Understanding diverging expectations between FDA and EMA with cell and gene therapy
Successfully bringing cell and gene therapies through the regulatory process requires preparation and knowing what the authorities want. That can be challenging, because regulatory agency expectations, approaches, and even nomenclature, can vary quite significantly.
In the US, for example, CBER differentiates between in vivo gene therapy and ex vivo gene therapy (or cell therapy). With in vivo, genetic material is delivered to target cells within the body, whereas with ex vivo, cells are modified outside the body and then transplanted back into the patient. This is different to the EU’s approach, which defines gene therapies as “recombinant genes transferred directly into the body” and cell therapies as those that insert the genetic modification into a cell and the cell becomes the drug product.
There are also some important differences with CMC requirements in the two regions.
When working with adeno-associated virus (AAV) vectors – the most common platform for gene delivery – the FDA requires specific information on the percentage of empty capsids from the AAV or capsids that might have other sequences in them. If the developer is using HEK293 cells to generate AAV then the agency may ask them to sequence the DNA that is in some of those capsids as there is a possibility that other human DNA including oncogene DNA could be present. Though the potential for human DNA to be transferred is less likely if the developer is using the baculovirus system to generate their AAV, the agency may ask for additional information on the percentage of capsids carrying foreign DNA.
One issue that has caught companies off guard is the difference in the starting materials. In Europe and Canada, plasmids that might be used to generate the AAV must be developed under good manufacturing practices (GMP), whereas developers in the US are unlikely to make their own plasmids and therefore this has not been a requirement. The EMA’s requirements are laid out in 2019 guidelines on investigational advanced therapy medicinal products in clinical trials[i].
While the FDA does not require that plasmids are developed under GMP, the agency does require that companies document how the plasmids are developed.
Another important consideration is when defining the critical quality attributes of an assay, developers must pay attention to what kind of an assay they are making and provide clear, reproducible data, since the EMA will not accept report results.
Both CBER and EMA will expect companies to conduct a comparability plan for any changes in manufacturing processes across the clinical trial lifecycle. It’s important, therefore, that companies keep samples from early manufacturing batches to conduct comparability assessments in later phase trials.
GMO in Europe
Another important difference is the requirement in Europe to have an environment risk assessment and comply with genetically modified organism (GMO) requirements for any investigational medicinal products that contains or consists of GMOs. This ERA must take into consideration potential adverse effects for humans (e.g., non-patients directly exposed to the therapy, such as clinic staff), for animals, for plants and micro-organisms, as well as for general impact on the environment[ii].
While the EMA has provided guidance on requirements under the GMO framework, it is important to understand the different GMO requirements for clinical trials in some depth, since they can vary from country to country in Europe. Indeed, the GMO issue in Europe is a contentious one, particularly in light of the lack of harmonization between EU member states.
The differences between the regulatory agencies can add complexity to global market approval strategies. Understanding those differences and preparing for them early in development will be key to successfully navigating the regulatory process and ultimately bringing cell and gene therapies to market.
[i] Guideline on quality, non-clinical and clinical requirements 5 for investigational advanced therapy medicinal products in clinical trials, EMA, Jan 2019. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy_en.pdf
[ii] Guideline on Scientific Requirements for the Environmental Risk Assessment of Gene Therapy Medicinal Products, CHMP, 2008, https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-scientific-requirements-environmental-risk-assessment-gene-therapy-medicinal-products_en.pdf