Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Dry Eye Disease: Regulatory Requirements Differ Around the Globe – with Implications for Product Development and Patient Access. A review of standards for new ophthalmic therapies in key pharmaceutical markets. ***

Johannes Korward (Abschlußjahr: 2021)

Summary
Language: English
Dry Eye Disease (DED) is a common ocular surface disease affecting millions of people worldwide. Typical symptoms include ocular discomfort and visual disturbance, having significant impact on the patients’ quality of life. The loss of homeostasis of the tear film leads to insufficient protection and therefore potential damage of the ocular surface. The current treatment options are limited and leave patients and ophthalmologists unsatisfied, resulting in a high unmet medical need. Additionally, increasing prevalence and several risk factors like aging population and screen work, make innovation and new treatment options necessary. But to date the available DED drugs are only approved in single key pharmaceutical markets.
To identify the underlying reasons for this observation, this thesis analyzed disease definition, market situation, diagnosis, and treatment guidelines as well as regulatory guidance for drug development in the key pharmaceutical markets United States of America (USA), European Union (EU), and Japan. Additionally, approved indications, clinical programs, and regulatory history of available DED drugs were analyzed.
The review showed that there is currently no common definition of DED in the different regions. In the USA and the EU inflammation is regarded as an essential part of the disease cascade and first focus of treatment, while the Asian definition considers tear film stability as the main component and focus of treatment.
The DED markets in all regions consist of two components: artificial tears and drugs. Artificial tears generally serve as the first treatment option, often positively influencing subjective symptoms, and are mainly available as OTC products, supporting self-treatment for milder versions of DED. The known effect of artificial tears complicates drug development as the efficacy of the active pharmaceutical ingredient (API) needs to be significantly greater than the vehicle, which is typically similar to artificial tears. This led to a high failure rate in clinical DED trials, resulting in several discontinued development projects in the past years.
Another aspect is the variety of diagnostic tools and outcome measures which are difficult to standardize and are associated with high variability. It remains debatable which level of improvement in a certain parameter is clinical meaningful, which further complicates harmonization. This might be a major reason for the variability in regulatory requirements in the geographies. The US FDA accepts for example studies with 1 day treatment duration if a significant improvement over vehicle can be demonstrated in signs and symptoms of DED. However, the European expectations are that treatment of a chronic disease like DED requires chronic treatment and persistent effect, so that effect demonstration after 6 months treatment period is recommended.
The comparison of available DED drugs showed that drugs targeting inflammation, like Restasis®, Ikervis® (both cyclosporine) or Xiidra® (lifitegrast), are available in the US and the EU markets only, mucin secretagogues, like Mucosta® (rebamipide) or Diquas® (diquafosol), are the only approved drugs in Japan (besides artificial tear products). The analysis revealed that clinical programs often required several trials to show the desired effects. Approval of formally not met primary endpoints in single regions lead to non-acceptance of the dossiers in other regions.
With increasing prevalence, medical need, and public interest further initiatives for harmonization of a common understanding of DED are expected. Additionally, identification and validation of robust clinical (bio-)markers for indicating disease severity and treatment effects will further help to promote harmonization of regulatory requirements. In conclusion, innovation is needed to better understand DED, and as a consequence bring regulatory agencies to common accepted standards and finally patients worldwide to new treatment options to improve their quality of life.
Pages: 59
Annexes: -