Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

A Comparative Analysis of Antibody Drug Conjugates in Europe and the US

Dr. Karin Kroboth (Abschlußjahr: 2021)

Summary
Language: English
With more than 19 million new cancer cases in 2020 resulting in 9.9 million deaths, cancer is one of the most prevalent lethal conditions worldwide, comprising of many different subtypes for which only very limited or no treatment options are available. Consequently, the development of antibody drug conjugates (ADCs) representing a novel class of targeted and highly efficacious anti-cancer therapies sparked considerable interest in the field.
ADCs combine the properties of a specific targeting antibody and a cytotoxic small molecule joined by a cleavable / stable linker. ADCs exploit antibody target specificity to selectively discriminate between cancer and normal tissue cells and thereby ensure on-target delivery of the toxic payload, which upon internalisation induces apoptosis of the cancerous cell. Critically, on-target delivery opens up the therapeutic window as compared to standard chemotherapies by lowering the minimum effective dose while at the same time increasing the maximum tolerated dose and the therapeutic index.
The optimisation of antibodies, drugs and linker stability allowed for considerable improvements, overcoming initial draw backs, such as off-target toxicity of first-generation ADCs, and led to the approval of 11 ADCs in the US and 8 of them in the EU over the past decade.
ADCs require a unique regulatory approval process, since they comprise a biotechnological manufactured molecule and a small drug entity, hence a combination of guidelines for large as well as small molecules needs to be considered during the developmental / approval process.
This master thesis investigates and compares the regulatory landscape specific to antibody drug conjugates in the US and EU. While manufacturing, pre-clinical and clinical development were found to be surprisingly similar in the two regulatory regions, the actual route to approval showed considerable regional divergence. This thesis summarises the differences in approval pathways for individual ADCs, finding regulatory bodies develop those very much on a case by case basis. The following key differentiators were identified: The FDA provided a higher number of incentives (e.g. break through therapy designation) and offered more direct contacts (e.g. pre submission meetings) per approved ADC compared to the EMA. In addition, the FDA provided specialised incentives e.g. the real-time oncology review (RTOR) which were found to be highly advantageous for the approval of ADCs targeting oncological conditions. The time taken from dossier submission to approval differed by no less than 222 days between the two regulatory regions. While showing high concordance in the final regulatory outcomes, the approval process was significantly faster in the US (219 days compared to 441 days in EU; p-value 0.003). In conclusion it can be postulated that closer interaction and alignment between the FDA and EMA would not only save resources but also help shorten approval times, especially in the EU.
With currently more than 80 conjugates in clinical development the market for ADCs is growing rapidly, comprising not only new antibodies, payloads and linkers but also entering novel therapeutic areas like autoimmune disease or immunomodulation for transplant patient.
This work highlights the need to develop a more streamlined interactive approval process tailored to the unique structure of ADCs, to ensure therapies become faster available to the patients’ benefit.
Pages: 70