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3	The Role of Biospecimen Resources in 21st Century Medicine Biospecimen Resources encompassing large quantities of high-quality, clinically annotated biospecimens are needed to: Identify and validate targets for detection, diagnosis, treatment, and prevention Identify disease mechanisms Develop a molecular-based taxonomy of cancer Develop screening tests for “biomarkers” associated with certain disease sub-types of a disease Group patients based on their genetic characteristics and likelihood of positive response, for testing of new drugs Group patients based on the “biomarkers” of their disease to determine which treatment is appropriate Biospecimen resources are critical to accelerate the development of molecular-based diagnostics and therapeutics for personalized medicine
4	Key requirements for Biospecimen Resources in the Post-Genomic Age Diversity of cancer types and populations based on continual review of researcher needs Access through a timely, centralized peer-review process Ethical and privacy compliance through a chain of trust Resources provided without intellectual property restrictions Pathology and clinical annotation (including longitudinal) State-of-the-art informatics system to streamline the research production process and create in silico research capabilities Communication and outreach efforts Best practice and data-driven based SOPs to enable reproducible and comparable (additive) results
5	NCI Biospecimen Issues Heterogeneity in practices among NCI-supported programs has led to a lack of: Common biospecimen resource SOPs, standards, and management principles Common definitions Computerized, common access to information on specimens and cases Common approaches to ethical, legal, and policy issues
6	NCI’s Biospecimen Activities
7	First-Generation Guidelines Objective: Unify policies and procedures for NCI-supported biospecimen resources* *previously “biorepositories”
8	Guidelines Process Guidelines were reviewed prior to publication by: NIH Office of Science Policy DHHS Office for Human Research Protections NIH Office of Intramural Research NIH Office of Extramural Research NIH Office of Technology Transfer NIH Office of the General Council Guidelines were published in the Federal Register: Open public comment period, April-July 3, 2006 Approximately 50 comments were received, on topics including: Biospecimen resource economics Informed consent requirements Definition clarity when designating biospecimen resources affected by the Guidelines
9	First-Generation Guidelines Overview First-Generation Guidelines include recommendations for: Common best practices for research biospecimen resources Quality assurance and quality control programs Implementation of enabling informatics systems Addressing ethical, legal, and policy issues Establishing reporting mechanisms Providing administration and management structure (creation of the OBBR)
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11	What Is a Biospecimen Resource? *
12	Specimen Collection, Processing, Storage, Retrieval, and Dissemination Handle specimens as appropriate for specimen type and study design Minimize collection/processing time as appropriate Develop a comprehensive Quality Management System, to include SOPs to document all protocols and a training program for all appropriate personnel Annotate specimens with key collection, processing, and storage data Monitor specimen inventory with a tracking system Store specimens in a stabilized state without unnecessary thawing/refreezing. Dispose of specimens according to clear rules Review and document storage equipment performance on a regular basis Follow specimen-appropriate biosafety, packaging, and shipping procedures Train personnel to adhere to specimen shipping regulations. Control and monitor required shipping temperature
13	Collecting/Managing Clinical Data/QA/QC Collect and store relevant clinical and epidemiologic data associated with a specimen, including longitudinal data, if applicable.* Use an informatics system that tracks all aspects of collection, processing and distribution Comply with applicable privacy rules and human subjects regulations
14	Biosafety/Biospecimen Resource Informatics Assume that all specimens are potentially infectious – provide appropriate vaccines, e.g., hepatitis Adhere to governmental and accrediting agency requirements Identify and address biosafety risks Record exposure incidents and provide personnel with appropriate treatment Establish indemnification agreements with users of biospecimens (except where prohibited by law) Develop additional policies and procedures as appropriate for chemical, electrical, fire, occupational, and radiological safety
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16	Informed Consent Use a sample consent template Consider allowing research participants to specify the types of research for which their specimens may be used Develop policies for handling specimens for which consent has been withdrawn Develop clear policies for specimen and data access Develop policies for obtaining consent for studies involving children Consider special Food & Drug Administration regulations Establish and document transparent policies to govern the retention of records and specimens
17	Access to Biospecimens and Data Develop clear guidelines for sample distribution and clinical data sharing (note: the Guidelines state that protocol-specific requirements should be met before other access is considered) Ensure that investigators have timely, equitable, and appropriate access, without undue administrative burden Charge for samples only to recover costs If a biospecimen resource needs to close, announce the availability of specimens for transfer Restrict access to subjects’ identities and medical, genetic, social, and personal histories via data access system with defined privilege levels
18	Privacy Protection/Custodianship Protect the privacy of information and follow applicable regulations Follow documented policies on employee access to data or specimens Provide levels of security that are appropriate to the type of biospecimen resource
19	Intellectual Property For the transfer of materials, use a Material Transfer Agreement (MTA) or similar formal agreement Biospecimen resource staff are not considered inventors within the meaning of U.S. patent law and have no inherent rights to future intellectual property MTAs should specify that research data obtained through the use of biospecimen resource specimens and/or associated data should be made available to the research community
20	Revising the Guidelines: Public Comments – Major Issues Technical and operational guidelines perceived to be beyond the capability of smaller biospecimen resources, in terms of both technical expertise and cost of compliance. Informatics requirements, particularly NCI’s caBIG^TM, that have not yet been fully developed and available for widespread adoption. Informed consent recommendations that went beyond current regulations and were not clearly related to biospecimen collection and usage. That overall the Guidelines were too prescriptive and difficult for smaller biospecimen resources to adopt.
21	Guidelines: Next Steps
22	NCI Advancement Towards Second-Generation Guidelines Office of Biorepositories and Biospecimen Research http://biospecimens.cancer.gov
23	"Functions and Priorities" Functions and Priorities: Serve as a resource for NCI initiatives with biospecimen components, such as The Cancer Genome Atlas and Clinical Proteomic Technologies for Cancer Program Continue to work with the NCI Biorepository Coordinating Committee, a group comprised of senior program managers who oversee biospecimen resource-related programs across NCI intramural and extramural divisions, to develop NCI biospecimen policies and procedures Initiate a Biospecimen Research Network Develop responses to comments on the First-Generation Guidelines, and plan for additional versions based on biospecimen research results Develop an educational program to inform NCI programs about the Guidelines and other biospecimen issues In the longer term, develop biospecimen resource evaluation, accreditation, and training programs
24	Biospecimen Science * What is Biospecimen Science? The multi-disciplinary field of study responsible for establishing tested and proven biospecimen resource-related procedures based on experimentation in the areas of specimen collection, processing, shipping, and storage Why is it needed? Biospecimens are comprised of active and reactive living cells or cell products, making them highly complex The collection, handling, and storage process can profoundly alter the molecular profile and quality of biospecimens Such alterations, though artificial, can be misinterpreted as disease-related or disease specific High degrees of sensitivity and specificity in new molecular techniques raise the bar for analyte (specimen) data and quality
25	The Premise of Biospecimen Science Quality is not a generic concept Quality of human biospecimens is multi-factorial and is determined by the: Type of specimen: (Normal tissue, Tumor tissue, Serum, Plasma) Physical state of the specimen Amount and type of specimen characterization data Amount and type of quality control exercised Amount and type of clinical data Permitted use of the specimen The analysis to be performed and the biomolecules targeted by the analysis The goal of the research (application of the data)
26	Variables Affecting the Molecular Integrity of Biospecimens Antibiotics and other drugs Anesthesia Type Duration Arterial clamp time Blood pressure variations Intra-op Blood loss Blood administration Fluid Administration
27	Pathway to Scientifically Validated Biorepository Practices
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29	Role of Automation in Biorepositories Excerpt from the OBBR strategic plan: Outreach to Industrial and Academic Developers of New Technologies In order for the NCI biorepository guidelines, both first and succeeding generations, to be effective, and for the Biospecimen Research Network’s work to be relevant, it is critical for the OBBR to enter into partnerships with companies and other entities that are developing new technologies. These technologies could involve, for example, new techniques for tissue fixation, new blood collection tubes with special additives, or new storage technologies. Examples: explore dry state storage; alternate methods to collect specimens for DNA (e.g. saliva); automation.
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31	Automation in Biorepositories Current examples: DNA extraction – Gentra AutoPure, Qiagen EZ-10, M-48 Aliquoting – Tecan Obstacles (e.g. to using automated storage systems): Diversity of sample types Diversity of storage vessels – cryovials, variety of test tubes, microplates Challenges/Opportunities: Growing collections of frozen samples are stretching budgets & space. Need to develop automation strategies for prospective collections based on pilot studies.
32	OBBR Communications to Stakeholders