ATMP-Development & Marketing Authorisation
Basic Research
Preclinical Development
GMP Process Development & Acquisition of a Manufacturing License
Clinical Trials
(Phase I–III)
Marketing Authorization
Market Launch / Start of clinical use
Negotiations and Determination of a Reimbursement Amount
Long-term follow-up after market release
ATMP-Development & Marketing Authorisation
Basic Research
Preclinical Development
GMP Process Development & Acquisition of a Manufacturing License
Clinical Trials (Phase I–III)
Marketing Authorization
Market Launch / Start of clinical use
Negotiations and Determination of a Reimbursement Amount
Long-term follow-up after market release
Basic Research
Preclinical Development
GMP Process Development & Acquisition of a Manufacturing License
Clinical Trials
(Phase I–III)
Marketing Authorization
Market Launch / Start of clinical use
Negotiations and Determination of a Reimbursement Amount
Long-term follow-up after market release
Objective
Identification of the therapeutic approach, feasibility, and initial safety assessments
Key Steps
- Genetic validation, biomarker identification, omics technologies, vector optimization, cell line testing, organoid models
- preliminary safety and toxicity assessments
- POC
Responsible Organisations/Institutions/ Authorities
Executing institution:
Typically, university and non-university research institutions (e.g., MPI, Helmholtz-Centers, Fraunhofer-Institutes)
Decision-makers:
University and non-university research institutions (e.g., MPI, Helmholtz-Centers, Fraunhofer-Institutes) and funding agencies (e.g., DFG; equiv. USA: NIH )
Technology Transfer Aspects
- Protection of IP through patent applications
- Collaboration agreements with industry partners
- Transfer of know-how
Validation of research findings for practical application and scale-up strategies
Regulatory Aspects
- Early ATMP Categorization / Product Classification
- Refine the mechanism of action, target population and product concept
- Consideration of starting materials, cell type/vector, and manufacturability
- Initial safety risks: immunogenicity, tumorigenicity, persistence
- Regulation as a guide for translation: from research idea to developable product
Typical Duration and Cost Range in EUR
3 – 6 years,
10 – 30 M
Example: CAR -T-cell-Therapy
Identifiaction of CD19 as target for CAR-T-cells
Objective
Evaluation of safety and pharmacokinetics in appropriate in vitro and animal models
Key Steps
- Selection of an appropriate in vitro or animal model to investigate the mechanism of action
- Toxicological studies and PK/PD analyses to identify adverse- and dose-related effects on individual organs, biodistribution studies, immunogenicity assessment to evaluate an immune response and investigation of long-term toxicity
- Start of drafting the required regulatory documentation (e.g., IMPD)
- Initiation of GMP process development in preparation for clinical trial approval
Responsible Organisations/Institutions/ Authorities
Executing institution:
University and non-university research institutions (e.g., MPI, Helmholtz-Centers, Fraunhofer-Institutes), CROs, pharmaceutical companies
Decision-makers:
University and non-university research institutions (e.g., MPI, Helmholtz-Centers, Fraunhofer-Institutes), pharmaceutical companies
Technology Transfer Aspects
- Consolidation of patent protection for (preclinical) therapy development, as well as IP protection
- Co-development and/or licensing to development partners
- Validation and transfer of preclinical data/methods/test systems
- Preparation for industrial manufacturing and scale-up
Regulatory Aspects
- Risk-based preclinical development plan
- Justify appropriate models: in vitro, ex vivo, animal model, organoid
- Safety: biodistribution, persistence, off-target effects, immunogenicity, tumorigenicity
- Dose justification for first-in-human
- Preparation of the IMPD, IB, protocol, and regulatory consultation
Typical Duration and Cost Range in EUR
1 – 3 years,
5 – 10 M
Example: CAR -T-cell-Therapy
Use of mouse models for an initial assessment of the safety and efficacy of CD19-CAR-T cells
Objective
Development of a GMP-compliant manufacturing process; manufacturing under GMP conditions with quality control; application for and obtaining authorization to manufacture a specific therapeutic product
Key Steps
GMP-Process Development & Validation: GMP-compliant development with stepwise qualification and validation of critical processes (aseptic, analytical, process-specific)
Production & Quality Control:
Manufacturing with continuous in-process controls (cell count, viability, transduction) as well as final product testing prior to release (sterility, mycoplasma, endotoxins). Supplementary stability studies for shelf life and storage conditions
Scaling & Approval:
Scale-up of production following successful validation, followed by the submission of an application for and receipt of a manufacturing authorisation upon confirmation of GMP compliance
Responsible Organisations/Institutions/ Authorities
GMP-Development
Executing institution:
University and non-university research institutions (e.g., MPI, Helmholtz-Centers, Fraunhofer-Institutes), pharmaceutical companies, CDMOs
Manufacturing Authorization
Regulatory decision-makers:
State authorities in consultation with the PEI
Technology Transfer Aspects
- Development of production processes (patent protection)
- Technology transfer from research to production scale
- Analytical method validation and transfer
- Automation technology
- Ensuring quality standards for regulatory approval / cleanroom technology
- Documentation of patent-protected manufacturing processes
- Training of personnel for quality-assured production
- Establishment of quality control for regulatory inspection
Regulatory Aspects
- GMP-compliant manufacturing process and quality strategy
- Define critical quality attributes and process parameters
- Efficacy testing, release criteria, stability, etc.
- Patient-product matching, traceability from collection to administration, as well as GMP-compliant manufacturing and quality control
- Manufacturing authorization and GMP compliance as prerequisites for clinical use
- Submission of a PIP or waiver
Typical Duration and Cost Range in EUR
1 – 3 years,
Process Development and QC
20 – 50 M
Regulatory fees, inspections, and manufacturing authorisation
5,000 – 20,000
Example: CAR -T-cell-Therapy
Development of a manufacturing process for patient-specific CD19 CAR-T cells in compliance with GMP conditions, followed by the acquisition of the corresponding manufacturing authorization
Objective
Evaluation of safety, efficacy, and optimal dosing in study participants
Key Steps
Clinical Trial Application:
Preparation of the required documents (Clinical Trial Protocol, IB, IMPD), submission to the relevant authorities
Phase I (small cohort):
Safety evaluation, dose escalation, biomarker analysis
Phase II (medium-sized cohort):
Dose determination, PD and efficacy
Phase III (large cohort):
e.g., multicenter clinical trial, long-term data
Responsible Organisations/Institutions/ Authorities
Executing institution:
Clinical trial sites, sponsors (e.g., academic institutions, pharmaceutical companies, etc.), CROs,
Regulatory advisory and decision-making bodies:
EMA (EU): initial consultations and ATMP- classification, PEI: evaluation of the clinical trial for quality and safety, ethics committees: ethical approval (in parallel with the PEI),
USA equiv.: FDA
Technology Transfer Aspects
- Transfer of confidential clinical trial data and protocols (one or more trial sites)
- Implementation of protected treatment protocols and strategies in clinical settings
- Training and competency assessment
- Supply chain from donor to reinfusion
- Ensuring patient safety through standardized procedures and patient recruitment strategies
Regulatory Aspects
- Approval by the relevant authorities and ethics committees
- Key documents: Protocol, IMPD, IB, GMP documentation etc.
Regulatory Advisors and Decision-Makers:
- Where applicable, GMO- related and environmental aspects and long-term follow-up
- Align evidence early on with marketing authorization and subsequent benefit assessment
Typical Duration and Cost Range in EUR
5 – 7 years,
100 – 300 M
Example: CAR -T-cell-Therapy
Kymriah® and Yescarta® underwent clinical trials for the treatment of B-cell leukemia and lymphoma
Objective
Official marketing authorization for the drug based on relevant preclinical and clinical data
Key Steps
- Submission of the marketing authorization application1, including all relevant data2 for scientific evaluation3, including mandatory components, e.g., PIP, and, if applicable, special regulatory status4
- Simultaneous preparation of an RMP to identify potential risks and define corresponding monitoring measures
- Thereafter, granting of a regular or conditional marketing authorization (additional data must be submitted for this)
1EU: MAA, (USA equiv. BLA)
2e.g., preclinical and clinical data etc.
3risk-benefit ratio
4e.g. ODD
Responsible Organisations/Institutions/ Authorities
Decision-makers:
EU: EMA
USA equiv.: FDA
Technology Transfer Aspects
- Submission of marketing authorization applications to, for example, the EMA (EU regulatory authority) and the FDA (U.S. regulatory authority)
- Transfer of regulatory dossiers
- Global regulatory strategy
- Post-marketing safety system
- International recognition of the therapy as a medical advancement through market approval
Regulatory Aspects
- Centralized EU marketing authorization via the EMA/CHMP
- Dossier: QUality/CMC, preclinical, clinical, GMP, RMP, PV
- Benefit-risk assessment as the core of the marketing authorization process
- Explore options: ODD, PRIME, accelerated or conditional approval
- Consider registries, risk minimization, and post-authorization requirements
Typical Duration and Cost Range in EUR
1 – 2 years,
Cost of regulatory approval:
2–3 M
Example: CAR -T-cell-Therapy
FDA- approval (in the U.S.) of Kymriah® (Novartis) in 2017 as the first CAR-T cell therapy
Objective
Safe and effective administration to the patient(s), including pre- and post-treatment care; scaling of logistics and production
Key Steps
- Patient selection
- Product manufacturing, if necessary
- Delivery, administration, monitoring
- Management of side effects, if necessary
Responsible Organisations/Institutions/ Authorities
Qualified Clinics
Qualified to administer ATMP treatments
Specialized Clinics
Qualified clinics with additional experience in administering ATMP treatments
Transfusion Centers
Focus on blood products
Decision-makers:
G-BA: Establishes minimum requirements for the centers
MD: Review of minimum requirements
Technology Transfer Aspects
- Integration of the therapy into routine clinical practice (e.g., product handling, logistics, data transmission, treatment protocols)
- Patient education and training of medical staff
Regulatory Aspects
- Implementation of approval requirements in clinical practice
- Qualified centers, trained staff, standardized procedures
- Logistics, including cryotransport and temperature control where necessary, and traceability
- Logistics, cryotransport and temperature control as required, traceability
- Adverse event management and measures minimize risks
- Safe application as part of the overall regulatory strategy
Typical Duration and Cost Range in EUR
6 – 12 months,
0.2 – 4 M per patient
Example: CAR -T-cell-Therapy
Production and subsequent infusion of CD19-CAR-T cells in patients with refractory B-cell lymphoma
Objective
Conducting an added-benefit assessment with the G-BA and subsequently negotiating a reimbursement amount with the GKV-Spitzenverband
Key Steps
- Preparation of a dossier by the manufacturer to demonstrate additional benefit
- Conducting the commenting procedure with the G-BA, taking clinical expertise into account
- Decision by the G-BA on the added benefit; this forms the basis for negotiations between the manufacturer and the GKV-Spitzenverband regarding the reimbursement amount
Responsible Organisations/Institutions/ Authorities
Added benefit assessment
Executing institution:
IQWiG (Scientific analysis and assessment report for the G-BA)
Decision-maker:
G-BA
Negotiation of reimbursement amounts
Executing institution:
GKV-Spitzenverband (representing statutory health insurance providers) and manufacturers. They reach a mutual agreement; if they don’t, an arbitration board decides
Technology Transfer Aspects
- Demonstration of added benefit in patient care compared to an appropriate comparative therapy
- Reimbursement amount negotiations, particularly based on the extent of the added benefit
- Possible acquisition of additional data from routine clinical practice
Regulatory Aspects
- Approval ≠ guaranteed patient access
- AMNOG: early benefit assessment, added benefit, comparative therapy
- Consider patient-relevant endpoints and evidence gaps early on
- Price negotiations with the GKV-Spitzenverband
- Align clinical development with future reimbursement and clinical practice
Typical Duration and Cost Range in EUR
Approx. 12 months,
1 – 4 M
Example: CAR -T-cell-Therapy
Contractually stipulated reimbursement of Kymriah® treatment expenses by health insurance companies following the AMNOG-assessment
Objective
Long-term monitoring of the safety and efficacy of the product during use
Key Steps
- Preparation of a PV, RMP, and post-authorization plan
- This includes for instance: PV for the continuous collection and evaluation of adverse events, long-term follow-up to monitor patients over an extended period, RMP, and regular safety reports
- Supplementary data from RWE registry studies
Responsible Organisations/Institutions/ Authorities
Executing institution:
Manufacturers (e.g., academic institutions, pharmaceutical companies, etc.), pharmacovigilance networks, clinical registries, healthcare professionals, and patients
Decision-maker:
EU: EMA
Approval of risk management plans and establishment of PASS und PAES
(USA equiv.: FDA)
Technology Transfer Aspects
- PV and RMP
- Registry integration: Collection and integration of real-world data from clinical practice
- Data transfer to continuously improve patient care
- Long-term maintenance of the production and availability of the developed therapies
Regulatory Aspects
- PV and RMP
- Long-term follow-up, registries, real-world data
- Monitoring of late-onset risks: e.g., persistence, late toxicity, secondary malignancies, loss of efficacy
- Compliance with PASS/PAES and regulatory requirements
- Post-authorization phase as part of the ATMP development model
Typical Duration and Cost Range in EUR
5 – 15 years,
0.5 – 1 M
Example: CAR -T-cell-Therapy
Long-term monitoring to assess efficacy and safety in patients treated with Kymriah®