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ATMP Sweden Process map Regulatory Process Map

Regulatory Process Map

Welcome to the landing site for ’Regulatory Affairs’. Your role is to identify an appropriate regulatory strategy for the product based on intended countries and regions of interest. You are also responsible for ensuring the product is developed in compliance with the chosen strategy.

Below you can see our ’process map’ that shows what you need to be considering at what stage of ATMP development. There are other process maps for product developer, manufacture, regulatory and clinical needs, that can give you tips on how to address these needs in your team. The objective here is to have the right people considering the right things at the right time to ensure that your ATMP pipeline moves forward as effectively as possible, good for patients in need, good for your pocket to not waste money and time on inefficiencies.

Regulatory

  • 1. Research adaptation

  • 2. Process Qualification

  • 3. GMP manufacturing

  • 4. Clinical Trials

  • 5. Market approval and reimbursement

  • 6. Standard of Care

Process Development

Process Qualification

  • Regulations and directives EudraLex – Volume 1 – European Commission
    • Dir. 2001/83/EC Medicinal Products for Human Use (2009/120/EG amendment)
    • Dir. 2004/23/EC Quality and safety for donation, procurement, testing of human tissues and cells
    • Dir. 2002/98/EC Quality and safety for donation, procurement, testing of blood and blood components
    • Dir. 2001/20/EC GCP for clinical trials
    • Reg. 726/2004 Authorisation and supervision of medicinal products
    • Reg. 1394/2007 Advanced Therapy Medicinal Products
  • Guidelines
    • EMA Quality Guidelines
    • Eudralex Vol. 4 Guidelines on GMP, including annexes 2, 13 and 16
    • GCP specific for ATMP
    • CTD Modul 3
    • Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to ATMPs
  • International compendia
  • Flowchart – EMA Quality Flowchart
  • Checklist – EMA Quality Checklist
  • Donation, procurement, and testing of human cell based products
  • Traceability
  • IMP, drug substance and drug product
  • Risk-based approach
  • Gene editing and genome editing
  • GMO and GMM
  • EMA support for ATMP developers – GMP requirements
  • Certification (Commission reg. (EG) no. 668/2009)
  • Applications to the authorities
    • Application for tissue establishment
    • Application for manufacturing permission
    • Permission for export-/import
    • Partihandels-tillstånd
    • Application for certification
  • Demonstrate the quality and safety of the product to enable the generation of reliable efficacy data.

Product Manufacture

  • Regulations and Directives – Dir. 2009/120/EG EudraLex – Volume 1 – European Commission
  • Guidelines
    • Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials
    • Good laboratory practice (GLP) principles in relation to ATMPs
    • EMA Nonclinical Guidelines
    • GCP specific for ATMP
    • Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to ATMPs
  • Flowchart – EMA Nonclinical Flowchart
  • Checklist – EMA Nonclinical Checklist
  • Data to demonstrate proof of concept are normally needed before human exposure in order to provide functional evidence of the relevant biological activity to support the therapeutic rationale and clinical testing of the product in the treatment of the intended disease or condition
  • Generally, animal disease models or experimentally induced models mimicking the condition to be treated are considered most relevant for demonstrating the proof of concept. In addition, in vitro and ex vivo cell and tissue-based models can be used to supplement or substitute in vivo animal studies to demonstrate the proof of concept.
  • Pivotal non-clinical studies;
    • Pivotal non-clinical studies should use material manufactured using the clinical manufacturing process.
    • Pivotal toxicity studies are expected to be conducted under GLP.
  • Application to authorities – Application for certification
  • Demonstrate the quality and safety of the product to enable the generation of reliable efficacy data. In many cases, the majority of non-clinical data may need to be available before human exposure.
  • Before human exposure, data supporting proof of concept, administration, biologically effective starting dose and safety are needed.
  • In general, the non-clinical data supporting the safe use of an ATMP in humans should provide information for the estimation of the safe and biologically effective dose(s) to be used in clinical trials, support the feasibility of the administration route and the appropriate application procedure, identify safety concerns and target organs for potential toxicity, and identify safety parameters to be followed in the clinical trials.
  • The dose levels for proof of concept should allow estimation of biologically effective dose and meaningful extrapolation to establish the clinical starting dose. It is expected to determine an effective dose without toxic effects of the product which exerts the desired pharmacological activity in the most suitable animal model.
  • The risk-based approach can be applied to identify the necessary non-clinical data on a case-by-case basis.

Clinical Trials

  • Regulations and Directives EudraLex – Volume 1 – European Commission
    • Reg. (EU) no. 536/2014
    • Dir. 2005/28/EG (GCP och tillstånd till tillverkning)
  • Guidelines
    • ICH E8 General considerations for clinical trials
    • Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials
    • The Guideline on strategies to identify and mitigate risks for First-in-Human Clinical Trials with Investigational Medicinal Products
    • GCP specific for ATMP
    • ICH E6 Good Clinical Practice Guideline
    • Guideline on clinical trials in small populations (in case of Orphan medicinal product)
    • Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to ATMPs
    • Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products
  • EMA Clinical Flowchart
  • EMA Clinical Checklist
  • Clinical trials involving ATiMPs are usually conducted in patients and not in healthy volunteers.
  • Exploratory studies with ATIMPs are often designed as phase I/II trials, combining features of phase I and phase II design. FIH studies are a subset of exploratory studies, when the ATIMP is the first time translated from non-clinical studies to humans. For the First-in-human (FIH) trials, the primary objectives are the safety and tolerability. Assessment of pharmacokinetics is another objective of the exploratory clinical trials. Pharmacodynamic (PD) assessments are intended to substantiate the proof-of-concept.
  • Confirmatory Trials and pivotal data¸ Confirmatory studies should be in accordance to the existing general guidelines for the specific therapeutic area. Clinical efficacy endpoints as defined in specific guidance for the studied indication or disease are the basis for the clinical evaluation of ATIMPs. The primary objective is to demonstrate or confirm therapeutic benefit. The detection of the risks should continue during confirmatory phase clinical trials to prevent and/or minimise the risks.
  • The ATMP developers should ensure that patients enrolled in clinical trials (starting with FIH trials) are appropriately followed-up in order to generate long-term efficacy and safety data sufficient to support the marketing authorisation application. The need for, the duration and the type of follow-up should be described in the clinical trial protocol.
  • The duration of efficacy and safety follow-up should be identified during the exploratory clinical trials, also taking into consideration results from non-clinical studies.
  • Applications to authorities
    • Clinical trial application for an ATIMP (Protocol, IB, IMPD)
    • GMO application
    • Clinical trial application for a combined ATIMP
    • Amendents
  • The distinctive characteristics and features of ATMPs are expected to have an impact on the trial design, specifically with regards to early phase trials and dose selection, pharmacodynamics, pharmacokinetics/biodistribution, while the general principles in late phase trials to demonstrate efficacy and safety in the specific therapeutic area are less affected and are essentially the same as for other products.
  • Confirmatory clinical trials should be conducted with a product based on a mature manufacturing process and specifications that match those for marketing authorisation as closely as possible.
  • Deviations from this principle will lead to comparability issues, a particular challenge for ATMPs, and may raise questions on the representativeness (validity) of the data obtained.

Market Approval and HTA

  • Regulations and Directives EudraLex – Volume 1 – European Commission
    • Reg. (EC) 1394/2007
    • Reg. (EC) 726/2004
    • Dir. 2001/83/EC
    • Dir. 2009/120/EG; Marketing authorisation applications for advanced therapy medicinal products, as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007, shall follow the format requirements (Modules 1, 2, 3, 4 and 5) described in Part I of this Annex.
  • Guidelines
    • Marketing authorisation guidelines
    • Guideline on the environmental risk assessment of medicinal products for human use
    • Guideline on environmental risk assessments for medicinal Products consisting of, or containing, genetically modified organisms (GMOs)
    • Guideline on scientific requirements for the environmental risk assessment of gene therapy medicinal products
  • An Environmental Risk Assessment (ERA) shall accompany an application for a marketing authorisation for a medicinal product for human use.
  • Applications to authorities – Marketing Authorisation Application (CTD Modules)
  • Demonstrate that the medicinal product can be produced consistently and with reproducible quality.

Clinical Routine

  • Regulations and Directives EudraLex – Volume 1 – European Commission
    • Reg. (EC) 1394/2007
    • Reg. (EC) 726/2004
    • Dir. 2001/83/EG
    • Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation)
    • Variations – Reg. (EC) 1234/2008
  • Guidelines
    • Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products
    • Good Pharmacovigilance Practices (GVP) Modules
  • Long term efficacy and safety follow-up and long term monitoring of patients treated with an ATIMP needs to take into account the nature of the ATIMP and its persistence.
  • Pharmacovigilance system
  • Pharmacovigilance System Master File (PSMF)
  • Risk Management Plan (RMP) (module 1.8.2.)
  • RMP template
  • Post-authorisation S&E follow-up studies and risk management
  • As part of the marketing authorisation evaluation, an assessment of the risks is carried out to determine the risks which should be minimised and/or further characterised post-marketing.

References

  • Läkemedelsverkets webbplats
  • EMA Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials 
  • EMA Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products.
  • EMA Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products.
  • EMA Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials
  • EMA Guidelines relevant for advanced therapy medicinal products

Other guidelines:

  • Guideline on xenogeneic cell-based medicinal products
  • Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products
  • Guideline on summary of product characteristics (SmPC)
  • Scientific guidance on post-authorisation efficacy studies
  • ICH E9 Statistical principles for clinical trials.
  • ICH E10 Choice of control group and related issues in clinical trials.
  • Reflection paper on in-vitro cultured chondrocyte containing products for cartilage repair of the knee
  • Reflection paper on clinical aspects related to tissue engineered products
  • ICH Considerations General Principles to Address Virus and Vector Shedding
  • CAT reflection paper on the management of clinical risks deriving from insertional mutagenesis
  • Guideline on follow-up of patients administered with gene therapy medicinal products

Additional information: