Masterstudiengang "Drug Regulatory Affairs"
Regulatory Strategies and Practical Aspects for the Development and Authorisation of Orphan Medicinal Products in the European Union ***
Dr. Matthias Dormeyer (Abschlußjahr: 2008)
The authorisation of orphan medicinal products in the EU is a two-step process. First the project has to receive orphan designation that qualifies for receiving the incentives such as free scientific advice. In a second step the product has to be authorized as an orphan medicinal product.
Initially, the product has to receive orphan designation prior to authorisation. This follows a clearly structured and well defined procedure. The most frequent reason for rejection is invalid definition of the subgroup of a disease. For this reason proper definition of the orphan condition is one of the factors of success for designation. During the designation procedure most issues arise from insufficient demonstration of medical plausibility or justification of a potential benefit for the affected patients.
One of the incentives for orphan products is the possibility to obtain free scientific advice, called protocol assistance for orphan drugs, at the EMEA. This procedure is a critical element of the regulatory strategy and is strongly recommended to pursue in particular as available data indicate that it contributes to a smoother authorisation process in the end.
The development of orphan medicinal products and non-orphan normal drugs are distinct with regard to several features. Most important, the number of pivotal studies is much lower for orphans and frequently no comparator group is included. Whereas the former is most likely due to the fact that only few patients are available the latter can be explained by the orphan characteristics. Due to the severity of the disease placebo controls might not be ethical. On the other hand, due to the fact that orphan diseases cannot be treated appropriately there might be no adequate active comparator. In any case the clinical development should aim at statistical significance in the primary endpoint. An underpowered study might be acceptable in case the rarity of the disease can adequately be demonstrated.
Orphan medicinal products are authorized under the centralized procedure. Overall, no difference is obvious in the review process by the CHMP for orphan and non-orphan products. On average, during the authorisation process two lists of questions are issued independent of the product type. Similarly, there is no significant difference of the review time or the overall inspection frequency. Authorisation under exceptional circumstances is a particular way to allow marketing authorisation with incomplete clinical data. One of the potential prerequisites for this procedure is rarity of the indication. For this reason, authorisation under exceptional circumstances is frequently seen for orphan products. However, despite the fact that the legislation states that such a procedure should be used if no complete data package can be expected comprehensive provisions will be defined to ensure that all important missing data will be provided finally.
Retrospectively, it is observed that orphan medicinal products fail significantly more often than non-orphans during the initial marketing authorisation. This can only in part be explained by difficulties in development. Accordingly, irrespective of the question if an orphan product is developed highest data quality should be ensured.