally, as a result of the different ATMP classifications, relevant consideration should be made on the newly published European Pharmacopoeia General monographs. This includes “Gene therapy medicinal products for human use” (monograph 3186) and General Chapter 5.34 “Additional information on gene therapy medicinal products for human use” that will repeal the only EP monograph 5.14 on Gene Therapy. 

Before manufacturing your ATMP, you should consider the appropriate controls for all raw and starting materials to ensure the quality, safety, and efficacy of the final product. Raw/ancillary materials are defined as components that aren’t present in the final product, and include antibiotics, growth factors, cytokines, and cell culture media components. Raw/ancillary materials should be qualified and tested based on a quality risk management strategy, and information on this can be found in European Pharmacopoeia 5.2.12 and US Pharmacopeia <1043>.  

Starting materials can generally be defined as components that directly contribute to the final product. For cell and gene therapies, this includes viral vectors, human-derived materials such as cells, tissues, blood components, as well as critical process components. As these starting materials directly affect product quality, a phase-appropriate GMP quality system should be adopted to ensure regulatory compliance and minimize risks. The EMA provides detailed guidance on this in the ‘Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials’, published in early 2025. In Europe, developers should also comply with the Cell and Tissue Directive (2004/23/EC and its amended Directives), which will be repealed by July 2027 by the SoHO regulation for human-derived starting materials.  

In the US, the FDA requires developers to provide detailed descriptions of the quality and control measures of all materials (including raw and starting materials) used in Cellular and Gene Therapy Product manufacturing. Specific guidance on this can be found in the FDA’s ‘Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)’.  

At the early stages of developing a cell-based therapy, a key consideration is whether autologous or allogeneic starting materials will be used. To date, many of the approved cell-based therapies are autologous, where cells obtained from a patient are genetically modified and reintroduced into the same individual. Autologous cell-based therapies offer several benefits, including the reduced risk of tissue/cell rejection, infection, and adverse immune responses. However, autologous therapies can be challenging to scale and may be cost-prohibitive due to their personalized nature. 

On the other hand, allogeneic cell therapies, such as off-the-shelf induced pluripotent stem cell (iPSC)-derived therapies, offer an innovative approach to overcome some of these hurdles. With this type of cell therapy, donor-derived iPSCs are differentiated into specific therapeutically relevant cell types. This approach allows for scalable batch production, enabling the treatment of larger numbers of patients. This strategy is expected to lower manufacturing costs and improve scalability but requires special attention for aspects such as viral safety and genetic stability. Additional challenges are faced when developing allogeneic therapies, including the need to build up cell banks (MCB/WCBs), the risk of immune rejection, and the potential risk of tumorigenesis. These factors introduce additional regulatory considerations that must be integrated into the development strategy to ensure success.

Determining the geographic regions where the Cellular and Gene Therapy Products will be marketed is essential early in the development process. In Europe, although CTAs are submitted through the centralized CTIS system, individual member states remain responsible for authorizing clinical trials. As a result, the countries of intended use, and their specific clinical trial requirements, should be a key consideration when developing your regulatory strategy. Additionally, defining the geographical origin of the donor procurement material is crucial for global development efforts.

The ATMP regulatory landscape is constantly evolving to improve patient access while ensuring safety and quality. In the EU, significant reforms are underway, with proposals to revise the existing pharmaceutical legislation, including Regulation 726/2004 and Directive 2001/83/EC. As part of this reform, recent updates include the implementation of CTIS for clinical trial applications, the adoption of the SoHO regulation for substances of human origin, and new guidelines for health technology assessments.  

Similarly to Europe, major updates to ATMP regulations are occurring in the US. In 2024, the FDA launched the START program (Support for clinical Trials Advancing Rare disease Therapeutics). Through ongoing engagement with sponsors in the program, the FDA hopes to gain new insights on how to accelerate the development of investigational CGTs. The FDA has also initiated the Collaboration on Gene Therapies Global Pilot (CoGenT) program, which aims to harmonize global Cellular and Gene Therapy Products regulations, particularly for gene therapies targeting rare diseases. During Cellular and Gene Therapy Product development, it is essential to adapt your strategy to the evolving regulatory landscape, ensuring your product remains compliant to reduce the risk of delays, or even failure. 

Navigating the regulatory landscape for Cellular and Gene Therapy Products is undoubtedly challenging. Our key recommendations are to always start with the end product in mind, maintain proactive communication with the relevant regulatory authorities, and stay up to date with evolving ATMP regulations. When starting to develop your regulatory strategy, it is crucial to determine your product’s classification, in addition to the regulatory frameworks required for the countries of intended use, and necessary controls for all manufacturing steps and materials. For cell-based therapies, special consideration should be made for the choice of autologous or allogeneic starting materials. While allogeneic “off-the-shelf” iPSCs are emerging as a promising and more accessible treatment, these will require unique safety and regulatory considerations.  

Given the intricacy of ATMP development, our final recommendation is to identify an experienced and reliable partner that can support your needs with a holistic and comprehensive offering. This enables access to deep regulatory and scientific support, in addition to integrated development and manufacturing facilities that help streamline workflows, enhance quality control, and accelerate the path to the clinic.  

Find out how Evotec can help you develop your ATMP.

1. Satwani P., Chao K., Lopez-Garcia M., et al. Establishing Costs for Commercial Chimeric Antigen Receptor T-Cell (Tisagenlecleucel; Kymriah) in Children and Young Adult B-Cell Acute Lymphoblastic Leukemia: A Merged Analysis from the Pediatric Real-World CAR Consortium (PRWCC) and Pediatric Health Information System (PHIS). Transplant Cell Ther 2024;30. https://doi.org/10.1016/j.jtct.2023.12.291.  

2. Callenbach MHE., Schoenmakers D., Vreman RA., et al. Illustrating the Financial Consequences of Outcome-Based Payment Models From a Payers Perspective: The Case of Autologous Gene Therapy Atidarsagene Autotemcel (Libmeldy®). Value in Health 2024;27:1046–57. https://doi.org/10.1016/j.jval.2024.05.010.  

3. Rueda J., de Miguel Beriain Í., Montoliu L. Affordable Pricing of CRISPR Treatments is a Pressing Ethical Imperative. CRISPR J 2024;7:220–6. https://doi.org/10.1089/crispr.2024.0042. 

4. CTIS Evaluation Timelines. Available at: https://www.ema.europa.eu/system/files/documents/other/ctis-evaluation-timelines_en_1.pdf. Accessed May 12, 2025. 

5. The evaluation of medicines, step-by-step. Available at: https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/evaluation-medicines-step-step#:~:text=The%20assessment%20of%20a%20marketing,of%20a%20marketing%20authorisation%20application. Accessed May 12, 2025.