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Biorepository Regulatory Frameworks: Building Parallel Resources that both Promote Scientific Investigation and Protect Human Subjects György Marko-Varga, Mark S. Baker, Emily S. Boja, Henry Rodriguez, and Thomas E. Fehniger J. Proteome Res., Just Accepted Manuscript • DOI: 10.1021/pr500475q • Publication Date (Web): 03 Oct 2014 Downloaded from http://pubs.acs.org on October 26, 2014

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Journal of Proteome Research

Biorepository Regulatory Frameworks: Building Parallel Resources that both Promote Scientific Investigation and Protect Human Subjects

György Marko-Varga1,2,5, Mark S. Baker2, Emily S. Boja3, Henry Rodriguez3, Thomas E. Fehniger1,

1 Center of Excellence in Biological and Medical Mass Spectrometry, BMC D13, Lund University, 22100 Lund, Sweden; 2Clinical Protein Science & Imaging, Biomedical Center, Dept. of Measurement Technology and Industrial Electrical Engineering, Lund University, BMC C13, 221 84 Lund, Sweden 3 Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia 4 Office of Cancer Clinical Proteomics Research, Center for Strategic Scientific Initiatives, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Email: 5 First Department of Surgery, Tokyo Medical University, 6-7-1 Nishishinjiku Shinjiku-ku, Tokyo, 160-0023 Japan KEYWORDS Biobank, regulatory, ethics, LIMS, [email protected] [email protected] [email protected]; [email protected] [email protected]

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ABSTRACT

Clinical samples contained in biorepositories represent an important resource for investigating the many factors that drive human biology. The biological and chemical markers contained in clinical samples provide important measures of health and disease that when combined with such medical evaluation data can aid in decision making by physicians. Nearly all disciplines in medicine and every "omic" depends upon the readouts obtained from such samples, whether the measured analyte is a gene, a protein, a lipid, or a metabolite. There are many steps in sample processing, storage, and management that need to understood by the researchers who utilize biorepositories in their own work. These include not only the preservation of the desired analytes in the sample, but also good understanding of the moral and legal framework required for subject protection irrespective of where the samples have been collected. Today there is a great deal of effort in the community to align and standardize both the methodology of sample collection and storage performed in different 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 based studies that address both active and silent non-symptomatic disease. Logistically these studies generate large numbers of clinical samples, and practically, place increasing demand upon health care systems to provide uniform sample handling, processing, and storage, documentation of both the sample and the subject as well as insuring that safegaurds exist to protect the rights of teh study 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 the framework 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 the regulatory environment governing their use.


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1. SO YOU WANT TO USE SAMPLES FROM THE BIOBANK

Modern medicinal practice relies on a variety of measurements to aid and support the clinical assessment of individual patients. Clinical samples are often utilized to provide point descriptions of the concentrations of specific analytes that reflect abnormal clinical conditions and which act as markers for further follow-up evaluation. The assembly of such samples into stores of ordered collections provide the frame work of modern biobanking and biorepository strategy. The samples stored in biobanks have many forms, from tissue to blood, and provide many different levels of biological index, from genes to proteins, and from histopathogy biopsies to singular cells. Such biobanks are invaluable resources for assessing disease in populations of subjects presenting with differing forms of pathology, genetic backgrounds, and environmental exposures.

Biomedical studies today are often designed to describe the comparative features that distinguish individuals, groups, and populations from one another whether by age, gender, genetic background, environmental exposure, healthy versus diseased, or treated versus unteated, In order to achieve the statistical power to observe such differences it is often seen that the "n" numbers of individual measurements needed for such studies are quite large. This then becomes a problem for the investigation team to find and identify these large sample numbers needed for sound statistical methods of comparison. Most investigators do not have direct access to large holdings of patient materials unless 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. The apparent solution of finding and being given access to such holdings 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 analyzing stored samples that you need to be concerned with. The average investigator may have good experience in assay development and a good understanding of the quality control of sample integrity, standardization in sample preparation, uniform storage conditions minimizing freezing and thawing, and the effect of long term storage on analyte fitness for measurement. However, the average investigator is not very well versed on the activity of creating and maintaining biobanks, nor the legal and ethical dependencies upon informed consent needed to use such singular samples.


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2. USING BIOREPOSITORIES TODAY

Today, many millions of clinical samples are acquired every day for use in companion diagnostic and prognostic tests that support every level of clinical decision making. Some of these samples are placed into storage facilities known as biobanks for use in future medical research projects that measure the quantitative and qualitative indices of gene and protein expression associated with disease processes.(1-2) The samples contained in such biobanks are unique in that they represent a given specific subject but also because the sample itself represents a specific cross-sectional time frame of life, composed 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. Modern healthcare is developing new strategies to treat disease that are both more effective, but also more cost saving. A part of this strategy 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 sample collections throughout the world (3). Depending on the purpose of the study, and the permissions given by the subject for future use of the samples, the samples may be stored for short term or long term study. Often the samples also can be registered into datasets that provide information about the demographic characteristics of the subject such as age, gender, and clinical phenotype. When Time magazine in 2009 named Biobanking as one of the “10 Ideas Changing the World Right Now” they used the banking metaphor to announce “relax - it's not your money they're after - it's your blood – in an effort to establish the US.'s first national biobank - a safe house for tissue samples, tumor cells, DNA and, yes, even blood, that would be used for research into new treatments for diseases” (4). Substantial progress in the process steps of biobanking have occurred since even that time, with the establishment of standardized practices applying modern methodology of automated sample preparation and long term storage facilities (5-8) Although many of samples held in biorepositories were originally obtained for diagnostic purposes measuring indices of active disease states, a new trend in healthcare activities, that relates to epigenetics and epidemiology, is the assembly of population-based research biobanks for use in both prospective and future research studies mapping the origins and outcomes of disease. In these studies samples are collected from earmarked groups, often asymptomatic healthy subjects, for special study on the effects of long term environmental contact, or association


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with specific lifestyle effects such as diet and smoking. These types of samples are valuable because they represent the antecedent state of disease that in the same subjects at later time points will develop some state of active disease. A number of countries have established National level Biobanks for the purposes of health surveillance studies in large populations of subjects representing both genetic and gender diversity, and the influence of environment and lifestyle on disease development. Such National Biobank programs can be seen in Sweden, The United Kingdom, Denmark, The United States, China, Finland, Estonia, Japan, New Zealand, and Austria.

Drug discovery and drug development within the pharmaceutical industry is also heavily dependent on biobank resources in order to find and validate targets for therapy and to validate the expression levels of these targets in the context of diseased tissue. In this respect, the new generation of Personalized Medicine (PM) therapies matching a giving drug to a given clinical phenotype, is an industrial objective with top priority (9-12). The latest refinement of this strategy, that of Precision Medicine, takes the clinical strategy to the level of individualized treatment plans based upon genetic makeup, genomic organisation, and levels of targeted protein expression.

What this boils down to is that in the drug development process, the success of any given drug project is linked to finding sufficient evidence for the existence and expression of a purported target in a clinical sample representing a disease state postulated 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 processing, and storage of those samples prior to analyses. A large amount of activity is currently being devoted to finding ways to measure sample integrity and sample fitness in order to insure that studies that are dependent upon the accurate reporting of these measures are evaluated optimally. This is especially an area that has been given special attention by the FDA Critical Path Initiative, in subsequent recommendations fromthe AACR–FDA–NCI (AACR, American Association for Cancer Research; NCI, US National Cancer Institute) Cancer Biomarkers Collaborative group. These workflow recommendations are directed towards the development of better evaluation tools for validating biomarkers and one of these principle recommendations is in the need for improved biobanking services and biospecimen quality control (13). High-throughput technologies that generates global expressions and analyses of biological systems are expected to allow better molecular understanding and dissemination of these heterogeneous and complex diseases. However to date, such technologies as global genome


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sequencing have shown only incomplete identification of inherited genes associated with risk for disease (18, 19). Future healthcare strategy will rely heavily on unraveling the changing environment of molecular interactions that accompany disease development. Key here is identifying not only the specific molecular interactions leading to pathological change but also finding suitable drugs for interfering with these biology's. These types of future studies will require the access to hundreds if not thousands of individual samples. Such collections cannot be collected prospectively due to logistical numbers of patients available for study. Such types of studies will also demand the access to retrospective samples stored in biorepositories. We expect that these future studies will require new understandings of the quantitative and qualitative information contained in well-documented, epidemiologically supported, and clinically annotated clinical samples from large cohorts of patients and healthy persons, that are made available through well designed sample repositories held in biobanks (6,7,8,).

3. LEGAL FRAMEWORK REGULATE THE USE OF PATIENT SAMPLES AND PERSONAL DATA

A Google search of "Biobank Law" in summer of 2014 yields only 113,000 total entries. This gives an immediate understanding of the lack of focus that the regulation of biobanking has today globally. For the individual investigator needing to utilize banked samples in collaborative studies done between centers or even countries, it is not easy to translate local practice into addressable levels of regulation and compliance. National level interests are being served independently by specific regulation, but today there are no international treaties in place that regulate and enforce sample collection or use. This is a great unmet need, however we see no activities on the global horizon currently that hold political support for adopting such regulations.

If we survey the field, there are basically two levels of regulatory guidelines that govern sample acquisition and use on this planet: 1) The Helsinki Accord (1975) signed by 35 countries that guaranteed with prosecution subject protection as a human right. and 2) The local institution review board that oversees all intervention studies that acquire samples in clinical studies. Between these two levels of domain, constitutional and operational, lie varying instances of National level law that describe how samples can be acquired, stored, and used. There are additional levels of recommendation that address medical research


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regarding human subjects such as the World Medical Association (WMA) Declaration of Helsinki (1964) but these recommendations have not been ratified into international law.

Beyond the sample, in the recent years, the ethical debate regarding the use of human samples in both academic and commercial settings, has focused on defining a standard practice which protects the interests of the donor as a basic right (8-9 20, 21). The principle of ownership by any individual over ones own body and any sub-fraction constituent thereof became widely discussed more than a decade ago. These public debates resulted in public policy changes in the process of sample acquisition and the protection of the personal information associated with these samples. As mentioned earlier, about a dozen countries have adopted Biobank law relating to the acquisition, storage, and uses of the samples. It is outside the scope of this report to compare their effectiveness or how and where resulting changes in behavior have occurred within practices in their respective countries. However we can give examples of two such cases of national legislation the Biobank Law enacted in Sweden in 2002 and the Human Tissue Act in the United Kingdom in 2004 (22-23). Both of these legislations changed the way in which human samples could be exploited or used even professionally in both private and public clinics. These rulings had particular impact on how, where, and by who, samples could be stored over long terms. These rulings also affected the form and level of stored personal information that could be coupled individual specific samples. The Biobank Law 2002 in Sweden was the first European legislation to require accountability for the ownership of samples that are traceable to an identifiable subject and which are collected and stored for more than two months and acquired at any government supported healthcare facilities, whether local or regional in their scope of primary or hospitalized care. The legislation stipulated that all such samples were the property of the Swedish Board of National Welfare, which also was provided guidelines for their use. Of key importance to the collection and storage was the principle of informed consent by the donor, the donor may stipulate the purposes for using the sample, and that the donor retains the right to withdraw their sample from the collection at any time and for any reason. The law particularly impacted on several levels of acquiring samples: the pre-requisite of obtaining informed consent from the donor, the pre-requisite of obtaining institutional approval for all research studies and the procedures used to obtain samples, the pre-requisite of de-identifying samples 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 location and for what purpose the permissions for use were granted for study. The provision ACS Paragon Plus Environment

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of the Biobank Law requiring institutional approval was reinforced by the Ethics Review Act (SFS 2003:460) that outlined regional administrative bodies for granting permissions for all human studies. This law primarily was implemented to protect patient safety and insure that subjects were not placed at risk or detrimentally effected by the procedures used in the study. The Biobank Law and the Ethics Review Act were not the only legislation that impacted upon the collection of samples into repositories in Sweden. There were also previously enacted directives relating to the personal information regarding individual subjects that could be stored in databases, as well as the storage of personal information that allowed samples to be traced directly to a given individual Secrecy Act (SFS 1980:100) and the Personal Data Act (SFS 1998:204). In Sweden, the right to privacy includes provisions forbidding the collections of individual identities into group registers, unless such permissions have been granted by the National Board of Health and Welfare. Regardless of the scope of the study, and irrespective if the study concerns small groups or whole populations, permissions for maintaining the databases holding individual patient records and clinical measurements must be obtained. In current practice, most biorepository collections in Sweden either study subjects with traceable identities failure to do so can have serious consequences. The relative importance of providing patient data protection within the scope of biobanking was illustrated by the experience of the LifeGene project centered at the Karolinska Institute in Stockholm . This prospective study which planned on investigating disease epidemiology and etiology in more than 250,000 healthy subjects was stopped by the Swedish Data Inspection Authority in 2011 for failures to meet standards in the experimental design of collecting and storing personal information as required by law. The study had not obtained permission to store raw forms of the personal data obtained in the study in the form it was being stored, thus infringing 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 2011. New legislation was approved in 2013 that provided new legal definitions of the forms of personal information allowed to be registered in such collective studies.

The second example of current best practice, The UK Human Tissue Act 2004, is likely the most comprehensive national program due to its regulation of not only public holdings, but also private, and commercial holdings of human samples anywhere in the country. By own account, The UK Human Tissue Act 2004 was adopted in the public interest to insure that human tissue was used safely, ethically, and under the rule of informed consent. The Human Tissue Act created a regulatory body, The Human Tissue Authority that became the


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operational instrument for implementing the law. This was achieved by establishing A Code of Practice, consisting of nine areas of governance applying to the public, private, and commercial uses of human samples: Consent, Donation of solid organs for transplantation, Post-mortem examination, Anatomical examination, Disposal, Donation of allogeneic bone marrow and peripheral blood stem cells for transplantation, Public display, Import and export, Research. One of the important aspects of the The Human Tissue Act was enforceability. It required all institutions holding tissue collections to be licensed with the Human Tissue Authority. It also requires individuals to be named as being legally responsible under penalty, for the activities performed at their respective institutions. Central to all of the codes of practice was the principle of informed consent for both present and future use of the donated samples. Interesting here was the allowance of different levels of consent being required for tissue acquired from either deceased or living individuals 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 purpose and/or funding resource for continual maintenance and power.

Currently, within the European Union countries, there is a great deal of activity to harmonize the best practice experiences of the member laboratories into standard practice. One such EU funded activity is the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI), a consortium of biorepositories located in 30 countries (24). The BBMRI currently is seen as a major resource within the bio-medical community and is especially impacting on the process of developing standard protocols of sample processing and storage as community standards for present and future studies. However, the recommendations of the BBMRI do not have a legal standing (legal enforcement, international treaty) , but rather exist under a framework of collaboration agreements.

The examples above indicate that there is a tremendous amount of money being spent on supporting the infrastructure of sample repositories. What happens to the biobank when the money dries up? Who becomes responsible for maintaining the chains of informed consent for continual use if the ownership changes? Who has the authority to dispose of samples under long term storage? What are the scientific consequences of losing rare sample types when they are destroyed? There are many other seemingly impossible questions that can be imagined in the realm of sample repository governance. We need to begin preparing for these inevitabilities already now. Local level engagement is very important here but national level


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interest must also be made accountable for the structures planning for the dismantling and inactivation of the samples held in biorepositores.

4. TECHNICAL ADVANCES IN SAMPLE PROCESSING AID IN COMPLIANCE We have recently provided best practice recommendations for standarsizing the collection , processing, storage, and quality control of samples in long term storage (5-9, 12 ) . There have been noteworthy advances in sample processing and sample labeling in the last few years that have dramatically changed the format of how we store individual samples. One main achievement is in the development of stable labels that withstand long term deep freezing conditions.(5,7, 8, 25-27) Along with this advancement was also the development of 2-D bar code labels that replace the nominal personal identification that potentially could be used to directly identify an individual from the labels content. The other areas of development is in the miniaturization in sample tube size such as the 384 tube format plates that are the size of typical 96 well plates (25-26). An additional advantage to the 384 tube format plates is that each tube is individually 2-D bar coded allowing singular tubes to be assayed only once thus minimizing freeze/thaw artifacts( 26 ) Finally, development of the automated robotic systems used to separate, fractionate, and aliquot samples in uniform sample volumes also has contributed to the establishment of uniform biorepositories (27). Another key component in building large 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 in terms of tracking the modular of each respective biobank sample in real time . The LIMS also plays the important role of maintaining the de-identified subjects identity throughout the lifetime of the sample. Such bar-coded tubes are much easier to register and use in the analyses phase of the sample within measurement experiments. The LIMS systems are also a vital tool in the expansion of international large scale studies, as they allows information to be shared as parallel versions of the original whole datasets between laboratories and with resulting less error produced in replication steps re-posting the original data. Such measures in monitoring the milestones of sample lifetime are also very important when submitting evidence to regulatory agencies such as the FDA, in applications for approval of new clinical assays. Not all LIMS systems are capable of producing the same level of readouts nor for automatically accepting independently collected forms of data from, for example, different types of instrument


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platforms. These incompatibilities will need to be addressed by both the biorepository and the instrument manufactures in order to fully integrate data acquisition. Common data formats are being recommended and adopted that should provide some solution to these data acquisitions.

5. LARGE META-DATA STUDIES UTILIZE BIOBANKS Thousands if not millions of samples will be collected and stored over the next decade in biorepositories. As example we can refer to the UK Biobank studies which recruited 500,000 people aged between 40-69 years from 2006-2010. Similar types of studies are also being conducted in Japan, the USA, Sweden, and China, Often these studies collect valuable information regarding the demography and health status of the subject, and even clinical performance measurements including imaging. Together these datasets provide both complementary and defining descriptions of the sample within the context of the whole subject under evaluation. Thus we approach the level of Systems Biology that was predicted a decade ago allowing both molecular, structural, and functional measurement of exact timeframes of individual presentations of health and disease

So where will archived samples play a role in the future? Archived samples will most assuredly play a major role in the discovery of new biomarkers and new diagnostic end points. Both 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 are proteins, we have less understanding of the content and function of the human proteome than the human genome. We identified all the genes in the human genome years ago, but have yet to identify the protein products of at least 30% of these genes. There is considerable activity now that principally addresses this problem and which seeks to consolidate the information on specific DNA sequences with specific protein identifications. Here, the ENCODE initiative has over the years produced an extensive DNA-sequence resource that is being utilized by the proteomics community (28). The human genome sequencing platforms including the latest generation of deep sequencing platforms, allows us to integrate new DNA sequence data with gene mutation registries, and epidemiological data on risk factor exposure Together with other global datasets from transcriptomics and proteomics analyses of biobank samples, we envision that these platforms offer the possibility of providing completely new opportunities to develop treatment paradigms and diagnostics that address common multifactor diseases of different genetic and genomic backgrounds.


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Furthermore, recent studies (The HapMap project) have demonstrated that people vary not only by single nucleotide polymorphisms (SNPs), but that some individuals differ in large blocks of DNA, which are deleted or inserted. Until recently, the major focus was to determine how genetic polymorphisms affected protein structure and function (coding SNPs). However, approaches with global analysis utilizing expression microarrays have demonstrated that small differences in an individual’s DNA may affect disease risk by altering the regulation of gene expression, thus modifying the amount of protein produced in cells of the body (regulatory SNPs). These disease associated polymorphisms provide a guide to possible molecular alteration. As we learn more about how these polymorphisms change the function of genes, proteins, cells and organs, there is an opportunity to link these observations to make predictions in the mechanisms by which DNA sequence alterations, occurring in certain phenotypes of disease presentation, provide patients with certain outcomes and responses to therapy.

6. CONCLUSIONS The purpose and intention of this report is to provide the average investigator, who is not an expert in biobanking practice, with some reference and understanding in the various complexities in collecting, storing, and using samples in biorepositories. We particularly highlight the issues of ethical use of samples, informed consent by donors of samples, and the importance of maintaining the personal integrity of the subject donors. We remind each reader that they themselves are the responsible persons in these studies and it is of benefit to themselves and their research teams to become functionally operative in assuring compliance with the local and higher forms of regulation directing the use of these samples. Our best advice to both new and established investigators initiating studies with biorepositories is to work closely with your local institutional review board to outline clearly the conditions for use accompanying the samples and to maintain a record of these agreements. Biorepositories are being developed today in higher sample numbers at higher and higher levels of sophistication, covering many more subjects and specific phenotypes 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 is local or global in its activities. The ethical and legal frameworks for managing such sample collections are in place throughout the globe. Biobanks are being developed at an ever increasing rate and our collective attention must be given to providing best practice processes to insure that rights of subjects for safety, consent of use, and personal integrity are established and adhered to.


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7. ACKNOWLEDGEMENT AND FUNDING This work was supported by grants from Mrs. Berta Kamprad Foundation, Swedish Academy of Pharmaceutical Sciences, the Swedish Foundation for Strategic Research, Vinnova, Ingabritt & Arne Lundbergs forskningsstiftelse and the Crafoord Foundation.

8. ABBREVATIONS SNPs - Single Nucleotide polymorphisms IRB - Institutional Review Board LIMS - Laboratory Intelligance Management Systems BBMRI - The Biobanking and Biomolecular Resources Research Infrastructure, EC - European Commission EU – European Union

9. REFERENCES (1) Riegman PHJ, Morente MM, Betsou F, De Blasio P, Geary P, Marble Arch Int Working G. Biobanking for better healthcare. Mol. Oncol. 2008, 2(3), 213-222. (2) Khleif SN, Doroshow JH, Hait WN. AACR–FDA–NCI Cancer Biomarkers Collaborative Consensus Report: advancing the use of biomarkers in cancer drug development. Clin Cancer Res. 2010, 16:3299–3318. (3) Lasso, R.O., The Ethics of Research Biobanking. JAMA. 2010, 304(8):908-910. (4) Park, A. Biobanks. "Ten Ideas Changing the World Right Now." TIME Magazine. 2009, March 9 2009 (5) Malm, J., Fehniger, T. E., Danmyr, P., Vegvari, A., et al., Developments in biobanking workflow standardization providing sample integrity and stability. Journal of proteomics 2013. (6) Eiseman E, Bloom G, Brower J, et al., editors. Case studies of existing human tissue .repositories: “best practices” for a biospecimen resource for the genomic and proteomic era. Santa Monica (CA): RAND Corp.; 2003. http://www.rand.org/pubs/monographs/MG120. (7) Marko-Varga, G., Vegvari, A., Welinder, C., Lindberg, H., et al., Standardization and utilization of biobank resources in clinical protein science with examples of emerging applications. J. Proteome Res. 2012, 11, 5124-5134


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Biorepository Regulatory Frameworks: Building ... - ACS Publications

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