PERSPECTIVE Tambuyzer will be individualized, and therefore, not pos- There are an estimated 6000-8000 rare sible by the patient him or herself by internet diseases that affect approximately 6% of the EU population, many of whom w ill not nec- essarily require treatment. Many of these What can personalized patients are not yet diagnosed. Most rare dis- healthcare learn from the field of eases have a prevalence of less than 1/100,000, orphan drugs? nd therefo Orphan drug regulations have been approved in than the prevalence number defined by the the USA in 1983, in Japan in 1993 and in 1999 EU regulation cutoff(for prevalence data, see by the EU. With more than 25 years of history Orphanet [1131). Some 70-80% of rare diseases n the USA [8], 17 years in Japan and 10 years are genetic in origin and most have no treatment in the EU [lol, and some experience in other available: the fewer patients affected, the less countries, there is much experience gathered that likely that a meaningful therapy already exists could inform the future development of person- [TAMBUYZER E: RARE DISEASES, ORPHAN DI alized healthcare. The author believes that this is REGULATIONS: ADDRESSING MISCONCEPTIONS he case for the linkage, in the clinical practice, MANUSCRIPTI[106 114]. In the case of one-third of of diagnosis to therapy, for the use of registries orphan drugs in Europe, no alternative treat- to collect clinical data, for some aspects in the ment to treat that disease(except supportive setup and running of clinical trials, for the need care)was available before the orphan drug was to educate the treating physicians, for the need approved. In two-thirds of the cases, another for networks of excellence, for the more detailed treatment(s) was available but the approved collection and use of patient-centered quality-of- orphan drug offers a 'significant benefit to the life data and other types of information coming patients treated, as agreed upon by the regula- directly from patients during drug development, tory approval body. This means that also from for the closer relationship of developers and reg- this perspective, while common diseases to be ulators with patient groups and finally for the treated with personalized healthcare may have need to optimally use scarce data to determine other treatment options, the situation for many he clinical added value of a treatment are diseases for which orphan drugs exist may Also, studying known monogenic disorders not be dissimilar will improve our understanding of genetic and Since, in addition to a severe shortage of avail- environmental modifiers of disease severity and able therapies, patients with a rare disease con- provide an ideal for the discovery, evaluation and front low disease awareness, limited information validation of novel bio-markers and -signatures is available and the knowledge about the disease for the prediction of severity that can be used is limited to few experts and expert centers with for personalized therapies. Rapid and afford- limited and late access to diagnostic testing. The able testing for inherited disorders will reduce challenge is therefore not only to develop thera- diagnostic delay, improve counseling and forge pies for these rare diseases but also to create a sus- the modernization of genetic diagnostic services tainable healthcare system capable of providing across Europe [lll care, from diagnosis to treatment ITAMBUYZER E RARE DISEASES, ORPHAN DRUGS AND THEIR REGULATIONS Rare diseases, orphan drugs ADDRESSING MISCONCEPTIONS. SUBMITTED MANUSCRIPT]. their The field of rare diseases became a precur ases, as defined 1 he eu by Regulation sor of future developments in human health EC 141/2000(112), are life-threatening or chroni- care (9.106, 1071, providing disease-modifying treat cally debilitating conditions affecting not more ments and targeting smaller patient populations than five in 10,000 persons in the European with high unmet medical needs. Once patients Community. This means fewer than 250,000 are diagnosed and their treatment decided, both citizens out of approximately 500 million inhab- the field of rare diseases and the field of person- itants in the 27 EU member states. Orphan alized healthcare work with clearly identified medicinal products-orphan drugs-as defined patient groups, which may be small or even very in the same EU Regulation, are medicines small. Because the costs of developing orphan for such rare diseases. They are called orphan drugs and also of personalized medicines can because,without the provisional economic be high, the economic rationale(on top of any ncentives, industry may be reluctant to invest safety concern) to provide such products only to in the development of a therapy because of the patients who benefit, is important. This is only absence of a foreseeable return on investment. possible in practice through centers of excellence 72 Personalized Medicine(2010)7(5) wPerrsppective Tambuyzer Tambuyzer will be individualized, and therefore, not pos￾sible by the patient him or herself by internet research alone. What can personalized healthcare learn from the field of orphan drugs? Orphan drug regulations have been approved in the USA in 1983, in Japan in 1993 and in 1999 by the EU. With more than 25 years of history in the USA [8], 17 years in Japan and 10 years in the EU [110], and some experience in other countries, there is much experience gathered that could inform the future development of person￾alized healthcare. The author believes that this is the case for the linkage, in the clinical practice, of diagnosis to therapy, for the use of registries to collect clinical data, for some aspects in the setup and running of clinical trials, for the need to educate the treating physicians, for the need for networks of excellence, for the more detailed collection and use of patient-centered quality-of￾life data and other types of information coming directly from patients during drug development, for the closer relationship of developers and reg￾ulators with patient groups and finally for the need to optimally use scarce data to determine the clinical added value of a treatment. Also, studying known monogenic disorders will improve our understanding of genetic and environmental modifiers of disease severity and provide an ideal for the discovery, evaluation and validation of novel bio-markers and -signatures for the prediction of severity that can be used for personalized therapies. Rapid and afford￾able testing for inherited disorders will reduce diagnostic delay, improve counseling and forge the modernization of genetic diagnostic services across Europe [111]. „ Rare diseases, orphan drugs & their regulations Rare diseases, as defined in the EU by Regulation EC 141/2000 [112], are life-threatening or chroni￾cally debilitating conditions affecting not more than five in 10,000 persons in the European Community. This means fewer than 250,000 citizens out of approximately 500 million inhab￾itants in the 27 EU member states. Orphan medicinal products – orphan drugs – as defined in the same EU Regulation, are medicines for such rare diseases. They are called orphan because, without the provisional economic incentives, industry may be reluctant to invest in the development of a therapy because of the absence of a foreseeable return on investment. There are an estimated 6000–8000 rare diseases that affect approximately 6% of the EU population, many of whom will not nec￾essarily require treatment. Many of these patients are not yet diagnosed. Most rare dis￾eases have a prevalence of less than 1/100,000, and therefore, may affect much fewer patients than the prevalence number defined by the EU regulation cutoff (for prevalence data, see Orphanet [113]). Some 70–80% of rare diseases are genetic in origin and most have no treatment available: the fewer patients affected, the less likely that a meaningful therapy already exists [Tambuyzer  E: Rare diseases, orphan drugs and their regulations: addressing misconceptions. Submitted Manuscript] [106,114]. In the case of one-third of orphan drugs in Europe, no alternative treat￾ment to treat that disease (except supportive care) was available before the orphan drug was approved. In two-thirds of the cases, another treatment(s) was available but the approved orphan drug offers a ‘significant benefit to the patients treated’, as agreed upon by the regula￾tory approval body. This means that also from this perspective, while common diseases to be treated with personalized healthcare may have other treatment options, the situation for many rare diseases for which orphan drugs exist may not be dissimilar. Since, in addition to a severe shortage of avail￾able therapies, patients with a rare disease con￾front low disease awareness, limited information is available and the knowledge about the disease is limited to few experts and expert centers with limited and late access to diagnostic testing. The challenge is therefore not only to develop thera￾pies for these rare diseases but also to create a sus￾tainable healthcare system capable of providing care, from diagnosis to treatment [Tambuyzer E: Rare diseases, orphan drugs and their regulations: addressing misconceptions. Submitted Manuscript]. The field of rare diseases became a precur￾sor of future developments in human health￾care[9,106,107], providing disease-modifying treat￾ments and targeting smaller patient populations with high unmet medical needs. Once patients are diagnosed and their treatment decided, both the field of rare diseases and the field of person￾alized healthcare work with clearly identified patient groups, which may be small or even very small. Because the costs of developing orphan drugs and also of personalized medicines can be high, the economic rationale (on top of any safety concern) to provide such products only to patients who benefit, is important. This is only possible in practice through centers of excellence 572 Personalized Medicine (2010) 7(5) future science group Lessons learned from the field of rare diseases Perspective