StatementofWork.pdf

Attachment 3 – Statement of Work

Clinical Proteomics Tumor Analysis Consortium (CPTAC) Biospecimen Core Resource

Statement of Work

Statement of Objectives

A. Background

A.1. General

The overall objective of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) is to improve our understanding of cancer biology by conducting proteogenomic analysis on selected cancer types (up to 10 cancer types, 200 cases each; see Tumor Types of Interest) where unanswered questions remain about the molecular biology of the disease. This analysis will add a complementary layer of protein molecular biology that facilitates refinement of driver genes, enhances understanding of the pathogenesis through proteomic subtyping, and illuminates dynamic alterations in post translational modifications responsible for the dysregulation of cancer signaling networks and pathways.

The purpose of this project is to utilize a pipeline to collect, process, qualify, genomically characterize, and distribute biospecimens for CPTAC and to collect, analyze, review, store, and distribute the data associated with this project.

The project involves several components, including:

Tissue Source Sites (TSS)

Biospecimen Core Resource (BCR)

Genome Characterization Center (GCC)

Quality Management System (QMS)

Operations and Technical Support , Comprehensive Data Resource (NCI‐OTS CDR)

Proteome Characterization Centers (PCC)

Proteo‐Genomic Data Analysis Centers (PGDAC)

Proteogenomic Translational Centers (PTC)

Data Coordinating Center (DCC)

The pipeline of these components will supply high‐quality biospecimens and data to a network of Proteome Characterization Centers (PCC), Proteogenomic Translational Centers (PTC), and Proteogenomic Data Analysis Centers (PGDAC). Ultimately, the samples will be characterized for copy number variation, single nucleotide polymorphisms, DNA, RNA, and protein expression and mutation analysis. De‐identified data will be made available through the CPTAC Data Coordinating Center and other NIH data resources. Overall quality for the entire project will be the responsibility of the QMS.

Tumor Types of Interest:

1. Thoracic: Non‐Small Cell Lung Carcinoma (Lung Adenocarcinoma)

2. Gastrointestinal: Pancreatic Ductal Adenocarcinoma (PDA)

3. CNS: Glioblastoma Multiforme (GBM)

4. Hematologic: Acute Myeloid Leukemia (AML)

5. Urologic: Clear Cell Renal Cell Carcinoma (ccRCC)

6. Head And Neck: Head And Neck Squamous Cell Carcinoma (HNSCC)

7. Skin: Cutaneous Melanoma

8. Soft Tissue: Sarcomas

9. Thoracic: Lung Squamous Cell Carcinoma (SQCC)

10. Gynecologic: Uterine Corpus Endometrial Carcinoma (UCEC)

A.2. CPTAC Biospecimen Core Resource

A major prerequisite of the CPTAC Program will be the acquisition of high quality biospecimens. To meet this need, NCI is establishing a network of Tissue Source Sites

(TSSs) to provide high quality, clinically annotated biospecimens for submission to a centralized quality control and processing facility. The TSSs will be procuring tumor tissue, normal tissue (when feasible) and blood (plasma and buffy coat/packed red cells) from patient volunteers suffering from up to 10 tumor types. The BCR will be the primary interface between the CPTAC Program and the TSSs.

It must be noted that the term “high quality” refers not only to the histological and molecular properties of the tissue, but also to characteristics such as degree and quality of clinical annotation, the existence of appropriate informed consent provisions for the intended use of the biomolecules and data, collection and subsequent distribution to

CPTAC participants under an Institutional Review Board (IRB) approved protocol, as well as unencumbered access for research use (e.g., intellectual property restrictions).

CPTAC project management chose to establish a centralized tissue processing model to standardize procedures such as histopathology, DNA/RNA isolation, sequencing, and other sample preparation processes. This centralization specifically means that all operations to process tissue for any single cancer studied by CPTAC occur at the BCR, utilizing SOPs. This standardization refers to the processes of biospecimen receipt, logistical and physical management, processing into analytes (the molecular extracts from tissue such as DNA and RNA), the subdivision of tissue or analytes, and dissemination to the research sites with rigorous QC of all intermediate and final products along the workflow.

The BCR will work closely with the Comprehensive Data Resource (NCI‐OTS CDR), which will manage biospecimen and clinical data, including sample identifiers.

B. Objectives

The objective of this SOW is to establish a core resource providing comprehensive logistical support for the CPTAC Program facilitating tissue sample and clinical data collection, histopathological analysis, storage, and internal dissemination. It is envisioned that the contractor will put in place a seamless pipeline for accepting clinical samples and associated data, analyzing frozen‐section slides (or images) for pathological analyses, storing the samples and data, preparing DNA and RNA from the samples, distributing the tissue samples to the PCCs and the DNA/RNA to the GCC, and conveying the clinical and sample data to the NCI‐OTS CDR. It is further envisioned that the BCR will employ rigorous quality control and assurance practices for all aspects of the work in collaboration with the QMS. Finally, it is envisioned the BCR shall actively engage in routine communication regarding all aspects of the work with the CPTAC leadership and the other components of CPTAC.

C. Scope

The contractor shall function as a fundamental resource and play a central logistical role in the CPTAC

Program. Key elements of the scope shall include:

1. Coordinating the procurement of biospecimen collection and shipping from the CPTAC TSSs,

2. Coordinating clinical data procurement and transmission from the CPTAC TSSs,

3. Storing and managing the CPTAC biospecimen collection,

4. Managing and storing the CPTAC clinical data associated with the biospecimens,

5. Processing biospecimens for pathology review,

6. Processing the biospecimens for DNA and RNA,

7. Distributing biospecimens and analytes to the PCCs and GCC,

8. Coordinating with and distributing clinical and biospecimen data to the NCI‐OTS CDR,

9. With the QMS, developing and implementing comprehensive quality control and assurance regimens for all aspects of the work,

10. Managing the operations of the BCR.

The contractor shall be able to perform as a single entity all the biospecimen and data processing capabilities described in this SOW. Currently, the goal of the program is to accumulate 200 qualified tissues from each of and up to the 10 cancer types. Tissues will be accrued and processed from

September 2015 through August 2019. Biospecimen and clinical data will continue to be processed until

September 2020. The Program estimates a qualification rate of 55% with a total of 364 consented patients enrolled in each of the ten tumor studies. Qualification includes:

‐ Case meets all CPTAC collection requirements

‐ Baseline case report form is complete

‐ > 80% tumor nuclei

‐ > 50% total cellularity

‐ < 20% necrosis

‐ Adequate quantity and quality of DNA and RNA (molecular qualification)

‐ Yields adequate genomic data from GCC

‐ Yields adequate proteomic data from PCC

For the purposes of this SOW, all estimates are based on complete collection of eight tumor types.

Tissues shall be received by the Contractor from contributing CPTAC Tissue Source Sites (TSSs) that will be vetted by the NCI to meet a set of preliminary evaluation criteria. To account for the more rigorous tissue collection protocols needed for proteomic analyses, the tissue procurement will be prospective in all cases.

D. Tasks

The objectives of the work will be realized through the following tasks and subtasks. Where needed, CPTAC requirements for the contractor executing on the tasks and subtasks are noted in Section E.

Many of the subtasks require direct communication between the CPTAC BCR and other components of the CPTAC Program. These communications will be done through or facilitated by the Contracting

Officer’s Representative (COR).

D.1. Task 1 ‐ Coordinating the Procurement of Biospecimen Collection and

Shipping from the CPTAC TSSs

D.1.a. Subtask 1.1 – Confirming that all regulatory and patient safety/confidentiality have been satisfied by the TSSs.

The contractor shall confirm that each TSS has obtained all needed, local approvals to perform the work and completed all the needed regulatory documents that are needed (e.g., Material Transfer Agreement (MTAs), etc.). Electronic copies of all documents will be made available through an electronic document storage system provided and hosted by a third party and available to the NCI COR.

D.1.b. Subtask 1.2 – Shipping of Biospecimens from the TSSs

The contractor shall provide for the shipping of biospecimens from the TSSs to the

BCR including providing appropriate ultra‐cold shippers that have temperature monitors. The contractor shall make the arrangements for shipping and pay for the costs. The contractor shall ensure that all specimens are tracked during shipping and relevant shipping parameters (e.g., temperature) collected and stored.

D.2. Task 2 ‐ Coordinating Clinical Data Procurement and Transmission from the

CPTAC TSSs

D.2.a. Subtask 2.1 – Providing an Electronic Clinical Data Submission Application

The contractor shall put in place and administer a secure, electronic clinical‐data management system that is capable of direct, internet‐based access by the TSSs for the entry of clinical data.

D.2.b. Subtask 2.2 – Creating CPTAC‐specific Clinical Case Report Forms

The contractor shall interact with the NCI COR and the CPTAC Program to create

Program‐specific clinical case report forms (CRF) and integrate these into the clinical data system from Subtask 2.1.

D.2.c. Subtask 2.3 ‐ Clinical Data Review

The contractor shall review clinical data submitted by the TSS within three (3) weeks of receipt to ensure completeness and internal consistency of the data.

Additionally, the contractor shall confirm that the clinical data and associated biospecimen collection data do not disqualify a case from the CPTAC collection.

D.3. Task 3 ‐ Storing and Managing the CPTAC Biospecimen Collection

D.3.a. Subtask 3.1 – Cryostorage of CPTAC Samples and Analytes

The contractor shall provide comprehensive biobanking facilities for the long‐term cryostorage of the CPTAC samples and derived analytes (vapor‐phase liquid nitrogen).

D.3.b. Subtask 3.2 ‐ Sample and Analyte Tracking

The contractor shall put in place and administer a secure, electronic sample tracking and laboratory information management system (LIMS) and utilize that system to track all CPTAC samples and analytes in its possession.

D.4. Task 4 – Storing and Managing the CPTAC Clinical and Biospecimen Data

D.4.a. Subtask 4.1 – Electronic Storing of CPTAC Clinical Data

The contractor shall put in place and administer a secure, computerized clinical data storage system with an external interface that can be made available to the TSSs and other stakeholders not on the contractor’s site.

D.4.b. Subtask 4.2 ‐ Electronic Storing of CPTAC Biospecimen Data and Tracking of

Biospecimen Logistics

The contractor shall put in place and administer a secure, computerized system for storing CPTAC Biospecimen data and tracking the logistics of biospecimen storage, handling, and shipping.

D.4.c. Subtask 4.3 – Providing Universally Unique Identifiers (UUIDs)

The contractor shall put in place and administer a computerized system for generating UUIDs.

D.4.d. Subtask 4.4 – Providing Comprehensive Electronic Data Storage for All CPTAC Data

The contractor shall identify any additional software systems that may be needed to ensure that all relevant CPTAC data (e.g., electronic histopathology images) are securely stored in electronic format. Any additional systems shall be itemized in the contractor’s initial proposal or brought to the attention of the NCI COR during the period of performance of the contract. The contractor shall be prepared to host and manage these systems if approved by the NCI COR.

Note that an exception to this is an electronic document inventory and storage system (e.g., SharePoint). A document storage and management system shall be hosted by a third party and supplied to the contractor.

D.4.e. Subtask 4.5 – Providing IT Security

The contractor shall develop and implement the needed administrative processes and policies to provide security for the information systems holding CPTAC data and information.

D.5. Task 5 ‐ Processing Biospecimens for Pathology Review

D.5.a. Subtask 5.1 – Preparing Frozen Histopathology Sections of CPTAC Samples

For all cases, the contractor shall create and securely store electronic images of the stained slides of representative frozen sections. TSSs will submit either slides or images to the BCR.

D.5.b. Subtask 5.2 – Pathologic Review of the Frozen Sections for Qualification

The contractor shall provide for the analysis of the frozen sections received at the

CPTAC BCR. The pathologic review of these sections shall include quantifying the percent of tumor nuclear profiles, the percent of necrosis in the section, and the total cellularity of the sample. For this requirement, tumor nuclear is the ratio of tumor nuclei to the total number of cell nuclei on the frozen tissue section image.

Total cellularity is the ratio of area occupied by cells to the total area of the frozen tissue section. In addition, the contractor shall coordinate with the TSSs for the acquisition of diagnostic histopathology slides on each case submitted by the TSSs.

D.5.c. Subtask 5.3 – Managing the Pathology Review Data

Along with the NCI‐OTS CDR and QMS, the contractor shall develop processes and an electronic system for managing the pathology data obtained from the frozen sections. The contractor shall also develop an archival system for the electronic images and physical slides that are part of this effort.

D.6. Task 6 ‐ Processing the Biospecimens for DNA and RNA

D.6.a. Subtask 6.1 – DNA and RNA Isolation

The contractors shall use contemporary biomolecular techniques to isolate and purify DNA and RNA from representative solid tissue samples (tumor and normal) and blood from each qualified case.

D.6.b. Subtask 6.2 – Analyte Storage and Tracking

The contractor shall store the analytes under conditions that preserve the quantity and quality of the analytes and track the analytes pending shipment to the GCC.

The contractor shall utilize an internal IT system for tracking.

D.6.c Subtask 6.3 – Processing the Biospecimens for Protein

Because protein extraction is performed by each PCC, the BCR will not isolate protein material. When optimal cutting temperature medium (OCT) is present, the

BCR will remove OCT prior to preparing a sample for proteomic analysis. To ensure the homogeneity between the sample portion undergoing genomic analysis and the portion undergoing proteomic analysis, the BCR shall have the capability to conduct a variety of sample processing methods, including, but not limited to: serial slicing, cryopulverization, and laser‐capture microdissection. The default method for preparing a sample shall be serial slicing, where a tissue sample is divided into 50 micrometer curls. The curls shall be alternately placed into separate vials such that the proteomics vial has approximately 100 mg of wet weight tissue and the nucleic acid vial has approximately 50 mg of wet weight tissue.

D.7. Task 7 ‐ Distributing Biospecimens and Analytes to the PCCs and GCC

D.7.a. Subtask 7.1 – Distributing Biospecimens to the Protein Characterization Centers

The contractor shall coordinate with the NCI COR and distribute tumor samples to the PCCs and/or PTCs. The samples shall be shipped frozen in cryo‐shippers.

D.7.b. Subtask 7.2 – Distributing Analytes to the Genome Characterization Center

The contractor shall coordinate with the GCC and ship the DNA and RNA analytes.

D.8. Task 8 ‐ Coordinating with and Distributing Clinical Data to the NCI‐OTS CDR

D.8.a. Subtask.8.1 – Developing Data Transmission Procedures with the CPTAC NCI‐OTS

CDR.

The contractor shall interact with the CTPAC NCI‐OTS CDR to develop the technological approach for transmitting the CPTAC clinical data to the NCI‐OTS CDR.

D.8.b. Subtask 8.2 – Distributing the CPTAC Clinical Data to the DCC

The contractor will electronically transfer the clinical data to the NCI‐OTS CDR on a routine schedule. The schedule will be determined in consultation amongst the

Contractor, CPTAC NCI‐OTS CDR, and NCI COR.

D.9. Task 9 ‐ Developing and Implementing Quality Control and Assurance

Regimens for the Preparation of DNA and RNA

The contractor shall develop, implement, and use a comprehensive QC/QA regimen for the preparation of the molecular analytes and biospecimens. The results of the regimen shall be regularly reviewed by BCR management and the QMS and any systemic issues addressed.

D.10. Task 10 ‐ Managing the Operations of the BCR

D.10.a. Subtask 10.1 – Document Management

The contractor shall manage all documents relating to the operations of the BCR.

Note that an electronic document storage system hosted and managed by a third party shall be provided for the contractor.

D.10.b. Subtask 10.2 – Preparing Routine Biospecimen Inventory and Status Summaries

The contractor shall prepare weekly inventory summaries of the inventory of the biospecimens that includes progress in each case towards qualification. The summaries shall be suitable for distribution to the CPTAC Program Staff, other

CPTAC entities, and CPTAC community in general.

D.10.c. Subtask 10.3 – Preparing Standard Operating Procedures

In consultation with the NCI COR, CPTAC Program Staff and the QMS, the contractor shall identify key, recurring procedures and processes in the BCR and create, maintain, and update SOPs covering these activities.

D.10.d. Subtask 10.4 – Preparing Monthly Status Reports

The contractor shall create monthly status reports covering all aspects of the operation of the BCR including financials.

D.10.e. Subtask 10.5 Project Close Out Plan

The contractor shall prepare a plan for project close out that describes the steps the contractor believes would be necessary for relocating the physical sample collection and downloading the electronic information stored at the BCR.

D.10.f. Subtask 10.6 Communication Plans

This contractor shall prepare Communication Plans for guiding interactions between or amongst the BCR and the CPTAC TSSs, CPTAC GCC, CPTAC NCI‐OTS CDR, CPTAC

QMS, CPTAC DCC, and CPTAC PCCs.

E. Requirements

The following sections contain additional details that apply to the specific tasks noted above. The information is organized to generally follow the major Task number.

E.1. Coordinating the Procurement of Biospecimen Collection and Shipping from the CPTAC TSSs

The contractor shall have staff able to support the procurement of biospecimens from ~50

TSSs to meet the overall biospecimen needs of the Program. Specific case and sample inclusion criteria are noted in the CPTAC Tissue Procurement Protocols. TSS interactions shall include the following activities as necessary to ensure that samples are collected, handled, shipped and received with full maintenance of quality:

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

b. Develop and deploy a support system in which the BCR works directly with the TSSs to rapidly analyze, understand, and correct any tissue sample quality issues involving the

TSSs that arise.

c. Develop and deploy a system for general support of the TSSs capable of rapid responses during normal working hours for the BCR and provisions for addressing issues that arise after normal working hours on the next business day.

d. Conduct biospecimen and data transfer training of TSS operators or other staff who shall physically collect and handle tissues and clinical data.

e. Travel to TSSs for onsite training may be conducted after approval by the NCI COR.

Travel for two (2) or more BCR staff may be approved if required for training of new

TSS staff.

f. Conduct a regular meeting (at least monthly) with the TSSs to determine TSS administrative status, sample and data review and retrieval status, and plans for future shipments to the BCR. It is envisioned this will minimally take the form of a teleconference hosted by the NCI COR with each TSS, NCI CPTAC Program personnel, and other relevant CPTAC personnel. If needed, routine one‐on‐one meetings with individual TSSs may be arranged through the NCI COR.

The contractor shall execute MTAs with each TSS for transfer of biospecimens. The NCI will provide draft MTA documents including a Cover Memo specifying the minimum requirements and NIH policy stipulations for the MTA. The MTA may be modified during negotiations providing 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 NCI COR prior to agreeing to any significant changes in MTA terms.

The MTA and terms therein, while required under this contract, is a standalone legal agreement between the contractor and the TSS; NCI is not a party to this MTA.

The contractor shall obtain from contributing TSSs the necessary human subjects documentation verifying that TSS has received IRB approval to participate in CPTAC. Such documented approval may include, but are not limited to:

a. An IRB approved protocol. In this case, an illustrative copy of the Informed Consent, the protocol, and the approval letter from the IRB must be provided.

b. A CPTAC‐specific IRB waiver has been granted.

c. A CPTAC‐specific letter that the IRB considers one of the exemptions in 45CFR46 applicable.

d. A CPTAC‐specific letter that the IRB does not consider the use of these data and materials to be human subject’s research.

e. Consent withdrawal process.

Once the BCR has established that a TSS has submitted appropriate regulatory documentation in good form, the BCR shall notify the TSS and the NCI CORs overseeing the TSS and the BCR that they may begin procuring tissue.

The contractor shall retain copies of the annual review and re‐approval of the aforementioned human subject’s documentation. Copies of such documentation shall be stored by the contractor and made available for inspection by NCI COR, NCI CPTAC

Program Office, and to CPTAC network entities as designated by the NCI COR.

The contractor shall coordinate and provide training as necessary with designated TSS 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; ground shipments in the United States shall conform to the

Department of Transportation (DOT) standards.

Once the TSS regulatory and training requirements have been met, but prior to sending cryoports and authorizing shipments, the “Submission” and “Baseline” forms required of the TSSs shall be reviewed for completeness by the BCR and discrepancies addressed by the TSS. The TSSs will be required to create a shipping manifest for each shipment. The contractor shall use the completed “Submission” form as a trigger to create a new CPTAC case for that procurement. The contractor shall develop and maintain a system for creating a unique CPTAC identifier that is independent of any more global system such as the Universally Unique Identifier (UUID) system noted below and assign and track a unique case identifier (see Section E.2.c below). The TSSs shall use that identifier for all activities surrounding that case. The contractor shall assume that 600 shipments (5 cases per shipment) will be required during the period of performance of the contract.

Upon receipt, samples shall be immediately inspected to ensure integrity after shipping and consistency with the shipping manifest. Irregularities in sample quality or quantity shall be immediately communicated to the TSS and the NCI COR via email per the TSS communication plan required above. This electronic confirmation should be received within 24 hours of arrival of shipment at the BCR, excluding weekends and holidays. For example, if a shipment is received at 5pm on a Friday afternoon, the TSS will be notified no later than Monday at 5pm unless Monday is a holiday (in which case the site would be notified no later than Tuesday at 5pm). Any shipment that arrives compromised (e.g., evidence of melting) and that fails quality control prior to entry into the BCR LIMS will be handled according to the shipment receipt SOP.

Biospecimens shall be uniquely identified and tagged by the contractor with machine readable mechanisms (e.g., UUID, barcodes, RFID) upon receipt and registered into an electronic inventory tracking system. The primary identifier will be the UUID, but additional IDs can be human‐readable IDs. The contractor shall be responsible for generating the IDs.

The contractor shall provide the TSSs pre‐labeled and pre‐weighed cryovials suitable for the tumor and normal tissue types expected from the TSS. The goal is to minimize tissue handling at the TSSs. Tissue weights will be obtained at the BCR. All frozen sections will be prepared by the TSSs. The TSSs will be submitting multiple pieces (sub‐sections) of tissue (up to five) obtained from each tumor. These pieces will be accessioned and treated as separate samples associated with a case. It is possible that situations will arise where the BCR receives multiple samples obtained from multiple independent tumors found in the same participant; the identification system should be able to account for this scenario.

E.2. Coordinating Clinical Data Procurement and Transmission from the CPTAC

TSSs

E.2.a. Subject and Sample Information

The contractor shall have the expertise and systems to receive and manage, at a minimum, the following information provided by the TSSs and associated with each case:

1. The CPTAC case Submission form (submitted electronically by the TSS)

2. The CPTAC case Baseline Case Report Form (submitted electronically by the TSS)

3. The surgical pathology report, in original source format modified by the TSS to meet de‐identification requirements. This document shall be scanned and stored in the electronic record system if received as paper.

4. Scanned images of representative histopathology slides generated at the TSS. If needed, the contractor may also be asked to accept physical slides from the TSS for imaging at the BCR and return the original slides to the TSS. If slides are submitted in lieu of images, they shall be scanned with a whole slide scanning system at an appropriate resolution to allow a pathological review. All image data shall be captured and annotated electronically. The contractor shall ensure that an appropriate MTA has been executed.

5. The CPTAC One‐Year Follow Up form

It is envisioned that the CPTAC Program will support following the patients providing tissue for up to five (5) years.

For histopathology images received from the TSSs, the BCR shall ensure that they are accompanied by appropriate data regarding magnification, etc. These data must be stored electronically in the contractor’s information systems associated with the images.

If necessary, the BCR shall transform the data to meet the BCR’s data standards.

E.2.b. Case Report Forms, Clinical Data Elements, Data Models, and Electronic Information

Systems

The CPTAC Program has developed a set of case report forms (CRFs) specific for each cancer type to be studied. These include:

1. Submission – Contains minimal information on the consented participant from which tissues are obtained. Completion and submission of this CRF by the TSS will be required at the time or surgery to provide the CPTAC Program with information regarding the inventory of samples at the TSS awaiting shipment to the BCR. The TSS must submit this information before shipping is scheduled.

2. Baseline – Contains relevant clinical information and diagnostic data on the consented participant from which tissues were obtained. Completion and submission of this CRF by the TSS will be required before shipping is scheduled.

3. One‐Year Follow Up – Contains status and relevant clinical information on the participant one (1) year after tissue procurement.

From time‐to‐time, other CRFs may need to be developed or the contents of the existing CRFs modified. The contractor shall work with the CPTAC Program Office, relevant CPTAC Working Groups, and the NCI COR to develop the contents of these forms. If changes are required, the contractor shall track the changes over time and assist the DCC in updating cases that may have been uploaded prior to the changes.

The contractor shall review these forms and develop the corresponding Clinical Data

Elements (CDEs) corresponding to the contents of the form. The term “clinical data elements” means all the patient data associated with biospecimens as required to be collected under this work, including, but not necessarily limited too, demography, pathology reports, other clinical history and data, and follow‐ up/outcomes data. Data elements may be provided to the contractor in list, paper case report form, various electronic formats, or other formats not necessarily compliant with Informatics requirements of this SOW. The contractor shall be responsible for conversion of such clinical data collection specifications into formats compliant with NCI standards as stated in Section E.4 of this SOW.

The CRFs will utilize common data elements in the NCI caDSR system

(https://wiki.nci.nih.gov/display/caDSR/caDSR+Wiki+Home+Page). New CDEs will be created as required and submitted to the caDSR. Any modifications needed to existing CDEs will be submitted to the caDSR system.

With the exception of the pathology report, the collection of the clinical data shall be by direct electronic input into the BCR systems by computer‐based input (i.e., electronic case report forms) systems, utilizing a software system capable of being deployed to the TSS via the internet and using web‐based interfaces. The contractor shall securely host and maintain the electronic system. It is envisioned that the primary mechanism for the TSSs to submit data will be through the internet‐based system although situations may arise from time‐to‐time where the BCR may need to manually enter data from paper‐based forms or other media. Data submission by methods other than the selected web‐based system will require the TSS to obtain approval by the NCI COR. It is not expected that additional electronic methods for the direct entry of data from the TSSs into the information system will be employed.

It is not currently envisioned that any of the contents of the pathology reports submitted to the BCR from the TSS will be extracted and stored in the BCR’s clinical data repository.

If not already present, patient clinical data shall be augmented to include

International Classification of Disease (ICD) codes for diagnosis and morphology, ICD‐10 and ICD‐O‐3, respectively. The current latest approved ICD version shall be used. These data elements shall be part of the upload to NCI‐OTS CDR.

E.2.c. Protection of Human Subjects Related to Receipt of Tissues and Data

The contractor shall be the custodian of data and samples 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 (e.g., HIPAA and the Common Rule), NIH policies covering CPTAC, and all related terms and conditions included in the contract. The contractor shall serve as the interface between the TSSs, which work with fully identified patient data and the CPTAC DCC database, which shall only have access to linked patient data that are stripped of direct identifiers.

Specific requirement(s) for patient protection include:

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

2. The contractor shall conform to all relevant human subjects and privacy regulations under HIPAA, 45CFR46, and any relevant state and local regulations.

Note that FDA regulations (e.g., CFR Title 21) do not apply to this requirement.

3. 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.

4. The contractor may receive clinical data that are considered Protected Health

Information (PHI) according to HIPAA; however, that data shall be provided by the source site in a form suitable to meet the “Limited Data Set” (LDS) requirements under the regulations. The contractor shall deploy a QC process to ensure that data meet the “Limited Data Set” specification. The contractor shall enter into HIPAA described “Data Use Agreements” with contributing sites.

The “Data Use Agreement” language is already part of the MTA document template that shall be provided by the NCI.

5. The contractor shall be able to operate with, and internally manage, PHI clinical data compliant with the HIPAA “Limited Data Set” specification.

6. The contractor shall submit its clinical data HIPAA compliance testing plan to

NCI upon contract execution, to ensure that received data meet the HIPAA LDS specification, and do not include direct identifiers.

7. The contractor shall have systems in place to effectively de‐identify those data to be HIPAA “Safe Harbor” De‐Identified compliant to support access of data by any external entity that does not have a HIPAA compliant “Data use agreement” in place with the Contractor. Only HIPAA De‐Identified compliant data will be distributed with tissues or molecular analytes to other CPTAC participants.

8. The contractor may receive and histopathologically review a biospecimen and find a discrepancy between its finding and the TSS diagnosis of clinical relevance to the patient. The contractor shall have an SOP in place to address this eventuality. The SOP shall include at least the following features:

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

b. Processes for communication back to TSS PI or TSS IRB, if necessary.

c. Decision tree for whether such samples can be used by CPTAC at the end of the discrepancy resolution process.

9. The contractor shall work with two (2) types of coded patient identifiers. TSS shall provide BCR samples and data that are coded with a TSS ID (the linkage database between a Patient ID and the TSS ID shall be maintained at each TSS).

The contractor shall further de‐reference the TSS ID by associating it to an information‐free CPTAC UUID generated by the contractor. The linkage database between the TSS ID and CPTAC primary ID shall be maintained by the contractor. All management, processing and distribution of samples, derivatives and data by the contractor shall use the CPTAC primary ID. Third party access to the contractor linkage database shall only be granted upon written approval by the NCI COR per the requirements stated in CPTAC Patient Protection and Data

Access policies, or by approval of the TSS Project Director.

10. 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 NCI COR and NCI CPTAC Program Office.

11. The contractor shall be responsible for determining that a TSS, and the samples and data it ships to the contractor, are done so in accordance with the human subjects protection requirements under which the contractor shall operate.

Specifically, the contractor shall be responsible for making the decision that all human subjects requirements have been met before receiving samples and data. These requirements are those placed upon the contractor by this SOW and by its own IRB approvals. Note, NCI may receive and review various TSS human subjects documentation, including informed consents, protocols, and

IRB approvals, and shall provide such documentation to the contractor when available; however, NCI is not responsible for making the determination that human subjects requirements have been met.

12. The contractor shall abide by NIH (including NCI) patient and data protection policies established for CPTAC.

13. The contractor shall have an SOP governing the withdrawal of a participant from

CPTAC. Notification of such withdrawal will come from the TSS. The SOP shall include suitable notification mechanisms to the DCC.

14. The contractor shall obtain an NIH Certificate of Confidentiality

(http://grants1.nih.gov/grants/policy/coc/appl_extramural.htm) to cover itself and the TSS providing samples to it within upon contract initiation.

E.2.d. Clinical Data Review

Data shall be Quality Controlled to meet interim quality checks (“sanity checks”) upon input into the contractor’s systems. Interim quality checks shall include, at a minimum:

1. Date sequences and continuity are reasonable.

2. Values are within permitted value domain lists, numerical range, and appropriate units.

3. Data submitted through the electronic system corresponds to information provided in the pathology reports and histopathology images submitted by the

TSS.

4. All TSS submitted data conform to the histopathology of the frozen sections obtained at the BCR.

5. The contractor shall review the clinical and biospecimen data for the purpose of qualification within nine (9) weeks of receipt of the sample.

E.3. Storing and Managing the CPTAC Biospecimen Collection

Biospecimen Management encompasses the logistics of biospecimen collections and receipt, annotation, storage management, location management, internal movement and distribution. To achieve this function, the contractor shall obtain or develop SOPs for all processes involved in tissue sample collection, 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.

E.3.a. Specific Requirements for Biospecimen Storage

E.3.a.(1). The contractor shall support the following storage environments:

a. Vapor phase liquid nitrogen freezers (‐186°C to ‐150°C).

b. ‐80°C and ‐20°C mechanical freezers.

c. Humidity and room temperature controlled areas.

E.3.a.(2). The contractor shall support repositories for:

a. FFPE slides.

b. Frozen tissue cryo‐vials.

c. Blood and blood components in liquid and pellet form.

d. DNA, RNA.

E.3.a.(3). The contractor shall be able to store long‐term, per tumor project:

a. 17455 total solid tissues in individual cryotubes in at ‐150°C. This number represents 2909 cases with 5 tumor sub‐samples and 1 normal sample in an individual cryotube per case.

b. 1600 buffy coat preparations at ‐150°C.

c. Up to one hundred 96 well plates of mRNA for RNA‐SEQ at ‐150°C.

d. Up to one hundred 96 well plates of mRNA for miRNA‐SEQ at ‐150°C.

e. Up to one hundred 96 well plates of tumor DNA at ‐150°C.

f. Up to one hundred 96 well plates of normal DNA at ‐150°C.

g. Up to 15000 2D Data Matrix tubes (bottom and side labeled), stored according the analyte within.

h. Up to 30,000 FFPE slides at room temperature

i. Up to 30,000 frozen‐section slides at room temperature

E.3.a.(4). Additional Requirements for Biospecimen Storage.

a. Additional working storage space in the above environments to support the internal operations of the BCR for activities such as processing, QC, backup, and working storage prior to shipment of analytes.

b. 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 have a protocol for personnel notification and action in the event of emergency.

c. Tissue biospecimens that are stored at liquid nitrogen vapor temperature shall be managed according to SOPs that minimize warming.

d. Before any personnel start work on this contract, each individual needs to have proper training to perform all tasks as described in SOPs. The BCR will be required to perform regular documented training of study personnel.

The BCR shall provide documentation of this required training in their monthly report to ensure that all staff is appropriately prepared to undertake the assigned work.

E.3.b. Each step of biospecimen logistics for all samples shall be supported and data collected in computer systems capable of exporting data according to the requirements to be developed for transmitting data to the CPTAC NCI‐OTS CDR

(Section E.8). A high throughput, production ready software system to support the logistics shall be required.

E.4. Managing and Storing the CPTAC Data

The contractor’s electronic systems shall support collection, management and distribution of all data described in this SOW in a secure and well‐described informatics environment.

This includes managing and storing the biological data associated with the biospecimens such as the clinical and biospecimen data obtained from the TSSs as well as biospecimen annotation data developed at the BCR (e.g., pathology annotation and specimen‐specific characterizations). Additionally, these systems shall support logistical and laboratory processes as described elsewhere in the SOW, and collect relevant tracking and QC data.

The contractor shall interact with the CPTAC DCC and CPTAC NCI‐OTS CDR as necessary to ensure that data conform to CPTAC Project requirements, NIH policy, are appropriately accessible and capable of integration with the molecular and proteomic data. The CPTAC

DCC shall be the ultimate repository of all outwardly accessible data generated as part of the CPTAC Project (see https://cptac‐data‐portal.georgetown.edu/cptacPublic/). The creation of a CPTAC‐wide database by the Contractor is not in the scope of this SOW. The contractor’s informatics responsibility is limited to biospecimen associated data including, but not necessarily limited to: TSS information and protocols, clinical data, pathology data, histological and molecular processing and QC and annotation, and biospecimen and molecular analyte tracking.

Syntactic and semantic interoperability of the data collected throughout the entire CPTAC program is a requirement for the project. The contractor shall ensure that the data delivered from its informatics systems to the CPTAC DCC are compliant with NCI compatibility guidelines for creating the Common Data Elements (CDE) that make up the

CRFs. (https://wiki.nci.nih.gov/display/caDSR/caDSR+Wiki+Home+Page). The contractor shall be given points of contact by the NCI COR in the NCI CBIIT that shall provide guidance and assistance.

Note that the requirements listed below describe functionality expected across the entire

IT infrastructure of the BCR and are not intended to describe the characteristics or specific functionality of any single IT solution or software suite used to create the infrastructure.

The contractor shall ensure that their overall informatics system is capable of meeting the requirements while providing the capability of efficiently extracting the information for transmission to the CPTAC DCC and creating reports and dashboards.

E.4.a. Specific Requirements for the Electronic Storage of CPTAC Clinical Data

The contractor shall securely deploy and maintain an informatics system that shall collect, store, and distribute biospecimen and clinical data from TSSs and any additional data generated at the BCR that is most appropriately stored in the clinical system. The contractor shall be aware that data elements and data models may change during the period of performance of the contract, but any changes do not diminish the requirements to have this system deployed and continually operational. Data associated with the patient cases and their biospecimens that shall be managed include, but are not necessarily limited to:

1. Allowable use, as obtained from the informed consent and IRB protocol.

2. Contractual status, related to terms from MTAs and other IP restrictions relevant to BCR operations and use of biospecimens and data within CPTAC.

3. Biospecimen and associated clinical data received from TSS.

4. Histopathology data from either the TSS or developed internally.

The contractor’s clinical data storage system shall allow conformance with the patient protection requirements described in Section E.2.c. The contractor’s clinical data storage system shall also allow the creation of the electronic CRF described in

Section E.2.c. and the secure, web‐based access required by the TSS for data entry into the CRFs.

E.4.b. Specific Requirements for Biospecimen Computer‐based Tracking: “Supply Chain”

Logistics, Receipt and Shipment, and Storage

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. The contractor shall implement a bioinformatics Laboratory Informatics System (LIMS), 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

CPTAC. 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 necessarily be limited to:

1. Shipment from TSSs, receipt, initial biospecimen registration, and the results of quality review of specimens at receipt.

2. Intended CPTAC 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 regular CPTAC data generation or part of a cancer‐specific pilot project to test new protein extraction techniques, new tissue processing techniques, etc.).

3. Tissue sample accesses for pathology 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.

4. Freezer and storage unit accesses.

5. Processing of tissue samples into subcomponents or derivatives.

6. Processing step that includes sample warming above its normal storage temperature

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

8. Sub‐dividing of tissue samples (including macro‐ or micro‐dissection, serial slicing, or cryopulverization of tissues).

9. Aliquotting of molecular derivatives.

10. Dilutions or concentrations of analytes.

All non‐transient biospecimens shall be uniquely identified with one or more alpha‐ numeric strings (barcodes). In addition to any CPTAC and the contractor’s specific identifiers, see the requirements section on UUIDs for additional requirements on sample IDs.

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.

The LIMS shall be linked to laboratory processing and analysis equipment used in production, and shall support automated upload of data from that instrumentation for any type of data reportable under this work.

E.4.c. CPTAC Universally Unique Identifier (UUID)

The contractor shall ensure that all CPTAC business objects under its purview are universally and uniquely identified. All non‐transient objects tracked in the BCR databases shall have a CPTAC UUID.

1. The contractor is responsible for obtaining or developing a system to generate

UUIDs.

2. The CPTAC UUID shall not necessarily supplant other identifiers currently used for regular operations, both human and machine, within CPTAC network.

3. The BCR shall implement software, data models, and other systems as necessary to be capable of:

a. Generating UUID locally, for association with any object received not already associated with at CPTAC UUID.

b. Receiving UUIDs, individually, within a range, or in batches, from other

CPTAC entities to associate with not‐yet‐ID’d objects in its databases.

c. Distributing the UUID as required with all data and sample distributions.

d. Maintaining the UUID association in all databases and data distributions required under this statement of work.

4. As needed, the contractor shall transmit UUIDs back to the TSSs.

E.4.d. Other System Requirements

1. The contractor shall utilize an electronic system to collect, store and share all comparable tissue and molecular analyte Quality Control data collected from

TSS and generated by the Contractor. These data shall include, but are not necessarily limited to:

a. Results of the analyses of frozen sections.

b. Contamination testing.

c. Laboratory processing steps hypothesized to affect quality.

d. DNA and RNA quality testing.

2. The overall system…