Academic Clinical Research in the Context of Rare Diseases – An Interview with Prof. Dr. med. Wolfgang Bethge

In the EU, a disease is considered rare if it affects no more than 5 out of every 10,000 people. Academic clinical research is essential for rare diseases (RD) in order to develop new therapeutic approaches. On International Rare Disease Day, Prof. Dr. Wolfgang Bethge offers us insights into this research.

As director of the ZKS Tübingen, he has been actively involved in clinical research on allogeneic stem cell transplants and cellular immunotherapies for many years. Among other things, he oversees studies on innovative therapeutic approaches such as CAR-T cell therapy. These studies open up new treatment possibilities for people with rare diseases and contribute to the development of effective therapeutic options.

In this interview, Prof. Dr. Wolfgang Bethge discusses the methodological challenges, the role of specialized study centers, and the prospects for innovative therapies for people with rare diseases.
 

Since there are relatively few patients available for clinical trials on rare diseases, conducting such trials is challenging. What methodological considerations must be taken into account when working with small patient cohorts?
 

Clinical trials for rare diseases pose significant methodological challenges, as traditional study designs involving large sample sizes are usually not feasible. At the ZKS Tübingen, we therefore collaborate with the Institute for Clinical Epidemiology and Applied Biometry (IKEAB) in Tübingen to provide statistical, methodological, and regulatory guidance starting in the planning phase, in order to define appropriate endpoints, biomarkers, study designs, and analysis strategies. The goal is to achieve valid, regulatory-compliant, and patient-relevant results even with small patient cohorts. Adaptive designs, registry data, historical control groups, and intra-individual comparisons are instrumental in achieving this.
 

The ZKS Tübingen collaborates, among others, with the Center for Rare Diseases (ZSE) and is distinguished by its expertise in investigator-initiated trials in the field of rare diseases. What role do specialized study centers play in the success of rare disease trials?
 

With regard to innovative cell and immunotherapies: Which developments do you consider particularly promising for clinical research on rare diseases?
 

Highly targeted therapies that directly address the molecular causes of a disease are currently particularly promising. These include cell-based therapies, as well as immunotherapies that specifically correct misdirected or inadequate biological processes.

This is particularly relevant for rare diseases, as many of them are attributable to clearly defined genetic or immunological defects. The increasing precision of these therapies opens up new possibilities for developing clinically effective treatments, even for very small patient groups.

For clinical research, however, this also means complex study protocols and stringent regulatory requirements. Here, we see an important role for the ZKS in safely and systematically advancing innovative therapies into early-phase clinical trials.
 

To what extent are new forms of therapy, such as gene, cell, or RNA-based techniques, relevant?
 

New forms of therapy, such as gene, cell, or RNA-based approaches, have the potential to fundamentally transform the treatment of rare diseases. Rather than alleviating symptoms, they aim to directly influence or correct the cause of the disease.

Particularly in the case of monogenic diseases, such therapies can achieve long-term or even permanent effects. For clinical research, however, this also presents new challenges—for example, regarding study design, safety assessment, and long-term follow-up. This makes structured clinical trials conducted under specialized conditions all the more important. These new forms of therapy require specialized expertise—such as in safety protocols, long-term follow-up, and regulatory requirements—which is concentrated in specialized study centers.
 

Is a trend toward SE emerging in clinical research in the coming years?
 

Yes, there is a clear trend toward personalized and molecularly defined treatment strategies. The lines between diagnosis and treatment are becoming increasingly blurred, as genetic and molecular characterizations are having an ever-greater influence on study design.

In addition, international collaborations, platform-based studies, high-quality registry studies, and the use of real-world data are continuing to gain importance. These developments help to evaluate new therapies more efficiently and quickly, despite small patient numbers.

The ZKS/KKS centers within the KKS network increasingly see their role as serving as a methodological and organizational hub that brings together academic research, clinical expertise, and regulatory requirements.
 

What is your key message regarding the importance of clinical research for rare diseases?
 

Clinical research is often the only path to effective therapies for people with rare diseases. It not only creates new treatment options but also generates knowledge, visibility, and hope for patients who, for a long time, were largely overlooked—particularly by the commercially driven research of pharmaceutical companies. Specialized institutions, such as the members of the KKS network, make a crucial contribution by translating innovative research approaches into high-quality and safe clinical trials.

Only through this structured framework can new therapies be developed and integrated into the long-term care of patients with rare diseases.