Attachment_4_Sample_TaskOrder_SOW.pdf

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Attachment 4: Center for Cancer Genomics (CCG) Biospecimen Core Resource (BCR) Sample Task Order Statement of Work (SOW)

Sample Task Order Statement of Work

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the

Government as needed to perform the Statement of Work.

I. TASK AREA A –Biospecimen Processing Center (BPC) Services

A. Scope

The Center for Cancer Genomics (CCG) Biospecimen Processing Center (BPC) provides biospecimen receipt, processing to molecular analyte, and distribution services for an expanding list of CCG-supported genomics projects and the Contractor shall provide the following services:

1) Biospecimen and Associated Data Procurement

2) Biospecimen Management and Biorepository Operations

3) Biospecimen Quality Control

4) Biospecimen Processing into Molecular Analytes

5) Informatics and Data Delivery

6) Other BPC-related Services

B. Objectives

The objective of this SOW is to acquire biospecimen processing services as described above for genomics studies supported by CCG.

The Contractor shall function as a fundamental resource and play a key role in the CCG program. Key goals shall include ensuring that standards are developed, implemented, continually improved, and maintained for all aspects of cancer-related annotated biospecimen management and processing to support genomic characterization. Processing variables shall be minimized until their effects on the results of molecular analyses become well understood, especially at the “front-end” of the biospecimen workflow for CCG.

Note

The “front end” refers to annotated biospecimen receipt, logistical and physical management, processing into analytes (the molecular extracts from tissue such as DNA and RNA), and distribution of those analytes and portions of original tissue to the research sites with rigorous Quality Assurance/Quality Control (QA/QC) of all functions.

High throughput, production ready Standard Operating Procedures (SOP) shall govern operations under which biospecimens are processed into biomolecules and their aliquots that will be shared across CCG characterization centers. The Contractor shall coordinate the distribution of aliquots of molecular analytes.

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All data transmitted from the BPC (but not necessarily the software applications performing these functions) for work performed under this contract shall be compatible with NCIP standards, which can be found here:

https://wiki.nci.nih.gov/display/EVS/EVS+Use+and+Collaborations;WIKISESSIONID=320A423C74B1C3C7 5F3F4477C9C2214C. Since the Contractor shall be the recipient of biospecimens and data transmitted from a clinical setting to a research setting, the Contractor shall also adopt and/or develop ethical, legal and policy SOPs and/or BPC policies that ensure the protection of patient privacy. Standard Operating Procedures (SOP) and policies shall be aligned with National Institutes of Health (NIH) policies (see The Cancer Genome Atlas (TCGA) example at http://cancergenome.nih.gov/abouttcga/policies/policiesguidelines).

The Contractor shall operate with a centralized and standardized protocol-driven tissue processing and distribution model to ensure that process variables are minimized. Contractor’s protocols shall include rigorous Quality Control (QC) of all intermediate and final products along the workflow. The Contractor shall work to minimize variation in the following three areas:

1) Logistics and informatics standards governing collection, transfer and receipt of biospecimens and associated data from various Tissue Source Sites (TSSs). For each genomics study, the Contractor shall include the use and distribution of training materials and consistent language with all TSSs to ensure uniformity in information and collections.

2) Internal operations to process tissues using high throughput, production-ready SOPs governing workflows under which biospecimens are reviewed and processed into biomolecules. Standard Operating Procedure (SOP) protocols shall be shared across research laboratories in CCG Centers and the National Cancer Institute (NCI). All protocols shall be available to the community and shall be up-to-date at all times.

3) Distribution of molecular analyte aliquots and other biospecimens shall be strictly controlled and documented.

The CCG Biospecimen Processing Center Contractor shall support an expanding list of CCG-supported genomics projects for which the following services are in scope:

1) Biospecimen and Associated Data Procurement – The Contractor shall receive samples and associated data from tissue and data providers comprised of NCI-supported or pharmaceutical industry trials and from other sources.

2) Biospecimen Management and Biorepository Operations – The Contractor shall provide biospecimen management services encompassing the logistics of the biospecimens collected and receipt, annotation, storage management, location management, internal movement and distribution.

3) Biospecimen Histological Review – The Contractor shall implement systems to provide histological verification services as a quality control measure on tumor and normal control solid tissue specimens. In addition, the Contractor shall process these materials into a large inventory of molecular derivatives. Starting materials, intermediates and final products shall be subject to

QC.

4) Biospecimen Processing into Molecular Analytes – The Contractor shall be adaptable to process different types of biospecimens, including surgical resections, biopsies, fresh frozen tissues, FFPE blocks, and FFPE scrolls; and the Contractor shall be responsible for all biospecimen processing into DNA, RNA, and other analytes.

file://///ncifs-p020.nci.nih.gov/home/phungqh/TCGA/Yellow%20Tasks/BCR_RFP/YT13-176NS/%20compatible https://wiki.nci.nih.gov/display/EVS/EVS+Use+and+Collaborations;WIKISESSIONID=320A423C74B1C3C75F3F4477C9C2214C https://wiki.nci.nih.gov/display/EVS/EVS+Use+and+Collaborations;WIKISESSIONID=320A423C74B1C3C75F3F4477C9C2214C http://cancergenome.nih.gov/abouttcga/policies/policiesguidelines

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5) Biospecimen and Analyte Distribution – The Contractor shall distribute molecular analyte aliquots and other biospecimens using strictly controlled procedures and documentations.

6) Other BPC-related Services – The Contractor shall perform other BPC-related services including performing microsatellite instability (MSI) testing, Human Papillomavirus (HPV) testing, Immunohistochemical stains (IHC) and Fluorescence In Situ Hybridizations (FISH) as needed.

7) Participate in various project working groups, steering committees, and in direct interactions with other CCG grantees and subcontractors as requested to get this work done.

C. Project Description and Requirements

C.1. Overview of BPC Capabilities

During the performance of tasks under this Agreement, the Contractor shall maintain the below required capabilities including, but not necessarily limited to, expertise, personnel, SOP protocols, systems, and technology to:

1) Procure biospecimens and assure that they are collected, stored, processed, and distributed under appropriate ethical, legal and contractual guidelines adherent to NIH policy for CCG.

2) Manage a biorepository, including biospecimen storage, tracking and logistics, shipping/receiving, analyte distribution, request processing, and incorporation of feedback from recipients of samples and data. The Contractor shall use live electronic tracking and reporting of inventory and inventory item status.

3) Perform biospecimen histological verification, including the capture of structured standardized data, pathology reports and digital images to confirm accuracy of original diagnosis and to qualify specimens for research use.

4) Perform specimen processing, including DNA and RNA isolation from a tissue sample, and biomolecule QC including development of laboratory protocols to successfully extract biomolecules from samples for which an SOP does not yet exist, due to accrual of samples with different biological and clinical characteristics, or different sample fixation and storage formats.

5) Distribution of analytes and other biospecimens to the Characterization Center(s).

6) Deploy BPC operating and management infrastructure, including governance and oversight interfaces, human subjects’ compliance, informatics, reporting systems, and necessary laboratory certifications, and personnel credentials.

7) Coordinate with the NCI Contracting Officers Representative (COR)

8) Coordinate with all participating TSSs, including providing ongoing training and guidance as it relates to the TSS biospecimen delivery requirements.

9) Coordinate with the NCI Center for Biomedical Informatics and Information Technology

(CBIIT), which has primary responsibility for maintenance of data standards to which BPC data submissions must comply.

10) Coordinate with NCI-designated collaborative investigators to ensure biospecimen data requirements are included in sample submission forms, and that such biospecimen data are appropriately Quality Controlled for use in analysis and publication.

11) Coordinate with the CCG project scientific structure, including rapid, detailed responses to inquiries from the NCI COR.

12) Rapidly report any incidents or deviations from SOPs to the NCI COR. Detailed description of incidents, resolution and adjustments to SOPs to prevent future incidents

Attachment 4 Page 4 of 35 should be provided proactively to the program. Significant incidents shall be submitted through NCI’s Quality Management System (QMS)/Information Management Services (IMS) Non-Conforming Event (NCE) reporting system.

13) Develop a management practice of quality which documents the policies, processes and procedures within the BPC in a manner that will be compliant with the QMS. As a component of the QMS, provide data to the QMS information management system to enable the QMS to measure quality and throughput, including the ability to determine trending, of biospecimen and data receipt, processing and distribution.

C.2. Biospecimen and Associated Data Procurement

The Contractor shall receive and process samples and associated data from Tissue Source Sites (TSSs) and other source entities.

C.2.a. Specific Requirements for Biospecimen Procurement

Requirements for biospecimen procurement include:

1) Specific case and sample inclusion criteria shall be developed and maintained in SOPs, and shall be subjected to modification by the CCG program office.

2) The Contractor shall procure biospecimens to meet the biospecimen needs for each genomics study. In coordination with TSSs and other source entities the Contractor shall ensure that samples are collected, handled, shipped and received with full maintenance of quality:

i) Develop and deploy a communication protocol that governs the Contractor’s communications with the TSS, NCI CCG, and potentially other organizations as needed to perform the work herein.

ii) Develop and deploy a support system to rapidly analyze, understand and correct tissue sample quality issues.

iii) Provide consistent, uninterrupted support for TSSs and other source entities to ensure the best possible customer service.

iv) Conduct remote biospecimen and data transfer training of TSS repository operators or other staff who shall physically collect and handle tissues.

3) The Contractor shall execute and maintain Material Transfer Agreements (MTAs)/Data Use Agreements (DUAs) with each TSS or other source entity for transfer of biospecimens.

Note: The NCI provides draft MTA/DUA documents including a Cover Memo specifying the minimum requirements and NIH policy stipulations for the MTA/DUA. The MTA/DUA may be modified during negotiations provided that the enumerated key requirements and policies in the Cover Memo are maintained as part of the terms. The Contractor shall seek guidance and authorization from the COR or designee prior to agreeing to any significant changes in MTA/DUA terms. As an example, the currently used Cover Memo for TCGA (as of June 2014) and MTA/DUA template are at the TCGA SOP site.

The MTA/DUA and terms therein, while required under this contract, is a

Attachment 4 Page 5 of 35 standalone legal agreement between the Contractor and the TSS; NCI is not a party to this MTA/DUA.

4) The Contractor shall receive from the CCG Clinical Data Center (CDC) a subject

ID for each case for which the BPC shall expect to receive samples from a TSS.

The Contractor shall have SOP in place to address the eventuality of receiving samples in the absence of “knowing” about their expected arrival. The SOP shall balance the decision between holding the samples and waiting for Subject IDs from the CDC versus returning un-notified samples to the TSS, based on guidance from the NCI COR.

5) The Contractor shall require a positive assertion from the CDC that any Subject’s samples that are accessioned have proof-positive documentation of IRB compliance on file with the CDC.

6) The Contractor shall support the receipt of biological material, including up to:

i) 2600 cases worth of Optimal Cutting Temperature (OCT) embedded or cryovial frozen solid tumor tissues or formalin fixed, paraffin embedded (FFPE) tissue blocks with minimum of 10mg of tissue;

ii) 2500 normal frozen solid tissues and/or blood samples (whole blood or fraction in DMSO and/or DNA isolated from blood or saliva);

iii) 24,000 slide mounted sections and corresponding whole slide scanned images from TSS diagnostic blocks, (assume 8 slides/images per successful case); and

iv) 2500 diagnostic surgical pathology reports in paper or electronic format.

7) The Contractor shall coordinate, with designated TSS or other source entity to ensure that biospecimens are packed appropriately to protect them from loss, damage, and temperature variations during transit. The Contractor shall use vapor phase liquid nitrogen containers to receive frozen biospecimens. The shipping and handling of biospecimens shall meet relevant Government regulations for packaging, labeling and shipping of such samples. Air shipments shall conform to the International Air Transport Association (IATA) standards, and ground shipments in the United States shall conform to the Department of Transportation (DOT) standards.

8) Upon receipt, samples shall be immediately visually inspected to ensure integrity after shipping. Irregularities in sample quality or quantity shall be immediately communicated to the TSS, the COR or designee via email per the TSS communication plan. This written confirmation should be received within 24 hours of arrival of shipment at the BPC, excluding weekends and holidays.

Any shipment that arrives compromised (e.g., evidence of melting) and that fails quality control prior to entry into the BPC Laboratory Information Management System (LIMS) shall be handled according to the shipment receipt SOP.

9) Biospecimens shall be uniquely identified and tagged with machine readable mechanisms (e.g., barcodes, Radio-frequency Identification (RFID)) upon receipt and registered into an electronic inventory tracking system. If biospecimens are received with such machine-readable labeling already in place, and the technical format of that labeling is supported by the Contractor’s inventory LIMS, samples

Attachment 4 Page 6 of 35 do not need to be relabeled and such original ID can be informatically linked to the genomics study case ID.

10) Pathology reports, shipping documents, and Sample Adequacy forms shall be Quality Controlled upon receipt to ensure all biospecimens meet CCG and TSS requirements as specified in the relevant SOP. All Sample Adequacy forms shall be signed by the TSS Principal Investigator or their delegated representative before registration of samples into the BPC inventory LIMS.

11) All non-transient samples and derivatives, and subdivisions and aliquots thereof, during all steps from receipt, storage, through processing, and shipment of aliquots to Characterization Center(s) shall be uniquely identified, tagged and tracked in that electronic inventory tracking system.

12) Frozen tissue biospecimens shall be stored at liquid nitrogen vapor temperatures, and managed according to SOPs that minimize warming.

13) The QC results of all inventory processes, and the status of samples as they progress through receipt and storage, shall be electronically recorded in the LIMS and made available to BPC and CCG project Quality Management Systems.

C.2.b. Specific Requirements for Procurement of Specimen-specific Associated Data

Unless otherwise directed by the COR, biospecimens received by the Contractor shall be accompanied by a simultaneously received de-identified surgical pathology report, provided by the Clinical Data Center (CDC). Such reports typically contain minimal donor demographic and clinical data along with the complete surgical pathology. A biospecimen inventory form will also be received from the TSS or other source entity.

The Contractor shall receive and manage, at a minimum, the following information provided by the CCG Clinical Data Center (CDC), arriving with each sample shipment from the TSS, and/or generated during internal processing and QC protocols:

1) CDC-provided documentation of Institutional Review Board (IRB) protocol approval for the TSS to collect and distribute tissue specimens.

2) Donor specific information, including but not limited to donor Subject ID, provided by the CCG Clinical Data Center.

3) Case specific information, including but not exclusive to:

i) Oncologic diagnosis; and

ii) Surgical pathology report for the case received from the CCG CDC, which may include:

a) Electronic text of surgical pathology report, in original source format modified to meet de-identification requirements specified elsewhere.

b) Structured data elements of information typically found in surgical pathology reports.

Additional case specific information may be specified by the NCI COR such as a de-identified diagnosis pathology report.

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1) Sample-specific information obtained from both the TSS, the CCG CDC and generated by the Contractor including:

i) Unique Sample ID. Samples include all samples received, and derivatives and extraction, and all sub-sections or aliquots there from.

ii) Physical characteristics: format, weight.

iii) Volume and number of aliquots of fluid specimens.

iv) Cell count of cellular suspension specimens.

v) Biorepository and specimen storage protocol from source institution, including documentation of appropriate storage environment maintenance in original TSS repository.

2) The QC results of all biospecimen data collection, storage, reformatting and distribution processes shall be electronically recorded in a LIMS and made available to BPC and CCG project Quality Management programs in a manner that allows for online access.

These annotation data shall be stored electronically in the Contractor’s information systems, and made available online according to the informatics requirements specified in the Informatics and Data Distribution section C.7 of this SOW. The Contractor is responsible for obtaining data from the TSS, contributing sites or other source entities, converting it to electronic format, if necessary, transforming the data to meet the data standards requirements stated below, entering the information into local data systems, and uploading the required data to the Genomic Data Commons (GDC).

Protection of Human Subjects Related to Receipt of Tissues and Data

The Contractor shall be the custodian of samples and sample-associated data received from patients enrolled as research subjects in IRB approved protocols at TSSs. The Contractor shall establish all the necessary policies, systems, and technologies to ensure patient protection as specified by regulation and by NIH policies covering CCG are met.

The Contractor shall not use the biospecimens or data to support its own research.

Specific requirement(s) for patient protection shall include:

1) The Contractor shall conform to all relevant human subjects and privacy regulations under HIPAA, 45CFR46, and any relevant state and local regulations for the specimens received.

Note: FDA regulations (CFR Title 21) do not apply to this project.

2) The Contractor shall abide by requirements in the IRB approved protocols under which the samples and data were originally collected and of which the Contractor is made aware by TSSs.

3) The Contractor shall address discrepancies between results of histological reviews and TSS diagnoses in accordance with the approved SOP. The SOP shall include at least the following features:

i) Plan for verifying the discrepancy to the greatest degree possible with internal (Contractor held) information.

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ii) Process to communicate this notification back to other relevant CCG

Centers and the Project Office.

iii) Decision tree for whether such samples can be used by the genomics study at the end of the discrepancy resolution process.

4) The Contractor shall work with several coded patient and sample identifiers provided by the TSS and the CCG Clinical Data Center (CDC). The TSS shall provide to the BPC samples and data that are likely coded with both a TSS Subject ID and a TSS Sample ID. Additionally, the CCG Clinical Data Center (CDC) will provide the BPC with a CCG Subject ID matching the TSS Subject ID for approved cases for which the BPC is expected to receive samples. The Contractor shall ascertain the match between CCG Subject ID and TSS Subject ID as a prerequisite to accessioning samples. The Contractor shall further de-reference the TSS Sample ID by associating it to an information-free CCG study-specific ID generated by the Contractor.

The linkage database between the TSS Sample ID and CCG study-specific Sample ID shall be maintained by the Contractor. All management, processing and distribution of samples, derivatives and data by the Contractor shall use the CCG genomics study-specific ID. Third party access to the Contractor linkage database shall only be granted upon written approval by the NCI COR. NCI Program Office staff, as designated by NCI COR, shall be granted access.

5) The Contractor shall receive its own IRB approval, in the form of a waiver, exemption or other documentation, to perform the work in this SOW, and provide such documentation to the COR or designee.

6) The Contractor shall abide by NIH patient and data protection policies established for this CCG genomics study.

(https://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm)

7) The Contractor shall have an SOP governing the withdrawal of a participant from a CCG genomics study. Notification of such withdrawal will come from the NCI COR. The SOP shall include documentation of notification mechanisms to all Characterization Centers that received BPC biospecimens from this participant.

C.3. Biospecimen Management and Biorepository Operations

Biospecimen Management encompasses the logistics of biospecimen receipt, storage management, location management, internal movement, and distribution. To achieve this function, the Contractor shall adopt and/or develop SOPs for all processes involved in cancer tissue sample receipt, storage, and distribution. The sample management function shall employ an informatics infrastructure to support workflow, and ensure complete logging of all sample access and sample movement transactions.

C.3.a. Specific Requirements for Biospecimen Storage

The Contractor shall implement SOPs, systems, software, and technology to ensure documentation of biospecimen access, control, and access logging.

1) The Contractor shall support and maintain the following storage environments:

i) vapor phase liquid nitrogen freezers (-190°C to -150°C)

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ii) -80°C and -20°C mechanical freezers

iii) humidity and room temperature controlled areas

2) The Contractor shall support and maintain repositories for:

i) FFPE blocks, FFPE scrolls, and slides

ii) frozen tissue in cryovials

iii) frozen tissue in OCT blocks

iv) tissue and cell pellets in cryotubes

v) blood and blood components in liquid and pellet form

vi) DNA and RNA in cryotubes

3) The Contractor shall be able to store the following per year (based on approximately 2500 cases/yr):

i) 22,000 glass slides stored at room temperature

ii) 1,000 tissue samples stored at -190° C

iii) 5,600 DNA samples stored at -80° C

iv) 2,800 RNA samples stored at -190° C

v) 2,800 blood-derived normal stored at -190° C or -80° C

vi) 2,800 FFPE blocks stored at 4° C; and

vii) 1,000 dilution plates stored in -80° C

The Contractor shall provide additional working storage space in the above environments to support the internal operations of the BPC for activities such as processing, QC, backup, and working storage prior to shipment of analytes.

4) For each genomics study, the BPC shall store materials for the expected duration of the study.

a. The Contractor shall receive expected duration information from the NCI

COR. Study durations generally are defined by the number of samples needed to complete the study, not necessarily time.

b. The Contractor shall develop plans and SOP to govern the eventual transfer of materials to a designated CCG long-term biorepository.

c. The Contractor shall execute any necessary MTAs with the long-term biorepository, with timing to have such MTA in place based upon the expected project duration.

d. The transfer of materials to the long-term biorepository shall only occur once the NCI COR has approved the plan and protocol, and issued a directive to do the transfer.

5) All biospecimens shall be stored according to best practices (and under the control of specific SOPs), including continuous temperature monitoring, systematic equipment maintenance, emergency preparedness, alarm systems, back-up storage capacity, back-up liquid nitrogen supply and back-up power supply. The Contractor shall follow an NCI COR approved protocol for personnel notification and action in the event of emergency.

6) Tissue biospecimens shall be stored at liquid nitrogen vapor temperature and shall be managed according to SOPs that minimize warming.

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7) Before any personnel start work on this Task Order, they shall have have proper training to perform all tasks as described in SOPs. The Contractor shall perform regular documented training of personnel. The Contractor shall provide documentation of this required training in their monthly report to ensure that all staff is appropriately prepared to undertake the assigned work.

C.3.b. Specific Requirements for Biospecimen Computer-based Tracking:

“Supply Chain” Logistics, Receipt and Shipment, and Storage

1) Each step of biospecimen logistics for all samples shall be supported and data collected by computer systems (see below) capable of exporting data according to the requirements stated below in “Informatics.” The Contractor shall utilize a high throughput, production ready software system to support the logistics.

2) The Contractor shall develop and maintain live online electronic computer-based records for biospecimen receipt, processing, quality control, storage, management and distribution operations for incoming tissue and their nucleic acid extracts; Laboratory Information Management System (LIMS). The Contractor shall implement a LIMS system which supports and logs all sample receipts, locations, accesses, movements, processes and modifications, process results, and distributions. The electronic recording system shall capture data at sufficient detail to be able to account for every non-transient biospecimen and derivative that is received or created for each genomics study. Data shall be captured at the level of individual samples and groups of samples. Minimally, “groups” includes collections of samples that represent samples received as a group, processed as various batches, and distributed as a batch. The system shall track sample transactions in sufficient detail to provide a complete audit trail. Such tracking shall include, but not limited to:

i) Shipment from TSSs or other sites, receipt, initial biospecimen registration, and the results of quality review of specimens at receipt.

ii) Intended purpose of the case and the samples associated with it, as known at accession or later modified while under the Contractor’s custody (e.g., is the sample for data generation on a genomics study or part of a cancer-specific pilot project to test new molecular extraction techniques, new tissue processing techniques, or new cancers).

iii) Tissue sample accesses for histological verification purposes, including biospecimen access and return to inventory, sections cut, and slides generated. This includes dates and time stamps for all transactions, and freeze-thaw cycles for OCT embedded tissues and other frozen biospecimens.

iv) Freezer and storage unit accesses.

v) In addition to any study-specific and the Contractor’s specific identifiers, all non-transient biospecimens shall be uniquely identified with one or more alpha-numeric strings (barcodes) in accordance with Universally Unique Identifiers (UUID).

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Note: See the Informatics and Data Distribution section C.7 requirements section on Universally Unique Identifiers (UUID) for additional requirements on sample IDs.

vi) Biospecimen genealogy shall be logged and maintained. “Genealogy” refers to the chain of biospecimens created from initial excision from the patient, through tissue grossing and subdivision, embedding, further subdivision, processing into molecular extracts, and then aliquots and lots. Additionally, if the Contractor multiplexes analytes, the matrix shall be documented. The entire parent to child chain shall be maintained for every biospecimen back to the donor from which it was obtained.

vii) Log of all major manipulations of samples and analytes, including, but not necessarily limited to, any aliquoting and sub-division of tissue samples (including macro- or micro-dissection of tissues) or molecular derivatives, any dilutions or concentrations of analytes, any processing into subcomponents or derivatives, and any processing step that includes sample warming above its normal storage temperature.

viii) Amount of sample distributed and to whom and when, along with tracking of residual quantities.

ix) Barcodes (or other machine readable tags, such as RFID) shall be used for all sample identification. All samples and aliquots shall be uniquely identified electronically and as otherwise specified. Physical objects labeled or tagged with the machine-readable ID (e.g., barcode, RFID) shall also include a human readable component if necessary to support manual manipulations of that object. Labels shall be documented to adhere within all processing and storage environments.

x) Ability to reserve and issue IDs (i.e., barcodes) for study-specific objects (e.g., aliquots, other portions of samples, other data) in the custody of any third parties (i.e., Contractors, consultants and any other CCG collaborating entity) when that object is a part of a CCG case registered in the Contractor’s system.

xi) Provide online access to the BCR biorepository for biospecimen inventory analysis, internal management processes, specimen tracking, and specimen processing status. The tracking system shall “know” at all times the location of every specimen under the Contractor’s custody, including while being shipped to and from the Contractor.

xii) Links to laboratory processing and analysis equipment used in production, shall support automated upload of data from that instrumentation for any type of data reportable under this work.

xiii) Biospecimen inventory QC data shall be electronically recorded and made available to BCR and CCG project Quality Management programs.

C.3.c. Biosafety Considerations

The Contractor is responsible for accumulating, maintaining and submitting data to the GDC in the standard biospecimen Extensible Markup Language (XML) format as required for other samples in CCG.

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The Contractor shall:

1) Be responsible for the instantiation and maintenance of external biospecimen UUID/metadata sets.

2) Work directly with relevant TSS and GDC to conduct the technical implementation of tracking barcodes. NCI Program Office is responsible for identifying situations where analyte aliquots have been created outside the normal BPC pipeline process, and then notifying the NCI COR and the Contractor.

3) Manage informatics system for unique aliquots created outside of normal pipeline. Such non-BPC generated aliquots may be from cases never processed by the BPC, or cases otherwise processed by the BPC.

Note: Contractor should be aware that their systems will need to co-manage and integrate aliquots generated locally with aliquots generated elsewhere.

4) Develop a specification and formal import system for biospecimen data provided in the format of a tab-delimited/comma-separated values (CSV) file(s) that contains all the necessary information to generate a biospecimen XML for submission to the DCC.

The system shall have the following capabilities:

i) The specification shall describe what a minimal required biospecimen data set comprises; however, the system shall be capable of importing data that may fully use the data model and all the elements in the biospecimen XML.

ii) The system shall be deployed over the web to enable remote users to submit biospecimen data compliant with the CSV format.

iii) The system shall have an option, selectable by the Contractor, to either incorporate the data into the Contractor’s LIMS for continued management by the Contractor, or to return to the user a copy of the biospecimen XML.

5) Be responsible for maintaining lists of such UUID/metadata sets under the informatics system, and forward migrating these data through data model and information system upgrades.

6) Be responsible for these UUID/metadata sample sets continued deposition into DCC/GDC systems in such a way that they meet DCC/GDC technical specifications for sample IDs, including updates to the XSD versions to which biospecimen XML must be compliant.

C.4. Biospecimen Verification and Quality Control

The Contractor shall implement systems to provide histological verification services as a QC measure on tumor and normal control solid tissue specimens. During this QC process, significant additional data points, specific to each research specimen, shall be collected.

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Histological verification and additional biospecimen data shall be captured electronically with online systems in compliance with the informatics requirements.

Specific Requirement for Biospecimen Histological Verification of Samples Prior to Isolating Analytes

1) The Contractor shall implement necessary systems and SOPs to implement histology laboratory services to verify and document (by digital imagery) the consistency of received research sample characteristics with the donor institution’s diagnostic result such as correct tissue and tumor content, and to evaluate each biospecimen’s suitability for use in its genomics study.

2) The system shall support histological verification of received samples in comparison to the donor institution diagnostic anatomic pathology finding Histology verification data shall be collected for the following purposes:

i) To measure TSS collection processes, repository and specimen quality.

ii) To verify the research specimen’s histological correlation with the clinical findings from TSS diagnostic anatomic pathology report.

iii) To obtain additional specimen specific parameters pertaining to tumor content and tissue adequacy.

3) The Contractor shall support the expedited histological review of:

i) Approximately 2500 cases per year of FFPE or frozen tumor specimens, and

ii) Approximately 2500 cases per year of FFPE or frozen normal tissue specimens.

4) Sections shall be cut, stained and reviewed, for the purpose of performing histological verification and additional data collection, from every FFPE block or frozen specimen selected for processing into molecular analytes. The process shall ensure that one or more sections are reviewed according to the current histology review criteria. The slide reviewed shall be the one generated by the pre-screen component of the review or the Contractor shall cut a new slide. In this case, however, it shall be clear that the slide from the TSS is confirmed to be from the same piece of tissue provided to the BPC. The histological review shall come from section(s) from the actual tissue sample (“portion”) selected for processing into molecular analyte, or tumor types. The Contractor shall work with the NCI COR to determine appropriate protocols to ensure sample quality where only biopsy samples are available and where tissue cannot be pre-screened directly from the tissue submitted to the Contractor due to the limited size of the sample.

5) The Contractor shall minimize handling and warming of frozen biospecimens where applicable.

i) The Contractor shall develop and/or implement all tissue handling SOPs in such a way that maximizes maintenance of biospecimens at vapor phase, liquid nitrogen temperature.

ii) The Contractor shall perform all processing on frozen tissue specimens at a single physical site, specifically avoiding additional transit that increases risk of biospecimen warming.

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6) SOP for portioning of originally received solid tissue shall be optimized to retain as much of the sample as possible in the original tissue format. The Contractor shall work to retain as much residual tissue as possible for future redistribution to CCG Characterization Centers or NCI-supported work. The amount of remaining tissue, after portions are created for biomolecule isolation, shall be tracked in the LIMS system.

7) Histological verification data shall be made available online to individuals designated by the NCI COR and shall be exported to the GDC according to relevant requirements enumerated in the Informatics and Data delivery section, C.7.

8) The Contractor shall provide histological quality control results to the TSS Principal Investigator (PI).

9) Any discrepancies between the source institution pathology report and histological verification findings shall be captured and reported. The following specific finding types shall be reported to the NCI COR:

i) Findings of inconsistent between histological review and original pathology review. Examples of this include a different and unexpected tissue. This finding shall be addressed as a quality issue regarding the source institution biorepository and the adequacy of the sample for further process discussed with the NCI COR.

ii) Consistent, but otherwise not useful to the genomics study.

10) The Contractor shall utilize histological review criteria established by CCG for each genomics study to determine whether a sample is suitable for processing into molecular analytes. Usability findings, review criteria values, and status shall be added to the electronic sample annotation during histological verification.

i) The Contractor shall implement tissue and cancer specific cellular composition values that qualify or disqualify a specimen for molecular processing. Tissue specimens shall be annotated with these values in the information system and a derived usability status shall be added to the annotation. The default criteria shall be set at a minimum of 50% tumor nuclei and a maximum of 20% necrotic tissue composition (or 50% necrosis for glioblastoma multiforme); however these criteria can vary depending on the genomics study and/or cancer. Any changes to these default “cut-off” values for any particular cancer or genomics study shall be approved by the COR or designee. Additional criteria may be added and changed by NCI during the course of the genomics study based upon feedback from CCG management and investigators.

ii) The Contractor shall establish, in consultation with the NCI COR, criteria for discarding or returning samples that have no chance of being useful to CCG. Criteria shall include technologies for macrodissection shall be investigated and implemented to isolate tumor cells from a specimen in which the cellular composition makes that specimen unusable for full sample processing.

iii) The Contractor shall not discard samples without the specific written approval of the NCI COR and source site IRB/PI. All samples shall be

Attachment 4 Page 15 of 35 discarded in compliance with federal, state and local laws and policies, and with the executed MTA in force between the TSS and the Contractor. By default, samples shall remain in the Contractor’s custody until either the end of the genomic project or the end of the task order period of performance.

11) The data to be collected during the histological verification process shall be specified by the current histological review criteria. The data elements specified in the SOP are developed by the genomics study Working Group and provided to the Contractor by the NCI COR. Data elements collected during QC review of biospecimens may vary per genomics study, per tumor type, and per the direction of CCG project management. The Contractor’s Project Management Plan shall address this potential change to minimize unexpected resource requirements to meet the informatics needs of this requirement. Minimally, those data shall include cellular and tissue composition evidence and values, including, but not limited to:

i) % tumor cells

ii) % tumor nuclei

iii) % necrosis

12) Digital images shall be collected with a whole slide scanning system (e.g., Aperio), at an appropriate resolution (40X) to allow all histological review described here to be performed on the digital image in the absence of the physical specimen. The image files shall be distributed to the GDC using a transmission technology and identification as agreed upon with the GDC.

References (i.e., URL pointers) to image files shall be maintained in the electronic system and shall comprise part of the data uploaded to the GDC.

13) The results of all histology QC processes, and the status of samples as they progress through histology QC, shall be electronically recorded in the LIMS and made available to the Contractor Quality Management team and the NCI COR.

C.5. Biospecimen Processing into Molecular Analytes

The Contractor shall be responsible for all biospecimen processing into DNA and RNA. All sample processing must be performed according to SOPs, with a full Quality Assurance (QA) plan in place to permit COR auditing of performance and resulting molecular quality. Each sample shall be tested as part of QC procedures to capture molecular characteristics relevant to the quality of analytes. QC data shall be captured electronically, and made available online via the inventory management system specified in the Informatics section.

C.5.a. Specific Requirements for Biospecimen Processing

The Contractor shall process biospecimens to derive, store, and analyze (for quality control purposes) DNA and RNA (the “analytes”) from tissues.

The Contractor shall store biospecimens as tissues, and initiate production of molecular analytes upon a schedule and batch size process to be determined with the COR or designee.

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1) Approval to isolate molecular analytes is not required on a case by case basis.

Samples shall enter production in batches. Batch content (i.e., the sample comprising a batch) shall be identified by the Contractor and designed to optimize production flow, also taking into account project needs. The samples that fail to meet QC criteria shall be evaluated on an individual basis and released for characterization at the discretion of the COR or designee.

2) The Contractor shall use the histopathology QC results to determine which specific cases and samples thereof undergo processing into analytes, and shall regularly report to the COR or designee on sample IDs, and the Processing Batch IDs within which the samples are grouped, entering processing.

3) When processing of a sample is initiated, sufficient tissue shall be processed to yield enough nucleic acid for the expected Characterization Center(s) receiving distributions from that sample. SOPs shall be optimized to attempt to retain as much of the sample as possible in the original tissue format.

4) The Contractor shall develop and implement SOPs for the handling and processing of solid tissues (normal and tumor, Optimal Cutting Temperature compound (OCT) embedded and free of embedding material, and FFPE tissue specimens) for the purpose of co-isolating Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA).

5) The Contractor shall process frozen tissue specimens into molecular analytes using SOPs that minimize the warming of tissues above liquid nitrogen temperature.

6) The Contractor shall process tissue into molecular analyte at the same physical site at which the biospecimen is stored, specifically minimizing additional transit.

7) The Contractor shall develop and implement SOPs for the handling and processing of blood and buccal cells for the purpose of isolating normal DNA.

8) The Contractor shall use the Qiagen AllPrep technology (or an improved SOP after review and approval by the COR or designee) for co-isolation of DNA and RNA from the same tissue specimen (FFPE, fresh frozen, or blood). The Contractor shall submit to the COR or designee any modification to the protocol for the isolation of DNA and RNA from flash frozen tissue, OCT embedded tissue, FFPE tissue, blood, and buccal cells. The protocols to be used shall be approved by the NCI COR.

9) After their preparation, all analytes and aliquots shall be stored according to the governing SOPs.

10) The Contractor shall perform the following biospecimen processing activities upon receipt of specimens:

i) DNA and RNA extraction from frozen or FFPE tumor tissue of up to approximately 2500 cases per year worth of tissue specimens using an approved protocol, and

ii) Germline DNA extraction from blood and/or lymphocytes and/or frozen normal solid tissue and/or buccal specimens totaling up to approximately 2500 cases per year of specimens using an approved protocol.

11) DNA and RNA extraction from tumor tissues shall meet the following requirements:

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i) Nucleic acid shall be aliquoted into 96 well polypropylene trays or data matrix tubes.

ii) The DNA aliquots shall be dissolved, stored and aliquoted according to the governing SOPs.

iii) The RNA aliquots shall be dissolved, stored and aliquoted according to the governing SOPs.

iv) The quality control steps, quantitation, electrophoresis and genotyping shall be performed and the data shall be electronically organized by batches, TSS, cancer, plate content, and other key variables, and accessible via the web site.

12) DNA extraction from germline-source tissues shall meet the following requirements:

i) All details applicable to processing of nucleic acids from tumor tissue apply to processing of normal tissue.

ii) The germline DNA aliquots shall be dissolved, stored and aliquoted according to the governing SOP.

iii) The quality control steps, quantitation, electrophoresis and SNP genotyping shall be performed.

13) The Contractor shall store stock plates of nucleic acids. DNA and RNA stocks shall not be depleted below a predetermined minimum level for each sample.

Minimum levels for DNA and RNA stocks for each genomics study will be determined and provided by the COR or designee. When the amounts of nucleic acids are within 50% of the boundary (i.e., 3ug), this status shall be flagged in the BCR LIMS system and the NCI COR shall be notified via regular reporting mechanisms.

14) The Contractor shall distribute nucleic acid according to written directions from the NCI COR.

15) For each genomics study, the Contractor shall distribute the aliquots of DNA and RNA at a frequency and batch-size determined by the NCI COR.

16) Analyte aliquots prepared shall be tracked as biospecimens in the informatics system in a similar manner to the tissue specimens from which they were prepared. The system shall track processing batches, lots, aliquots, dilutions, quantities, decrements of units/volumes, and remaining amounts.

17) The Contractor shall use laboratory automation whenever possible to improve economy of scale.

i) Laboratory automation may be utilized in molecular analyte isolation from tumor samples or blood, plating aliquots of molecular analytes for storage or distribution, creating dilution of molecular analytes and other automatable processes.

ii) SOPs shall be specifically developed for automated laboratory procedures.

iii) An automation team, distinct from production personnel, shall be used to develop, validate and implement laboratory automation.

iv) QA/QC tracking of automated processes shall be utilized. The QC results of all automated processes shall be electronically recorded in the

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LIMS and made available to the COR, NCI CCG Program Office, and CCG project Quality Management programs.

The Contractor shall develop and implement SOPs for analyte preparation it proposes to use together with supporting data on the resulting sample stability over time. The protocols implemented by the Contractor shall be approved by the NCI COR.

C.5.b. Additional Considerations

The Contractor shall be flexible and be prepared to develop and implement new isolation technologies for different cancer tissues, different types of analytes and/or initiate different methods of preparation if the genomics study will require it. The Contractor shall adapt to changing protocols in molecular biology, immunochemistry, microscopy, imaging and genomics; sample storage, processing and logistics; bio- and clinical informatics; and histology, cytology, and pathology.