Tony Hitchcock, Technical Director at Cobra Biologics, a Charles River Company, is joined by Karin Agerman, Chief Research and Development Officer at CombiGene, to explore the effects of the latest regulatory guidelines from both a CDMO and drug development perspective.
As the scale and number of clinical studies performed using Advanced Therapy Medicinal Products (ATMP’s) including gene therapy vectors, and the number of patients being treated with these types of therapies, increases, then the volume of clinical data generated also expands significantly. In any therapies trialed on patients, adverse events are to be expected, and in rare instances unfortunate deaths. Although ATMP candidates often are trialed on patients suffering from life threatening conditions and are of a highly transformative nature, all adverse events should raise concerns. The regulatory bodies and sponsors of the study need to address and understand these events to ensure confidence in the safety of products prior to progression of further clinical studies or product licensing.
Product safety and potential adverse effects may relate not only to the product design and clinical usage such as dosage and routes of administration; but may also relate to the manufacturing of the products and consistency of processes used. Initially, viral vector and modified cell products were largely produced within academic facilities or small CMO’s, using scaled up laboratory procedures for studies on a handful of patients, with relatively limited product testing, characterization and regulatory oversight. These were seen as “proof of principle” studies, with regulators seeking to support the early development of these innovative and life changing medicines on a small number of often seriously ill patients.
“The ATMP industry has now gone beyond the proof of principle position, with over 1200 products in clinical development and 1000 companies operating in the sector, with many of these companies being very well funded.”
However, the ATMP industry has now gone beyond the proof of principle position, with over 1200 products in clinical development and 1000 companies operating in the sector, with many of these companies being very well funded. 2020, despite COVID-19, saw a record breaking $20bn being pumped into the sector and on top of that significant investment from Big Pharma.
Tony Hitchcock: “Karin, to date much of this investment has been targeted towards the treatment of ultra-rare conditions with small patient populations, what do you see as the trends and opportunities going forward?”
Karin Agerman: “Gene therapy is now moving towards larger patient populations to treat not only rare life-threatening diseases, but also more common but devastating diseases. Addressing a large population of patients puts new demands on the continuity of production method and production output. If they are to be used as ground for market approval, toxicology programs and clinical trials need to be performed with material from the production process that will be used for commercial volumes.”
The complexity of manufacturing of viral vectors and ATMPs, and the limitations of analytical procedures, means that from a regulatory perspective “the product is defined by the manufacturing process”, and whilst we have seen a huge increase in the knowledge base around these products, the implication is that we need to have an in depth understanding of the manufacturing process and the critical process parameters that impact not only process yields but the functionality and safety of the products used in clinical trials and later commercial supplies.
It is unsurprising that over recent years the regulatory authorities, such as the EMA and FDA, have issued updated guidelines around the production of gene therapy products, many of which focus on the manufacturing processes for these products and the materials used to produce them.
In 2018, the EMA issued “Quality, preclinical and clinical aspects of gene therapy medicinal products”, which was followed in 2020 by “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) Guidance for Industry”, from the FDA.
The most recent set of guidelines published in February 2021 is from the EMA and relates to the quality of the plasmid DNA being used to produce ATMP’s including mRNA therapies, AAV and Lenti viral vectors; “Questions and answers on the principles of GMP for the manufacture of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs”.
Plasmid DNA is defined as a critical starting material for many ATMP products, including CombiGene’s epilepsy gene therapy candidate CG01, and the integrity and identity of the plasmid used in manufacturing processes is critical to producing the desired vector product.
“The new EMA guidelines seek to provide clarity around, and emphasize the need for, extensive quality systems to be applied for plasmid production, including the establishment of quality agreements and risk assessments on the quality systems applied by the plasmid producers in relationship to the intended use of the plasmids.”
Regulators have accepted for a number of years that plasmid should be of a “high quality” but does need not be produced to GMP especially for early phase clinical materials. This phase dependent approach has led to a range of interpretations of “high quality”, by suppliers and end users alike. The new EMA guidelines seek to provide clarity around, and emphasize the need for, extensive quality systems to be applied for plasmid production, including the establishment of quality agreements and risk assessments on the quality systems applied by the plasmid producers in relationship to the intended use of the plasmids.
TH: As a drug developer how do you see these updated guidelines impacting your business, are these welcome changes?
KA: “As a small company with limited resources, CombiGene appreciates a clear and durable regulatory framework to operate within as this gives us the possibility to run our projects effectively towards well defined and agreed targets. Operating within well-defined regulatory framework also makes it easier to negotiate relevant content and price with partners such as CROs and CDMOs since a regulatory framework provides a common understanding of scope and quality.”
“Operating within well-defined regulatory framework also makes it easier to negotiate relevant content and price with partners such as CROs and CDMOs since a regulatory framework provides a common understanding of scope and quality.”
Whilst these new guidelines provide the option for vector producers to use both plasmids and, in the case of engineered cells, vectors produced outside of GMP quality systems, there is a drive to tighten up quality systems around the starting materials used for vector production with regards to assessment and justification of quality systems.
Going forward it is clear that, as with other therapeutic products, as the regulatory authorities gain increased knowledge and experience of these products in the clinic and see increased numbers of CMC applications, there will develop a greater understanding of the required clinical standards and of ‘best practice’ amongst manufactures and more specific guidance on product testing and specifications.
TH: Do you have any final comments on the current regulatory position?
KA: “When you are breaking new ground, as the gene therapy industry and academia have done during the past decades, it always takes time before firm regulatory standards can be set, since new experiences and new knowledge are constantly developing. However, the gene therapy industry has now matured to the point where it was not only possible but necessary to establish a regulatory framework, and as a small company CombiGene welcomes the regulatory guidelines that now are in place.”
TH: Thank you for your insight into the gene therapy space and good luck with your on-going projects.
Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-clinical-aspects-gene-therapy-medicinal-products_en.pdf
Quality, preclinical and clinical aspects of gene therapy medicinal products: www.ema.europa.eu/en/quality-preclinical-clinical-aspects-gene-therapy-medicinal-products
Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs): www.fda.gov/regulatory-information/search-fda-guidance-documents/chemistry-manufacturing-and-control-cmc-information-human-gene-therapy-investigational-new-drug
Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs: www.ema.europa.eu/en/documents/other/questions-answers-principles-gmp-manufacturing-starting-materials-biological-origin-used-transfer_en.pdf