Lessons learned from the field of rare diseases PERSPECTIVE for a specific disease or disease group, and only a consequence, the cost of develo m, less expen by treating patients using a confirmed diagnosis for a rare disease is not necessarily and treat according to treatment guidelines. Such sive than for other drugs. Similarly, the risks links between diagnosis and therapy is highly to obtain a positive result in drug development important for orphan drugs and we believe is a for a rare disease are higher, especially if no pre- commonality with personalized healthcare. The vious treatment yet exists [TAMBUYZER E: RARE DIS field of orphan drugs is expected to drive future EASES, ORPHAN DRUGS AND THEIR REGULATIONS: ADDRESSING healthcare developments such as the emerging MISCONCEPTIONS. SUBMITTED MANUSCRIPTI collaboration of regulatory agencies and third- Once clinical proof of principle has been estab- party payers on relative efficacy of drugs [ol, lished and because some rare diseases will affect hich is also of high importance of the field of small children, the manufacturer may be and often personalized healthcare. Examples of rare disease is under pressure from patients, physicians, and/or treatments are given in Box 1& FIGURE I politicians to provide the therapy in development compassionate-use material. This is also an The development of drugs for rare diseases faces healthcare, when applied to severe diseases ized a Specificities of orphan drugs difficult and complex challenges, related to the rarity of the diseases and their heterogeneous n Registers rare disease registries nature.Rarity does not climinate the need dur- Registers and registries are used to collect ing drug development to understand the disease information about rare diseases and their being addressed, to testing potential solutions treatments. They may also be important tools and selecting the best approach to move forward. in the framework of personalized medicine In addition, the developed products also require in the future, and therefore, we define and a sustainable manufacturing process that can be describe such databases and discuss their use scaled up. The cost of developing such a process A(patient)register is a database containing can be substantial, certainly if the product is baseline information about patients with cer- a biological. All of these costs are irrespective tain disorders, without any longitudinal fol- of the size of the patient population for which low-up. Such registers are setup, for example, the product is developed. Subsequently, safety at a national or regional basis by authorities and efficacy testing in animal models(which to map rare diseases in their area and colle may not be available), and confirming results in information on the prevalence of a rare diseas Phased clinical trials are needed Italy is an example of a country using such an Disease rarity can have a significant impact on approach, but this may become a more com- the clinical development pathway. Prior to devel- mon practice in the future. A(disease)registry opment, very little may be known about that is a specifically designed database to collect rare disease as no treatment may exist. Many mostly on a voluntary basis, observational physicians will not have heard of the disease, clinical data from treating physicians, and let alone had experience with patients affected. is intended to explore and define the natura This causes 25% of the patients ive a course and clinical characteristics of a disease delayed diagnosis of between 5-30 years from as well as to track and characterize response to the of clinical symptoms [1151, and many treatment [116]. Such registries may be setup by different doctors consulted. On the one hand, either clinicians or researchers to collect data this is very different for common diseases as we on a disease or on the use of a medicine for a know about them today. However, those diseases specific disease, or by companies in conjunction become increasingly stratified into subsets and with treating physicians when clinical trials for are classified differently, and many physicians a treatment of a rare disease are started. They are or will not be familiar with those subsets and may also be required by the regulatory approval new classification either bodies as part of the approval process of the Therefore developing a therapy for a rare medicine, to continue to collect data about the disease faces amplified challenges: few patients treatment after approval. Rare disease registries may be available for study, the regulatory path- are often setup on a global basis, instead of way may not be well-established, clinical end on a national or regional basis, because of the points may not be addressable over the short number of patients. Such registry is open to term and validated biological markers, which all physicians managing the disease and for all would allow for confirmation of clinical benefit data of patients with the disease, whether they in a reasonable period of time, may not exist. As are treated or not. w. futuremedicine cor 573Perrsppective Tambuyzer Tambuyzer for a specific disease or disease group, and only by treating patients using a confirmed diagnosis and treat according to treatment guidelines. Such links between diagnosis and therapy is highly important for orphan drugs and we believe is a commonality with personalized healthcare. The field of orphan drugs is expected to drive future healthcare developments such as the emerging collaboration of regulatory agencies and third￾party payers on relative efficacy of drugs [10], which is also of high importance of the field of personalized healthcare. Examples of rare disease treatments are given in Box 1 & Figure 1. „ Specificities of orphan drugs The development of drugs for rare diseases faces difficult and complex challenges, related to the rarity of the diseases and their heterogeneous nature. Rarity does not eliminate the need dur￾ing drug development to understand the disease being addressed, to testing potential solutions and selecting the best approach to move forward. In addition, the developed products also require a sustainable manufacturing process that can be scaled up. The cost of developing such a process can be substantial, certainly if the product is a biological. All of these costs are irrespective of the size of the patient population for which the product is developed. Subsequently, safety and efficacy testing in animal models (which may not be available), and confirming results in phased clinical trials are needed. Disease rarity can have a significant impact on the clinical development pathway. Prior to devel￾opment, very little may be known about that rare disease as no treatment may exist. Many physicians will not have heard of the disease, let alone had experience with patients affected. This causes 25% of the patients to receive a delayed diagnosis of between 5–30 years from the onset of clinical symptoms [115], and many different doctors consulted. On the one hand, this is very different for common diseases as we know about them today. However, those diseases become increasingly stratified into subsets and are classified differently, and many physicians are or will not be familiar with those subsets and new classification either. Therefore developing a therapy for a rare disease faces amplified challenges: few patients may be available for study, the regulatory path￾way may not be well-established, clinical end points may not be addressable over the short term and validated biological markers, which would allow for confirmation of clinical benefit in a reasonable period of time, may not exist. As a consequence, the cost of developing a therapy for a rare disease is not necessarily less expen￾sive than for other drugs. Similarly, the risks to obtain a positive result in drug development for a rare disease are higher, especially if no pre￾vious treatment yet exists [Tambuyzer E: Rare dis￾eases, orphan drugs and their regulations: addressing misconceptions. Submitted Manuscript]. Once clinical proof of principle has been estab￾lished and because some rare diseases will affect small children, the manufacturer may be and often is under pressure from patients, physicians, and/or politicians to provide the therapy in development as compassionate-use material. This is also an aspect that we can learn from for personalized healthcare, when applied to severe diseases. „ Registers & rare disease registries Registers and registries are used to collect information about rare diseases and their treatments. They may also be important tools in the framework of personalized medicine in the future, and therefore, we define and describe such databases and discuss their use. A (patient) register is a database containing baseline information about patients with cer￾tain disorders, without any longitudinal fol￾low-up. Such registers are setup, for example, at a national or regional basis by authorities to map rare diseases in their area and collect information on the prevalence of a rare disease. Italy is an example of a country using such an approach, but this may become a more com￾mon practice in the future. A (disease) registry is a specifically designed database to collect, mostly on a voluntary basis, observational clinical data from treating physicians, and is intended to explore and define the natural course and clinical characteristics of a disease, as well as to track and characterize response to treatment [116]. Such registries may be setup by either clinicians or researchers to collect data on a disease or on the use of a medicine for a specific disease, or by companies in conjunction with treating physicians when clinical trials for a treatment of a rare disease are started. They may also be required by the regulatory approval bodies as part of the approval process of the medicine, to continue to collect data about the treatment after approval. Rare disease registries are often setup on a global basis, instead of on a national or regional basis, because of the number of patients. Such registry is open to all physicians managing the disease and for all data of patients with the disease, whether they are treated or not. future science group www.futuremedicine.com 573 Lessons learned from the field of rare diseases Perspective