《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