Utrecht University:

By: Lourens Bloem (assistant professor of Clinical Therapeutics and clinical pharmacologist in training), and Marjon Pasmooij (affiliate associate professor of Drug Regulatory Science and head of the Science Department at the Dutch Medicines Evaluation Board (College ter Beoordeling van Geneesmiddelen; CBG))

What kind of research does your research group conduct?

The Division of Pharmacoepidemiology and Clinical Pharmacology includes three research centers: the Centers for Pharmacoepidemiology, Clinical Therapeutics and Pharmaceutical Policy and Regulation. Our research aims to improve the safe and effective use of medicines by patients and society through multidisciplinary research.

How is this related to rare diseases/orphan drugs?

There is a clear link between the aims of the Division of Pharmacoepidemiology and Clinical Pharmacology and rare diseases and orphan drugs. Studying the use and effects of medicines of course may include the use and effects of orphan drugs. In addition, the orphan legislation (set of European laws) came into effect in April 2000 including incentives to stimulate the development of medicines for rare diseases. Studying the effects of this orphan legislation is part of drug regulatory science. For instance, we aim to answer the research question how many new orphan drugs have been developed over time, and for which rare diseases, to evaluation how innovative these drugs are.

What has been your latest “discovery” related to rare diseases/orphan drugs?
Three examples:

• We are currently developing the European Medicines Regulatory Database (EMRD), which is a website-based dashboard that centralizes and contextualizes data about medicines authorized and orphan designations (ODs) granted by the European Medicines Agency (EMA). An OD is a status assigned to a medicine intended for use against a rare condition, provided that it fulfills certain criteria for designation so that it can benefit from incentives such as market protection. The EMRD dashboard provides explanations of different characteristics of each medicine and their legal and regulatory history, as well as options to download, visualize or analyze selected data. For example, information on orphan drugs is real-time available. In the timeframe 2001-2023 (when drugs could receive an OD), 1,561 drugs were authorized of which 244 drugs (16%) had at least one OD at time of marketing authorization. In this project we collaborated with two teams of informatics/data science students, of whom one data science student is still involved in the project. The development of the EMRD is supported by the Dutch Cancer Society, among others.

• In another project, where a master student contributed to, we are looking into the maintenance of the OD. An OD is granted already during the development, but once a medicine is authorized the OD status is assessed again. At time of marketing authorization (MA) the OD is not maintained for all medicines. The reasons for non-maintenance of the orphan status at the time of MA might be various, e.g. change in prevalence or failure to support the claim of significant benefit with sufficient data. A loss of the orphan status might have impact on downstream decision making including placing on the market in different member states, health technology assessment assessment, pricing and reimbursement and final accessibility of the medicine for patients. Currently there is no comprehensive overview of the proportion of medicines that maintain or lose their OD at time of MA, about the trends and underlying reasons. We aim to provide such a comprehensive overview, including more insight in trends and reasons for non-approval, and to identify potential barriers of the maintenance of the OD.

• The last topic that we would like to highlight is outcome measures for rare skin diseases, specifically epidermolysis bullosa (EB) and ichthyosis. For an adequate evaluation and comparison of clinical studies, well-defined outcomes (= ‘what to measure’) and outcome measurements instruments (= ‘how to measure’) are necessary. A recent review paper demonstrated that in the past 30 years even within studies for a similar type of intervention and EB subtype a considerable heterogeneity in outcome domains and measurement instruments was found. To ensure that the most important outcome domains are consistently measured and reported in future clinical trials, the initiative Core Outcome Sets for Epidermolysis Bullosa (COSEB) was started. In the coming two years COSEB’s aim is to define core outcome sets for each EB type. The patient voice in this process is paramount, therefore, a recent writing assignment from a master student focused on a review of the patients’ needs and perspectives on outcome domains for EB. The results of this writing assignment is taken into account in COSEB, and will help to determine the demand for additional surveys and/or focus groups with patients and caregivers.

What do you find the most fascinating about rare diseases/orphan drugs?
Marjon: “During my PhD studies, which I performed on the rare disease EB at the Center for Blistering Diseases at the University Medical Center Groningen, I was in close contact with many patients. At that time the pathogenic variants for a large proportion of families were not yet found. Since then, DNA analysis has taken flight, reducing the time to diagnosis significantly. A better understanding of a rare disease may open up the possibility for therapy development. The change in the last 20 years from publishing case reports of single families, to therapy development, and also in recent years seeing therapies getting approved is fascinating. This brings of course also other challenges, such as the one mentioned above regarding adequate outcome measures in clinical trials. What hasn’t changed in those 20 years is that the rare disease field is a community where different stakeholders work internationally closely together. The fact that the number of patients in a single country is small, of course also stimulates to join forces. That being said, the dedication of everyone involved, such as expertise centers for rare diseases that are studying drug repurposing to possibly treat their own patients, is inspiring.”

Lourens: “Having been trained as a pharmacist, we never learned much about rare diseases and their treatment options. I mostly learned about rare diseases and orphan drugs during my PhD studies. The general lack of satisfactory treatments and the difficulty to identify and develop new treatments because of the very small patient populations, combined with the advent of increasingly promising biomedical innovations –such as cell and gene therapies– and innovative methods to study treatment effects –using for example real-world data– inspire me. There really is much hope that for more rare diseases a satisfactory treatment option will come available. I hope to contribute to that development even a tiny bit, for example through the EMRD that we are developing.”

How big is your research group?
Our research group/division at Utrecht University currently consists of approximately 80 researchers and teachers. We typically host around 10-15 students that perform their MSc research projects.

The Medicines Evaluation Board has 500 employees, from which 350 employees daily perform assessments on quality, non-clinical, clinical and pharmacovigilance aspects of the medicines dossiers. About 30 assessors regularly supervise bachelor/master/PhD students. The Science Department coordinates the different research projects; we are involved in 24 PhD projects, and typically host between 25-30 bachelor/master students per year for their research project.

Where is your research group located at the Campus?
Our research group is located in the David de Wied-building at the Utrecht Science Park. The Dutch Medicines Evaluation Board is located at the Graadt van Roggenweg in Utrecht.

Can students do an internship at your research group? And if yes, who should they contact?
It is certainly possible to do an internship at our research group. For contact-details: Lourens Bloem (l.t.bloem@uu.nl) and Marjon Pasmooij (am.pasmooij@cbg-meb.nl).

https://www.uu.nl/en/research/pharmacoepidemiology-and-clinical-pharmacology/research