Risk Management Plans for ATMPs
by Maria Schacker
Scientific and medical research has led to great progress in the fields of genetics, cellular and molecular biology and the subsequent advent of a new medicinal product class. The advanced therapy medicinal products (ATMPs) entail gene therapies, somatic cell therapies, and tissue engineered products. Although these innovative therapies have the huge potential to provide curative options for genetic disorders or to treat diseases that are currently difficult to impossible to treat and where the unmet medical need is high, they also come with a number of known and still unknown risks, many of which are unique to this product class.
At the time of marketing authorisation, the benefit-risk balance of any medicinal product is judged based on the information available from pre-clinical and clinical studies. However, these studies are typically run under controlled conditions, with a limited number of carefully selected patients and for a restricted period of time, so that certain adverse reactions and safety risks, especially those that are rare, may only be characterised post-authorisation. Therefore, marketing authorisation holders (MAHs) are required to implement a suitable risk management system to identify, characterise and minimise a medicinal product’s risks, and to describe this system in the form of a risk management plan (RMP).
These principles are even more important for ATMPs. Acknowledging the novelty, complexity and technical specificity of these products, Regulation No 1394/2007 on advanced therapy medicinal products (hereafter referred to as “the ATMP Regulation”) was issued by the European parliament and the Council in 2007. In addition to the basic pharmacovigilance requirements, the ATMP Regulation lays out requirements for a risk management system that is able to capture ATMP-related risks and includes the need for post-authorisation surveillance of efficacy and safety, as well as an appropriate traceability system (EMA/CHMP, 2018; Regulation (EC) No 1394/2007, 2007).
Frameworks for identification and mitigation of risks specific to ATMPs
Due to their novel mechanisms of action, ATMPs may cause new risks to patients and it is very important to employ a flexible approach to risk identification, evaluation and mitigation. However, not just the biological activity of the ATMP, but also the quality attributes, the manufacturing process steps and the therapeutic administration procedures are important risk factors that must be considered. Therefore, risk identification should consider all areas of development as shown on a high level in Figure 1 exemplary for cell-based products, such as allogeneic CAR T cell therapies. In addition, Table 1 gives examples of specific safety concerns that could be applicable for ATMPs. However, this list is not exhaustive and the safety concerns specific to each individual product must be identified, considering all relevant guidance documents. Based on these identified safety concerns, the Applicant should then provide a discussion on the safety specifications that need further risk management activities (grouped into “important identified risks”, “important potential risks” and “missing information”).
Not just the identification of risks specific to ATMPs, but also the risk minimisation measures require special considerations. While many risk minimisation activities are routine measures, additional tools and approaches specific to ATMP-related risks may be necessary. These could include offering specialized trainings for experienced physicians at selected, accredited centers, as well as providing targeted educational materials for treating physicians, pharmacists, patients, caregivers, family members and any other relevant group.
Table 1: Specific safety concerns associated with ATMPs
Special pharmacovigilance activities – Post-authorisation surveillance of efficacy and safety and traceability
Given the nature of their mode of action, and taking into account that clinical studies with ATMPs very often only involve a limited number of patients as they are frequently intended for the treatment of rare diseases, uncertainties around the safety and efficacy of the product typically remain at the time of marketing authorisation. Therefore, safety and efficacy data obtained in a “real-life” setting from post-authorisation safety studies (PASS) and post-authorisation efficacy studies (PAES) are absolutely crucial for ATMPs. The design of such post-authorisation follow-up studies and the use of disease registries must be considered early during development.
The objectives, as well as the extent and duration of the individual PASS and PAES will be decided on a case-by-case basis. They depends on the specific characteristics of each ATMP and the resulting scientific uncertainty, the important risks or missing information as determined during the risk identification exercise described above, as well as the intended indication. Nevertheless, the following general concepts should be taken into account when designing follow-up studies and writing the RMP.
Sustained, long-term clinical benefit and evidence of cure are generally difficult to demonstrate and thus require several years of efficacy follow-up. For example, products which require engraftment and persistence of cells, may require longer efficacy-follow up of the therapeutic effect. In this context, immunogenicity and the necessity of re-administration are also important factors to be considered.
Similarly, any products which have a risk of tumorigenesis due to insertional oncogenesis will have very stringent requirements for long-term follow-up of safety. In fact, for any gene therapy medicinal products which use integrating vectors, or for which there is a risk of re-activation, a follow-up of 15 years is typically required (EMA/CHMP, 2009). The “Reflection paper on management of clinical risks deriving from insertional mutagenesis” is also an important source of information and should be consulted (EMA/CAT, 2013). ATMPs also have a high risk of causing unwanted immune reactions. Therefore, assessment of long-term immunity or rejection of specific cell types requires extended safety follow-up. Furthermore, it is important to closely monitor the occurrence of infections, which can be caused either by persistent or reactivated biological activity of a viral vector, or by transmission of infectious diseases from cells or other materials used during product manufacture.
The latter is also the reason for specific traceability obligations. Transmission of diseases through viral, bacterial or parasitic infections can originate directly from donors of cells (for example in the case of lymphocytes derived from healthy donors for the production of allogeneic CAR T cells) but also from other raw and/or starting materials that are used during the manufacturing process (for example bovine serum used for culturing cells). Therefore, the requirements for donors of human cells and tissues are very strict and the quality and safety of any raw and starting materials used during manufacture of the drug substance and drug product must be demonstrated.
Nevertheless, there are specific traceability obligations for ATMPs (Regulation (EC) No 1394/2007, 2007) which intend to allow for the tracing and examination of all materials that were used during the manufacturing of each product batch. The system must be set up in a way that it allows complete and bi-directional traceability of the entire history of a drug product batch, including all raw and starting materials, as well as all other substances that came into contact with the cells or tissues the drug product may contain.
At Biopharma Excellence we have a great deal of experience working on numerous ATMP projects and assisting our clients in identifying the specific risks of their products. Interested in learning more about how we can support your ATMP risk management plan? Get in contact with us.
EMA/CAT. (2013). Reflection paper on management of clinical risks deriving from insertional mutagenesis (EMA/CAT/190186/2012). Retrieved from https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-management-clinical-risks-deriving-insertional-mutagenesis_en.pdf
EMA/CHMP. (2009). Guideline on follow-up of patients administered with gene therapy medicinal products (EMEA/CHMP/GTWP/60436/2007). Retrieved from https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-follow-patients-administered-gene-therapy-medicinal-products_en.pdf
EMA/CHMP. (2018). Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products – Draft (EMEA/149995/2008 rev.1). Retrieved from https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-safety-efficacy-follow-risk-management-advanced-therapy-medicinal-products-revision_en.pdf
Regulation (EC) No 1394/2007. (2007). of the European parliament and of the council of 13 November 2007 on advanced medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union.