Overcoming diverging regulatory expectations to bring CGTs to market

EU and US flags

Lung-I Cheng, Vice President and Head of Cell & Gene Therapy Service Line at AmerisourceBergen, and Cori Gorman, Senior Director of CMC and Regulatory Affairs at Biopharma Excellence, offer advice on navigating the different and sometimes contradictory regulatory requirements in the US and EU.

Over the past few decades, the incredible progress in personalised medicine has led to the development of life-saving cell and gene therapies (CGT). These advanced therapies are revolutionising treatment options and opening new avenues for targeted and individualised healthcare, offering tremendous promise to patients worldwide, including those living with life-threatening or debilitating diseases.

While CGT is still an emerging market, its growth has accelerated over the last five years, resulting in a wave of products approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Within the past year, the sector saw the EU’s landmark approval of the first allogeneic T cell therapy as well as the approval of several new gene therapies in the US.

And the robust CGT pipeline suggests there could be an influx of new approvals on the horizon. Driven by the rapid pace of innovation, the market for CGTs is expected to grow from $4.4 billion in 2020 to $15.5 billion in 2025 at a rate of 28.7% globally. By 2030, it’s expected to more than double, to $34.3 billion1.

Navigating varying and rapidly changing regulatory requirements

While the sector’s upward trajectory offers tremendous promise, the companies developing these innovative therapies must understand and plan for the varying – and evolving – regulatory requirements to efficiently bring their products to market.

A Mutual Recognition Agreement (MRA)2 for inspections of manufacturing sites for certain human medicines, signed and implemented by the United States and EU in July 2019, served as an important milestone in harmonising certain regulatory aspects in developing a global drug.

Yet, there remains important regulatory differences between the EMA and the FDA, such as varying standards, approaches and even nomenclature for CGT.

For example, the FDA’s Center for Biologics Evaluation and Research (CBER)3, which regulates biological products for human use, differentiates between in vivo gene therapy (new genes are inserted into the body to target cells) and ex vivo gene therapy (cells are modified outside the body and then administered back into the patient). The EU, however, defines all gene therapies as “recombinant genes transferred directly into the body” and cell therapies as those that insert genetic modification into a cell and the cell becomes the drug product.

More importantly, the FDA and EMA have divergent interpretations of Chemistry, Manufacturing, and Controls (CMC) requirements, though one difference was recently clarified by the EMA. Both agencies now agree that some starting materials, such as plasmids, do not need to be manufactured under full Good Manufacturing Practice (GMP) conditions, though they both require detailed manufacturing documentation for starting materials.

Despite this step, there remain divergent views on other regulatory aspects. For instance, in a trial where patients are selected based on a specific human leukocyte antigen (HLA) type, the FDA requires the use of a fully certified, FDA approved Companion Diagnostic. The EMA, however, doesn’t require the use of an agency-approved diagnostic. The agencies also have different requirements for the selection of healthy donors in the development of allogeneic cell therapies.

When working with adeno-associated virus (AAV) vectors – an engineered technology and 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 uses the baculovirus system to generate their AAV, the agency may ask for additional information on the percentage of capsids carrying foreign DNA.

When defining the critical quality attributes of an assay, companies must pay close attention to what kind of assay they are making and provide clear, reproducible data, as the EMA requires specific data and will not accept ‘report results’.

While seemingly benign on the surface, these nuances add a layer of time and effort for CGT developers seeking approvals around the globe. If not properly planned for, the regulatory requirements can delay market entry and patient access to these therapies.

Complying with GMO requirements

In the EU, companies must comply with an environmental risk assessment and genetically modified organism (GMO) requirements to determine if their CGTs contain any harmful material to patients, animals, plants, or micro-organisms, and assess their general impact on the environment4.

While the EMA has provided guidance on GMO requirements, it is important that companies understand the different requirements for clinical trials considering they can vary across EU countries.

Preparing early is tantamount to success

The varying regulatory requirements and expectations add complexity and potential hurdles to an already complex commercialisation process. Companies looking to launch CGT products globally should establish a robust regulatory strategy early in the development process, as a well-defined strategy helps to mitigate the risk of delays and optimise the pathway to commercial launch efficiently.

Plans should include a mechanism to easily compare a Phase III investigational drug with the drug used in Phases I and II. This is imperative considering that both CBER and EMA will expect companies to conduct a comparability plan for any changes in manufacturing processes across the clinical trial lifecycle. Archiving samples from the early manufacturing stages is key.

Thorough documentation and adherence to guidelines is critical as the CMC framework requires comprehensive information about the manufacturing process, validation, data control, and analytical methods.

CGT developers can engage commercialisation partners to help them integrate regulatory considerations into their development process, enabling them to navigate the regulatory landscape more efficiently.

Preparing early and understanding those differences – while also working with regulators toward common ground approaches – will be key to successfully navigating the approval process, ultimately bringing CGTs to patients who need them, more quickly.


  1. https://www.businesswire.com/news/home/20210712005409/en/Global-Cell-and-Gene-Therapy-Market-Report-2021-Opportunities-Strategies-COVID-19-Impacts-Growth-and-Changes-to-2030—ResearchAndMarkets.com
  2. https://www.ema.europa.eu/en/news/eu-us-reach-milestone-mutual-recognition-inspections-medicines-manufacturers
  3. https://www.fda.gov/about-fda/fda-organization/center-biologics-evaluation-and-research-cber
  4. https://www.biopharma-excellence.com/articles/managing-complex-gmo-requirements-for-gene-therapy-clinical-trials/

About the authors:

Lung-I Cheng, PhD, is Vice President and Head of Cell & Gene Therapy Service Line at AmerisourceBergen and Cori Gorman, PhD, is Senior Director of CMC and Regulatory Affairs at Biopharma Excellence (a part of AmerisourceBergen).


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