《学术英语（医学）》拓展阅读资料：Towards a framework for personalized healthcare lessons learned from the field of rare diseases

PERSPECTIVE Forreprintorderspleasecontactreprints@futuremedicine.com Towards a framework for personalized healthcare lessons learned from the field of rare diseases A large percentage of medicines do not work for the patient populations they are intended to treat. Increased knowledge regarding genomics and the underlying biological mechanism of diseases should help us be able to stratify patients into groups of likely responders and nonresponders, and to identify those patients for whom a treatment might do more harm than good. This article sets out different policy perspectives for the healthcare systems, and draws in on 25 years of particular experience from the rare disease and orphan drug field, to illuminate the pathway forward in relation to key implementation aspects of personalized healthcare. In principle, we submit that targeting medicines to preidentified groups for whom we can predict a beneficial outcome is a good thing for everyone- first of all for the patients, but also for all the other stakeholders, including payers, treating physicians and industry- because it has the potential to create sustainable and functioning healthcare systems directed to better health and prevention of disease. Personalized healthcare over time could also lead to shorter drug-development times because of lower rates of failure in late-stage drug development. Using orphan medicines to treat well-diagnosed patients suffering from a life-threatening or seriously debilitating rare disease, is an attempt to work according to these principles. As there is much that needs to be done to turn the promise into reality, we need to identify the barriers and challenges to transform the potential opportunities into real-life benefits, and what needs to be done in order to overcome them. Learning from the field of rare diseases and orphan drugs may provide, perhaps unexpectedly, some of the answers to public policy questions related to future (personalized) healthcare, but of course not all aspects, are common between the two fields KEYWORDS: biomarkers business models diagnostic testing education ethics Erik Tambuyzer incentives multistakeholder collaboration orphan drugs patients outcomes personalized healthcare pharmacogenomics rare diseases registries atem, Belgium regulatory framework Some form of personalized healthcare has been personalized'therapies. Society in Europe practiced since the dawn of modern medicine. across stakeholders, seems to broadly embrace The concept of personalized healthcare today, personalized healthcare across different stake- however, is something very different, and its holders, as proven by a survey done in central emergence is based on the development of the Europe [1o1]. The new findings may be used, for fields of life sciences and genomics. It is tar- example, to facilitate clinical translation and geted at the genetic and biological make-up of subsequent availability of beneficial drugs by the individual, or groups of individuals. This stratifying patient populations during clinical paradigm shift in science has created a much trials, and by using input by the patients on logical mechanisms of discase nding of the bio- quality of life, to guide clinical development more comprehensive understan and the lucida- of a product. This would increase the likeli tion of the genome and of epigenome is still hood of showing benefit and, subsequently ongoing. In turn, this has led, and still leads, allows the physician to use patient-specific to a better understanding of a larger number diagnostic information to guide the choice of of life-threatening or seriously debilitating rare therapy most likely to benefit that patient, if diseases, for which treatments are being devel- the right biomarker can be identified early in oped. Such treatments are called "orphan drugs, the development phase. The benefits of such a as they had no 'sponsoring parents' in the past targeted approach are multiple but would have to develop them. an impact on the entire healthcare framework The new scientific findings provide an from patients to industry; and from academic opportunity for stakeholders across the health- researchers to payers. It has the potential to care spectrum to move towards the develop- move us away from the current trial-and re ment,use and reimbursement of targeted or error' paradigm of medicine -depending on edicine fsg 10.2217/PME 10.52@ 2010 Future Medicine Ltd Personalized Medicine(2010)7(5), 569-586 ssN1741-0541 569

Towards a framework for personalized healthcare: lessons learned from the field of rare diseases Some form of personalized healthcare has been practiced since the dawn of modern medicine. The concept of personalized healthcare today, however, is something very different, and its emergence is based on the development of the fields of life sciences and genomics. It is tar￾geted at the genetic and biological make-up of the individual, or groups of individuals. This paradigm shift in science has created a much more comprehensive understanding of the bio￾logical mechanisms of disease, and the elucida￾tion of the genome and of epigenome is still ongoing. In turn, this has led, and still leads, to a better understanding of a larger number of life-threatening or seriously debilitating rare diseases, for which treatments are being devel￾oped. Such treatments are called ‘orphan drugs’, as they had no ‘sponsoring parents’ in the past to develop them. The new scientific findings provide an opportunity for stakeholders across the health￾care spectrum to move towards the develop￾ment, use and reimbursement of targeted or ‘personalized’ therapies. Society in Europe, across stakeholders, seems to broadly embrace personalized healthcare across different stake￾holders, as proven by a survey done in central Europe [101]. The new findings may be used, for example, to facilitate clinical translation and subsequent availability of beneficial drugs by stratifying patient populations during clinical trials, and by using input by the patients on quality of life, to guide clinical development of a product. This would increase the likeli￾hood of showing benefit and, subsequently allows the physician to use patient-specific diagnostic information to guide the choice of therapy most likely to benefit that patient, if the right biomarker can be identified early in the development phase. The benefits of such a targeted approach are multiple but would have an impact on the entire healthcare framework, from patients to industry; and from academic researchers to payers. It has the potential to move us away from the current ‘trial-and￾error’ paradigm of medicine – depending on A large percentage of medicines do not work for the patient populations they are intended to treat. Increased knowledge regarding genomics and the underlying biological mechanism of diseases should help us be able to stratify patients into groups of likely responders and nonresponders, and to identify those patients for whom a treatment might do more harm than good. This article sets out different policy perspectives for the healthcare systems, and draws in on 25 years of particular experience from the rare disease and orphan drug field, to illuminate the pathway forward in relation to key implementation aspects of personalized healthcare. In principle, we submit that targeting medicines to preidentified groups for whom we can predict a beneficial outcome is a good thing for everyone – first of all for the patients, but also for all the other stakeholders, including payers, treating physicians and industry – because it has the potential to create sustainable and functioning healthcare systems directed to better health and prevention of disease. Personalized healthcare over time could also lead to shorter drug-development times because of lower rates of failure in late-stage drug development. Using orphan medicines to treat well-diagnosed patients suffering from a life-threatening or seriously debilitating rare disease, is an attempt to work according to these principles. As there is much that needs to be done to turn the promise into reality, we need to identify the barriers and challenges to transform the potential opportunities into real-life benefits, and what needs to be done in order to overcome them. Learning from the field of rare diseases and orphan drugs may provide, perhaps unexpectedly, some of the answers to public policy questions related to future (personalized) healthcare, but of course not all aspects, are common between the two fields. KEYWORDS: biomarkers n business models n diagnostic testing n education n ethics n incentives n multistakeholder collaboration n orphan drugs n patients outcomes n personalized healthcare n pharmacogenomics n rare diseases n registries n regulatory framework Erik Tambuyzer Genzyme Belgium NV/SA, 53 Ikaroslaan, Zaventem, Belgium Tel.: +32 2714 1740 Fax: +32 2714 1747 erik.tambuyzer@genzyme.com 569 Review 10.2217/PME.10.52 © 2010 Future Medicine Ltd Personalized Medicine (2010) 7(5), 569–586 ISSN 1741-0541 Perspective For reprint orders, please contact: reprints@futuremedicine.com

PERSPECTIVE Tambuyzer the disease treated, between 20 and 75% of As society looks to evolve its public policies the medicines in use today do not seem to work around the emergence of personalized health properly for a broad set of patients [1.2]. The care, it may be useful to examine the approaches WHO estimates that, worldwide, half of all used in the field of rare diseases. Learning from medicines are inappropriately prescribed, dis- this field may provide answers to some of the p pensed or sold, and that half of all patients fail icy questions as the field also features small(er) to take their medicine properly [102]. Therefore, patient populations and rare diseases are fre is in society's best interest to dramatically quently of genetic origin [105]. For that reason, change these numbers for the better. we will discuss herein, from a policy perspective, There are already several examples of this some of these commonalities although not all pproach to personalized medicine [103], but answers will obviously come from this field. the concept is still in its early days, albeit with This article is expanded from a presentation approximately 10% of US FDA-approved On'Commonalities between Personalized med- the potential to grow much larger. Today and Orphan Drugs by Erik Tambuyzer drugs contain pharmacogenomic informa- that was presented at the annual European tion [3]. The potential is also expressed by Forum for Good Clinical Practice(EFGCP) the Pharmacogenomics Working Party of the Conference, January 2010 [1061, and a subse- Committee for Human Medicinal Products at quent presentation by Wills Hughes-Wilson at the European Medicines Agency (EMA)indi- a Europa Bio Workshop on 19 March 2010 [1071 ating in their draft guideline that the high- Apart from a paper in social sciences [5l,we est level of pharmacokinetic polymorphism could not find another paper in the literature lism 1o4).Pharmacokinetics will indicate how medicine, which is quise hat e able In" is found in genes involved in drug metabo- regarding orphan drugs and personalized tration. This process can be affected by genetic similarities in terms of registration and in social factors causing differences in how the drug will and economic impacts, and are regarded both perform, which are called polymorphisms. positively and negatively at the same time Much time is still needed to turn all that new Much lies between the emergey are ce and the knowledge into practical progress. Incentives frequent application of personalized and disincentives for reimbursement and data In many ways, the current healthcare systems exclusivity also need to be addressed. Ethically, are indeed not designed to reward personalized it is also important to ensure that the emer- approaches but to rather favor standardization gence of a more stratified approach to groups of of approaches to patient groups, and there patients does not prematurely deny beneficial fore, a shift towards personalized healthcare treatment to an individual, because knowledge will require a major shift in healthcare systems, is still being added. A good but not yet per- as well as in the business models of research fect combination of a test with a therapy can based pharmaceutical companies. This will indeed inspire health technology assessment also affect the other stakeholders agencies to advice to delay reimbursement While rare diseases and orphan drugs share while the proposed treatment solution could some features with personalized medicine, they already benefit patients immediately. Such an are also different in other aspects. Rare diseases attitude was initially seen from the National may still not be economically interesting, are nstitute for Clinical Excellence(NICE)in the confronted with low awareness and expertise, UK, in the case of Herceptin, but has since and are very heterogeneous. By contrast, per- sonalized healthcare is aimed at subgroups of Of course, the practice of medicine will mostly well-known large patient populations remain part science and part art. Hippocrates often already addressed by the healthcare sys- already recognized that it's far more important tems and with well established infrastructures to know what person the disease has, than what We will mainly discuss the commonalities of disease the person has. Personalized healthcare both in this article. must continue to take some uncertainty of sci- entific results and the realities of human behav- What is personalized healthcare? ior into account, but the margins for uncer- One of the issues with the concept of personalized tainty will be made smaller. Even if sequencing healthcare is that it does not have a universally is 99.9999% accurate, a full genome sequence accepted working definition, which would be the will contain 6000 errors [4] first element to clarify the concept for broader use Personalized Medicine(2010)7(5) future science group

Perrsppective Tambuyzer Tambuyzer the disease treated, between 20 and 75% of the medicines in use today do not seem to work properly for a broad set of patients [1,2]. The WHO estimates that, worldwide, half of all medicines are inappropriately prescribed, dis￾pensed or sold, and that half of all patients fail to take their medicine properly [102]. Therefore, it is in society’s best interest to dramatically change these numbers for the better. There are already several examples of this approach to personalized medicine [103], but the concept is still in its early days, albeit with the potential to grow much larger. Today, approximately 10% of US FDA-approved drugs contain pharmacogenomic informa￾tion [3]. The potential is also expressed by the Pharmacogenomics Working Party of the Committee for Human Medicinal Products at the European Medicines Agency (EMA) indi￾cating in their draft guideline that the high￾est level of pharmacokinetic polymorphism is found in genes involved in drug metabo￾lism [104]. Pharmacokinetics will indicate how the body ‘digests’ a specific drug after adminis￾tration. This process can be affected by genetic factors causing differences in how the drug will perform, which are called polymorphisms. Much time is still needed to turn all that new knowledge into practical progress. Incentives and disincentives for reimbursement and data exclusivity also need to be addressed. Ethically, it is also important to ensure that the emer￾gence of a more stratified approach to groups of patients does not prematurely deny beneficial treatment to an individual, because knowledge is still being added. A good but not yet per￾fect combination of a test with a therapy can indeed inspire health technology assessment agencies to advice to delay reimbursement while the proposed treatment solution could already benefit patients immediately. Such an attitude was initially seen from the National Institute for Clinical Excellence (NICE) in the UK, in the case of Herceptin®, but has since been changed. Of course, the practice of medicine will remain part science and part art. Hippocrates already recognized that ‘it’s far more important to know what person the disease has, than what disease the person has’. Personalized healthcare must continue to take some uncertainty of sci￾entific results and the realities of human behav￾ior into account, but the margins for uncer￾tainty will be made smaller. Even if sequencing is 99.9999% accurate, a full genome sequence will contain 6000 errors [4]. As society looks to evolve its public policies around the emergence of personalized health￾care, it may be useful to examine the approaches used in the field of rare diseases. Learning from this field may provide answers to some of the pol￾icy questions as the field also features small(er) patient populations and rare diseases are fre￾quently of genetic origin [105]. For that reason, we will discuss herein, from a policy perspective, some of these commonalities although not all answers will obviously come from this field. This article is expanded from a presentation on ‘Commonalities between Personalized med￾icine and Orphan Drugs’ by Erik Tambuyzer that was presented at the annual European Forum for Good Clinical Practice (EFGCP) Conference, January 2010 [106], and a subse￾quent presentation by Wills Hughes-Wilson at a EuropaBio Workshop on 19 March 2010 [107]. Apart from a paper in social sciences [5], we could not find another paper in the literature regarding orphan drugs and personalized medicine, which is quite remarkable. In that paper, the conclusion is that there are many similarities in terms of registration and in social and economic impacts, and are regarded both positively and negatively at the same time. Much lies between the emergence and the frequent application of personalized healthcare. In many ways, the current healthcare systems are indeed not designed to reward personalized approaches but to rather favor standardization of approaches to patient groups, and there￾fore, a shift towards personalized healthcare will require a major shift in healthcare systems, as well as in the business models of research￾based pharmaceutical companies. This will also affect the other stakeholders. While rare diseases and orphan drugs share some features with personalized medicine, they are also different in other aspects. Rare diseases may still not be economically interesting, are confronted with low awareness and expertise, and are very heterogeneous. By contrast, per￾sonalized healthcare is aimed at subgroups of mostly well-known large patient populations often already addressed by the healthcare sys￾tems and with well established infrastructures. We will mainly discuss the commonalities of both in this article. What is personalized healthcare? One of the issues with the concept of personalized healthcare is that it does not have a universally accepted working definition, which would be the first element to clarify the concept for broader use 570 Personalized Medicine (2010) 7(5) future science group Lessons learned from the field of rare diseases Perspective

Lessons learned from the field of rare diseases PERSPECTIVE in society. The lack of this makes communication discussed further herein. Early detection offers and advances in the policy debate quite challeng- the potential to preserve health and avoid irrevers- ing. Often the concept of personalized healthcare ible damage, with the early institution of monitor- is used negatively, owing to the glamorized pic- ing and treatment, and therefore, may contribute ture painted for genetic tests for designer babies, greatly to improved patient outcomes, but may partner traits for dating or marriage, and ancestry also raise ethical questions such as the diagnosi tests such as for the daughters of Eve, a test that of disease without potential to treat. Progressing determines from which of the so-called seven in diagnostic, and even, preventative testing will daughters of Eve (the first woman) you might require an examination of the current ethical, have descended from (1081 gulatory and reimbursement schemes associated Current personalized healthcare is not solely with such testing and with the related therapy oriented towards monogenic disorders but also paves the way in which new diagnostic and ther- ls personalized really personal? apeutic approaches to common multifactorial Personalized healthcare requires the development ons are emerging [4] of products for targeted patient populations,a The US National Cancer Institute's Trans- task primarily taken up by industry. These thera- lational Research Working Group defines transla- pies will be further personalized in the practice tional research as research that transforms scien- of medicine by the physician, who will be using tific discoveries arising from laboratory, clinical, test information and other knowledge about the or population studies into clinical applications patient at his or her disposal, possibly coming to reduce cancer incidence, morbidity and mor- up with an individual treatment plan for each tality(109). Translational research is a combina- patient, and adapting dosing, treatment regimens tion of data from research in preclinical studies and so on, to that individual patients require- and in human trials with research to adopt best ments. The outcome of personalized healthcare practices. Personalized healthcare is the con- is, therefore, personal. The shared responsibility ept that uses the results of such translational between therapy developer, treating physician and research combined with patients'information, in patient will necessarily lead to a higher degree the delivery of treatment and treatment protocols of co-responsibility, because treatments need to to stratified patient populations. From there, it be developed with individual patient outcomes may be further individualized by physicians and in mind, and will not be standardized for very counselors using individual genetic information. large patient groups as may be the case today with Therefore, we propose to define personalized many treatments. healthcare as the use of modern biology's new Personalized medicine should result in fewer methods and tools that bring the right treatment adverse events [104), and thus should (at least over for the right patient at the right dose and at the the long term) reduce healthcare costs [7]. The right time, in a sustainable way author expects that its application will increase the In the development of personalized health- need of counseling, from diagnosis to treatment care applications, the major challenge will be because the finer details, and the implications of the discovery and validation of biomarkers, espe- certain choices to be made, need to be conveyed cially for multifactorial, common diseases and to the patient. If done right, it may additionally to define patients and patient populations that result in better patient compliance/adherence an be predicted to either react positively to a to treatment because the treatment will work in treatment, or to be susceptible to an unwanted almost all patients, which is a motivating fac adverse reaction or safety issue. tor for the treated patients. This in turn, can be An important component of the delivery of expected to not only lead to a more cost-effective personalized healthcare to patients will be the use of medicines but also to more consistent clini- use of diagnostic tests to identify genetic or pos- cal outcomes. At the same time, the implementa- sibly other variations such as those involving tion will require a higher degree of education of environmental factors, diet, behavior or social treating physicians on an ongoing basis circumstances (61. Those diagnostic tests may be The above described process is already in derived from biomarkers previously used in clin- use in treating rare diseases, where education ical trials, but not all biomarkers are expected to is needed on an almost permanent basis, for gnostIc tests. treating physicians and for the patient. The Diagnostic testing may be able to identify author believes that this, in times of the inter- patients at a very early stage of disease or pre- net patient, will enable physicians to regain a dict preventative measures, the latter not b loser link with their patient, as counseling w. futuremedicine cor 571

Perrsppective Tambuyzer Tambuyzer in society. The lack of this makes communication and advances in the policy debate quite challeng￾ing. Often the concept of personalized healthcare is used negatively, owing to the glamorized pic￾ture painted for genetic tests for designer babies, partner traits for dating or marriage, and ancestry tests such as for ‘the daughters of Eve’, a test that determines from which of the so-called seven daughters of Eve (‘the first woman’) you might have descended from [108]. Current personalized healthcare is not solely oriented towards monogenic disorders but also paves the way in which new diagnostic and ther￾apeutic approaches to common multifactorial conditions are emerging [4]. The US National Cancer Institute’s Trans￾lational Research Working Group defines transla￾tional research as ‘research that transforms scien￾tific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence, morbidity and mor￾tality’ [109]. Translational research is a combina￾tion of data from research in preclinical studies and in human trials with research to adopt best practices. Personalized healthcare is the con￾cept that uses the results of such translational research combined with patients’ information, in the delivery of treatment and treatment protocols to stratified patient populations. From there, it may be further individualized by physicians and counselors using individual genetic information. Therefore, we propose to define personalized healthcare as the use of modern biology’s new methods and tools that bring the right treatment for the right patient at the right dose and at the right time, in a sustainable way. In the development of personalized health￾care applications, the major challenge will be the discovery and validation of biomarkers, espe￾cially for multifactorial, common diseases and to define patients and patient populations that can be ‘predicted’ to either react positively to a treatment, or to be susceptible to an unwanted adverse reaction or safety issue. An important component of the delivery of personalized healthcare to patients will be the use of diagnostic tests to identify genetic or pos￾sibly other variations such as those involving environmental factors, diet, behavior or social circumstances [6]. Those diagnostic tests may be derived from biomarkers previously used in clin￾ical trials, but not all biomarkers are expected to become diagnostic tests. Diagnostic testing may be able to identify patients at a very early stage of disease or pre￾dict preventative measures, the latter not being discussed further herein. Early detection offers the potential to preserve health and avoid irrevers￾ible damage, with the early institution of monitor￾ing and treatment, and therefore, may contribute greatly to improved patient outcomes, but may also raise ethical questions such as the diagnosis of disease without potential to treat. Progressing in diagnostic, and even, preventative testing will require an examination of the current ethical, regulatory and reimbursement schemes associated with such testing and with the related therapy. „ Is personalized really personal? Personalized healthcare requires the development of products for targeted patient populations, a task primarily taken up by industry. These thera￾pies will be further personalized in the practice of medicine by the physician, who will be using test information and other knowledge about the patient at his or her disposal, possibly coming up with an individual treatment plan for each patient, and adapting dosing, treatment regimens and so on, to that individual patient’s require￾ments. The outcome of personalized healthcare is, therefore, personal. The shared responsibility between therapy developer, treating physician and patient will necessarily lead to a higher degree of co-responsibility, because treatments need to be developed with individual patient outcomes in mind, and will not be standardized for very large patient groups as may be the case today with many treatments. Personalized medicine should result in fewer adverse events [104], and thus should (at least over the long term) reduce healthcare costs [7]. The author expects that its application will increase the need of counseling, from diagnosis to treatment, because the finer details, and the implications of certain choices to be made, need to be conveyed to the patient. If done right, it may additionally result in better patient compliance/adherence to treatment because the treatment will work in almost all patients, which is a motivating fac￾tor for the treated patients. This in turn, can be expected to not only lead to a more cost-effective use of medicines but also to more consistent clini￾cal outcomes. At the same time, the implementa￾tion will require a higher degree of education of treating physicians on an ongoing basis. The above described process is already in use in treating rare diseases, where education is needed on an almost permanent basis, for treating physicians and for the patient. The author believes that this, in times of the inter￾net patient, will enable physicians to regain a closer link with their patient, as counseling future science group www.futuremedicine.com 571 Lessons learned from the field of rare diseases Perspective

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) w

Perrsppective 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

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 573

Perrsppective 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

PERSPECTIVE Tambuyzer Box 1. Examples of rare disease treatments and their analogy to personalized healthcare Enzyme replacement therapies for lysosomal storage disorders Enzyme replacement therapies(ERTs) are used as treatment for very rare genetic disorders such as lysosomal storage disorders. We elieve that they represent some good examples of personalized healthcare applications in practice, which are used in the medic. practice outside the field of oncology. Some of the disorders which are treated, are life-threatening or seriously debilitating. They are very rare diseases as indicated in FIGURE l, and relate to a genetic defect in the lysosomes, vesicles that are part of the human cell containing enzymes, which are each responsible for the elimination of a specific substrate used by the cell. If that does not happen, partially or totally the cell will store these substrates and after a while this will make the cell malfunction. Each enzyme defect can cause a different lysosomal storage disorder, and each type can be very heterogeneous in its clinical manifestation Before ERTs are used, the disease needs to be confirmed by a dna test to ensure that the treatment will benefit the patient and will justify the cost of treatment. Clinical trials are setup with small patient groups and a registry is developed to follow-up the treatment longitudinally by registering patient data Infrastructure, education, treatment guidelines and protocols had to be developed from scratch. Each disease can ave subtypes in which the treatment may work better or worse. Examples of such already approved ERTs are: Cerezyme for Gaucher disease, Fabrazyme and Replagal for Fabry disease, Myozyme for Pompe disease, Elaprasee for Mucopolysaccharidosis-lI (MPS-lI[Hunter diseaseD), Aldurazyme for MPS-I(Hurler-Scheie disease) and Naglazyme for MPS VI ene therapy applications Gene therapy is the correction of a genetic defect by providing a correct copy of the defected gene combined with a way to build this corrected copy into the cells expressing the gene. Gene therapy will need a confirmed diagnosis and strict clinical trials to show positive patient outcomes, and may also have to be controlled very tightly in terms of safety aspects, but it has the potential to dramatically change the life of the treated patients Gene therapy will be another excellent example of personalized healthcare's commonalities with the rare disease field. No gene therapy-based medicines are approved yet, but it is believed that this will happen in the future, and very likely for rare diseases first. Successful cinical results have been shown recently in treating some Parkinsons disease patients [130]. An example of a gene therapy application for a rare disease that is moving forward in clinical trials is the correction of Leber Congenital amaurosis Type 2, a form of hereditary blinding disorder belonging to the group of retinitis pigmentosa [131]. Theodor Karl Gustav von Leber described a form of nherited blindness in 1869, known as Leber's congenital amaurosis(LCA). In 1997, a related genetic defect in LCA2 was traced to gene RPE65, an enzyme required for photopigment generation. In 1998, the same blinding mutation was found in Briard dogs, and transgeni knockout mice were developed with the RPE65 gene deleted resulting in visual impairment so an animal model is available. That made bsequent clinical trials possible and three independent clinical trials are now underway, of which two are in the US and one is in the UK. Treatment of nonsense mutations Ataluren[132] is an investigational (experimental)drug that is designed to enable the formation of a functioning protein in a patient with a genetic disorder due to a nonsense mutation. The complexity of the product and its delivery to patients is that it will only be possible to use for the treatment of genetic disorders that are caused by nonsense mutations, and not in patients who have other types of mutations. Nonsense mutations are single-point alterations in the genetic code that prematurely stop the translation process, thereby preventing production of a full-length, functional protein. This product is an excellent example of the promise that healthcare holds to address significant unmet medical needs across different diseases, with the potential to make a major positive difference in the lives of patients and their families. It is being studied in several rare diseases, indluding duchenne muscular dystrophy (DMD), a degenerative genetic muscular disorder, cystic fibrosis and hemophilia. Its use in medical practice will require gene sequencing to identify the patients that may benefit from the treatment. a case study by students at the Karolinska Institute, Stockholm, Sweden, as part of a study organized by Science/Business(Brussels, Belgium) notes the following Duchenne muscular dystrophy is a complex, inherited disorder-a perfect target for the potential of personalized medicine. The ailment affects one in 3500 males worldwide, making it the most common form of about 20 kinds of muscular dystrophy. Average life expectancy is less than 30 years. There is no cure- just inadequate treatment, with many side effects, by corticosteroids to slow or manage the disease progression. DMD sufferers cannot produce dystrophin, a protein that is an essential component of muscle. This is caused by a variety of genetic faults, which interrupt the production of the protein. Now, a number of potential treatments for DMD are in clinical development, targeting different ways of overriding the genetic faults to permit normal protein synthesis. Different treatments will be needed for different segments of the patient population, and patients will need to be genotyped to see which mutation they carry Enter personalized medicine .. not just the treatment will be personalized; the delivery mechanism could end up having to be tailormade, as well, depending on where the patient lives"[roll Gene sequencing brings us a step closer to personal genome sequencing, discussed in a recent article published in The Lancet. Genome sequencing comes with many practical challenges before it will enter the clinical practice [19, 201, but holds enormous potential. In terms of costs, the goal of completely sequencing a human genome for USS 1000 is believed to be in sight While a company may provide the financ- The objectives of such disease registries are: ing and IT backbone, patient and physician confidentiality for the registry is strictly main- To enhance the understanding of the variabl tained and the registry itself is often governed ity, progression and natural history of the dis- by an independent scientific or medical board ease with the ultimate goal of better guiding of advisors and assessing therapeutic interventions Personalized Medicine(2010)7(5) w

Perrsppective Tambuyzer Tambuyzer While a company may provide the financ￾ing and IT backbone, patient and physician confidentiality for the registry is strictly main￾tained and the registry itself is often governed by an independent scientific or medical board of advisors. The objectives of such disease registries are: ƒ To enhance the understanding of the variabil￾ity, progression and natural history of the dis￾ease with the ultimate goal of better guiding and assessing therapeutic interventions; Box 1. Examples of rare disease treatments and their analogy to personalized healthcare. Enzyme replacement therapies for lysosomal storage disorders ƒ Enzyme replacement therapies (ERTs) are used as treatment for very rare genetic disorders such as lysosomal storage disorders. We believe that they represent some good examples of personalized healthcare applications in practice, which are used in the medical practice outside the field of oncology. Some of the disorders which are treated, are life-threatening or seriously debilitating. They are very rare diseases as indicated in Figure 1, and relate to a genetic defect in the lysosomes, vesicles that are part of the human cell containing enzymes, which are each responsible for the elimination of a specific substrate used by the cell. If that does not happen, partially or totally, the cell will store these substrates and after a while this will make the cell malfunction. Each enzyme defect can cause a different lysosomal storage disorder, and each type can be very heterogeneous in its clinical manifestation. ƒ Before ERTs are used, the disease needs to be confirmed by a DNA test to ensure that the treatment will benefit the patient and will justify the cost of treatment. ƒ Clinical trials are setup with small patient groups and a registry is developed to follow-up the treatment longitudinally by registering patient data. Infrastructure, education, treatment guidelines and protocols had to be developed from scratch. Each disease can have subtypes in which the treatment may work better or worse. Examples of such already approved ERTs are: Cerezyme® for Gaucher disease, Fabrazyme® and Replagal® for Fabry disease, Myozyme® for Pompe disease, Elaprase® for Mucopolysaccharidosis-II (MPS-II [Hunter disease]), Aldurazyme® for MPS-I (Hurler-Scheie disease) and Naglazyme® for MPS VI. Gene therapy applications ƒ Gene therapy is the correction of a genetic defect by providing a correct copy of the defected gene combined with a way to build this corrected copy into the cells expressing the gene. Gene therapy will need a confirmed diagnosis and strict clinical trials to show positive patient outcomes, and may also have to be controlled very tightly in terms of safety aspects, but it has the potential to dramatically change the life of the treated patients. ƒ Gene therapy will be another excellent example of personalized healthcare’s commonalities with the rare disease field. No gene therapy-based medicines are approved yet, but it is believed that this will happen in the future, and very likely for rare diseases first. Successful clinical results have been shown recently in treating some Parkinson’s disease patients [130]. An example of a gene therapy application for a rare disease that is moving forward in clinical trials is the correction of Leber Congenital Amaurosis Type 2, a form of hereditary blinding disorder belonging to the group of retinitis pigmentosa [131]. Theodor Karl Gustav von Leber described a form of inherited blindness in 1869, known as Leber’s congenital amaurosis (LCA). In 1997, a related genetic defect in LCA2 was traced to gene RPE65, an enzyme required for photopigment generation. In 1998, the same blinding mutation was found in Briard dogs, and transgenic knockout mice were developed with the RPE65 gene deleted resulting in visual impairment so an animal model is available. That made subsequent clinical trials possible and three independent clinical trials are now underway, of which two are in the US and one is in the UK. Treatment of nonsense mutations ƒ Ataluren® [132] is an investigational (experimental) drug that is designed to enable the formation of a functioning protein in a patient with a genetic disorder due to a nonsense mutation. The complexity of the product and its delivery to patients is that it will only be possible to use for the treatment of genetic disorders that are caused by nonsense mutations, and not in patients who have other types of mutations. Nonsense mutations are single-point alterations in the genetic code that prematurely stop the translation process, thereby preventing production of a full-length, functional protein. This product is an excellent example of the promise that personalized healthcare holds to address significant unmet medical needs across different diseases, with the potential to make a major positive difference in the lives of patients and their families. It is being studied in several rare diseases, including Duchenne muscular dystrophy (DMD), a degenerative genetic muscular disorder, cystic fibrosis and hemophilia. Its use in medical practice will require gene sequencing to identify the patients that may benefit from the treatment. A case study by students at the Karolinska Institute, Stockholm, Sweden, as part of a study organized by Science/Business (Brussels, Belgium) notes the following: “Duchenne muscular dystrophy is a complex, inherited disorder – a perfect target for the potential of personalized medicine. The ailment affects one in 3500 males worldwide, making it the most common form of about 20 kinds of muscular dystrophy. Average life expectancy is less than 30 years. There is no cure – just inadequate treatment, with many side effects, by corticosteroids to slow or manage the disease progression. DMD sufferers cannot produce dystrophin, a protein that is an essential component of muscle. This is caused by a variety of genetic faults, which interrupt the production of the protein. Now, a number of potential treatments for DMD are in clinical development, targeting different ways of overriding the genetic faults to permit normal protein synthesis. Different treatments will be needed for different segments of the patient population, and patients will need to be genotyped to see which mutation they carry. Enter personalized medicine … not just the treatment will be personalized; the delivery mechanism could end up having to be tailormade, as well, depending on where the patient lives” [101]. ƒ Gene sequencing brings us a step closer to personal genome sequencing, discussed in a recent article published in The Lancet. Genome sequencing comes with many practical challenges before it will enter the clinical practice [19,20], but holds enormous potential. In terms of costs, the goal of completely sequencing a human genome for US$1000 is believed to be in sight [4]. 574 Personalized Medicine (2010) 7(5) future science group Lessons learned from the field of rare diseases Perspective

Lessons learned from the field of rare diseases PERSPECTIVE To assist the medical community with the community of treating specialists and stimulates development of recommendations for physician and patient education and exchange monitoring patients of knowledge To assist patients in learning about their dis., To be useful for health technology assessment, the data queried for, need to be incorporated ease and to report on patient outcomes to help the regis for registries setup for the follow- design, which may often not (ye ptimize patient care; To evaluate the long-term effectiveness of up of clinical trials or postapproval regulatory the treatments, to report outcomes to demands, and therefore, we may need adaptive The challenges faced in developing registries To provide clinical data for further product and the methods for capturing patient data and outcomes may be important for personal The supranational or global nature of such ized healthcare applications in real-life settings egistry will increase understanding (natural Nevertheless, registries also have limitations history, ethnicity and genetics)of and aware- the data gathered are less controlled than in a ness about the rare disease and the therapy(tim- clinical trial setting and related to all patients of ng, dosing and outcomes), facilitate physician which data are stored, and not to a specifically patient monitoring and setup of therapeutic defined cohort of patients. These data may there- goals, support the development of diagnosis, fore also contain bias. Moreover, registries only disease-monitoring and disease-management contain data as defined at the time of the design uidelines, and analyze(long-term)treatment of the registry, and therefore, may be limited in outcomes. It helps develop an international the responses that can be obtained from them Sandhoff No CNS involvement orde GM1 gangliosides Gaucher Infantile Batten Mixed Scheie(MPS-I S) Hurler-Scheie(MPS-l H/S) Juvenile Batten Niemann-Pick A Maroteaux-Lamy(MPS-vI) Hurler(MPS-l H) leukodystrophy Late infantile Batten Morquio MPS-v) Krabbe Hunter(MPS-l Figure 1. An overview of the relative frequency of lysosomal storage diseases. There are diseases caused by deficient enzymes in the liposomes. If they have involvement in the CNS, replacement enzymes are not able to pass through the blood-brain barrier because of their size. This means that such diseases are not targets for enzyme replacement therapies, and that another therapeutic approach is neede MPS: Mucopolysaccharidosis. w. futuremedicine cor

Perrsppective Tambuyzer Tambuyzer ƒ To assist the medical community with the development of recommendations for monitoring patients; ƒ To assist patients in learning about their dis￾ease and to report on patient outcomes to help optimize patient care; ƒ To evaluate the long-term effectiveness of the treatments, to report outcomes to the authorities; ƒ To provide clinical data for further product development for the disease. The supranational or global nature of such registry will increase understanding (natural history, ethnicity and genetics) of and aware￾ness about the rare disease and the therapy (tim￾ing, dosing and outcomes), facilitate physician patient monitoring and setup of therapeutic goals, support the development of diagnosis, disease-monitoring and disease-management guidelines, and analyze (long-term) treatment outcomes. It helps develop an international community of treating specialists and stimulates physician and patient education and exchange of knowledge. To be useful for health technology assessment, the data queried for, need to be incorporated in the registry design, which may often not (yet) be the case for registries setup for the follow￾up of clinical trials or postapproval regulatory demands, and therefore, we may need adaptive registries in the future. The challenges faced in developing registries and the methods for capturing patient data and outcomes may be important for personal￾ized healthcare applications in real-life settings. Nevertheless, registries also have limitations: the data gathered are less controlled than in a clinical trial setting and related to all patients of which data are stored, and not to a specifically defined cohort of patients. These data may there￾fore also contain bias. Moreover, registries only contain data as defined at the time of the design of the registry, and therefore, may be limited in the responses that can be obtained from them. Gaucher No CNS involvement CNS involved Mixed Juvenile Batten Fabry Metachromatic leukodystrophy Sanfilippo A (MPS-IIIA) Late infantile Batten Krabbe Hunter (MPS-II) Morquio (MPS-IV) Pompe Niemann-Pick C Tay-Sachs Hurler (MPS-I H) Sanfilippo B (MPS-IIIB) Maroteaux-Lamy (MPS-VI) Niemann-Pick A Cystinosis Hurler-Scheie (MPS-I H/S) Scheie (MPS-I S) Infantile Batten GM1 gangliosidosis MPS-II/III Sandhoff Other (9 disorders) Figure 1. An overview of the relative frequency of lysosomal storage diseases. There are diseases caused by deficient enzymes in the liposomes. If they have involvement in the CNS, replacement enzymes are not able to pass through the blood–brain barrier because of their size. This means that such diseases are not targets for enzyme replacement therapies, and that another therapeutic approach is needed. MPS: Mucopolysaccharidosis. Data taken from [21]. future science group www.futuremedicine.com 575 Lessons learned from the field of rare diseases Perspective

PERSPECTIVE Tambuyzer Collaboration with patient groups partnerships such as the European Innovative One of the characteristics of the field of rare Medicines Initiative(IMI; Brussels, Belgium) diseases is the existence of well-organized, cross- have been setup [1221 to foster more biological border patient groups. Patient groups such as and other knowledge development. At the same the National Organization for Rare Disorders time, industry is facing downward pressure organized nationwide in the USA, with NORD complex reimbursement and market acess B& a (NORD)[117l and Genetic Alliance [118 are on prices because of patent expiry, and a m as the driving force behind the US Orphan tiation process based on clinical effectiveness, Drug Act approved in 1983. Rare Diseases and soon ce ive or relative effectiveness Europe(EURORDIS), [119] and the European requirements. Moving into the development of Genetic Alliance Network(EGAN)[120] are personalized healthcare applications will require organized at a EU level. EURORDIS, which the full integration of genomics and genetics into is strongly allied with NORD in the USA, a company's research and development programs was the driving patients' voice in the discus- and planning. The most adaptive companies sions about the European Orphan Medicinal have been doing this for more than a decade Products Regulation. Those rare disease patient but for those that have not yet done so groups,and their members that are organized eral barriers remain. The first barrier is when by disease but operate internationally, are not a company cannot build the link between the only involved in awareness building but also in integration of the genomics/ genetics knowledge the discussion of public policies as mentioned into its research and development, and a fore above, and operate more and more as the seeable and appropriate return on investment. the tC Df new policy initiatives. In addition, in Such investment will then be very vulnerable they negotiated for representation in and may require careful, long-term research and regulatory bodies such as the Committee for development planning: getting over the valley Orphan Medicinal Products, the Pediatrics of death' as this is being called [3]. This barrier Committee and the Committee for Advanced is made higher by the lack of legal certainty for Therapies [121]. Patient groups also get involved regulatory requirements of efficacy and safer in research about their disease and even fund for personalized medicine candidates, which are company research for that purpose. not(yet)harmonized internationally, and may The unique setup and activity of rare disease decrease the will to invest in entering the field patient groups has also led them to work very The regulators are aware of this need and are proactively with industry and act as a pulling working, both in the eU and in the USA, on fill- force for information regarding the status of ing these gaps. Those efforts entail the definition development projects. The collaboration and of what can be done in terms of co-regulating sharing of information between companies, a companion'diagnostic test with a therapy, patients and scientists have also led to produc- defining what will be required for biomarkers tive mechanism of progress to discuss patient- in clinical trials and in terms of data for the relevant quality of life factors, communication approval of a therapeutic and a diagnostic pair, pathways and novel forms of sharing informa- or only a therapy, are producing guidelines on tion without breach of sensitive commercial con- pharmacogenetics as referenced in the text[1041 fidentiality. The special ways of collaboration Other aspects include the definition of clinical will also serve as a model for the way forward utility and validity for diagnostic tests in personalized healthcare, both in terms of Surely also the lack of availability of collaboration with industry as in terms of col- fed/validated biomarkers to test the pro laboration with regulators as both collaboration very important and for common diseases models are regarded as very positive in terms is a long way to go in order to map phenotypes of productiveness and outcomes and is also the with genotypes and determine the way forward author's personal experience. Companies should also plan to deal with such The impact of personalized latory requirements. Those with healthcare on industry regulatory fexibility and expertise, and the will Currently, industry is not only facing attrition, ingness to confirm clinical utility via diagnostics but also vastly increasing costs, driven by the will Fourish. At the same time, harmonization of increased demand for clinical data, stricter regu- regulatory regimes at international level will be latory requirements and by evermore complex required, where appropriate, for industry to cope clinical trials. For this reason, public/private with more stringent regimes and control costs, 576 Personalized Medicine(2010)7(5)

Perrsppective Tambuyzer Tambuyzer „ Collaboration with patient groups One of the characteristics of the field of rare diseases is the existence of well-organized, cross￾border patient groups. Patient groups such as the National Organization for Rare Disorders (NORD) [117] and Genetic Alliance [118] are organized nationwide in the USA, with NORD as the driving force behind the US Orphan Drug Act approved in 1983. Rare Diseases Europe (EURORDIS), [119] and the European Genetic Alliance Network (EGAN) [120] are organized at a EU level. EURORDIS, which is strongly allied with NORD in the USA, was the driving patients’ voice in the discus￾sions about the European Orphan Medicinal Products Regulation. Those rare disease patient groups, and their members that are organized by disease but operate internationally, are not only involved in awareness building but also in the discussion of public policies as mentioned above, and operate more and more as the ini￾tiators of new policy initiatives. In addition, in the EU, they negotiated for representation in regulatory bodies such as the Committee for Orphan Medicinal Products, the Pediatrics Committee and the Committee for Advanced Therapies [121]. Patient groups also get involved in research about their disease and even fund company research for that purpose. The unique setup and activity of rare disease patient groups has also led them to work very proactively with industry and act as a pulling force for information regarding the status of development projects. The collaboration and sharing of information between companies, patients and scientists have also led to produc￾tive mechanism of progress to discuss patient￾relevant quality of life factors, communication pathways and novel forms of sharing informa￾tion without breach of sensitive commercial con￾fidentiality. The special ways of collaboration will also serve as a model for the way forward in personalized healthcare, both in terms of collaboration with industry as in terms of col￾laboration with regulators as both collaboration models are regarded as very positive in terms of productiveness and outcomes and is also the author’s personal experience. The impact of personalized healthcare on industry Currently, industry is not only facing attrition, but also vastly increasing costs, driven by the increased demand for clinical data, stricter regu￾latory requirements and by evermore complex clinical trials. For this reason, public/private partnerships such as the European Innovative Medicines Initiative (IMI; Brussels, Belgium) have been setup [122] to foster more biological and other knowledge development. At the same time, industry is facing downward pressure on prices because of patent expiry, and a more complex reimbursement and market access nego￾tiation process based on clinical effectiveness, and soon comparative or relative effectiveness requirements. Moving into the development of personalized healthcare applications will require the full integration of genomics and genetics into a company’s research and development programs and planning. The most adaptive companies have been doing this for more than a decade but for those that have not yet done so, sev￾eral barriers remain. The first barrier is when a company cannot build the link between the integration of the genomics/genetics knowledge into its research and development, and a fore￾seeable and appropriate return on investment. Such investment will then be very vulnerable and may require careful, long-term research and development planning: getting over the ‘valley of death’ as this is being called [3]. This barrier is made higher by the lack of legal certainty for regulatory requirements of efficacy and safety for personalized medicine candidates, which are not (yet) harmonized internationally, and may decrease the will to invest in entering the field. The regulators are aware of this need and are working, both in the EU and in the USA, on fill￾ing these gaps. Those efforts entail the definition of what can be done in terms of co-regulating a ‘companion’ diagnostic test with a therapy, defining what will be required for biomarkers in clinical trials and in terms of data for the approval of a therapeutic and a diagnostic pair, or only a therapy, are producing guidelines on pharmacogenetics as referenced in the text [104]. Other aspects include the definition of clinical utility and validity for diagnostic tests. Surely also the lack of availability of quali￾fied/validated biomarkers to test the process is very important and for common diseases, there is a long way to go in order to map phenotypes with genotypes and determine the way forward from there. Companies should also plan to deal with such increased regulatory requirements. Those with regulatory flexibility and expertise, and the will￾ingness to confirm clinical utility via diagnostics will flourish. At the same time, harmonization of regulatory regimes at international level will be required, where appropriate, for industry to cope with more stringent regimes and control costs, 576 Personalized Medicine (2010) 7(5) future science group Lessons learned from the field of rare diseases Perspective

Lessons learned from the field of rare diseases PERSPECTIVE nd not face another wave of increasing regulatory if this is not always culturally easy (9.11,1231 costs by nonharmonization, which would make Whether a company is owning or developing innovative products even more costly to develop. its own diagnostics business or not, is a com Furthermore, some of the questions of what is pany-specific choice. This may not dramatically ethically allowedin research and clinical trials, influence its ability to be successful in person- including about predictive genetic testing, are not alized healthcare, as long as the understand- yet fully answered in society: there is not yet ethi- ing of the link with diagnostic testing is there al agreement on all aspects of what should be More importantly, companies will need to adapt allowed and what would be socially unacceptable. from purely supplying a product to providing a Many issues that came up in genetics research full service to the patient, and to making sure or in the application of genetic testing in medi- that a full service is in place to guarantee the cal practice, such as the right of the individual best possible patient outcomes. By contrast patients-to know or not to know the result of a personalized healthcare may have far-reaching particular test for a severe disease-are amplified and significant structural implications on the if used more broadly. In addition, personalized healthcare industry and on its business models, healthcare may also bring up some ethical issues and have profound effects on healthcare systems lated to gender overall. Some traditional pharmaceutical com- Such barriers are amplified because of the panies may encounter a great deal of trouble volume of information gathered in the research evolving their business model away from a core and development phase, and by potential lack competency of selling drugs that only work for of a system to allow effective management and a portion of treated patients using broad-based new approach become ethical issues, for example, the lack of face difficulties in including existing drugs sufficient quality assurance in genetic testing a personalized healthcare approach to optimize would be an ethical issue. Key to this is the their value, rather than hoping that their sales standardization of collection processes, quality of will not falter and that regulatory bodies will samples, full annotation(clinical, demographic not require new data to allow their further use and so on)of those biological samples and ready For all of this to materialize, it is clear that a access by investigators in both the public and pri- company needs to be willing to plan for the vate sectors. The further development of person- long view, and not expect quick results but for alized healthcare will also require a societal out- a pharmaceutical company used to working on reach component, which will need a collaborative development timelines in the order of 12 years, effort with all involved stakeholders this should not be an impossible requ The growing interest of industry in the field of A company should be prepared for sustained are diseases is not only a consequence of the need engagement with the patient groups, treating for diversification after the research and devel- physicians as well as other stakeholders. The field opment machine stalled. It is also because only of rare diseases and orphan drugs is a valuable 10-20%of rare diseases have some kind of treat- and appropriate model for such engagement, and ment today (n1o), and those treatments can still be these elements are a prerequisite for sustained improved, thus the medical need remains high. activity in the field However, even more important is that rare dis- Some believe that those companies that are eases as researched as models for more common slower to develop personalized targeted thera diseases in a different field, such as oncology, neu- pies risk losing substantial market share[12]. It is, rology, autoimmune and infectious diseases, and however, in society's best interest that companies provide a pathway to explore personalized medi- that adapt can be sure of an appropriate return cine because of the many commonalities between on investment. By giving much more predictable the fields [1101, or help identify molecularly dis- treatment outcomes, it is also expected that per- tinct subtypes of some common diseases, which sonalized healthcare will have a beneficial effect may lead to new therapeutic possibilities [31 image, if the industry can stay away from hyping the concept and advo cate true a Changing business models patient value. in industry At the same time, the premise that, in a future Despite industry's changing role, companies will dominated by personalized healthcare, there will need to change their view of a market that is no longer be 'blockbusters, is wrong-if we moving towards personalized healthcare, even low the commonly used definition of blockbuster w. futuremedicine cor 577

Perrsppective Tambuyzer Tambuyzer and not face another wave of increasing regulatory costs by nonharmonization, which would make innovative products even more costly to develop. Furthermore, some of the questions of what is ‘ethically allowed’ in research and clinical trials, including about predictive genetic testing, are not yet fully answered in society: there is not yet ethi￾cal agreement on all aspects of what should be allowed and what would be socially unacceptable. Many issues that came up in genetics research or in the application of genetic testing in medi￾cal practice, such as the right of the individual patients – to know or not to know the result of a particular test for a severe disease – are amplified if used more broadly. In addition, personalized healthcare may also bring up some ethical issues related to gender or race. Such barriers are amplified because of the volume of information gathered in the research and development phase, and by potential lack of a system to allow effective management and interrogation of all that information internally. Without rigorous processes, process issues may become ethical issues, for example, the lack of sufficient quality assurance in genetic testing would be an ethical issue. Key to this is the standardization of collection processes, quality of samples, full annotation (clinical, demographic and so on) of those biological samples and ready access by investigators in both the public and pri￾vate sectors. The further development of person￾alized healthcare will also require a societal out￾reach component, which will need a collaborative effort with all involved stakeholders. The growing interest of industry in the field of rare diseases is not only a consequence of the need for diversification after the research and devel￾opment machine stalled. It is also because only 10–20% of rare diseases have some kind of treat￾ment today [110], and those treatments can still be improved, thus the medical need remains high. However, even more important is that rare dis￾eases as researched as models for more common diseases in a different field, such as oncology, neu￾rology, autoimmune and infectious diseases, and provide a pathway to explore personalized medi￾cine because of the many commonalities between the fields [110], or help identify molecularly dis￾tinct subtypes of some common diseases, which may lead to new therapeutic possibilities [3]. „ Changing business models in industry Despite industry’s changing role, companies will need to change their view of a market that is moving towards personalized healthcare, even if this is not always culturally easy [9,11,123]. Whether a company is owning or developing its own diagnostics business or not, is a com￾pany-specific choice. This may not dramatically influence its ability to be successful in person￾alized healthcare, as long as the understand￾ing of the link with diagnostic testing is there. More importantly, companies will need to adapt from purely supplying a product to providing a full service to the patient, and to making sure that a full service is in place to guarantee the best possible patient outcomes. By contrast, personalized healthcare may have far-reaching and significant structural implications on the healthcare industry and on its business models, and have profound effects on healthcare systems overall. Some traditional pharmaceutical com￾panies may encounter a great deal of trouble evolving their business model away from a core competency of selling drugs that only work for a portion of treated patients using broad-based sales and marketing teams, to a new approach targeting smaller populations. They may also face difficulties in including existing drugs in a personalized healthcare approach to optimize their value, rather than hoping that their sales will not falter and that regulatory bodies will not require new data to allow their further use. For all of this to materialize, it is clear that a company needs to be willing to plan for ‘the long view’, and not expect quick results but for a pharmaceutical company used to working on development timelines in the order of 12 years, this should not be an impossible requirement. A company should be prepared for sustained engagement with the patient groups, treating physicians as well as other stakeholders. The field of rare diseases and orphan drugs is a valuable and appropriate model for such engagement, and these elements are a prerequisite for sustained activity in the field. Some believe that those companies that are slower to develop personalized targeted thera￾pies risk losing substantial market share [12]. It is, however, in society’s best interest that companies that adapt can be sure of an appropriate return on investment. By giving much more predictable treatment outcomes, it is also expected that per￾sonalized healthcare will have a beneficial effect on the industry’s image, if the industry can stay away from hyping the concept and advocate true patient value. At the same time, the premise that, in a future dominated by personalized healthcare, there will no longer be ‘blockbusters’, is wrong – if we fol￾low the commonly used definition of blockbuster future science group www.futuremedicine.com 577 Lessons learned from the field of rare diseases Perspective

PERSPECTIVE Tambuyzer as'a drug with more than(E or $)I billion in Role value of diagnostic testing les. If the definition of a blockbuster is taken Diagnostics and how to combine them with rather as 'a drug for a large patient population, therapeutics in terms of regulatory approval, then this premise may be more correct, but that clinical use and reimbursement now are looked definition is not the commonly used one for a at in terms of healthcare systems that are setup blockbuster. We do, however, expect the nature to look at standard solutions, for large patient of future blockbusters so-called 'nichebusters', groups, and not for small patient groups. This is to be different. Indeed, the value created by pro- what th e rare orld has bec viding targeted therapies that address the real with, and is only slowly changing unmet medical need is enormous, so some of According to the WHO, much greater use these products will still reach blockbuster sta- of evidence-based diagnostic and treatment tus, while bringing great value to a relatively guidelines by health professionals is needed (102) small patient group. Examples may be a disease- The use of diagnostics to predict individ- odifying treatment in a subset of Alzheimer's ual response to treatment will also offer more patients or in life-threatening cancer indications. safety and effectiveness [14]. The imperative use Regarding the development of diagnostics, the of diagnostic testing in personalized healthcare most optimistic scenario is for those diagnostics applications will require that the physicians are that enhance drug use and appropriate delivery. educated about rigorously using those diagnostic In this case, the company that has developed and testing capabilities and about interpreting their is selling the drug has an incentive to so pro- results to explain them to the patients. If not, vide the diagnostic test(e.g, the case of Roche's this would make personalized medicine fail. Herceptin ). If a therapeutic product requires the The introduction of the diagnostic test may be testing of a candidate population, a pharmaceuti- another layer of complexity but will improve al company will seek (a) partner(s)to develop patient outcomes, make them largely predict- biomarkers, which can hopefully be used as a able and reduc ty for the phy diagnostic test for global use Current healthcare may also be one of the reasons that personalized systems leave diagnostic companies financially medicine will be put into practice in a hospital vulnerable, especially in a case where the com- and specialized medicine setting and, only much pany selling the therapy is not also providing the later to primary care, if ever. This is another diagnostic test. Healthcare systems often reim- commonality with the field of rare diseases that burse testing activity and not the value brought by is also hospital controlled and highly specialized the test [1]. In the end, most probably, the major- Molecular genetic testing - looking for muta ity of pharmaceutical companies will not develop tions in human genes-is used to identify sin- and market tests with in-house resources, but will gle gene(Mendelian) disorders characterized by look for diagnostic companies to do so [13. 1241, this the absence of a critical protein or the presence is an important consideration that needs to be of an abnormal protein. Examples include cystic solved. In fact, that is a very recognizable situation fibrosis, muscular dystrophy, Gaucher's disease for the field of rare diseases nd Huntington disease, although also subsets of Surely not all diseases and approaches will common diseases may fall in this category in the benefit from personalized healthcare? Some future. Many common disorders have a genetic cientists, including Dr Malcolm Law of the component, which may involve several genes, as Wolfson Institute of Preventive Medicine, UK well as interactions of these genes with the envi- dvocate that polypills, a combination of several ronment, diet and lifestyle. The quality of, espe- medicines into one pill, may actually be a better cially genetic, testing has not always been guar- solution, for example, in the cardiovascular field. anteed, but the extensive use of diagnostic tests in This approach is going the other way compared the process will start to put much more emphasis with personalized healthcare [106] Also vaccines on the aspects of quality and quality control of will continue to be important preventative and such tests. Because treating physicians will heavily therapeutic tools in the future. The current rely on reliable diagnostic results, more rules for article is therefore not intended to criticize the quality control and quality assurance as well, and research to discover and develop medicines to diagnostic testing laboratory accreditation, includ- treat broad patient populations. Whatever works ing for genetic testing, are being put in place. In best in practice to treat a disease or a patient Europe, the project Euro Gentest was setup for population should be pursued, and personalized this reason [125]. Patients should be confident that healthcare adds another pathway to achieve that, diagnostic tests reliably give correct results when but will not be the only one used in making major medical decisions [3] 8 Personalized Medicine(2010)7(5)

Perrsppective Tambuyzer Tambuyzer as ‘a drug with more than (€ or $) 1 billion in sales’. If the definition of a blockbuster is taken rather as ‘a drug for a large patient population’, then this premise may be more correct, but that definition is not the commonly used one for a blockbuster. We do, however, expect the nature of future blockbusters so-called ‘nichebusters’, to be different. Indeed, the value created by pro￾viding targeted therapies that address the real unmet medical need is enormous, so some of these products will still reach blockbuster sta￾tus, while bringing great value to a relatively small patient group. Examples may be a disease￾modifying treatment in a subset of Alzheimer’s patients or in life-threatening cancer indications. Regarding the development of diagnostics, the most optimistic scenario is for those diagnostics that enhance drug use and appropriate delivery. In this case, the company that has developed and is selling the drug has an incentive to also pro￾vide the diagnostic test (e.g., the case of Roche’s Herceptin®). If a therapeutic product requires the testing of a candidate population, a pharmaceuti￾cal company will seek (a) partner(s) to develop biomarkers, which can hopefully be used as a diagnostic test for global use. Current healthcare systems leave diagnostic companies financially vulnerable, especially in a case where the com￾pany selling the therapy is not also providing the diagnostic test. Healthcare systems often reim￾burse testing activity and not the value brought by the test [11]. In the end, most probably, the major￾ity of pharmaceutical companies will not develop and market tests with in-house resources, but will look for diagnostic companies to do so [13,124], this is an important consideration that needs to be solved. In fact, that is a very recognizable situation for the field of rare diseases. Surely not all diseases and approaches will benefit from personalized healthcare? Some scientists, including Dr Malcolm Law of the Wolfson Institute of Preventive Medicine, UK ,advocate that polypills, a combination of several medicines into one pill, may actually be a better solution, for example, in the cardiovascular field. This approach is going the other way compared with personalized healthcare [106]. Also vaccines will continue to be important preventative and therapeutic tools in the future. The current article is therefore not intended to criticize the research to discover and develop medicines to treat broad patient populations. Whatever works best in practice to treat a disease or a patient population should be pursued, and personalized healthcare adds another pathway to achieve that, but will not be the only one. Role & value of diagnostic testing Diagnostics and how to combine them with therapeutics in terms of regulatory approval, clinical use and reimbursement now are looked at in terms of healthcare systems that are setup to look at standard solutions, for large patient groups, and not for small patient groups. This is what the rare disease world has been confronted with, and is only slowly changing. According to the WHO, much greater use of evidence-based diagnostic and treatment guidelines by health professionals is needed [102]. The use of diagnostics to predict individ￾ual response to treatment will also offer more safety and effectiveness [14]. The imperative use of diagnostic testing in personalized healthcare applications will require that the physicians are educated about rigorously using those diagnostic testing capabilities and about interpreting their results to explain them to the patients. If not, this would make personalized medicine fail. The introduction of the diagnostic test may be another layer of complexity but will improve patient outcomes, make them largely predict￾able and reduce liability for the physician. This may also be one of the reasons that personalized medicine will be put into practice in a hospital and specialized medicine setting and, only much later to primary care, if ever. This is another commonality with the field of rare diseases that is also hospital controlled and highly specialized. Molecular genetic testing – looking for muta￾tions in human genes – is used to identify sin￾gle gene (Mendelian) disorders characterized by the absence of a critical protein or the presence of an abnormal protein. Examples include cystic fibrosis, muscular dystrophy, Gaucher’s disease and Huntington disease, although also subsets of common diseases may fall in this category in the future. Many common disorders have a genetic component, which may involve several genes, as well as interactions of these genes with the envi￾ronment, diet and lifestyle. The quality of, espe￾cially genetic, testing has not always been guar￾anteed, but the extensive use of diagnostic tests in the process will start to put much more emphasis on the aspects of quality and quality control of such tests. Because treating physicians will heavily rely on reliable diagnostic results, more rules for quality control and quality assurance as well, and diagnostic testing laboratory accreditation, includ￾ing for genetic testing, are being put in place. In Europe, the project EuroGentest was setup for this reason [125]. Patients should be confident that diagnostic tests reliably give correct results when used in making major medical decisions [3]. 578 Personalized Medicine (2010) 7(5) future science group Lessons learned from the field of rare diseases Perspective