1. 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

2. Outline ISBER Best Practices Biospecimen Science
Quality Control and Proficiency Testing
NCI Best Practices
Human Biological Materials
Special Ethical Considerations

3. Acknowledgments 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

4. 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

5. 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.

6. 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)

7. 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:
Glenn GC, Hathaway TK. Effects of specimen evaporation on quality control.
Am. J. Clin. Pathol. 1976;66:
Calam RR. Reviewing the importance of specimen collection.
J. Am. Med. Tech. 1977;39:
« confirmation through provision of objective evidence
that requirements for a specific intended use or application are fulfilled », ISO9000:2000

8. Integrated Quality Control Systems
QC / Validation
Biobank
Biobank or Research Lab
Sample Processing Method
Quality Control Assay
Method Validation / Proficiency Testing

9. 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

10. 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

11. 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)

12. SPREC-01 Biospecimen preanalytical code
Standard Preanalytical Coding for Biospecimens
Cancer Epidemiology Biomarkers and Prevention 2010;19:

13. Ideal QC Biomarkers Measurable by widely accessible methods
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:

14. Why validate QC methods ?
give full confidence in sample quality
use samples after a long time
provide « reference materials »
ensure validity of research results

15. 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

16. 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)

17. 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

18. 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

19. 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.

20. Collecting/Managing Clinical Data/QA/QC
Collecting and Managing Clinical Data
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.
Quality Assurance/ Quality Control
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.

21. Biosafety
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

22. 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

23. 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.

24. 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.
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.

25. Types of Human Biological Materials
Germline vs. Somatic cell
Germline
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
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26. Types of Human Biological Materials
Unidentifiable vs Identifiable
Unidentifiable
Anonymous
Anonymized
Identifiable
Coded (Linked)
Identified
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27. Ethical Principles The Belmont Report
Respect for persons (personal autonomy)
Beneficence
Justice

28. 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
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29. 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
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30. 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.
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31. Definition of a Human Subject-The Common Rule
Does NOT include:
Deceased persons (autopsy specimens)
Publicly available information
Unidentifiable (Anonymous, Anonymized) Samples
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32. 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 individual
Impracticable
Notification
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33. 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
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34. 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

35. OHRP Repository Guidance
Tissue collector
Recipient Investigator
Repository Storage
and
Data Management
Center
Tissue collector
Recipient Investigator
Tissue collector
Recipient Investigator
IRB Review
Informed Consent
Submittal Agreement
Assurance of Compliance
IRB Review
Sample Informed Consent
Certificate of Confidentiality
Assurance of Compliance
Recipient Agreement
Local Policies

36. Ethical Principles for the 21st Century
Respect for persons (personal autonomy):
Informed consent
Respect for privacy and confidentiality
Beneficence
Justice