Biospecimen Science is the multidisciplinary field of study

Best Practices of Biobanking and
Specimen Collection:
Quality Control Systems in Biobanking and Impact
on Validity of Research Results
Lunch and Learn
ASIP Annual Meeting at Experimental Biology 2012
April 23, 2012
Mark E. Sobel, MD, PhD
ASIP Executive Officer
ISBER Best Practices
Biospecimen Science
Quality Control and Proficiency Testing
NCI Best Practices
Human Biological Materials
Special Ethical Considerations
Fay Betsou, PhD
Integrated Biobank of Luxembourg
Presentation at ASIP Annual Meeting at Experimental
Biology 2011
Carolyn Compton, MD
Office of Biorepositories and Biospecimen Research
National Cancer Institute
National Institutes of Health
OBBR slides in this presentation have been revised
International Society for Biological and
Environmental Repositories
Best Practices for Repositories:
Collection, Storage, Retrieval and Distribution of
Biological Materials for Research
Second Edition: Cell Preservation Technology,
Volume 6, Number 1, 2008
Third Edition: Biopreservation and Biobanking
Volume 10, Number 2, 2012
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.
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
• The goal of the research (application of the data)
Quality Control - definition
« the operational techniques and activities that are
used to satisfy quality requirements », ISO9000:2000
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
« confirmation through provision of objective evidence
that requirements for a specific intended use or
application are fulfilled », ISO9000:2000
Integrated Quality Control Systems
QC / Validation
Sample Processing Method
Biobank or Research Lab
Quality Control Assay
Method Validation / Proficiency Testing
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
- Caffeine :
- phosphodiesterase
 cAMP degradation
- Smoking
- adrenalin secretion 
- Stress
- triglycleride lipase
 lipid acids linked to albumin
- Circadian rhythms
 # of albumin-available sites
- Menstrual cycle
- Pregnancy
- Physical excercise
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)
Biospecimen preanalytical code
Standard Preanalytical Coding for Biospecimens
Cancer Epidemiology Biomarkers and Prevention 2010;19:1004-11
Ideal QC Biomarkers
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
ISBER BS WG, Cancer Epidemiol Biomarkers Prevention 2009;18:1017-25
Why validate QC methods ?
give full confidence in sample quality
• use samples after a long time
• provide « reference materials »
• ensure validity of research results
NCI Best Practices for Biospecimen Resources
Office of Biorepositories and Biospecimen Research
National Cancer Institute
National 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
• The goal of the research (application of the data)
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 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
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-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.
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.
• Adhere to a written quality management system that describes QA and QC
• 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.
• 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.
Biospecimen Resource Informatics
Control, and
• 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.
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.
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.
• 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.
Types of Human Biological Materials
• Germline vs. Somatic cell
• 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 Principles
The 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
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
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
An IRB may grant a waiver of informed consent
under the Common Rule (not the FDA) if four
criteria are met:
• Minimal risk
• Respect for autonomy and the rights of the
• Impracticable
• Notification
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)
• 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
OHRP Repository Guidance
Tissue collector
Tissue collector
Tissue collector
Repository Storage
Data Management
IRB Review
Informed Consent
Submittal Agreement
Assurance of Compliance
Recipient Investigator
Recipient Investigator
Recipient Investigator
IRB Review
Recipient Agreement
Sample Informed Consent
Local Policies
Certificate of Confidentiality
Assurance of Compliance
Ethical Principles for the 21st Century
• Respect for persons (personal autonomy):
– Informed consent
– Respect for privacy and confidentiality
• Beneficence
• Justice

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