Personalized medicine a new medical and social challenge

At the 55th Plenary Session of the committee ofEuropean Medical Research Council, European Research Foundation in Copenha-gen, Denmark, one of the authors of this paper put forward the p

Europeanization and Globalization 2

A New Medical and Social Challenge

Kresˇimir Pavelic´ • Gerald G Sander

Editors

Personalized Medicine

A New Medical and Social Challenge

Nada Bodiroga-Vukobrat

Jean Monnet Department of

European Public Law

University of Rijeka

Rijeka

Croatia

Daniel RukavinaCroatian Academy of Sciences and ArtsRijeka

LudwigsburgGermany

Europeanization and Globalization

ISBN 978-3-319-39347-6 ISBN 978-3-319-39349-0 (eBook)

DOI 10.1007/978-3-319-39349-0

Library of Congress Control Number: 2016956105

© Springer International Publishing Switzerland 2016

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The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

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The registered company is Springer International Publishing AG Switzerland

When we use the term personalized medicine, it implies the systematic use ofinformation about the individual patient with the goal of choosing optimal preven-tion and/or welfare therapy The main focus of personalized medicine in currentmedical treatment is to generate innovative treatments and drugs while reducingnegative side effects Recent achievements in life science have created novelopportunities to monitor and assess the progression of each individual patient’scondition The merit of these new capabilities lies mainly in the development andapplication of high-throughput technologies that provide global insights into thegenomic-proteomic profile of diseases New accomplishments in high-throughputtechnologies such as transcriptomics that provides an entire insight into geneactivity in an organism, proteomics that gathers knowledge on global protein pro-files, or metabolomics that provides information on metabolite status, will dramat-ically change molecular medicine and life science At the same time, it should benoted that genes and proteins cannot explain everything One needs to considerother complex elements, including molecular pathways, protein structure, second-ary protein modifications, epigenetics, and many others New methods to providesome novel insights into biological mechanisms could include lipidomics,glycomics, metabolomics, nutrinomics, and even complex structural genomicsmethodologies and approaches The use of these methods in medicine may allow

an individualized service for each patient and boost the progression in medicinefrom the traditional focus on discovering new drugs to a new and more preemptiveapproach This change will bring about substantial social shifts that will changesocio-humanistic relationships and raise a whole series of important questions:moral-ethical, legal, and socio-economic These issues will result from currentchallenges in medicine and humanity that are both faced with multiple processes

of globalization and fast changes in society Some of the current issues relate to newsevere and fast-spreading infectious diseases, changes in the “behavior pattern” ofcertain diseases, demographic change resulting from an aging population, and fastand dramatic climate changes

v

This book offers comprehensive coverage of the various aspects of personalizedmedicine as an original approach to classifying, understanding, treating, andpreventing disease based on individual biological differences In the introductorysection, it defines personalized medicine as a way toward new medical practicesand addresses the question: what can personalized medicine offer citizens, medicalprofessionals and reimbursement bodies, and stakeholders? Subsequent chaptersdiscuss the technological aspects of personalized medicine: data collection, com-prehensive integration and handling of data, together with key enabling factors indeveloping the requisite technological support for personalized medicine Lastly,the book explores the main issues shaping the implementation and development ofpersonalized medicine—education, stakeholder participation, infrastructure, arevised approach to the classification of disease and medical tests, regulatoryframeworks, and new reimbursement models—together with ethical, legal, andsocial issues Ultimately, the book calls for interdisciplinarity and a radical change

in the way we approach the health and well-being of individuals

Target groups are medical doctors and researchers in the field of biomedicine, aswell as experts from social sciences dealing with legal, economic, and socialaspects of health system issues in general The primary beneficiaries are thereforefrom these groups of professional experts, but the presented content may attract thewidest possible readership as it deals with the issue of paradigm change in one ofthe major society pillars—the health system

We express our thanks to the University of Rijeka for their helpful support thatwas essential for this enterprise This publication is supported by the CroatianScience Foundation project No 5709 “Perspectives of maintaining the socialstate: towards the transformation of social security systems for individuals inpersonalized medicine” and the University of Rijeka project No 13.08.1.2.03

“Social security and market competition.”

Finally, we owe our sincere gratitude to theSpringer Verlag for recognizing thevalue of our efforts and for its continuous support to our scientific endeavors

10 March 2016

Personalized Medicine: The Path to New Medicine 1Kresˇimir Pavelic´, Sandra Kraljevic´ Pavelic´, and Mirela Sedic´

Legal Aspects of Personalized Medicine 21Ulrich Becker

Challenges of Personalized Medicine: Socio-Legal Disputes

and Possible Solutions 31Nada Bodiroga-Vukobrat and Hana Horak

Embryonic Stem Cell Patents and Personalized Medicine

in the European Union 53Jasmina Mutabžija

Personalised Medicine and Public Health 81Vladimir Mic´ovic´, Iva Sorta-Bilajac Turina, and Ðulija Malatestinic´

Personalized Medicine and Technology Transfer 95Petra Karanikic

Economic Evaluations of Personalized Health Technologies:

An Overview of Emerging Issues 107Ana Bobinac and Maja Vehovec

Computational Methods for Integration of Biological Data 137Vladimir Gligorijevic´ and Natasˇa Pržulj

The Role of Proteomics in Personalized Medicine 179Djuro Josic´ and Urosˇ Andjelkovic´

The Role of Radiology in Personalized Medicine 219

D Miletic´, P Valkovic´-Zujic´, and R Antulov

vii

Implantation of Toric Intraocular Lenses: Personalized Surgery

on the Lens 231Iva Dekaris, Nikica Gabric´, Ante Barisˇic´, and Alma Bisˇcˇevic´

Personalized Medicine of Central Nervous System Diseases

and Disorders: Looking Toward the Future 241Miranda Mladinic´ Pejatovic´ and Srđan Anzic´

Personalized Medicine in Gastroenterology 257Davor Sˇtimac and Neven Franjic´

Personalized Medicine in Clinical Pharmacology 265Dinko Vitezic´, Nada Božina, Jasenka Mrsˇic´-Pelcˇic´, Viktorija Erdeljic´ Turk,and Igor Francetic´

Kresˇimir Pavelic´, Sandra Kraljevic´ Pavelic´, and Mirela Sedic´

Abstract Personalised medicine is a new paradigm that represents a shift fromcurrent simplified consideration of the patient as a member of the populationsharing common fate of disease towards the view that each patient is a uniqueindividual Every person has specific genomic/proteomic and metabolic signaturethat could account for specific clinical features of disease, response to treatment anddisease severity Therefore, disease and the treatment itself should be consideredindividually Due to a number of reasons for introduction of new paradigm inmedicine, implementation of personalised medicine is envisaged in several con-secutive steps where projections of the levels of technology, medicine and integra-tion need to be coordinated

Modern medicine faces great challenges, including rapid social changes resultingfrom globalization, emerging new infectious diseases that spread quickly, alter-ations in clinical patterns of some diseases (e.g., drug-resistant tuberculosis),and abrupt climate and demographic changes (i.e., aging) These are only some

of the issues that traditional medicine is likely to cope with great difficulties

Professor Kresˇimir Pavelic´, M.D Ph.D., Head of Laboratory for High-Throughput Analytics, University Centre for High-Throughput Technologies, Department of Biotechnology, University

of Rijeka, Rijeka, Croatia.

Professor Sandra Kraljevic´ Pavelic´, Ph.D., University Centre for High-Throughput Technologies, Department of Biotechnology, University of Rijeka, Rijeka, Croatia.

Assistant Professor Mirela Sedic´, Ph.D., University Centre for High-Throughput Technologies, Department of Biotechnology, University of Rijeka, Rijeka, Croatia.

K Pavelic´, M.D., Ph.D ( * )

Laboratory for High-Throughput Analytics, Department of Biotechnology, University Centre for High-Throughput Technologies, University of Rijeka, Rijeka, Croatia

e-mail: pavelic@biotech.uniri.hr

S Kraljevic´ Pavelic´, Ph.D • M Sedic´, Ph.D.

Department of Biotechnology, University Centre for High-Throughput Technologies,

University of Rijeka, Rijeka, Croatia

© Springer International Publishing Switzerland 2016

N Bodiroga-Vukobrat et al (eds.), Personalized Medicine, Europeanization and

Globalization 2, DOI 10.1007/978-3-319-39349-0_1

1

Consequently, the need for new, personalized medicine has arisen that would bringabout radical changes in health care systems Such approach represents a shift fromthe era of blockbuster drugs designed to treat all patients suffering from the samedisease towards individualized treatment based on unique features of each patient.Medicine has been lately fragmented, which has produced a certain fragmentedapproach towards patients A paradoxical situation occurs where medicine hasreached a high level of technological advancement on the one hand, but on theother hand, an integrated perception of the patient functioning as a result of overallorgan activities has been neglected It is the personalized medicine approach thatplaces emphasis on the patient with all his/her biological features.1Personalizedmedicine is a new paradigm that represents a shift from current simplified consid-eration of the patient as a member of the population sharing common fate of diseasetowards the view that each patient is a unique individual Indeed, medicine shouldprimarily deal with an individual rather than with the majority Every person hasspecific genomic/proteomic and metabolic signature that could account for specificclinical features of disease, response to treatment and disease severity Therefore,disease and the treatment itself should be considered individually Previously, thepharmaceutical industry assumed an attitude that “one drug fits all.” However, suchconcept is about to change Today, personalized medicine supports the idea thatdrugs should be designed and prescribed according to an individual pharmaco-genomics profile.2To put it simply, up to now science and medicine have studieddiseases and drawn conclusions based on only a few parameters Nowadays, weknow that humans have more than 20,000 genes and million different protein forms.

If we want to ascertain the roles of all these genes and proteins along with differentmetabolites, lipids, glycolipids, etc in disease pathogenesis, we have to explore all

of them This makes the essence of new, complex, and comprehensive molecularview of life and the world It is rather naive to believe that studying a fewparameters would allow us to learn more about disease mechanisms and thusprevent or treat diseases Medicine has been so far successful in studying diseases

on the basis of the reductionist view However, reductionism provides limitedanswers to basic questions such as how biological systems function as a whole,how they process dynamic information, and how they respond to perturbations such

as diseases It is the complexity of biological systems that urges us to adopt a newapproach to medical research Biological functions are the result of combinedactivities of multiple molecular and cellular functions Live systems act in anonlinear fashion, i.e., one input often produces multiple outputs Therefore, thereare justified reasons to introduce a new paradigm in medicine so as to expandcurrent knowledge of disease origins and causes, biological markers for earlydetection or disease stage, and molecular factors that affect the efficiency ofpotential drugs.3

1 Pavelic´ et al ( 2015 ).

2 Bosˇnjak et al ( 2008 ) and Kralj and Pavelic´ ( 2003 ).

3 Catchpoole et al ( 2010 ).

It is easy to imagine that the application of such new paradigm, i.e studying thecomplex patterns of life, would contribute to early disease detection even before theoccurrence of clinical symptoms, discovery of new more efficient drugs, and moreprecise disease diagnosis The implementation of high-throughput methods intomedical practice holds great promise to facilitate development of personalizedmedicine The main application of these methods in medicine is prevention, andsecondary, design of new, more efficient drugs.4

New challenges that medicine has to cope with, its relative inefficiency anddevelopment of sophisticated high-throughput global analytical methods that could

be easily implemented into clinical practice have led to the idea of establishing awhole new paradigm in medicine At the 55th Plenary Session of the committee ofEuropean Medical Research Council, European Research Foundation in Copenha-gen, Denmark, one of the authors of this paper put forward the project termed

“Forward look on personalized medicine for European citizens”, whose goal is toimplement state-of-the-art scientific and technological achievements (the so-calledhigh-throughput analytical methods) into everyday medical practice so as to makehealth care better and more efficient It comes without saying that an innovativeapproach in medicine raises many scientific and social issues The project has beensuccessfully completed, and personalized medicine has become one of the mostimportant medical topics under Horizon 2020.5

Personalized medicine is a term coined to describe systematic usage of information

on individual patients with the aim to select and optimize prevention and treatment

In other words, personalized medicine is a model of health care that customizesindividual differences of the patient in all phases—form prevention, diagnosis andtreatment up to post-treatment monitoring Synonyms like genomic medicine,stratification medicine, and precise medicine can be commonly found in literature.Although these are undoubtedly important aspects, the term personalized medicine

is multidimensional and broader and encompasses pharmacogenetics, genomics, pharmacoproteomics, predictive medicine, rational drug selection, sys-tems medicine, individually tailored therapy, translational medicine, etc All ofthem represent elements of one integrated, new medicine.6

pharmaco-Genomic medicine is an important part of personalized medicine The necessityfor development of personalized medicine stems from large quantity of dataobtained by the human genome sequencing Personalized medicine largely relies

on predicting disease risk, treatment response, and safety profile based on genomesequence data Several important projects, in particular human genome sequencing

4 Bosˇnjak et al ( 2008 ), Kraljevic et al ( 2006 ), and Van ’t Veer and Bernards ( 2008 ).

5 ESF Forward Look ( 2012 ).

6 Aspinall and Hamermesh ( 2007 ).

in 2003, preceded personalized medicine, followed by the phase 1 and Hap-Mapprojects in 2005 aimed at haplotypic mapping of human genome The ENCODEpilot project ensued, i.e., generation of the DNA elements encyclopedia in 2007(identification and analysis of functional elements in 1 % of the genome) Subse-quently, DNA sequencing of the genome was carried out with the aim to establishdiversity in 1000 human genomes.7

The most common perception of genomic medicine is providing information on

an individual risk of developing disease based on obtained genome sequence Thesedata should be combined with other -omics methods, data gained by collectingenvironmental samples, and data on the lifestyle of the patient Only one approach,e.g genome sequencing, is not sufficient Genome does not remain stable duringlifetime somatic mutations in different cell types can play the key role in thedevelopment of many different diseases such as cancer, as well as in other poly-genic diseases During lifetime, changes can occur at both genomic sequence andepigenetic level It is not recommended to confine analysis to only one genomicsequence and one cell type Many valuable data can be lost if analysis is restrictedsolely to peripheral blood cells, which are most commonly used due to theiravailability For personalized medicine, tissue analysis is more important thanperipheral blood cells, but invasive approach for collecting tissue samples doesnot allow the usage of tissues as primary sample source for analysis For this reason,

it is indispensable to figure out noninvasive methods, minimally invasive methods,and single cell analyses.8

Stratified medicine is limited to identification of the patient subgroups withparticular diagnosis that respond to a specific treatment, and therefore it representsonly one but important element of personalized medicine, as evidenced by a fewexamples of its current clinical application, including the drugs gefitinib anderlotinib used to treat nonsmall cell carcinoma patients bearing the mutation inEGF-R gene or vemurafenib designed for treating metastatic melanoma patientswith the V600 mutation inBRAF gene.9

Third and most commonly used synonym for personalized medicine is precise or-omics-based medicine that points to specific elements underlying pathology of aparticular subject at a single point in time Simply, it means getting the right drug tothe right patient at the right time This term encompasses stratification tools andtakes into account a huge number of diverse factors that can impact diseasedevelopment in a particular subject (not only genomic and biological but alsoenvironmental factors and lifestyle as well) and efficiently predicts disease (pre-ventive medicine) In summary, personalized medicine should be perceived as awhole, genomic, layered, and precision medicine involving four proactive princi-ples It also implies the transfer or responsibility from medical personnel toindividual subjects (excluding old and helpless subjects and infants).10

3 Difference Between Traditional and Personalized

Medicine

Even now one can notice great differences and advantages of personalized cine Traditional medicine relies on the trial-and-error method The patient presentswith symptoms, and the doctor establishes the most probable diagnosis and treat-ment Drug dose is determined by the subject’s weight If the drug does not work,the new dosage or drug is prescribed Alternatively, the doctor establishes newdiagnosis and new treatment The cycle is repeated until the right or more accuratediagnosis has been reached and the new treatment plan has been set On the otherhand, personalized medicine means to diagnose more precisely onset of the exactdisease This is followed by selection of the most adequate treatment and dosage byusing personalized medicine tools taking into consideration the patient’s specificphysiology, tumor, viral or bacterial physiology (if possible), and patient’s ability tometabolize a specific drug What stands in the way of the transition from traditional

medi-to personalized medicine? According medi-to Aspinall and Hamermesh, there are severalkey obstacles, among which the pharmaceutical industry stands out, i.e., historicalsuccess of blockbuster drugs (one drug fits all) The next obstacles include regula-tory environment, which is not fit for personalized approach, and irrational econ-omy, which is reflected by exaggerate costs of medical examinations and drugsinstead of supporting diagnosing in the function of prevention One of the hurdles isalso linked with medial doctors’ habits heavily relying on trial-and-errormedicine.11

Pharmaceutical industry nowadays is most likely faced with a breakdown ofblockbuster drug system Although the financial support for drug R&D hasincreased (almost three times since 1990), the number of new molecular entitiesapproved by FDA (1993–1997) has dropped from 33 to 26 a year This resulted inthe inability of the pharmaceutical industry to design a sufficient number of newdrugs There is the impression that in spite of this, the pharmaceutical industry doesnot express too much interest in developing targeted therapy and does not approvedrugs associated with prevention and diagnostics

There are certain disciplinary presumptions for personalized medicine, above allradical changes in the mode of an individual approach to the patient The challenge

of personalized medicine is, besides interdisciplinary, how to reach ary consensus that allows specific challenges—regional, organizational, and disci-plinary Furthermore, it is of utmost importance to integrate data at multiple levels:statistical biological data with dynamic physiological data, data on environment,lifestyle, and geographical location of the patient

interdisciplin-Key factors that may influence the development and implementation of alized medicine include education, participation of the third, multidisciplinarity(and beyond), infrastructure, revised disease classification, revised test models,

person-11 Pavelic´ et al ( 2015 ) and Aspinall and Hamermesh ( 2007 ).

regulatory frameworks, models of health service payment, and ethical, legal, andsocial issues All participants in this process will be assigned some new roles.Health professionals will have to make decisions based on complex biological andenvironmental information and lifestyle Bioscientists and technologists will have

to closely cooperate and fulfill the needs of medical professionals responsible forpatients’ care Citizens will have a unique opportunity as well as responsibility fortheir own healthvia active monitoring, prevention and measures, and even directtreatment selection

This question should be considered from the point of view of individuals, medicalstaff, and health insurance, i.e., stakeholders When it comes to an individual, thisprimarily means a deviation from the one-size-fits-all approach towards the system

in which health care is based on the individual biological feature of each subjectwithin the framework of specific sociocultural and environmental context For apatient, it implies safer and more efficient treatment For those wishing to partic-ipate in such system for a long-term period, it means individually tailored therapyand preventive strategy based on continuous monitoring of biological profile.When it comes to health professionals, safety and accuracy of therapeuticdecision will be raised due to more efficient individualized therapy Better therapywill be the consequence of better diagnostics (and improvement of the decision-making system due to the advancement of information and communication tech-nology) All of these will result in better relation between the patient and medicaldoctor Great amount of information poses new challenges to the medical doctors,including education Personalized medicine will be developing in parallel withdisease reclassification Current classification is based on the symptoms character-istic for one organ or system With the advent of biology, classification will bebased on molecular pathways involved in the process This change in diseasetaxonomy is of particular importance to chronic diseases (e.g., inflammatory), asmany of them share common aetiology in spite of differences in individual pheno-types New disease reclassification will allow the current drugs to be administeredwith higher success rates and will provide the opportunity to successfully applythose drugs in particular stratified patient groups that were previously shown to beineffective Personalized medicine will allow collection and monitoring of dataduring lifetime Such approach allows better prevention and an early intervention.Individuals will be able to create their own databases of physiological data and topromptly identify pathological changes without the need to study data obtained inlarger population

5 Influence of Personalized Medicine on Participants

Great impact of personalized medicine will be visible in the health insurancesystem and stakeholders Although personalized medicine is often referred to as

an expensive medicine, a personalized approach will eventually reduce healthinsurance costs The examples of savings are numerous, particularly those found

in stratification medicine For example, EGFR mutation testing in France required1.7 million€ but led to the savings of 69 million € during the treatment of nonsmallcell lung carcinoma with gefitinib Similarly, savings of 30,000 € per patientafflicted with colon cancer bearing K-Ras mutation and tested for EGFR wereachieved in nonresponders to EGFR antagonists There are many other similarexamples

Initially, the costs of expensive diagnostics may rise, but in the perspective, thesavings will be evident due to more efficient prevention and early intervention,especially in chronic patients The costs of investment into new technologies andinfrastructure will provide cheaper and more efficient protection for future gener-ations Drugs inefficient in a preponderance of the population members may proveefficient in the particular defined cohort Although perhaps more expensive at thebeginning, health care will be ultimately cheaper for the aforementioned reasonsderived from personalized medicine

When speaking about the influence on medical industry, it is difficult to predictthe outcome Maybe drugs will be produced that would be efficient in the particulardefined cohort, which is useful for both the industry and patients Clinical investi-gations could be more accurate by selecting more adequate patient samples Newtest models will have to be developed.In silico studies will represent an importantstep forward in the development of precise clinical tests It is likely that thedevelopment of biotechnological and medical technology will be fostered in com-parison with the drug industry

Destiny of personalized medicine will depend on the ability to integrate complexinformation derived from multiple sources and on the preconditions; among themost important ones includes advanced technology (with the aim to produce andmanage data) Technological and other preconditions include, among others,advanced high-throughput -omics technology (genomics, epigenomics, proteomics,metabolomics, lipidomics, etc.), microbiomics, molecular imaging, physiologicalmonitoring, environmental exposure, lifestyle, the ICT analysis and data manage-ment, and their conversion to useful outcome

The following scenario is possible: collection of clinical data is ensued by-omics analysis in one day that encompasses individual metabolic profile, proteinexpression and localization, mRNA expression, epigenomic signature in specificcell type, data integration and interpretation and prediction of individual risk anddisease course, and finally treatment response, i.e., adverse side effects.Informatics-computational technology is an important component of personalizedmedicine So far, it has been exploited in physics for demanding experiments andshow business In biomedicine, its application commenced with genomic era

Quantity of data obtained by -omics methods significantly exceeds current ical ability Data storage currently represents an irresolvable issue There is neithercareful and systematic storage nor genuine data integration.

One of the keys of success of personalized medicine is infrastructure Development

of European infrastructure will facilitate harmonization of protocols, integration,and interpretation of data derived from multiple population This poses a challenge

of interdisciplinarity: the concept of personalized medicine, although ward, includes radical changes in the approaches of health care system towards anindividual person Therefore, there is a need for restructuring the health caresystem—detachment of health care professionals from the so-called organ-basedspecialities

straightfor-In order to understand technological challenges for future personalized cine, it is indispensable to focus on three areas: (1) defining the requirements ofmedicine and the health care system – determine if technology can meet theexpectations of the key groups involved in the implementation of personalizedapproach; (2) what the technology has to offer to personalized medicine – due tosignificant technological improvements in the field, one can expect major break-through in the future; (3) how to efficiently integrate information as to ensurecomplete systematic “readout” of individual health status in defined environment

medi-It is necessary to say a few words about the importance of high-throughputmethods to make personalized medicine become a reality, although this issue hasalready been specifically covered by several chapters in this book Development ofhigh-throughput methods and their application in medicine are the key to thedevelopment of personalized medicine High-throughput methods andnanomedicine representing the technological foundation of -omics are generallyexpected to bring about more personalized approach to treatment of many diseases,increase efficacy of pharmaceutical therapy, reduce adverse drug effects The-omics methods such as transcriptomics, proteomics, metabolomics, lipidomics,glycomics, structural genomics, etc are already based on nanotechnologies Thisparticularly applies to the so-called DNA and protein arrays The term -omicsencompasses global characterization method of all or majority of members belong-ing to the particular molecular family in a single step or analysis Transcriptomicsrepresents systematic analysis of all genes in an organism, while proteomicsdenotes systematic analysis of protein expression under specific conditions, whichinclude separation, identification, and characterization of protein in an organism.The term proteome, which was coined in 1994 as a linguistic equivalent of the termgenome (Protein complement to a genome), denotes complete protein content that

genome expresses during lifetime.12These methods can give a global insight intothe molecular profile of the affected subject.

Human genome studies involving around 23,000 genes encoding for much largernumber of different transcripts result in better understanding of disease process atmolecular level However, changes at genome and transcriptome level are mirrored

by proteome aberrations Challenge in the comprehension of proteome complexitylies in the determination of a number of different protein species that may surpassone million and in a large number of regulatory levels of protein expression andactivity that sustain cellular function and tissue homeostasis.13

Functional components such as molecular complexes, signalling networks, andwhole organelles are very important regulators of cellular processes Proteins areindividual components of these functional parts with multiple levels of regulation,which includes protein “circulation” (recycling and degradation), posttranslationalmodifications, subcellular localization, and protein–protein interactions The latterleads to formation of complexes such as those implicated in the cell signal trans-duction or cellular architecture It is a huge challenge and, at the same time, ofenormous importance to integrate knowledge gained through global high-throughput studies, in particular genomics and proteomics, in order to obtain betterunderstanding of the molecular nature of diseases and develop a “cellular map.”14Proteomics is a method with progressive and fast development that greatlybenefits from the development of mass spectrometry and other high-throughputanalytical tools with the aim of comprehensive bioinformatic analysis Obtainedresults are already encouraging and complementary to those obtained at genomeand transcriptome level The result is better understanding of the disease, such asglioma, from the perspective that includes protein expression, interaction, andfunction The potential benefit of understanding disease process based on proteome

is not questionable since it includes the possibility of diagnosis, classification,prognosis, and assessment of therapeutic effect and ultimately leads to genuinepersonalized medicine based on the patient’s proteome.15

The impact of personalized medicine will be significant for both patients and themedical profession Medical doctors will expect integrated information from manydifferent sources, including -omics and molecular imaging Obtained data shouldprovide support for the right decision and the sequence of actions for each individ-ual patient One can presume that proof of principle would be achieved in the

12 Petricoin et al ( 2002 ) and Espina et al ( 2004 ).

13 Editorial ( 2003 ).

14 ESF Forward Look ( 2012 ), Editorial ( 2003 ), and Ferrari ( 2005 ).

15 Sedic´ et al ( 2014 ).

following 5 years Clinicians should be convinced that the new technology willoffer tangible results It is important to prove clinical applicability, value, andrelevance of all new technologies; identify stable biomarkers; validate knownbiomarkers; and confirm their application in the risk assessment and prediction ofoutcome Diagnostic tests for preselective screening should be 100 % reliable Itwill be indispensable to prove to health professionals the clinical benefit of newbiomarkers, in particular in asymptomatic, apparently healthy subjects There isalso a possibility of inflating the risk of overdiagnostics and false positive results It

is necessary to forward particular technological steps and interpretations such asexploitation of biobanks and clinical sample collection program so as to ensureglobal approach to technological support and infrastructure (path to integratedmodel, including central reference database) Perhaps in this context of proof ofprinciple the focus should be placed on some specific diseases such as diabetes,asthma, rheumatoid arthritis, cardiometabolic diseases or on some subgroups, e.g.,nonsmall cell lung carcinoma, where tangible results could be observed in a shortperiod.16

One can presume that implementation of personalized medicine will last for

20 years In the first 5 years, it will be necessary to confirm the personalized-omicsproof of principle Determination of genomic, transcriptomic, proteomic,metabolomics and auto-antibody profiles means that the same type of analysiswill be carried out several times in the same individual The generation of dynamicintegrative personalized-omics profile (iPOP) will ensue; destiny of personalizedmedicine is an emphasis on individual data rather than on an average populationdata Important data obtained individually can be lost or masked in populationstudy iPOP can serve to guide lifestyle changes in order to prevent disease It will

be necessary to address the issues such as data interpretability, patient’s choice,privacy, ethical usage of personalized data, etc

In the next 10 years, one could expect that health professionals would be moreeager to accept and support personalized approach once the technology confirmsclinical value It is a must to develop algorithms based on the interaction betweendifferent -omics and environmental data (e.g., lifestyle) These data would beintegrated with those obtained by molecular imaging methods Technology wouldhave to be developed and adapted for a lifetime monitoring of individual health.Long-term vision means the creation of personalized database that will accompanyeach individual from birth (and even prenatal), taking also into account geograph-ical locations in which this person resides This also implies management of datathat are sensitive and personal, construction of sensor for real-time data monitoringfor each subject, the matter of exchange and limitation of those personalized data.One of the greatest challenges would be translation from “bench to bedside.”When personalized medicine enters clinics, technological requirements would

be to increase preciseness and reduce the time necessary to respond Molecularimaging technologies may possibly undergo changes The current problem lies in

16 Walker and Mouton ( 2006 ), Pavelic´ et al ( 2015 ), and Kraljevic´ et al ( 2004 ).

data processing and interpretation It is necessary to integrate imaging technologywith real-time monitoring of health status and treatment efficiency The processingperiod should be shortened while maintaining preciseness Advancement in thisarea will be crucial for the complete integration of personalized medicine intoclinics This will largely depend on the availability of nanodevices and nanotools.

It is important to identify which technologies could be realistically employed inclinics One must validate technology and gain insight into its reproducibility fortechnological procedures, data collection, and manipulation Quality assuranceprotocols for laboratories have to be developed and made available at all levels.Harmonization represents a decent basis for data management and obtaining real-istic databases that can be used later The current problem is that more data arecollected than can be processed or even stored.17

One option includes the application ofin silico models that use only variabledata, which represents a significant reduction in the volume of invariable data to bestored In the next 20 years, the implementation of integrated models follows: theneed for systematic, longitudinal data collection, then setting rigid standards fordata collection, processing, and recording Harmonization and establishment of aframework for data disposal will be the key to success of personalized medicine.One could also expect the establishment of electronic data and personalizedmedicine portals like the existing PatienstLikeMe and Quantified Self.PatientsLikeMe is an electronic source of clinical and scientific data, i.e., electronicplatform generated with the aim to help affected subjects to share and learn fromreal-world, outcome-based health data This includes information on symptoms,quality of life, treatment options, specific disease variables, and other factors.Quantified Self is a platform for citizens who collect their own data on theirlifestyle, eating habits, physical activities, physiological variables, and emotionalcondition The usefulness of such data for personalized medicine is generation ofdata on profitability and monitoring of long-term effects of personalizedinterventions

One of the major goals of personalized medicine is setting up efficient diseaseprevention Preventive medicine implies disease discovery before symptoms appear

or detection of disease susceptibility with the aim to prevent It will be important tointegrate novel genetic information on epidemiologic studies so as to reveal thecausal relation between lifestyle and genetic factors in order to assess the risk ofdisease An illustrative example is given by atherosclerosis: arachidonic acid(polyunsaturated n-6 fatty acids) in the presence of enzyme 5-lipoxygenase givesrise to inflammatory mediators leukotrienes Variants of 5-lipoxygenase genotype

17 Bosˇnjak et al ( 2008 ) and Kraljevic´ and Pavelic´ ( 2005 ).

are identified in the individuals with increased susceptibility to atherosclerosis.There is also a relationship between genes and diet: n-6 polyunsaturated fatty acidsfacilitate, while n-3 fatty acids originating from sea inhibit leukotriene-mediatedinflammation leading to atherosclerosis.18

Nutrition plays the key role in health and disease With the development ofmolecular biology, there had been a shift from epidemiology and biochemistry tounderstanding the molecular mechanisms of action of diet A new discipline hasemerged, nutrigenomics, which represents the study of the effects of nutrition ongenomic level Nutrigenomics analyzes the complex relation and consequences ofthe interaction between individual genes and environment, including diet.Nutrigenetics is related to nutrigenomics, and it investigates the effects of geneticvariations on diet–disease interaction Food components may have adverse effects

on molecular processes like DNA structure, gene expression, and metabolism.Major methodological challenges would be to integrate genomics, transcriptomics,proteomics and metabolomics to define the so-called healthy phenotype Classical

nanobiotechnology There is urgent need for generation of big versatile ethicaldatabase of genomic profile.19

Nutrigenomics and functional food create the need for further and intensivestudies on interactions between genes and diet so as to achieve rational selection offunctional food, which paves the way for optimal health and reduction of risks ofchronic diseases The purpose of such approach is to establish useful personalizednutritional counselling Individual genetic variations are important determinants ofdifferences for nutritional ingredients This is exemplified by common geneticpolymorphism C/T substitution in the gene coding for methylene tetrahydrofolatereductase (MTHFR), which results in metabolic changes that modulate the risk ofchronic disease defects of neural tubes in the absence of folate Increased folateuptake has different consequences in affected subjects (T/T) in comparison withnormal (C/C) or heterozygotes (C/T)

In future, it will be necessary to adapt nutritional advice on the basis of genotypeand establish a so-called personalized diet Nutrigenomics is likely to revolutionizeclinical and public nutritional practice by providing more precise “targeting” ofnutritional interventions In particular, this will prove useful for diseases related tometabolism and diet such as diabetes, cardiovascular diseases, some neurologicaldisorders, age-related diseases, cancer Individual response to diet varies.Chemicals from food can bind to receptors and thus regulate gene activity Forexample, genistein (coumarin-like isoflavone derivative) from soya binds to estro-gen receptors (ER) and induces gene regulation Individual variations in ERdetermine different response to genistein Interaction between genotype and diet

18 Pavelic´ et al ( 2014 ), Catchpoole et al ( 2010 ), Subbiah ( 2007 ), and European Science Foundation ( 2005 ).

19 Astley ( 2007 ).

influences severity of disease such as obesity, atherosclerosis, asthma, and otherchronic diseases.20

Functional food represents nutrients with beneficial effects on human healthirrespective of supply of essential physiologic needs Due to varying individualresponse, it is difficult to make general recommendations and statements Efficacy

of nutrients is affected by polymorphisms in genes regulating absorption, tion, and metabolism An example is n-3 polyunsaturated fatty acids orepigallocatechin-3-gallate More research into interaction between genes and dietshould be conducted to achieve rational selection of functional food, which leads tooptimal health and reduction of the risk of chronic diseases with the aim to establishuseful personalized nutritional counselling.21

circula-Important component of personalized medicine is the role of citizens in maintainingtheir own health and prosperity and in providing data that will aid in achievingprosperity for others through understanding individual variations, population needs,and response to therapy and preventive measures Development of individually tai-lored therapy and preventive medicine will depend on our ability to interpret therelevance of biological and environmental variations by using data obtained in largepopulation Patients can no longer be only passive acceptor of information given bymedical professionals but should be active participants in the generation and interpre-tation of own data Medical doctors are expected to actively participate in the devel-opment and adoption of new technologies and decision-making systems anddiagnostic algorithms The sustainability level of the trial-and-error approach isastonishing, even in cases where knowledge of the abovementioned exists!22

Medicine

Similar to clinical investigations, studies necessary for the development of alized medicine include analysis of data obtained from large population studies(groups of individuals sharing the same or similar characteristics such as theenvironment in which they were born or grew up, age, etc.) and collection ofbiological samples (biobanks).23

person-Combination of carefully classified biological samples and detailed relevantclinical information obtained from biobanks comprise the instrumental components

of research infrastructure that will facilitate the generation of much better, moredetailed classification of disease subtypes and act as impetus for the development ofpersonalized medicine of the twenty-first century

20 M €uller and Kersten ( 2003 ).

21 Ries and Castle ( 2008 ).

22 Aspinall and Hamermesh ( 2007 ).

23 Hewitt ( 2011 ) and Spaventi et al ( 1994 ).

In order to better comprehend factors responsible for the biological basis ofindividual differences and environmental and lifestyle factors, it is necessary toanalyze data from hundreds and thousands of subjects covered by these studies.Such studies are extremely expensive, so that it is important to manage their results

in the right and professional way It is the results of such studies that are importantfor the development of personalized medicine Methods for collection of data onphenotype, diagnostic criteria, lifestyle, and environment will be used Some ofthese parameters change during lifetime Furthermore, with the advancement ofknowledge, new questions would arise demanding new studies and new patientcohorts, demographic data, which may not exist in the previous research Therefore,

it is crucial to update and improve phenotypic and environmental databases toadvance research that should lead to truly personalized medicine For this reason,the path to truly personalized medicine is long.24

Studies in particular groups provide knowledge of diseases with respect to thecombination of internal and environmental factors Even more important is the factthat they ensure a prospective approach in which disease development can beanalyzed during time in the population that is better defined

It is assumed that genetics is an important factor that determines susceptibility ofthe particular individual to disease In the last years, a breakthrough in methodssuch as genome sequencing and whole genome association studies has resulted inthe identification of link between 1888 single nucleotide polymorphisms (SNP) in

210 different diseases.25 Although this link accounts for only a small portion ofgenetic predisposition to common diseases, such and similar studies have alreadyyielded numerous potentially significant results

Genetics is only one path towards understanding individual disease variations.Research priorities in personalized medicine include analysis of data on life eventsand environmental factors in relation to epigenomic, proteomic, metabolomics, andtranscriptomic features To make sure that the results of these studies are trulyvaluable, data should be carefully processed and continuously updated so as to takeinto account demographic changes and progress in knowledge

of Personalized Medicine

According to some scenarios, implementation of personalized medicine could take

up to 20 years All the while, projections of the levels of technology, medicine, andintegration need to be coordinated (Table1) In the EFC Forward Look document,predictions over the period of 5, 10, and 15 years with tasks and phases defined todetail can be found (Table2)

24 ESF Forward Look ( 2012 ).

25 http://www.genome.gov/26525384 , accessed on January 1st 2016.

Table 1 Projections for technological, medical, and integrational consideration for tion of personalized medicine (modified from ESF Forward Look 2012 )

implementa-Projections

Technology Linear technologies Building interaction

networks

Measuring dynamic networks in vivo Genomics,

Remote sensing

Responsive user interfaces

refinement Target available technol-

ogy on one disease area

Cumulative data to follow the person

Integration of imaging technology in physio- logical monitoring Identify available

resources (electronic

health records, cohorts,

etc.)

Dynamic titative measures

qualitative/quan-In silico model for individual patients

Enhance biobanks and

clinical sampling

Synergistic outputs from multiple markers

Real-time monitoring (nanomaterials) Expand measures for

healthy individuals

ICT infrastructure to port real-time health care delivery across regions

sup-Remote monitoring/ personalized telemedicine Noninvasive information

collection and sharing Increased precision of imaging technologies and therapy

Core, -omics

technologies

Definition of purpose Nanotechnology

Prototype model Testing of infrastructure Systematic data

collection Enforcemet of standards Data sharing E-learning

The development and the implementation of personalized medicine will occur inthree precisely defined phases In the first phase, next to education and regulatoryframework, an important role will be played by the dialogue with the users,stakeholder participation, standardization, and proof of principle.

The second phase will be marked by action harmonization, creation of aninteracting network (molecularly as well as environmentally), data integration,and monitoring.26

The third phase will be labeled byin silico models, systematic collecting of data,and nanomedicine implementation All the while, one has to keep in mind possibleissues and key factors that could influence the development and implementation ofpersonalized medicine, e.g., education, participation of a third party,multidisciplinarity, infrastructure, revised disease classification, regulatory frame-work, models for compensating the costs of medical care, ethical, social and legalquestions (Figs.1and2)

Acknowledgements This text is supported by the Croatian Science Foundation project “5709 – Perspectives of maintaining the social state: towards the transformation of social security systems for individuals in personalized medicine” and University of Rijeka research grants 13.11.1.1.11 and 13.11.1.2.01 We greatly acknowledge the project RISK “Development of University of Rijeka campus laboratory research infrastructure”, financed by European Regional Development Fund (ERDF).

Table 2 Timeline for the development and implementation of personalized medicine (modified from ESF Forward Look 2012 )

Biomarker validation Data sharing

Data standardization Dynamic monitoring

26 Huser et al ( 2014 ).

Systems approach:

Shift away from current symptom-based disease model Describe phenotypes Systemic insights

Infrastructure:

Access to technology Biobanks Human resources Cohorts

Sharing mechanisms

Legal and ethical frameworks Public-private partnership Systemic data collection

Personalised medicine issues

Fig 1 Key issues affecting the development and implementation of personalized medicine

Catchpoole DR, Kennedy P, Scillicorn DR et al (2010) The curse of dimensionality: a blessing to personalized medicine J Clin Oncol 28:e723–e724

Clark GM, Zborowski DM, Culbertson JL et al (2006) Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib J Thorac Oncol 1:837–846

Editorial (2003) Nanomedicine: grounds for optimism Lancet 362:673

Espina V, Dettloff KA, Cowherd S et al (2004) Use of proteomic analysis to monitor responses to biological therapies Expert Opin Biol Ther 4:83–93

ESF Forward Look (2012) Personalised medicine for the European citizen Towards more precise medicine for the diagnosis, treatment and prevention of disease (iPM) European Science Foundation, Strasburg

European Science Foundation (2005) Nanomedicine An ESF-European Medical Research cils (EMRC) Forward look report, ESF, Strasbourg, France

Coun-Ferrari M (2005) Cancer nanotechnology: opportunities and challenges Nat Rev Cancer 5:161–171

Goldstein DB, Tate SK, Sisodiya SM (2003) Pharmacogenetics goes genomic Nat Rev Genet 4:937–947

Hewitt RE (2011) Biobanking: the foundation of personalized medicine Curr Opin Oncol 23 (1):112–119

Huser V, Sincan M, Cimino JJ (2014) Developing genomic knowledge bases and databases to support clinical management: current perspectives Pharmgenomics Pers Med 7:275–283 Kralj M, Pavelic´ K (2003) Medicine on a small scale How molecular medicine can benefit from self-assembled and nanostructured materials? EMBO Rep 4:1008–1012

Kraljevic´ S, Pavelic´ K (2005) Navigare necesse est EMBO Rep 6:695–700

Kraljevic´ S, Stambrook PJ, Pavelic´ K (2004) Accelerating drug discovery EMBO Rep 5:837–842 Kraljevic S, Sedic M, Scott M et al (2006) Casting light on molecular events underlying anti- cancer drug treatment: what can be seen from the proteomics point of view? Cancer Treat Rev 32:619–629

Li X, Quigg RJ, Zhou J et al (2008) Clinical utility of microarrays: current status, existing challenges and future outlook Curr Genomics 9:466–474

M €uller M, Kersten S (2003) Nutrigenomics: goals and perspectives Nat Rev Genet 4:315–322 Pavelic´ K, Martinovic´ T, Kraljevic´ Pavelic´ S (2014) Translational and personalized medicine In: Kraljic´ S, Rebersˇek-Gorisˇek, J, Rijavec V (eds) Medicina in pravo, Sodobne dileme III Univerza u Mariboru, Maribor, pp 255–263

Pavelic´ K, Martinovic´ T, Kraljevic´ Pavelic´ S (2015) Do we understand the personalized medicine paradigm? EMBO Rep 16:133–136

Petricoin EF, Zoon KC, Kohn EC et al (2002) Clinical proteomics: translating benchside promise into bedside reality Nat Rev Drug Discov 1:683–695

Ries NM, Castle D (2008) Nutrigenomics and ethics interface: direct-to-consumer services and commercial aspects OMICS 12(4):245–250

Sedic´ M, Pavelic´ K, Josic´ D, Kraljevic´ Pavelic´ S (2014) Peptidomics to study age-related diseases: spotlight on cancer and neurodegeneration Peptidomics 1:65–76

Spaventi R, Pecˇur L, Pavelic´ K et al (1994) Human tumour bank in Croatia: a possible model for a small bank as a part of the future European tumour bank network Eur J Cancer 30A:419

Subbiah MTR (2007) Nutrigenetics and nutriceuticals: the next wave riding on personalized medicine Transl Res 149:55–61

Van ’t Veer LJ, Bernards R (2008) Enabling personalized cancer medicine through analysis of gene-expression patterns Nature 452:564–570

Walker B, Mouton CP (2006) Nanotechnology and nanomedicine: a primer J Natl Med Assoc 98:1985–1988

Ulrich Becker

Abstract Personalized medicine (PM) aims at improving the efficiency of medicalmeasures by determining the health care measure on the basis of the patient’sbiological information It can be applied in the preventive field, as well as withinthe framework of medical therapies A combination of diagnostics and therapiesrepresents the main scope of PM in today’s health care systems, especially regard-ing cancer treatment In this sense, PM allows to tailor the treatment according tothe genetic information of the patient

PM gives rise to a number of legal questions First, personalized diagnostics andpharmaceuticals face difficulties in accessing the market and the health caresystems under the current conditions, as these do not take into account the specialfeatures of the individualized health care approach Second, the issue of dataprotection deserves particular attention, concerning the right to privacy of thepatient and his or her relatives, as well as the collection and use of data for researchpurposes

Personalized medicine is a somewhat glittering generality, and it is a phrase thatseems to have the effect to divide the world—at least the world of those personswho work for, and within, public health systems, pharmaceutical industries, healthprofessions, and the health science and health media in a broad sense To one part ofthem, it gives rise to very high-flying expectations: that personalized medicine is akey element that can make the efforts to provide effective health care become true

In this sense, personalized medicine is an important instrument to achieve betterefficiency of medical measures, both in an economical as well as in a medicalperspective To the other part, it is not much more but an empty promise, a dreamthat will one day, like a balloon with too much air, simply burst The scepticism is

Professor Ulrich Becker, Ph.D LL.M Director of Max Planck Institute for Social Law and Social Policy, Munich, Germany.

U Becker, Ph.D ( * )

Max Planck Institute for Social Law and Social Policy, Munich, Germany

e-mail: beckersek@mpisoc.mpg.de

© Springer International Publishing Switzerland 2016

N Bodiroga-Vukobrat et al (eds.), Personalized Medicine, Europeanization and

Globalization 2, DOI 10.1007/978-3-319-39349-0_2

21

based on the difficulties to implement progress through personalization of cine, but even to a greater extent on the fear that personalized medicine will lead to

medi-a considermedi-able rise in hemedi-alth cmedi-are expenditure In this view, it is rmedi-ather medi-a new strmedi-ategy

of providers, namely of the pharmaceutical industry, to advertise and marketizetheir products

Whether the hopes or the fears are well founded is a question that very muchdepends in the first place on our understanding of personalized medicine Before wecan assess a certain phenomenon, be it new or not, we have to make clear what weare speaking about Therefore, my first point will deal with the concept of person-alized medicine (Sect.2) After this rather short observation, I will come to the legalquestions that might be brought up by the introduction of personalized medicine asdefined before There are two different sets of those questions: one concerns theaccess to markets and to public health systems (Sect.3); the other one is about dataprotection (Sect.4)

Before I start, I should add that my observations are mainly drawn from theparticipation in an interdisciplinary project that has been founded by the GermanMinistry for Education and Science and that has brought together researchers fromthree different disciplines, medical ethics, economics, and law.1The main findings

of this project are based on our experiences with the German health care system, but

I will try to present them in a more general way in order to allow for some generalconclusions

What is personalized medicine? A systematic review of the literature that has beenpublished over the last years and based on PubMed has led to the following result:

“Personalized medicine seeks to improve tailoring and timing of preventive andtherapeutic measures by utilizing biological information and biomarkers on thelevel of molecular disease pathways, genetics, proteomics as well asmetabolomics.”2

The main elements of this concept are information, based on biomarkers or otherbiological information, on the one hand and a health care measure on the other.Both elements have to be combined with each other in order to improve the effects

of the health care measure The main ways to do so are to change the procedure inwhich respective measures are being realized or to target health care measures tocertain individuals

1 See the final report: Individualised Health Care: Ethical, Economic and Legal Implications for the German Health Care System, Subproject C “LAW.” Available at: http://opac.tib.uni-hannover.de/

DB ¼1/LNG¼DU/

2 Schleidgen et al ( 2013 ) The concept of Personalised Medicine varies broadly; see, for example, FDA, Paving the Way for Personalized Medicine, 2013 Available at: http://www.fda.gov/ scienceresearch/specialtopics/personalizedmedicine/default.htm , p 7.

In this regard, personalized medicine has nothing to do with a person as such, or

to put it in other words, it has nothing to do with the personality of a patient It isabout a specific biological predisposition that can be found in a specific person This

is why we have chosen the term individualized health care3instead of personalizedmedicine, although the bulk of the medical literature quite obviously would useboth terms in the same way And in a more technical but less appealing way,personalized medicine can be regarded as a strategy of stratification: because itaims at detecting subgroups of patients who benefit from a certain measure

As a result, two points need to be stressed: on the one hand, the concept issomewhat restricted Personal preferences are not taken into account, and the veryinteresting questions of whether medical treatments can be improved by more andbetter communication between the medical personnel and patients4are cut down tothe question how far the consent of patients is needed in order to gather theinformation necessary for personalized medicine On the other hand, personalizedmedicine can cover a broad range of medical interventions It may be used in order

to prevent people from a certain illness In this sense, it can be seen as a specificpreventive measure And it can consist of the combination between diagnostics and

a therapeutic measure This measure as such may consist in a specific medicalmethod or in the mere prescription of a drug

If we look at the current situation, it becomes clear that the state of personalizedmedicine is a rather limited one.5By far, most of its applications cover pharma-ceutical therapies, and the main field to which these therapies belong is oncology Inits present core, personalized medicine is a pharmacogenomical instrument This iswhy personalized medicine is tightly combined with the fight against cancer and hasgained much attention last year in the context of the WHO’s predicament that ourglobe is facing a “tidal wave” of cancer.6It is not by chance thatJames Watson,codiscoverer of the double helix and Nobelist, wrote an article in the New YorkTimes in 2009 under the heading “To Fight Cancer, Know the Enemy”7 And someoncologists even state that “the concept of personalized medicine demands thatevery cancer has to be treated uniquely”.8This level of individualism is far frombeing realistic at the moment But it is evident that medical treatment tailoredaccording to genetic information becomes more and more important in the fightagainst cancer and some other diseases Personalized medicine probably has the

3 See also for the term individualised medicine Fischer et al ( 2014 ), Grabe et al ( 2014 ), and Ma and Lu ( 2011 ).

4 W €ohlke et al ( 2013 ), p 25, Nekhlyudov et al ( 2014 ), Ullrich et al ( 2014 ), Alvarado et al ( 2014 ), and Denford et al ( 2014 ).

5 Although the US American FDA states that “the era of personalized medicine has clearly arrived”; see FDA, Paving the Way for Personalized Medicine (footnote 2), p 54.

6 So Bernhard Stewart, one of the editors of the World Cancer Report 2014 Available at: http:// www.iarc.fr/en/publications/books/wcr/wcr-order.php

7 Published: August 5, 2009 Available at: http://www.nytimes.com/2009/08/06/opinion/06watson html?pagewanted ¼all&_r¼0

8 Mehta et al ( 2011 ), pp 20–26.

capability to develop further and to cover a much broader field of applications Yet

it is already there—which leads to the question how it can get on the markets and tothe patients

As far as the access to the market in general and the public health care systems inparticular is concerned, there are two points worth to be mentioned

First, the simple fact that personalized medicine in most cases consists of acombination of a diagnostic measure and a pharmaceutical one causes difficultiesfor many public health care systems The background for these difficulties is thatthere are certain pathways into the systems that differ from one member state of the

EU to another, albeit the existing EU legislative framework on medicinal products

as the centralized Community authorization procedure established by Regulation

No 2309/93,9the Directive 2001/83 on the Community code relating to medicinalproducts for human use,10or Council Directive 89/105/EEC relating to the trans-parency of measures regulating the prices of medicinal products for human use andtheir inclusion in the scope of national health insurance systems,11which is underrevision at the moment Those pathways do, generally speaking, concentrate on onetype of medical measure: be it a medical product, a pharmaceutical, or a particularmethod of treatment

If we take Germany as an example, the access of a pharmaceutical to the markethas to be granted on the basis of the law on pharmaceuticals (Arzneimittelgesetz).12

In order to gain this marketing authorization, a pharmaceutical has to be beneficial

in terms of health and, therefore, to fulfill certain requirements concerning peutic efficacy, safety, and quality.13 For patent-protected drugs, it is up to theproducer to set up the marketing prize—which is, by the way, an important factorfor marketing within the EU as some member states take these prize tags as areferential basis for their prize regulation In order to enter the statutory health careinsurance, no further admission is necessary According to the existing rules,14

thera-9 Available at: http://ec.europa.eu/health/files/eudralex/vol-1/reg_1993_2309/reg_1993_2309_en pdf

10 Available at: http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_ 2001_83_cons_2012_en.pdf

11 Available at: http://ec.europa.eu/enterprise/sectors/healthcare/competitiveness/pricing-reim bursement/transparency/index_en.htm

12 AMG of 12.12.2005 (BGBl I, p 3364).

13 §§ 21 et seq of Pharmaceutical Act (Arzneimittelgesetz): the marketing authorization shall only

be refused if documents provided by the applicant are not in accordance with § 25 par 2 AMG; for the centralized procedure, see Regulation (EC) No 726/2004 Available at: http://eur-lex.europa eu/LexUriServ/LexUriServ.do?uri ¼CONSLEG:2004R0726:20120702:EN:PDF

14 § 31 par 1 s 1 of Social Code (Sozialgesetzbuch) V.

drugs that have received market authorization automatically become part of thebenefits package of the insurance system.15 Yet there is a specific procedure ofbenefit assessment in order to regulate the prize of the pharmaceutical.16

Up to now, no similar provisions exist for companion diagnostics Some arguethat these diagnostics would have to be dealt with as an integral part of therespective drug,17 but this is not a common opinion and especially not followed

in practice That leads on the one hand to the problem that the combination as such

is never subject to an assessment of the competent authorities—although tics can be rather complex in not only few cases, and the prescription of the drugconcerned is always closely linked to the results of the diagnostics Or, as the USAmerican FDA has put it: “The specific challenges for any particular set of productsdepend in part on the nature of their relationship to each other.”18This is why in theUSA the regulatory framework has recently undergone changes.19The draft of aRegulation on in vitro diagnostic medical devices as proposed by the EuropeanCommission20also addresses companion diagnostics.21

diagnos-On the other hand, the separation of companion diagnostics and companiondrugs regarding the access to the health care system also means that diagnostics donot receive a specific tariff position on the list of medical treatments This may seem

to be a simple technicality, but it means that the companion diagnostics, though anecessary measure in order to apply the pharmaceutical, will not be paid for—atleast when the patient does not stay in a hospital Also with respect to reimburse-ment, it is quite clear that a procedure is needed that pays attention to the combi-nation of two otherwise separated medical measures

Second, also the evaluation of an individualized treatment or pharmaceuticalmay lead to new problems Today, most health care systems follow the idea ofevidence-based medicine.22 The necessary evidence can be derived from testingthat follows certain standards As a rule, the assumption that a pharmaceutical orother therapy is effective has to be based on a sufficient number of cases Butpersonalized medicine reduces the cases: as we have seen, it tries to target a therapy

15 See for more details German Federal Social Court (Bundessozialgericht), Dec of 28.2.2008, B

1 KR 16/07 R, and Dec of 3.7.2012, B 1 KR 23/11 R ( www.juris.de ).

16 § 35a of Social Code (Sozialgesetzbuch) V.

17 Huster and Gottwald ( 2013 ), pp 16 et seq.

18 FDA, Paving the Way for Personalized Medicine (footnote 2), pp 32/33.

19 Sawyers and van ’t Veer ( 2014 ), Waltz ( 2014 ), and Noweski et al ( 2013 ) See also the nonbinding recommendations of the U.S Department of Health and Human Services, Food and Drug Administration, Center for Devices and Radiological Health, Center for Biologics Evalua- tion and Research, Center for Drug Evaluation and Research, In Vitro Companion Diagnostic Devices: Guidance for Industry and Food and Drug Administration Staff of 6.8.2014 Available at: http://www.fda.gov/ScienceResearch/SpecialTopics/PersonalizedMedicine/ucm372544.htm

by means of stratification The existence of subgroups of patients also means thatthere are subgroups of indications In turn, this may not only raise the sheer number

of studies needed in order to prove the effectiveness of a given therapy but alsomake the burden of proof more difficult.23 Whether this is the case or not isdisputed—and it only becomes a legal problem in an indirect way and as far asthe legal requirements refer to the standards of evidence-based medicine

As far as the first point is concerned, it is essential to notice that most tions of personalized medicine rely on genetical information.24Those informationhave to be qualified as personal data that may only be used if the person whose dataare concerned has given his or her consent The use of genetical data is strictlylimited under the existing laws This concerns the collection of data as well asfurther processing Furthermore, most jurisdiction draws a distinction betweengenetic data in general and those genetic variants that are inherited.25The use ofthe latter data falls under even stricter requirements and is subject to stricterprohibitions than the former ones.26

applica-Future legislation will have to take two aspects into account As we have seen,personalized medicine is often used to combat diseases in a more effective way, and

to this end, it will in many cases need to identify acquired genetic disorders and thespecific features of tumor cells When those examinations will become more andmore common and widespread than today, we might have to rethink the vulnera-bility of the respective genetic data in order to make health care systems moreeffective On the other hand, advanced personalized medicine—especially when it

is used for preventive care—will also deploy new diagnostic procedures thatsupposedly reveal which individuals are more likely to develop a severe disease

23 Hardenberg and Wilman ( 2013 ), p 79.

24 Bericht des Ausschusses f €ur Bildung, Forschung und Technikfolgenabscha¨tzung v 17.2.2009, BT-Drs 16/12000, p 153, Hardenberg ( 2014 ), p 115.

25 See, e.g., for Switzerland the Human Genetic Testing Act (Bundesgesetz €uber genetische Untersuchungen beim Menschen—GUMG) of 8.10.2004 and the Regulation on Human Genetic Testing (Verordnung €uber genetische Untersuchungen beim Menschen—GUMV) of 14.2.2007; for Austria the Genetic Engineering Act (Gentechnikgesetz—GTG) of 1.1.1995.

26 See for Germany § 3 of Genetic Diagnostic Act (Gendiagnostikgesetz).

in the course of their lives and therefore will have to deal with information in thegenetic hereditary property.

Let me give you an example that is taken from a case study that has beenmodeled and calculated through by the economists in the framework of ourbefore-mentioned interdisciplinary project.27For some variants of colorectal can-cer, we know that a specific genetic predisposition can lead to the outbreak of thedisease If persons who have already felt ill were tested, those with the said geneticpredisposition could be identified And if, in a second step, it was also possible toidentify the close relatives of these index persons, the relatives could undergo atesting procedure, and in case they also showed the same genetic predisposition,measures could take place preventing the relatives from falling ill The costs of thispreventive personalized medicine vary according to the testing procedure Yet theoverall cost-benefit analysis shows that its efficiency depends mainly on the con-dition that it is possible to identify more than one relative in average This leads tothe first question whether those suffering from the particular variant of colorectalcancer can be subject to the obligation to undergo testing.28The second question isunder what circumstances they might be obliged to disclose information about thenames of their relatives.29And the third question is whether these relatives have aright to not be informed, a right to ignorance, or a right not to know about theirgenetic predisposition.30 All three questions are highly relevant but sometimesdifficult to answer from a legal point of view, and they might gain more attention

in the foreseeable future

As far as further research is concerned, the information collected in the course ofmedical treatments has to be stored in order to allow for new examinations in thefuture as we have to assume that our knowledge will keep on increasing Both theright to research31and the right to privacy32have to be considered in order to shape

a consistent, open, and appropriate legal basis for the so-called biobanks

The challenges can be summarized by a quotation taken from a report for theGerman Parliament: “One question for politics and society is whether the basicconditions shaped by existing law are sufficient to ensure the protection and at thesame time the appropriate use of what are extremely personal data stored inbiobanks The objective would have to be both not to endanger the protection ofthe donors’ samples and data, while at the same time providing the opportunity for

27 The case study is not yet published.

28 The answer is, presumably in all jurisdictions, clearly no, but it might come under discussion in the future (see §§ 8, 9 of Genetic Diagnostic Act for the current legal situation in Germany).

29 Again, under the existing rules in most countries, and especially in Germany, this possibility has

to be denied; see §§ 10 par 3 s 4, 11 par 3 of Genetic Diagnostic Act and for more details, e.g., Wollenschla¨ger ( 2013 ), p 161.

30 Chadwick et al ( 2014 ), Juth, ( 2014 ), pp 38–52.

31 Legally protected under Art 13 ECHR.

32 Legally protected under Art 8 ECHR; see for example CJEU, Case C-131/12 Google Spain, Judgment of 13.5.2014, ECLI:EU:C:2014:317; CJEU, Case C-291/12 Schwarz, Judgment of 17.10.2013, ECLI:EU:C:2013:670.

the optimal exploitation of these materials and data in terms of their ‘ethicallysound’ use.”33

Let me resume my observations in the following very preliminary way: ized medicine will raise new legal questions or will, at least, shed new light on thosequestions that are generally relevant for the provision of health care At this stage ofour knowledge, it is not easy to come to clear results We still have to understandand to identify the legal implications of personalized medicine and its possiblemeaning for the development of any legal order This appears to be of little help.Yet it is a first and necessary step for further research And research is, to aconsiderable extent, the art to ask the right questions

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Socio-Legal Disputes and Possible

Solutions

Nada Bodiroga-Vukobrat and Hana Horak

Abstract We are living in an era of epic transformation and advancement ofmedical science and technology, which allows us to gather comprehensive infor-mation about a person’s health and predict and even prevent a disease The focus onpersonalized or individualized medicine presents new challenges, not only in thefields of medical sciences, biotechnology, and nanotechnology but also in the fields

of social law and economy, where the consequences of medical activities aremanifested The existence of technically available and possible methods of diag-nostic and treatment raises the question whether there could be a constitutionallyguaranteed fundamental right of access to them What consequences would theintroduction of personalized medicine in compulsory health insurance systemshave? Is it possible, would it destruct or reconstruct the essential features ofcompulsory health insurance? These are just some of the issues this paper aims toaddress

Human life and health enjoy the highest constitutional legal status, and variousfacets of their protection are guaranteed and regulated in practically every sphere oflaw, particularly social, medical, and criminal laws We are living in an era of epictransformation and advancement of medical science and technology, which allows

us to gather comprehensive information about a person’s health and predict and

Professor Nada Bodiroga-Vukobrat Ph.D., Head of Department of EU Public Law, Faculty of Law, University of Rijeka, Rijeka, Croatia.

Professor Hana Horak, Ph.D., Head of Department of Law, University of Zagreb Faculty of Economics and Business, University of Zagren, Zagreb, Croatia.

© Springer International Publishing Switzerland 2016

N Bodiroga-Vukobrat et al (eds.), Personalized Medicine, Europeanization and

Globalization 2, DOI 10.1007/978-3-319-39349-0_3

31

even prevent a disease, without ever giving it a chance to show its symptoms.Health information is a strong currency But it is also a liability.

It seems that the existing regulatory patterns and solutions for the protection ofprivacy and personality rights of patients are no longer satisfactory Traditionaldivision, where public law provisions lay the foundations for private law regulation

of patients’ rights, fades away in the face of new challenges There is no cleardistinction of competence: some protected values are subject to both private andpublic law regulation, and there is no shortage of theoretical disputes about therelation between public and private laws in this context.1

It is generally accepted that the principle of protection of patients’ privacyincludes the right to confidentiality and privacy of information regarding healthcondition, family circumstances, course of treatment and prognosis, as well as allother pertinent information In order to be able to provide the best quality oftreatment, a doctor needs to obtain a lot of personal and sensitive informationfrom the patient This in turn necessitates a complete trust of a patient in confiden-tiality and protection of all the information, which he/she voluntarily communicates

to a physician of his/her choice

But is this information truly susceptible to full protection? What about the rights

of other subjects, such as family members, insurance companies, or employers, whoare directly or indirectly affected by the patient’s health record? The question is,under which conditions and circumstances should the information about a person’shealth condition be made available, or even must be revealed? A bulletproofprotection of personal health data and patient’s personality rights is a necessity,but even the hardest armor is not impenetrable

The right of personality denotes the totality of psycho-social state, i.e., mines one’s personality or identity, as well as the degree of that personality Inobjective terms, right of personality is defined as a set of norms of legal-ethicalorder regulating the right of each legal subject to expression and development ofhis/her own personality, in accordance with the degree of psycho-social develop-ment Subjective definition of the right of personality describes it as the right of aparticular legal subject to demand and achieve respect and development of his/herown personality in accordance with the degree of the psycho-social development.2This request is directed to everyone, including the state

deter-General right of personality includes the right to know, and also the right not toknow one’s own genetic constitution, or “Everyone has an indefeasible right toknow one’s own genes; but he must also have an equal right not to know them.”3When we take the right of personality as our starting point for the protection ofpatients’ rights, we immediately stumble upon the notion of personalized and/orindividual medicine, which has become the buzzword in the recent years Here,everything we have postulated so far about the protection of the right of personality

1 Radolovic´ ( 2006 ), p 134; Dulcˇic´ and Bodiroga-Vukobrat ( 2008 ), p 372.

2 Radolovic´ ( 2006 ), p 133.

3 Authors ’ translation from German, see Damm ( 2009 ), pp 303 and 312.

is tested It becomes questionable whether personal health information is truly one’sown to reveal, hide, or give access to because it almost always involves healthinformation about blood relatives as well, meaning that their rights and interests are

at stake too

This paper is not about confidentiality of health information It is not about theprotection of personality rights of patients either or about legal and ethical conun-drums in connection with predictive and preventive modern medical technologies

It is about a combination of all of these issues, and more

Scientists who analyze social, legal, economic, and ethical issues encounterextreme demographic changes, which can exhort a dramatic pressure on socialsecurity systems, especially the health care system

Multiple questions arise in the context of personalized medicine

Personalized, stratified, individualized or even P4 medicine (personalized, tive, preventive, and participatory) are just some of the most commonly used terms

predic-in literature, describpredic-ing the same concept.4

Personalized medicine is basically about a comprehensive doctor–patient tion based on individual genome-oriented diagnosis (thousands of cell-based pro-cesses) and treatment, specific customized drug design, and, ultimately, targeteddrug delivery Or, as Niederlag et al.5 define it, personalized medicine meansoptimized, patient-based medicine/health care, which includes individualized diag-nostic (predict and prevent), especially obtaining information about individualdisease risk based on genetic biomarkers (individual prediction) and, in connectiontherewith, creation of preventive instruments (disease prevention), individualizeddrug treatment, individualized autologous cell therapy, patient model-based therapy

rela-in the operatrela-ing room, electronic patient records, rela-individual care of patients rela-in theirhome environment with the use of technical systems and services We agree withthese authors, but special attention should also be given to important issues of dataprocessing, or the so-called “Big Data.”

The objective of individualized, personalized, or stratified medicine is toenhance and raise efficiency of medical treatment through modern diagnostic pro-cedures and reduce undesired side effects and costs of treatment.6 Targeted orpersonalized medicine reduces drug consumption and at the same time has asignificant impact on overall health costs

4 For various definitions of these terms, see, e.g., Radder et al ( 2014 ), Bottinger ( 2007 ), Niederlag

et al ( 2010 ), Qattan et al ( 2012 ), Pavelic´ et al ( 2015 ), and Taupitz ( 2011 ) and references contained therein.

5 Niederlag et al ( 2010 ), p 776.

6 Kroemer ( 2012 ), p 12.