Biorepository Regulatory Frameworks-Building Parallel Resources

7232019 Biorepository Regulatory Frameworks-Building Parallel Resources

httpslidepdfcomreaderfullbiorepository-regulatory-frameworks-building-parallel-resources 16

Biorepository Regulatory Frameworks Building Parallel ResourcesThat Both Promote Scienti1047297c Investigation and Protect HumanSubjectsGyo rgy Marko-Varga dagger Dagger sect Mark S Baker∥ Emily S Bojaperp Henry Rodriguezperp

and Thomas E Fehnigerdagger Dagger

daggerCenter of Excellence in Biological and Medical Mass Spectrometry Lund University BMC D13 Klinikgatan 32 22100 LundSwedenDaggerClinical Protein Science amp Imaging Biomedical Center Department of Biomedical Engineering Lund University BMC D13 22184Lund SwedensectFirst Department of Surgery Tokyo Medical University 6-7-1 Nishishinjiku Shinjiku-ku Tokyo 160-0023 Japan∥ Australian School of Advanced Medicine Macquarie University 2 Technology Place Sydney New South Wales 2109 AustraliaperpOffice of Cancer Clinical Proteomics Research Center for Strategic Scienti1047297c Initiatives National Cancer Institute National

Institutes of Health 31 Center Drive MS 2580 Bethesda Maryland 20892 United States

ABSTRACT Clinical samples contained in biorepositoriesrepresent an important resource for investigating the many factors that drive human biology The biological and chemicalmarkers contained in clinical samples provide importantmeasures of health and disease that when combined withsuch medical evaluation data can aid in decision making by physicians Nearly all disciplines in medicine and every ldquoomicrdquo

depend upon the readouts obtained from such samples whether the measured analyte is a gene a protein a lipid or ametabolite There are many steps in sample processingstorage and management that need to understood by theresearchers who utilize biorepositories in their own work

These include not only the preservation of the desired analytesin the sample but also good understanding of the moral andlegal framework required for subject protection irrespective of

where the samples have been collected Today there is a greatdeal of eff ort in the community to align and standardize boththe methodology of sample collection and storage performedin diff erent locations and the necessary frameworks of subject protection including informed consent and institutional review of the studies being performed There is a growing trend in developing biorepositories around the focus of large population-basedstudies that address both active and silent nonsymptomatic disease Logistically these studies generate large numbers of clinicalsamples and practically place increasing demand upon health care systems to provide uniform sample handling processingstorage and documentation of both the sample and the subject as well to ensure that safeguards exist to protect the rights of thestudy subjects for deciding upon the fates of their samples Currently the authority to regulate the entire scope of biorepository usage exists as national practice in law in only a few countries Such legal protection is a necessary component within theframework of biorepositories both now and in the future In this brief overview we provide practical information to the potential

users of biorepositories about some of the current developments in both the methodology of sample acquisition and in theregulatory environment governing their use

KEYWORDS biobank regulatory ethics LIMS

1 SO YOU WANT TO USE SAMPLES FROM THEBIOBANK

Modern medicinal practice relies on a variety of measurementsto aid and support the clinical assessment of individual patientsClinical samples are often utilized to provide point descriptionsof the concentrations of speci1047297c analytes that re1047298ect abnormal

clinical conditions and which act as markers for further follow-

up evaluation The assembly of such samples into stores of

ordered collections provides the framework of modern

Received May 13 2014Published October 3 2014

Perspective

pubsacsorgjpr

copy 2014 American Chemical Society 5319 dxdoiorg101021pr500475q | J Proteome Res 2014 13 5319minus5324



biobanking and biorepository strategy The samples stored in biobanks have many forms from tissue to blood and providemany diff erent levels of biological index from genes to proteinsand from histopathology biopsies to singular cells Such

biobanks are invaluable resources for assessing disease inpopulations of subjects presenting with diff ering forms of pathology genetic backgrounds and environmental exposures

Biomedical studies today are often designed to describe thecomparative features that distinguish individuals groups andpopulations from one another whether by age gender genetic

background environmental exposure healthy versus diseasedor treated versus untreated To achieve the statistical power toobserve such diff erences it is often seen that the ldquonrdquo numbers of individual measurements needed for such studies are quitelarge This then becomes a problem for the investigation teamto 1047297nd and identify these large sample numbers needed forsound statistical methods of comparison Most investigators donot have direct access to large holdings of patient materialsunless their institutions have established such holdings as

biobanked samples often in frozen storage At this point most would agree that the most difficult hurdle to overcome is to try to identify individual samples within the biobank with the

correct phenotype for population-based comparisons Theapparent solution of 1047297nding and being given access to suchholdings seemingly solved the problem of these everyday investigations But does it really Overcoming the problem of sample group size is only one of the many caveats in analyzingstored samples that you need to be concerned with Theaverage investigator may have good experience in assay development and a good understanding of the quality controlof sample integrity standardization in sample preparationuniform storage conditions minimizing freezing and thawingand the eff ect of long-term storage on analyte 1047297tness formeasurement However the average investigator is not very

well versed on the activity of creating and maintaining biobanksor the legal and ethical dependencies upon informed consent

needed to use such singular samples

2 USING BIOREPOSITORIES TODAY

Today many millions of clinical samples are acquired every day for use in companion diagnostic and prognostic tests thatsupport every level of clinical decision making Some of thesesamples are placed into storage facilities known as biobanks foruse in future medical research projects that measure thequantitative and qualitative indices of gene and proteinexpression associated with disease processes1 2 The samplescontained in such biobanks are unique in that they represent agiven speci1047297c subject but also because the sample itself represents a speci1047297c cross-sectional time frame of lifecomposed in total of all the products of cells and the

biochemical constituents of the exact biological processes that were ongoing at the time the sample was obtained Modernhealthcare is developing new strategies to treat disease that arenot only more eff ective but also more cost-saving A part of thisstrategy is being directed to the establishment of large-scale

biobank repositories both locally and in National programs of directed research Worldwide it is estimated that over one

billion clinical samples are assembled and stored in such samplecollections throughout the world3 Depending on the purposeof the study and the permissions given by the subject for futureuse of the samples the samples may be stored for short-term orlong-term study Often the samples also can be registered intodata sets that provide information about the demographic

characteristics of the subject such as age gender and clinicalphenotype

When Time magazine in 2009 named Biobanking as one of the ldquo10 Ideas Changing the World Right Now rdquo they used the

banking metaphor to announce ldquoRelax itrsquos not your money they rsquore after Itrsquos your bloodrdquo in ldquoan eff ort to establish the USrsquos1047297rst national biobank a safe house for tissue samples tumorcells DNA and yes even bloodthat would be used forresearch into new treatments for diseasesrdquo4 Substantialprogress in the process steps of biobanking has occurredsince even that time with the establishment of standardizedpractices applying modern methodology of automated samplepreparation and long-term storage facilities5minus8 Although many of the samples held in biorepositories were originally obtainedfor diagnostic purposes measuring indices of active diseasestates a new trend in healthcare activities that relates toepigenetics and epidemiology is the assembly of population-

based research biobanks for use in both prospective and futureresearch studies mapping the origins and outcomes of diseaseIn these studies samples are collected from earmarked groupsoften asymptomatic healthy subjects for special study on theeff ects of long-term environmental contact or association withspeci1047297c lifestyle eff ects such as diet and smoking These types of samples are valuable because they represent the antecedentstate of disease that in the same subjects at later time points willdevelop some state of active disease A number of countrieshave established national level Biobanks for the purposes of health surveillance studies in large populations of subjectsrepresenting both genetic and gender diversity and thein1047298uence of environment and lifestyle on disease developmentSuch National Biobank programs can be seen in SwedenUnited Kingdom Denmark United States China FinlandEstonia Japan New Zealand and Austria

Drug discovery and drug development within the pharma-ceutical industry is also heavily dependent on biobank resourcesto 1047297nd and validate targets for therapy and to validate the

expression levels of these targets in the context of diseasedtissue In this respect the new generation of personalizedmedicine (PM) therapies matching a giving drug to a givenclinical phenotype is an industrial objective with top prior-ity9minus12 The latest re1047297nement of this strategy that of precisionmedicine takes the clinical strategy to the level of individualizedtreatment plans based on genetic makeup genomic organ-ization and levels of targeted protein expression

What this boils down to is that in the drug developmentprocess the success of any given drug project is linked to1047297nding sufficient evidence of the existence and expression of apurported target in a clinical sample representing a disease statepostulated to be linked to that target Business decisions are

being supported by certain samples and more importantly the

physical integrity of those samples dependent on the processingand storage of those samples prior to analyses A large amountof activity is currently being devoted to 1047297nding ways to measuresample integrity and sample 1047297tness to ensure that studies thatare dependent on the accurate reporting of these measures areevaluated optimally This is an area that has been given specialattention by the FDA Critical Path Initiative in subsequentrecommendations from the AACR minusFDA minusNCI (AACR

American Association for Cancer Research NCI US NationalCancer Institute) Cancer Biomarkers Collaborative groupThese work 1047298ow recommendations are directed toward thedevelopment of better evaluation tools for validating bio-markers and one of these principle recommendations is the

Journal of Proteome Research Perspective

dxdoiorg101021pr500475q | J Proteome Res 2014 13 5319minus53245320



need for improved biobanking services and biospecimen quality control13

High-throughput technologies that generate global expres-sions and analyses of biological systems are expected to allow

better molecular understanding and dissemination of theseheterogeneous and complex diseases However to date suchtechnologies as global genome sequencing have shown only incomplete identi1047297cation of inherited genes associated with risk for disease14minus19Future healthcare strategy will rely heavily onunraveling the changing environment of molecular interactionsthat accompany disease development The key here is not only identifying the speci1047297c molecular interactions leading topathological change but also 1047297nding suitable drugs forinterfering with these biologies These types of future studies

will require access to hundreds if not thousands of individualsamples Such collections cannot be collected prospectively dueto logistical numbers of patients available for study Such typesof studies will also demand access to retrospective samplesstored in biorepositories

We expect that these future studies will require new understandings of the quantitative and qualitative informationcontained in well-documented epidemiologically supported

and clinically annotated clinical samples from large cohorts of patients and healthy persons that are made availa ble through

well-designed sample repositories held in biobanks6minus8

3 LEGAL FRAMEWORK REGULATES THE USE OFPATIENT SAMPLES AND PERSONAL DATA

A Google search of ldquo biobank law rdquo in summer of 2014 yieldsonly 113 000 total entries This gives an immediate under-standing of the lack of focus that the regulation of biobankinghas today globally For the individual investigator needing toutilize banked samples in collaborative studies done betweencenters or even countries it is not easy to translate localpractice into addressable levels of regulation and complianceNational level interests are being served independently by speci1047297c regulation but today there are no international treatiesin place that regulate and enforce sample collection or use Thisis a great unmet need however we see no activities on theglobal horizon currently that hold political support for adoptingsuch regulations

If we survey the 1047297eld there are basically two levels of regulatory guidelines that govern sample acquisition and use onthis planet (1) the Helsinki Accord (1975) signed by 35countries that guaranteed with prosecution subject protectionas a human right and (2) the local institution review board thatoversees all intervention studies that acquire samples in clinicalstudies Between these two levels of domain constitutional andoperational lie varying instances of national level law thatdescribe how samples can be acquired stored and used There

are additional levels of recommendation that address medicalresearch regarding human subjects such as the World Medical

Association (WMA) Declaration of Helsinki (1964) but theserecommendations have not been rati1047297ed into international law

Beyond the sample in the recent years the ethical debateregarding the use of human samples in both academic andcommercial settings has focused on de1047297ning a standard practicethat protects the interests of the donor as a basic right8920 21

The principle of ownership by any individual over one rsquos own body and any subfraction constituent thereof became widely discussed more than a decade ago These public debatesresulted in public policy changes in the process of sampleacquisition and the protection of the personal information

associated with these samples As mentioned earlier about adozen countries have adopted Biobank law relating to theacquisition storage and uses of the samples It is outside thescope of this report to compare their eff ectiveness or how and

where resulting changes in behavior have occurred withinpractices in their respective countries However we can giveexamples of two such cases of national legislation the Biobank Law enacted in Sweden in 2002 and the Human Tissue Act inthe United Kingdom in 20042223 Both of these legislationschanged the way in which human samples could be exploited orused even professionally in both private and public clinicsThese rulings had particular impact on how where and by whosamples could be stored over the long term

These rulings also aff ected the form and level of storedpersonal information that could be coupled to individualspeci1047297c samples

The Biobank Law 2002 in Sweden was the 1047297rst Europeanlegislation to require accountability for the ownership of samples that are traceable to an identi1047297able subject and whichare collected and stored for more than 2 months and acquiredat any government-supported healthcare facilities whether localor regional in their scope of primary or hospitalized care Thelegislation stipulated that all such samples were the property of the Swedish Board of National Welfare which also wasprovided guidelines for their use Of key importance to thecollection and storage were the principles of informed consent

by the donor that the donor may stipulate the purposes forusing the sample and that the donor retains the right to

withdraw their sample from the collection at any time and forany reason The law particularly impacted several levels of acquiring samples the prerequisite of obtaining informedconsent from the donor the prerequisite of obtaininginstitutional approval for all research studies and the proceduresused to obtain samples the prerequisite of deidentifyingsamples with personal information allowing direct association

with the donor and the prerequisite of showing a chain of

custody outlining what samples were being stored by locationand for what purpose the permissions for use were granted forstudy The provision of the Biobank Law requiring institutionalapproval was reinforced by the Ethics Review Act (SFS2003460) that outlined regional administrative bodies forgranting permissions for all human studies This law primarily

was implemented to protect patient safety and ensure thatsubjects were not placed at risk or detrimentally aff ected by theprocedures used in the study The Biobank Law and the EthicsReview Act were not the only legislation that impacted thecollection of samples into repositories in Sweden There werealso previously enacted directives relating to the personalinformation regarding individual subjects that could be storedin databases as well as the storage of personal information that

allowed samples to be traced directly to a given individualSecrecy Act (SFS 1980100) and the Personal Data Act (SFS1998204) In Sweden the right to privacy includes provisionsforbidding the collection of individual identities into groupregisters unless such permissions have been granted by theNational Board of Health and Welfare Regardless of the scopeof the study and irrespective of if the study concerns smallgroups or whole populations permissions for maintaining thedatabases holding individual patient records and clinicalmeasurements must be obtained In current practice most

biorepository collections in Sweden study subjects withtraceable identities failure to do so can have seriousconsequences The relative importance of providing patient





data protection within the scope of biobanking was illustrated by the experience of the LifeGene project centered at theKarolinska Institute in Stockholm This prospective study

which planned on investigating disease epidemiology andetiology in more than 250 000 healthy subjects was stopped by the Swedish Data Inspection Authority in 2011 for failure tomeet standards in the experimental design of collecting andstoring personal information as required by law The study hadnot obtained permission to store raw forms of the personal dataobtained in the study in the form it was being stored thusinfringing on the personal integrity of the subjects guaranteed

by the Swedish Data Registry Law More than 20 000 samples were already collected at the time the study was halted in 2011New legislation was approved in 2013 that provided new legalde1047297nitions of the forms of personal information allowed to beregistered in such collective studies

The second example of current best practice the UKHuman Tissue Act 2004 is likely the most comprehensivenational program due to its regulation of not only publicholdings but also private and commercial holdings of humansamples anywhere in the country On its own account the UKHuman Tissue Act 2004 was adopted in the public interest toensure that human tissue was used safely ethically and underthe rule of informed consent The Human Tissue Act created aregulatory body The Human Tissue Authority that became theoperational instrument for implementing the law This wasachieved by establishing a Code of Practice consisting of nineareas of governance applying to the public private andcommercial uses of human samples consent donation of solidorgans for transplantation post-mortem examination anatom-ical examination disposal donation of allogeneic bone marrow and peripheral blood stem cells for transplantation publicdisplay import and export and research One of the importantaspects of the Human Tissue Act was enforceability It requiresall institutions holding tissue collections to be licensed with theHuman Tissue Authority It also requires individuals to be

named as being legally responsible under penalty for theactivities performed at their respective institutions Central toall of the codes of practice was the principle of informedconsent for both present and future use of the donated samplesInteresting here was the allowance of diff erent levels of consent

being required for tissue acquired from either deceased or livingindividuals but done so under strict scheduling An area of law and ethics that is pertinent but rarely discussed is the fate of

biorepositories once they have outlived their original purposeor funding resource for continual maintenance and power

Currently within the European Union countries there is agreat deal of activity to harmonize the best practice experiencesof the member laboratories into standard practice One suchEU-funded activity is the Biobanking and Biomolecular

Resources Research Infrastructure (BBMRI) a consortium of biorepositories located in 30 countries The BBMRI currently isseen as a major resource within the biomedical community andis especially impacting the process of developing standardprotocols of sample processing and storage as community standards for present and future studies However therecommendations of the BBMRI do not have a legal standing(legal enforcement international treaty) but rather exist undera framework of collaboration agreements

The examples above indicate that there is a tremendousamount of money being spent on supporting the infrastructureof sample repositories What happens to the biobank when themoney dries up Who becomes responsible for maintaining the

chains of informed consent for continual use if the ownershipchanges Who has the authority to dispose of samples underlong-term storage What are the scienti1047297c consequences of losing rare sample types when they are destroyed There aremany other seemingly impossible questions that can beimagined in the realm of sample repository governance Weneed to begin preparing for these inevitabilities now Local level

engagement is very important here but national level interestmust also be made accountable for the structures planning forthe dismantling and inactivation of the samples held in

biorepositories

4 TECHNICAL ADVANCES IN SAMPLE PROCESSINGAID IN COMPLIANCE

We have recently provided best-practice recommendations forstandardizing the collection processing storage and quality control of samples in long-term storage5minus912

There have been noteworthy advances in sample processingand sample labeling in the past few years that have dramatically changed the format of how we store individual samples One

main achievement is in the development of stable la bels that withstand long-term deep-freezing conditions5 7 8 24minus26 Along with this advancement was also the development of 2-D barcode labels that replace the nominal personal identi1047297cationthat potentially could be used to directly identify an individualfrom the labelrsquos content The other areas of development are inthe miniaturization of sample tube size such as the 384 tubeformat plates that are the size of typical 96-well plates24 25 Anadditional advantage to the 384 tube format plates is that eachtube is individually 2-D barcoded allowing singular tubes to beassayed only once thus minimizing freezethaw artifacts25

Finally the development of the automated robotic systemsused to separate fractionate and aliquot samples in uniformsample volumes also has contributed to the establishment of

uniform biorepositories26 Another key component in buildinglarge-scale automated repositories is the use of laboratory information management systems (LIMS) that are capable of monitoring individual samples at each of the process steps interms of tracking the modular of each respective biobank sample in real time The LIMS also plays the important role of maintaining the deidenti1047297ed subjects identity throughout thelifetime of the sample Such barcoded tubes are much easier toregister and use in the analysis phase of the sample withinmeasurement experiments The LIMS systems are also a vitaltool in the expansion of international large-scale studies as they allow information to be shared as parallel versions of theoriginal whole data sets between laboratories and with less

resulting error produced in replication steps reposting theoriginal data Such measures in monitoring the milestones of sample lifetime are also very important when submittingevidence to regulatory agencies such as the FDA in applicationsfor the approval of new clinical assays Not all LIMS systemsare capable of producing the same level of readouts or forautomatically accepting independently collected forms of datafrom for example diff erent types of instrument platformsThese incompatibilities will need to be addressed by both the

biorepository and the instrument manufacturers to fully integrate data acquisition Common data formats are beingrecommended and adopted that should provide some solutionto these data acquisitions





5 LARGE METADATA STUDIES UTILIZE BIOBANKS

Thousands if not millions of samples will be collected andstored over the next decade in biorepositories As an example

we can refer to the UK Biobank studies that recruited 500 000people aged between 40 and 69 years from 2006 to 2010Similar types of studies are also being conducted in Japan theUSA Sweden and China Often these studies collect valuable

information regarding the demography and health status of thesubject and even clinical performance measurements includingimaging Together these data sets provide both complementary and de1047297ning descriptions of the sample within the context of the whole subject under evaluation Thus we approach thelevel of systems biology that was predicted a decade agoallowing molecular structural and functional measurement of exact timeframes of individual presentations of health anddisease

So where will archived samples play a role in the future Archived samples will most assuredly play a major role in thediscovery of new biomarkers and new diagnostic end pointsBoth commercial and academic enterprises are investing in and

developing new approaches to improve on the success rate of the discovery process Although most targets of drugs areproteins we have less understanding of the content andfunction of the human proteome than the human genome Weidenti1047297ed all of the genes in the human genome years ago buthave yet to identify the protein products of at least 30 of thesegenes There is considerable activity now that principally addresses this problem and which seeks to consolidate theinformation on speci1047297c DNA sequences with speci1047297c proteinidenti1047297cations Here the ENCODE initiative has over the yearsproduced an extensive DNA-sequence resource that is beingutilized by the proteomics community27 The human genomesequencing platforms including the latest generation of deep-sequencing platforms allow us to integrate new DNA sequence

data with gene mutation registries and epidemiological data onrisk factor exposure Together with other global data sets fromtranscriptomics and proteomics analyses of biobank samples

we envision that these platforms off er the possibility of providing completely new opportunities to develop treatmentparadigms and diagnostics that address common multifactordiseases of diff erent genetic and genomic backgrounds

Furthermore recent studies (The HapMap project) havedemonstrated not only that people vary by single nucleotidepolymorphisms (SNPs) but also that some individuals diff er inlarge blocks of DNA which are deleted or inserted Untilrecently the major focus was to determine how geneticpolymorphisms aff ected protein structure and function (coding

SNPs) However approaches with global analysis utilizingexpression microarrays have demonstrated that small diff er-ences in an individualrsquos DNA may aff ect disease risk by alteringthe regulation of gene expression thus modifying the amountof protein produced in cells of the body (regulatory SNPs)These disease-associated polymorphisms provide a guide topossible molecular alteration As we learn more about how these polymorphisms change the function of genes proteinscells and organs there is an opportunity to link theseobservations to make predictions in the mechanisms by

which DNA sequence alterations occurring in certainphenotypes of disease presentation provide patients withcertain outcomes and responses to therapy

6 CONCLUSIONS

The purpose and intention of this report is to provide theaverage investigator who is not an expert in biobankingpractice with some reference and understanding in the variouscomplexities in collecting storing and using samples in

biorepositories We particularly highlight the issues of ethicaluse of samples informed consent by donors of samples and the

importance of maintaining the personal integrity of the subjectdonors We remind each reader that they themselves are theresponsible persons in these studies and it is of bene1047297t tothemselves and their research teams to become functionally operative in assuring compliance with the local and higherforms of regulation directing the use of these samples Our bestadvice to both new and established investigators initiatingstudies with biorepositories is to work closely with your localinstitutional review board to outline clearly the conditions foruse accompanying the samples and to maintain a record of these agreements Biorepositories are being developed today inhigher sample numbers at higher and higher levels of sophistication covering many more subjects and speci1047297cphenotypes of clinical presentation Developing the skills to

interact with these new biorepositories is an area of study of high importance irrespective of whether the biorepository islocal or global in its activities

The ethical and legal frameworks for managing such samplecollections are in place throughout the globe Biobanks are

being developed at an ever increasing rate and our collectiveattention must be given to providing best-practice processes toensure that rights of subjects for safety consent of use andpersonal integrity are established and adhered to

AUTHOR INFORMATION

Notes

The authors declare no competing 1047297nancial interest

ACKNOWLEDGMENTS

This work was supported by grants from Mrs Berta KampradFoundation Swedish Academy of Pharmaceutical Sciences theSwedish Foundation for Strategic Research Vinnova Ingabrittamp Arne Lundbergs forskningsstiftelse and the CrafoordFoundation

ABBREVIATIONS

SNPs single nucleotide polymorphisms IRB InstitutionalReview Board LIMS Laboratory Intelligance ManagementSystems BBMRI The Biobanking and Biomolecular ResourcesResearch Infrastructure EC European Commission EU

European Union

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(1) Riegman P H J Morente M M Betsou F De Blasio PGeary P Marble Arch Int Working G Biobanking for betterhealthcare Mol Oncol 2008 2 (3) 213minus222

(2) Khleif S N Doroshow J H Hait W N AACR minusFDA minusNCICancer Biomarkers Collaborative Consensus Report advancing theuse of biomarkers in cancer drug development Clin Cancer Res 2010 16 3299minus3318

(3) Lasso R O The Ethics of Research Biobanking JAMA J Am Med Assoc 2010 304 (8) 908minus910

(4) Park A 10 Ideas Changing the World Right Now BiobanksTIME Magazine March 9 2009





(5) Malm J Fehniger T E Danmyr P Vegvari A Developmentsin biobanking workflow standardization providing sample integrity andstability J Proteomics 2013 95 38minus45

(6) Case Studies of Existing Human TissueRepositories ldquo Best Practicesrdquo For a Biospecimen Resource for the Genomic and Proteomic Era EisemanE Bloom G Brower J et al Eds RAND Corp Santa Monica CA2003 httpwwwrandorgpubsmonographsMG120

(7) Marko-Varga G Vegvari A Welinder C Lindberg H et al

Standardization and utilization of biobank resources in clinical proteinscience with examples of emerging applications J Proteome Res 2012 11 5124minus5134

(8) Baker M Biorepositories Building better biobanks Nature 486 141minus146

(9) Hewitt R E Biobanking the foundation of personalizedmedicine Curr Opin Oncol 2011 23 (1) 112minus119

(10) Margaret A Hamburg M A Collins F S The Path toPersonalized Medicine The Path to Personalized Medicine N Engl J

Med 2010 363 301minus304(11) Marko-Varga G Ogiwara A Nishimura T et al Personalized

medicine and proteomics Lessons from non-small cell lung cancer J Proteome Res 2007 6 (8) 2925minus2935

(12) Ve gva ri A Rezeli M Do me B Fehniger T E Marko-VargaG Translation Science for Targeted Personalized Medicine Treat-ments In Selected Presentations from the 2011 Sino-American Symposium

on Clinical and Translational Medicine Sanders S Ed ScienceAAAS Washington DC 2011 pp 36minus37

(13) Karsdal M A Henriksen K Leeming D J Mitchell PDuffin K Barascuk N Klickstein L Aggarwal P Nemirovskiy OByrjalsen I Qvist P Bay-Jensen A C Dam E B Madsen S HChristiansen C Biochemical markers and the FDA Critical Path how biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development

Biomarkers 2009 14 (3) 181minus202(14) Daly M J Untangling the Genetics of a Complex Disease

JAMA J Am Med Assoc 1998 280 (7) 652minus653(15) Goh K I Cusick M E Valle D Childs B Vidal M

Baraba si A L The human disease network Proc Natl Acad Sci U S A 2007 104 (21) 8685minus8690

(16) Hardy J Singleton A Genomewide Association Studies and

Human Disease N Engl J Med 2009 360 1759minus

1768(17) Hao D Wang G Yin Z Li C Cui Y Zhou M Systematiclarge-scale study of the inheritance mode of Mendelian disordersprovides new insight into human diseasome Eur J Hum Genet 2014 22 (11) 1260minus1267

(18) Kraft P David J Hunter D J Genetic Risk Prediction Are We There Yet N Engl J Med 2009 360 1701minus1703

(19) Dewey F E Grove M E Pan C Goldstein B A Bernstein J A Chaib H Merker J D Goldfeder R L Enns G M David SP Pakdaman N Ormond K E Caleshu C Kingham K Klein TE Whirl-Carrillo M Sakamoto K Wheeler M T Butte A JFord J M Boxer L Ioannidis J P Yeung A C Altman R B Assimes T L Snyder M Ashley E A Quertermous T Clinicalinterpretation and implications of wholegenome sequencing JAMA J

Am Med Assoc 2014 311 (10) 1035minus1045(20) Lasso R O The Ethics of Research Biobanking JAMA J Am

Med Assoc 2010 304 (8) 908minus

910(21) Simenon-Dubach D Perren A Better provenance for biobank

samples Nature 2011 475 (7357) 454minus455(22) Human Tissue Act 2004 httpwwwlegislationgovukukpga

200430contents(23) Swedish Biobanks in Medical Care Act (SFS 2002297) http

w w w r i k s d a g e n s e s v D o k u m e n t - L a g a r L a g a r SvenskforfattningssamlingLag-2002297-om-biobanker-i-_sfs-2002-297

(24) Malm J Danmyr P Nilsson R Appelqvist R Ve gva ri AMarko-Varga G Blood plasma reference material a global resourcefor proteomic research J Proteome Res 2013 12 (7) 3087minus3092

(25) Malm J Ve gva ri A Rezeli M Upton P Danmyr PNilsson R Steinfelder E Marko-Varga G Large scale biobanking of

blood - the importance of high density sample processing procedures J Proteomics 2012 76 116minus124

(26) Welinder C Jonsson G Ingvar C Lundgren L et alEstablishing a Southern Swedish Malignant Melanoma OMICS and biobank clinical capability Clin Transl Med 2013 2 7

(27) ENCODE Project Consortium A users guide to theencyclopedia of DNA elements (ENCODE) PLoS Biol 2011 9 (4)e1001046





biobanking and biorepository strategy The samples stored in biobanks have many forms from tissue to blood and providemany diff erent levels of biological index from genes to proteinsand from histopathology biopsies to singular cells Such

biobanks are invaluable resources for assessing disease inpopulations of subjects presenting with diff ering forms of pathology genetic backgrounds and environmental exposures

Biomedical studies today are often designed to describe thecomparative features that distinguish individuals groups andpopulations from one another whether by age gender genetic

background environmental exposure healthy versus diseasedor treated versus untreated To achieve the statistical power toobserve such diff erences it is often seen that the ldquonrdquo numbers of individual measurements needed for such studies are quitelarge This then becomes a problem for the investigation teamto 1047297nd and identify these large sample numbers needed forsound statistical methods of comparison Most investigators donot have direct access to large holdings of patient materialsunless their institutions have established such holdings as

biobanked samples often in frozen storage At this point most would agree that the most difficult hurdle to overcome is to try to identify individual samples within the biobank with the

correct phenotype for population-based comparisons Theapparent solution of 1047297nding and being given access to suchholdings seemingly solved the problem of these everyday investigations But does it really Overcoming the problem of sample group size is only one of the many caveats in analyzingstored samples that you need to be concerned with Theaverage investigator may have good experience in assay development and a good understanding of the quality controlof sample integrity standardization in sample preparationuniform storage conditions minimizing freezing and thawingand the eff ect of long-term storage on analyte 1047297tness formeasurement However the average investigator is not very

well versed on the activity of creating and maintaining biobanksor the legal and ethical dependencies upon informed consent

needed to use such singular samples

2 USING BIOREPOSITORIES TODAY

Today many millions of clinical samples are acquired every day for use in companion diagnostic and prognostic tests thatsupport every level of clinical decision making Some of thesesamples are placed into storage facilities known as biobanks foruse in future medical research projects that measure thequantitative and qualitative indices of gene and proteinexpression associated with disease processes1 2 The samplescontained in such biobanks are unique in that they represent agiven speci1047297c subject but also because the sample itself represents a speci1047297c cross-sectional time frame of lifecomposed in total of all the products of cells and the

biochemical constituents of the exact biological processes that were ongoing at the time the sample was obtained Modernhealthcare is developing new strategies to treat disease that arenot only more eff ective but also more cost-saving A part of thisstrategy is being directed to the establishment of large-scale

biobank repositories both locally and in National programs of directed research Worldwide it is estimated that over one

billion clinical samples are assembled and stored in such samplecollections throughout the world3 Depending on the purposeof the study and the permissions given by the subject for futureuse of the samples the samples may be stored for short-term orlong-term study Often the samples also can be registered intodata sets that provide information about the demographic

characteristics of the subject such as age gender and clinicalphenotype

When Time magazine in 2009 named Biobanking as one of the ldquo10 Ideas Changing the World Right Now rdquo they used the

banking metaphor to announce ldquoRelax itrsquos not your money they rsquore after Itrsquos your bloodrdquo in ldquoan eff ort to establish the USrsquos1047297rst national biobank a safe house for tissue samples tumorcells DNA and yes even bloodthat would be used forresearch into new treatments for diseasesrdquo4 Substantialprogress in the process steps of biobanking has occurredsince even that time with the establishment of standardizedpractices applying modern methodology of automated samplepreparation and long-term storage facilities5minus8 Although many of the samples held in biorepositories were originally obtainedfor diagnostic purposes measuring indices of active diseasestates a new trend in healthcare activities that relates toepigenetics and epidemiology is the assembly of population-

based research biobanks for use in both prospective and futureresearch studies mapping the origins and outcomes of diseaseIn these studies samples are collected from earmarked groupsoften asymptomatic healthy subjects for special study on theeff ects of long-term environmental contact or association withspeci1047297c lifestyle eff ects such as diet and smoking These types of samples are valuable because they represent the antecedentstate of disease that in the same subjects at later time points willdevelop some state of active disease A number of countrieshave established national level Biobanks for the purposes of health surveillance studies in large populations of subjectsrepresenting both genetic and gender diversity and thein1047298uence of environment and lifestyle on disease developmentSuch National Biobank programs can be seen in SwedenUnited Kingdom Denmark United States China FinlandEstonia Japan New Zealand and Austria

Drug discovery and drug development within the pharma-ceutical industry is also heavily dependent on biobank resourcesto 1047297nd and validate targets for therapy and to validate the

expression levels of these targets in the context of diseasedtissue In this respect the new generation of personalizedmedicine (PM) therapies matching a giving drug to a givenclinical phenotype is an industrial objective with top prior-ity9minus12 The latest re1047297nement of this strategy that of precisionmedicine takes the clinical strategy to the level of individualizedtreatment plans based on genetic makeup genomic organ-ization and levels of targeted protein expression

What this boils down to is that in the drug developmentprocess the success of any given drug project is linked to1047297nding sufficient evidence of the existence and expression of apurported target in a clinical sample representing a disease statepostulated to be linked to that target Business decisions are

being supported by certain samples and more importantly the

physical integrity of those samples dependent on the processingand storage of those samples prior to analyses A large amountof activity is currently being devoted to 1047297nding ways to measuresample integrity and sample 1047297tness to ensure that studies thatare dependent on the accurate reporting of these measures areevaluated optimally This is an area that has been given specialattention by the FDA Critical Path Initiative in subsequentrecommendations from the AACR minusFDA minusNCI (AACR

American Association for Cancer Research NCI US NationalCancer Institute) Cancer Biomarkers Collaborative groupThese work 1047298ow recommendations are directed toward thedevelopment of better evaluation tools for validating bio-markers and one of these principle recommendations is the














































biorepositories
























6 CONCLUSIONS







AUTHOR INFORMATION

Notes


ACKNOWLEDGMENTS


ABBREVIATIONS


European Union

REFERENCES





















































































biorepositories
























6 CONCLUSIONS







AUTHOR INFORMATION

Notes


ACKNOWLEDGMENTS


ABBREVIATIONS


European Union

REFERENCES
























































biorepositories
























6 CONCLUSIONS







AUTHOR INFORMATION

Notes


ACKNOWLEDGMENTS


ABBREVIATIONS


European Union

REFERENCES























































6 CONCLUSIONS







AUTHOR INFORMATION

Notes


ACKNOWLEDGMENTS


ABBREVIATIONS


European Union

REFERENCES













































































Documents

Biorepository Regulatory Frameworks-Building Parallel Resources