Essential safety considerations for cell and gene therapies

David Koziel

by David Koziel

The number of advanced therapy medicinal products (ATMPs, EMA term) or cell and gene therapy (CGTs, FDA term) products in clinical development is continuously increasing, with 1,066 ongoing clinical trials as of the end of 2019 marking a 32% increase on the number of studies since 2014. Currently, these products are still typically discovered and initially developed by pharmaceutical startups and university spin-offs with limited infrastructure, financial resources, and experience in the context of drug development and translation of complex medicines into the clinic [1,2].

To allow a product’s successful take-off into clinical development, the central element of early clinical studies has to be extensively addressed long before hitting the runway: Safety. EMA and FDA offer an extensive array of documents (over 80 by the EMA alone) to outline and facilitate the development and approval of these medicines. Within this jungle of agency guidelines and the complex and highly individual nature of ATMPs, getting on the right track from the very beginning is a challenging and daunting task, and yet essential for success. Exemplary central aspects for early product safety considerations are outlined in Figure 1 and the following lessons learnt based on hands on experience.

Figure 1: Exemplary considerations for ATMP safety

Mitigation strategies concerning potential safety risks of ATMPs are generally highly product specific and already start at manufacturing level. However, standard Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP) still apply for the manufacture and development of any ATMP. Product-specific measures start with the thorough characterization and understanding of highly variable properties of the partially donor derived starting materials, individual processing steps and their collective impact on product manufacturing and quality. Where a product contains multiple active agents, or an active agent and impurities or subpopulations, these may interact with each other in an unanticipated manner both during manufacturing and in the patient. For products based on genetic material, assessment of off-target events (both in product and in patient) and genetic stability require special attention. Release criteria should be set based on continuously growing process knowledge and be supported by nonclinical safety data. In all cases, the early understanding and definition of suitable quality attributes and appropriate controls already significantly contribute to the effective mitigation of failed early manufacturing runs and late-arising safety and efficacy risks.

In parallel, nonclinical and clinical development schemes should consider additional product-specific safety aspects, including potential acute or delayed infusion reactions or local intolerances, graft failure, graft versus host disease (GVHD), oncogenic potential, and even effects of media components or donor-related product attributes, like adventitious agents. The likely persistence of both the product and its activity (wanted and unwanted) in the recipient has to be defined sufficiently to ensure optimal safety. Exemplary further points for cell therapy products include undesirable product properties such as migration from the target site (localized treatments), ectopic tissue formation (stem cell derived products) and triggering of unwanted immune responses (allogeneic products). For gene therapy products, possible further aspects include viral shedding, reactivation and/or clonal outgrowth in case of genome- integrating vectors.

Finally, for the start of clinical development phases, a close patient follow-up strategy is central for the discovery of both foreseeable and unforeseeable events. Patient monitoring should be defined by the sum of product characteristics, nonclinical findings, experience with related products and additional applicable scientific information. The follow-up duration for therapeutic cell and gene products should begin during potential pretreatment and span a period considered sufficient to enable the detection of any post-administration safety-related issues. For most cell and gene therapies, a year or more of follow-up is appropriate for participants in early-phase clinical trials. For integrating gene-vector therapies, this observational period may be extended for up to fifteen years. Even with a thoroughly characterized product and obvious safety measures in place, ongoing clinical studies may raise previously unforeseen effects that require anticipatory considerations to continue the clinical development. For example, possible infertility as a consequence of myeloablation, a necessary clinical procedure prior to the administration of certain ATMP treatments, may be mitigated before product administration by cryopreservation of patient gametes.

Biopharma Excellence offers extensive hands-on experience based on many successful cell and gene therapy development programs. We understand the unique challenges and have proven expertise which we continuously provide for our clients’ benefit and for expert committees, like the Safety Pharmacology Society (SPS). Just recently, Diane Seimetz and David Koziel from the Biopharma Excellence team shared their insights during the 19th SPS annual meeting and followed up with a publication on central ATMP development and safety aspects.

Interested in learning more about how to streamline YOUR gene therapy and gene editing product strategy and how to profit from our expertise? Get in contact with us


[1] de Wilde S, Guchelaar HJ, Zandvliet ML, et al. Clinical development of gene-and cell-based therapies: overview of the European landscape. Mol Ther Methods Clin Dev. 2016;3:16073.

[2] Pearce KF, Hildebrandt M, Greinix H, et al. Regulation of advanced therapy medicinal products in Europe and the role of academia. Cytotherapy. 2014;16:289–297.

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