ATMP blogpost #3 : Harmonizing European ATMP regulatory landscape
In the previous post we outlined the various regulatory documents relevant to ATMP developers in the European Union. The landscape is quite complex and many levels of administration, from the EU to local authorities, do not make it easier. Fortunately, this issue is noted and efforts are underway to harmonize regulatory processes across the EU.
To recap some main points made in this series - ATMPs are medical products for human use based on genes or cells that offer potentially ground-breaking opportunities for the treatment of injury and disease, particularly in cases of severe, untreatable or chronic diseases which do not respond adequately to conventional treatments.
ATMPs can be classified into four main groups: gene therapy medicinal products, somatic cell therapy medicinal products, tissue engineered medicines and combined ATMPs.
In the EU, these products are governed by Regulation 1394/2007 on advanced therapy medicinal products (“ATMP Regulation”). The cornerstone of the Regulation is that a marketing authorisation must be obtained prior to the marketing of ATMPs. The evaluation of these products is led by a specialised committee within EMA (the Committee for Advanced Therapies - “CAT”) and the authorisation is granted by the European Commission. The ATMP Regulation also empowers Member States to permit the use of advanced therapies that have not been authorised by the Commission under certain conditions (so-called "hospital exemption").
The multiple directives, regulations and guidance documents applying to ATMPs set out a goal for all EU countries and ATMP developers to achieve.
Research and development
Support for advanced therapy developers (GxP requirements)
The European Commission and the European Medicines Agency, in collaboration with the authorities of the Member States, have initiated, already few years ago, a number of initiatives to improve the regulatory environment for ATMPs so as to facilitate the development and authorisation of these products in the EU for the benefit of patients. The intended actions are wide-ranging and target challenges identified by various stakeholders at all stages of development, including manufacturing, early and later phases of development, marketing authorisation process and post-marketing setting. The EU is committed to support the development of these products and will keep monitoring developments in the field to ensure that the regulatory framework supports —and not hinders — the development of ATMPs.
It is expected that the implementation of the proposed actions as outlined in “ANNEX — List of proposed actions to improve the regulatory framework for ATMPs” will increase the opportunity for patients to be treated with novel therapies (through enrolment in clinical trials and authorisation of new products). Moreover, an improved regulatory framework will also contribute to promoting innovation, investments and competitiveness of the EU biotechnology sector, whilst striving to ensure patient access.
Although the majority of identified action points have been completed over the past years, some point remain to be addressed and clarified:
Finalization of the Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials
Revision of the Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products
The European Commission to initiate a reflection process with the Member States on the hospital exemption
Exchange of information on GMP inspections within the network.
Another part of to deal with the local and European differences is the clinical trial regulation (CTR) No 536/2014 which will replace clinical trial directive 2001/20/EC. The CTR became effective on 31 January 2022 with a transition period of 3 years. Clinical trials with medicinal products that contain or consist of GMOs (Genetically modified organisms) are subject to both clinical trials and GMO legislations. Dissemination of information about national regulatory requirements in respect of GMO aspects is expected to facilitate the development of gene therapy medicinal products in the EU. A repository of national regulatory has been created to this effect, the country fiches provide an overview of national regulatory requirements for medicinal products containing GMOs (more info).
Managing these levels of complexity is a challenging task, particularly for organisations still at an early development stage. Therefore, currently it is advised to seek advice from regulatory authorities at an early stage. This will be covered in more detail in the next part of our ATMP series, so stay tuned!
If you have any questions regarding regulations do not hesitate to reach out to QbD experts.
For custom process development and manufacturing solutions reach out to Antleron.
ATMP blogpost #2 : ATMP regulatory documents
The European Advanced Therapeutic Medicinal Product (ATMP) regulation 1394/2007 came into force on 30.12.2008. This happened to give a regulatory framework to the scientific progress that is made in cellular and molecular biotechnology which led to the development of ATMPs. The complexity and technical specifications of gene, somatic cell and tissue engineered therapies required special tailored and harmonized rules to safely enable patient access. However, stakeholders are often academic or small and medium enterprises with little or no experience in pharmaceutical regulation. As a result, the European ATMP regulatory framework has often been mentioned as being too fragmented and complex for these stakeholders. The overlapping competences of national and European bodies, as well as documents that have been published over the last 2 decades contribute to the confusion.
What regulatory documents are relevant for ATMPs
The overall legislative framework for ATMPS is Regulation No 1394/2007, which amended directive 2001/83/EC relating to medicinal products and regulation 726/2004 on procedures for the authorization and supervision of medicines for human and veterinary use. Regulation No 1394/2007 mandates the European Commission to set out guidelines on good manufacturing practices for ATMPs which are published in Part IV of the GMP requirements. Marketed, investigational and ATMPs administrated to the patient under hospital exemption need to comply with the GMP requirements as described in GMP part IV. However, part IV of the GMPs also refers to Annex 1, 11 and 12 of Part I of the GMP requirements and therefore are applicable too.
The starting and raw materials of ATMPs are highly variable and fall under another regulatory framework. In case the ATMP contains human blood and blood components or genetically modified organisms Directive 2002/98/EC and directive 2001/18/EC apply respectively. For tissues and cells used as starting materials directive 2004/23/EC covering standards for donation, procurement and testing, processing, preservation, storage and distribution of human tissues and cells is applicable. The technical implementation of tissues and cells used as starting materials is set out in directive 2006/17/EC, directive 2006/86/EC, directive 2015/565 and directive 2015/566.
GMP guideline part IV and the regulations are often mentioned as incomplete and lacking detail. In order to tackle this hurdle, a variety of extra specific guidelines are introduced.
The last documents introduced by EMA are flowcharts and checklists to clarify the expectations related to non-clinical, clinical and quality needs in the ATMP development and should give guidance to (early) developers.
This was part one of three of Regulatory insights, by our QbD colleague and expert – Frederik Schietekat. We will be returning with an overview of European and local competences in ATMP regulations as well as the importance of early interaction with regulatory bodies.
The sheer number of documents regulating the ATMP landscape in the EU may seem a daunting barrier, not to mention the other challenges facing advanced therapy developers. If you have any questions regarding regulations do not hesitate to reach out to QbD experts.
For custom process development and manufacturing solutions reach out to Antleron.
Blogpost #1 : ATMPs, promising new therapies
Welcome to the first post of the blog series focused on Advanced Therapy Medicinal Products (ATMPs). We will focus on the most important aspects of ATMPs and address several critical issues faced by ATMP developers and manufacturers. ATMPs are among the most promising new therapies offering unprecedented opportunities to replace existing approaches of treating various medical conditions. Moreover, they often target indications with no pre-existing medical solution.
What specifically are ATMPs?
According to the European Medicines Agency (EMA), the European Union (EU) regulatory body, Regulation 1394/2007, ATMPs include gene and cell therapies (GT & CT), but also tissue engineered products (TEP). For those of you who are more familiar with the FDA regulatory environment, the Centre for Biologics Evaluation and Research is the body dealing with tissue, cell and gene therapies in the US. Since ATMPs often employ cells, an important distinction has to be made, depending on the cell source. An allogeneic therapy is one where the cells are obtained from a donor, that is not the recipient of the therapy itself. In case of autologous products, the patient will be treated using their own cells.
Although extremely innovative, ATMPs still suffer from a number of challenges rooted in the complexity of the products themselves, which makes it intrinsically difficult to deal with. The challenges we are focusing on in this series are:
1. Regulations – in the EU a centralized regulatory framework exists, however Good Manufacturing Practice (GMP) rules continue to be a demanding issue to be navigated, despite the existing Part IV GMP guidelines dedicated to ATMPs. Moreover, in some cases genetically modified organism (GMO) regulations of EU member states can prevent the marketing of certain ATMPs.
2. Reimbursement – the price tag of an ATMP can rise to hundreds of thousands of euros per treatment dose, which is totally unaffordable for a single patient. Therefore, alternative payment models for innovative medicines are being developed (most notably are ‘value-based payments’).
3. Manufacturing – the inherent variability and complexity of raw materials (cells) as well as the often-personalized nature of the final product make this extremely challenging for manufacturing departments and regulatory affairs offices across the globe.
4. Clinical studies – some ATMPs target orphan indications, which poses further challenges in regard to clinical trial design. However, EMA offers some solutions to support the marketing of such products under a conditional authorization.
Given the above, it is not surprising that despite the promising opportunities offered by this novel category of medicines (the ATMPs), there are only a few of them available on the European market.
Where and how does Antleron fit in?
We are a team of bright and creative minds that challenges the current paradigms of advanced therapy manufacturing by combining the Quality-by-Design methodology with innovative technologies, such as biomaterials, 3D-printing, soft sensing and bioreactors. Through partnerships and collaborations, we aim to support ATMP manufacturers and developers to accelerate the engineering of advanced therapies, eventually empowering patients with personalized and regenerative care.
We envision to bring our expertise together with all kinds of like-minded parties to develop complex tissues and organs. Not only for research purposes, but also to accelerate personalized medicine from lab to patient.
ATMPs offer huge opportunities to increase treatment efficacy. Companies, research institutions and regulatory bodies are tackling the various remaining hurdles to allow for a more continuous stream of ATMPs entering the market. Stay tuned for the upcoming blogpost on the ATMP regulatory environment: learn which regulations are key in the context of ATMPs and discover the global ATMP regulatory landscape and its implications. Later posts in the blog series will cover cell therapy, reimbursement, tissue-engineered products, manufacturing, gene therapy, etc.