Best Practices of Biobanking and Specimen Collection:
Quality Control Systems in Biobanking and Impact
on Validity of Research Results
Mark E. Sobel, MD, PhDASIP Executive Officer
http://www.asip.org/about/executive_officer.cfm1
Lunch and LearnASIP Annual Meeting at Experimental Biology 2012
April 23, 2012
Outline
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ISBER Best PracticesBiospecimen ScienceQuality Control and Proficiency TestingNCI Best PracticesHuman Biological Materials Special Ethical Considerations
Acknowledgments
Carolyn Compton, MDOffice of Biorepositories and Biospecimen Research
National Cancer InstituteNational Institutes of Health
http://biospecimens.cancer.gov/default.aspOBBR slides in this presentation have been revised
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Fay Betsou, PhDIntegrated Biobank of Luxembourg
Presentation at ASIP Annual Meeting at Experimental Biology 2011
International Society for Biological and Environmental Repositories
Second Edition: Cell Preservation Technology, Volume 6, Number 1, 2008
Third Edition: Biopreservation and BiobankingVolume 10, Number 2, 2012
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Best Practices for Repositories:Collection, Storage, Retrieval and Distribution of
Biological Materials for Research
Biospecimen Science
What is biospecimen science?Biospecimen Science is the multidisciplinary 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 composed 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.
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Biospecimen Science
Quality of human biospecimens is multifactorial and is determined by:
• 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)
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Quality Control - definition
Nestler W. Effect of Quality Control programs on the organizational structure of the hospitals. Bull. NY Acad. Med. 1976;52:157-163
Glenn GC, Hathaway TK. Effects of specimen evaporation on quality control. Am. J. Clin. Pathol. 1976;66:645-652
Calam RR. Reviewing the importance of specimen collection. J. Am. Med. Tech. 1977;39:297-302
« the operational techniques and activities that are used to satisfy quality requirements », ISO9000:2000
« confirmation through provision of objective evidence that requirements for a specific intended use or application are fulfilled », ISO9000:2000
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Integrated Quality Control Systems
Sample Processing Method Quality Control Assay
Biobank Biobank or Research Lab
QC / Validation
Method Validation / Proficiency Testing
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ISBER Proficiency Testing Program:Interlaboratory comparisons to identify problems in laboratories
and interlaboratory differences
Launched in 2011•DNA Quantification•RNA Integrity and Quantification
Plans for 2012 (to be confirmed May 2012)•Cell Viability•Tissue Histology•Tissue Antigenicity
in vivo Preanalytical Variables
- Position
- Fasting
- Smoking
- Stress
- Circadian rhythms
- Menstrual cycle
- Pregnancy
- Physical excercise
- Caffeine : - phosphodiesterase cAMP degradation
- adrenalin secretion - triglycleride lipase
lipid acids linked to albumin # of albumin-available sites
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in vitro Preanalytical Variables• Collection tubes
• shedding of components from the tube• silicones, polymeric surfactants, clot inhibitors or activators, rubber
stoppers and plastics• adsorption of serum proteins, RNA, DNA to the tube
• Anticoagulants• citrate (dilution)• heparin (binding)• EDTA (platelet clumping)
• Clotting time and time of incubation before centrifugation
• Storage conditions• RT, changes after 8h (m/z<3000)• 4°C, changes after 48h
• freeze-thaw cycles, controversy (peptide aggregation, precipitation and adsorption) 11
SPREC-01Biospecimen preanalytical code
Standard Preanalytical Coding for Biospecimens
Cancer Epidemiology Biomarkers and Prevention 2010;19:1004-1112
Ideal QC Biomarkers Ubiquitous
Measurable by widely accessible methods On/Off response
Stability :capability of a sample material to retain the initial value of a measured quantity for a defined period of time within specific limits when stored under defined conditions
ISBER BS WG, Cancer Epidemiol Biomarkers Prevention 2009;18:1017-2513
Why validate QC methods ?
• give full confidence in sample quality• use samples after a long time• provide « reference materials »• ensure validity of research results
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NCI Best Practices for Biospecimen ResourcesOffice of Biorepositories and Biospecimen Research
National Cancer InstituteNational Institutes of Health
U.S. Department of Health and Human Services
The Premise of Biospecimen Science
Quality of human biospecimens is multifactorial 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)
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 subtypes • Group patients for testing of new drugs based on their genetic
characteristics and likelihood of positive response• 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
The Role of Biospecimen Resources in 21st Century Medicine
Key Requirements for Biospecimen Resources inthe 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-based and data-driven SOPs to enable reproducible and
comparable (additive) results
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.
• 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.
Collecting/Managing Clinical Data/QA/QC
• Adhere to a written quality management system that describes QA and QC procedures.
• Maintain QA/QC training records for personnel.• Adhere to and periodically review SOPs.• Have security systems in place, including alarms and backup power.• Include a computerized inventory tracking system in the data
management plan.• Develop a facility disaster plan.• Maintain all equipment properly according to SOPs.
Collecting and
Managing Clinical
Data
Quality Assurance/
Quality Control
• 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.
Biosafety
Biosafety
Biospecimen Resource Informatics
• Assign a unique identifier (number and/or barcode) to each specimen.• Update the biospecimen resource database each time the specimen is
moved or modified.• Use informatics systems that support the linking of specimens with
associated data and protect the health information of patients.• Adhere to or initiate review of NCI Center for Bioinformatics guidelines
and tools; caBIG™ “silver-level” compatibility is recommended.
Biospecimen Resource
Informatics: Data
Management, Inventory
Control, and Tracking
Access to Biospecimens and Data
• Develop clear policies for specimen and data access.• Develop clear guidelines for sample distribution and clinical data sharing (note:
NCI Best Practices 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.
• 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.
Privacy Protection/Custodianship
• Include plans for custodianship of collected specimens and associated data in biospecimen resource protocols.
• Develop plans to handle/dispose of specimens and associated data:• At end of the budget period of the grant• At completion of the specific research objectives of the study
• Identify and disclose financial conflicts of interest.• In informed consent language, disclose that specimens may help to
develop products, tests, or discoveries that may have commercial value.
Privacy Protection
Custodianship
Types of Human Biological Materials
• Germline vs. Somatic cellGermline
•Inheritability•Implications for immediate and extended family•Implications for ethnic group•Use of “normal” tissues
Somatic cell•Acquired mutations•Use of diseased tissues•No implications for family
Types of Human Biological Materials
• Unidentifiable vs Identifiable• Unidentifiable
• Anonymous• Anonymized
• Identifiable• Coded (Linked)• Identified
Ethical PrinciplesThe Belmont Report
• Respect for persons (personal autonomy)• Beneficence• Justice
Federal Regulations• Department of Health and Human Services Common
Rule, 45 CFR 46• Food and Drug Administration: 50 CFR 56
• Institutional Review Boards• Informed consent
• OHRP: Office of Human Research Protections• HIPAA- April, 2003
• Inconsistencies between HIPAA and the Common Rule
Human Subjects Protection:Use of Human Biological Materials
• HBMs include:• Tissue samples• Blood, sputum, urine, bone marrow, etc.• Freshly obtained and archived materials
• HBMs are subject to the same regulations as human subjects directly enrolled in studies
• Therefore, informed consent and approval by an IRB may be required before using HBMs
Identifiable HBMs- The Common Rule
• Any HBM that can be identified by any one person, anywhere, is an identifiable sample
• If a sample is coded, and any investigator keeps a key to the code, the sample is identifiable
• Exception: If the recipient of the HBMs signs an agreement that there is no intent to identify the samples, the sample may be considered unidentifiable.
Definition of a Human Subject-The Common Rule
• Does NOT include:– Deceased persons (autopsy specimens)– Publicly available information– Unidentifiable (Anonymous, Anonymized) Samples
Waivers of Informed Consent-Common Rule
• Minimal risk• Respect for autonomy and the rights of the
individual• Impracticable• Notification
An IRB may grant a waiver of informed consentunder the Common Rule (not the FDA) if fourcriteria are met:
Waivers of Informed Consent-Common Rule
• Waivers are rarely granted for identified samples • Waivers are usually (but not always) granted for
collecting anonymous samples • Waivers are usually (but not always) granted for using
anonymous or anonymized samples• Waivers are occasionally granted for coded (linked)
samples:• Germline• Somatic cell
OHRP Guidance: Components of Repositories
Repository activities involve three components, each of which must satisfy certain requirements:
• collectors of tissue samples • repository storage and data management center• recipient investigators
Tissue collector
Tissue collector
Tissue collector
Repository Storageand
Data Management Center
Recipient Investigator
Recipient Investigator
Recipient Investigator
OHRP Repository Guidance
IRB ReviewInformed Consent Submittal AgreementAssurance of Compliance
IRB ReviewSample Informed Consent Certificate of ConfidentialityAssurance of Compliance
Recipient AgreementLocal Policies
Ethical Principles for the 21st Century
• Respect for persons (personal autonomy):– Informed consent– Respect for privacy and confidentiality
• Beneficence• Justice
