Challenges in the clinical development of orphan drugs

Rare diseases are characterised by a low prevalence. There are so many different rare diseases, that millions of people are affected.The vast majority of these diseases suffer from a lack of approved treatment options and orphan drugs (ODs) therefore represent a huge unmet medical need. ODs face regulatory and operational challenges during their development , i.e. few and heterogeneous patients for study, complicated diagnostics, ethical issues, limited clinical expertise, lack of validated biomarkers and more importantly, lack of return of investment in the small target population. Several incentives have been put in place in Europe, to stimulate orphan drug development. Nonetheless, many obstacles may still frustrate research and product development for rare diseases.

This thesis focusses on the clinical development process of ODs in general, paediatric ODs and two specific ODs, artesunate for the treatment of severe malaria and levamisole for nephrotic syndrome in children. Formulation issues and pharmacology in children have been addressed for levamisole. We were able to develop small tablets for children aged 2 - 18 years that were found to be suitable in terms of palatability, acceptability, dosing flexibility and stability without compromising dissolution. The pharmacokinetic profile was established in the same patient population, revealing PK estimates comparable to those in adults, but with a greater interindividual variability. A dose effect relationship still has to be established.

For IV artesunate, a named patient program (NPP) was set up to collect clinical data of European malaria patients. The results from this program support several European guidelines that replaced IV quinine by IV artesunate as the drug of first choice for severe malaria. Furthermore, it was also found that manual exchange transfusion does not contribute to parasite clearance with artesunate treatment and is therefore no longer recommended. A hitherto unknown adverse effect, late haemolytic anaemia 2-3 weeks after start of treatment, was found that requires attention during the follow up after treatment.



The European regulatory framework has been used as an overlapping theme to discuss differences in availability and accessibility of (paediatric) ODs. Considerable differences exist across Europe regarding patient access. It is important to reduce inequalities between countries, for both unauthorised and authorised ODs. Firstly by harmonisation of NPPs at European level, to ensure equal availability of unauthorised ODs without compromising patient safety. NPPs provide a unique opportunity to study both the benefits and risks of unregistered products for rare diseases, provided that the patients are actively registered and monitored in a central and strictly controlled (electronic) database, managed by an independent authority (eg. EMA). Secondly, accessibility of registered ODs should be equal across Europe. This could be achieved by instalment of a European pricing and reimbursement procedure as proposed by Eurordis. Lastly, collaboration between all stakeholders is the key to success in ODs. Especially academia-industry collaborations with clear and transparent agreementsare essential to the continued development of ODs.