Attachment3.pdf

Attachment 3: Statement of Work Page 1 of 27

Attachment 3: Statement of Work – Clinical Trials Monitoring Service

List of Acronyms and Definitions

AdEERS: Adverse Event Electronic Reporting System – any serious, fatal or life-threatening clinical experience which is thought to be drug or treatment related.

AE: Adverse event

APIs: Application Programmatic Interfaces

BRIDG: Biomedical Research Integrated Domain Group caBIG™: Cancer Biomedical Informatics Grid – caBIG™ is an initiative being used to accelerate research discoveries and improve patient outcomes by linking researchers, physicians, and patients throughout the cancer community. The vision of caBIG™ is a full cycle of integrated cancer research, extending from bench to bedside, and back again.

caGRID: A voluntary virtual informatics infrastructure that connects data, research tools, scientists, and organizations to leverage their combined strengths and expertise in an open federated environment with widely accepted standards and shared tools.

caDSR: Cancer Data Standards Repository

Cancer Centers: NCI-designated cancer centers are characterized by scientific excellence and the capability to integrate a diversity of research approaches to focus on the problem of cancer.

They play a vital role in advancing towards NCI’s goal of reducing morbidity and mortality from cancer.

CBIIT: Center for Biomedical Informatics and Information Technology

CCOP: Community Clinical Oncology Program – CCOP is a cooperative agreement supported program which provides support to community-based oncologists to allow them to participate in clinical trials sponsored by the clinical cooperative groups and/or cancer centers. Each CCOP is expected to enter a minimum of 50 patients per year on NCI-approved research protocols. There are currently 52 funded programs located throughout the United States.

CCOP Research Base: Community Clinical Oncology Program Research Base – an institution or cooperative group that assumes a broad range of responsibilities and functions for the support of clinical research participating sites. The Research Base(s) support clinical trial research protocols.

CDE: Common Data Elements – a unique language for cancer clinical trials; it was developed to standardize the terminology utilized in clinical trials and to promote the uniform collection of

Attachment 3: Statement of Work Page 2 of 27 study data.

CDISC: Clinical Data Interchange Standards Consortium

CDMS: Clinical Data Management System- a software package to be purchased by NCI for distribution to institutions free of charge for use in clinical trials.

CDS: Clinical Data System

CDUS: Clinical Data Update System – a CTEP trial monitoring and summary system

CGCB: Clinical Grants and Contracts Branch, CTEP, DCTD, NCI

CIB: Clinical Investigations Branch, CTEP

CIP: Cancer Imaging Program, Division of Cancer Treatment and Diagnosis

Cooperative Groups: Cooperative study Groups are composed of investigators who join together to develop and implement common protocols. Each group is governed by a constitution written and agreed to by the membership. A chairperson elected by the membership leads the group..

The distinguishing characteristic of cooperative groups is the central operations and statistical offices that support the administrative requirements of the research and perform central data collection and analysis.

COTR: Contracting Officer’s Technical Representative

COTS: Custom off-the-shelf product is a product which can be purchased without being specifically developed for a client. The contractor installs and maintains the product for the client.

CRA: Clinical Research Associate

CRC: Clinical Research Coordinator

CSD: Clinical Studies Detail

CSS: Clinical Studies Summary

CTCAE: Common Terminology Criteria for Adverse Events- a standardized vocabulary for defining and grading adverse events.

CTEP – Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, NCI.

CTEP-ESYS: Cancer Therapy Evaluation Program Enterprise System

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CTMB: Clinical Trials Monitoring Branch, CTEP, DCTD, NCI, NIH

CTMB-AIS: CTMB Audit Information System- an electronic system for scheduling audits, submitting audit reports and tracking audit follow-up.

CTMS - Clinical Trials Monitoring Service

CTSU: Cancer Trials Support Unit. This project coordinates participation in NCI sponsored clinical trials.

CTWG: Clinical Trials Working Group

DARF: NCI Drug Accountability Record Forms used for tracking NCI-supplied investigational agents.

DCP: Division of Cancer Prevention, NCI

DCTD: Division of Cancer Treatment and Diagnosis, NCI

DHHS: Department of Health and Human Services

EVS: Enterprise Vocabulary System

FDA: Food and Drug Administration

FISMA: Federal Information Security Management Act

FOCUS: Database software application

Form FDA 1572: Referred to as a “Statement of Investigator”; it is a requirement of section 505(i) of the Food, Drug and Cosmetic Act and paragraph 312.1 of Title 21 CFR, that an investigator complete this form as a condition for receiving and conducting clinical trials involving investigational drug(s). It includes the investigator’s training and experience and provides for legal certifications.

FTP: File transfer protocol

GCP: Good Clinical Practices

ICH: International Conference on Harmonization

HIPPA: Health Insurance Portability and Accountability Act (HIPAA) was enacted in 1996 with the intent of protecting health insurance for workers when they change or lose their jobs as well as requires the establishment of national standards for electronic health care transactions and national identifiers for providers, health insurance plans, and employers. The Administration

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Simplification provisions also address the security and privacy of health data. The standards are meant to improve the efficiency and effectiveness of the nation's health care system by encouraging the widespread use of electronic data interchange in the U.S. health care system.

HL7: Health Level Seven

HTTP: Hypertext transfer protocol

IDB: Investigational Drug Branch, CTEP

IND: Investigational New Drug Application – submitted to the Food and Drug Administration in order to receive an exception from the New Drug Application approval requirements so that experimental clinical trials may be conducted.

IRB: Institutional Review Board

IT: Information Technology

MD: Monitors Detail Report

MedDRA: Medical Dictionary for Regulatory Activities

MS: Monitors Summary

NCI: National Cancer Institute

NDA: New Drug Application

NIH: National Institutes of Health

OPEN: Oncology Protocol Enrollment Network

PATS: Protocol Approval and Tracking System, a component of the CTEP Enterprise System.

PLA: Product Licensing Application

PIO: Protocol and Information Office, CTEP, DCTD, NCI

PMB: Pharmaceutical Management Branch, CTEP, DCTD, NCI

PO: Contracting Officer’s Technical Representative

PRC: Protocol Review Committee, CTEP

QA: Quality Assurance http://en.wikipedia.org/wiki/Electronic_data_interchange

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QASP: Quality Assurance Surveillance Plan

RAID: Rapid Access to Intervention Development- Program designed to assist in translation to the clinic of novel anticancer therapeutic intervention, either synthetic, natural product, or biologic, arising in the academic community.

RSS: Regulatory Support System

SAS: Statistical analysis software

Site: Used as a general term to describe the institution where the patient signed the Informed Consent. Each institution is assigned a unique NCI Institution Code. The institution may be an NCI designated Cancer Center, academic medical center, government-owned hospital (Veteran’s Administration Hospital, military hospital, etc.) community hospital or physician/group practice office.

SPORE: Specialized Programs of Research Excellence

TAC: Treatment Assignment Code

XML: Extensible Markup Language - general-purpose markup language. It is classified as an extensible language because it allows its users to define their own tags. Its primary purpose is to facilitate the sharing of structured data across different information systems, particularly via the Internet. It is used both to encode documents and serialize data.

Notes: Reference Web sites http://cancercenters.cancer.gov/cancer_centers/index.html http://www.cancer.gov/cancertopics/factsheet/NCI/clinical-trials-cooperative-group http://en.wikipedia.org/wiki/Markup_language http://en.wikipedia.org/wiki/Extensible_language http://en.wikipedia.org/wiki/Tags http://en.wikipedia.org/wiki/Internet http://en.wikipedia.org/wiki/Serialization http://cancercenters.cancer.gov/cancer_centers/index.html

Attachment 3: Statement of Work Page 6 of 27

Background Information

The Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI) is responsible for the administration and coordination of the majority of extramural clinical trials supported by the DCTD. The DCTD also coordinates an international program of cancer research concerned with the development and testing of new therapies for the treatment of cancer. The Division has five major programs. Each of these Programs has separate and distinct responsibilities involving the discovery of new agents and treatment modalities, pre-clinical testing, and development of new agents and treatment modalities through the various phases of the clinical trials process. This includes the development and evaluation of new and innovative methods for diagnosis, treatment and management of cancer and related symptoms and side effects for the control and the mitigation of the burden of cancer utilizing all modes of therapy. NCI-sponsored clinical trials are conducted both intramurally at the NIH Clinical Center and extramurally at academic medical center, hospitals, clinics and physician offices through a variety of funding mechanisms such as cooperative agreements, grants, contracts, and transfer of funds to other Federal agencies.

DCTD/CTEP is responsible for the oversight, compliance, adherence to federal regulations, and monitoring and auditing to assure the highest quality of data and the protection of human subjects.

The CTEP is responsible for sponsoring and monitoring clinical trials of Investigational New Drug Applications (INDs) of anticancer compounds that have been approved for testing in clinical research studies in humans by the Food and Drug Administration (FDA). In addition, CTEP/DCTD also provides support to the clinical trials programs of the Division of Cancer Prevention (DCP) and other NCI programs such as the Cancer Imaging Program (CIP). CTEP oversees clinical trials that are funded through a variety of mechanisms, the largest being the Cooperative Groups. The Phase 0, 1, 2, and 3 clinical trials are conducted by numerous investigators in facilities throughout the United States and abroad. The DCTD also supports clinical trials through a variety of cooperative agreements, consortium agreements, grants, contracts or by supplying NCI-sponsored investigational agents. CTEP is comprised of seven Branches which include: the Operations and Informatics Branch (OIB) (formerly known as the Protocol and Information Office), the Clinical Grants and Contracts Branch (CGCB), the Clinical Investigations Branch (CIB), the Clinical Trials Monitoring Branch (CTMB), the Investigational Drug Branch (IDB), the Pharmaceutical Management Branch (PMB), and the Regulatory Affairs Branch (RAB).

The NCI/DCTD has developed standardized Common Terminology Criteria for Adverse Events (CTCAE), common data elements (CDEs) and electronic reporting systems including the Clinical Data System (CDS) and the Adverse Event Expedited Reporting System (AdEERS), which are both integral components of the CTEP Enterprise System (CTEP-ESYS). Further information pertaining to the electronic reporting systems CDS and AdEERS can be found at:

http://ctep.info.nih.gov/reporting/. DCTD’s informatics and technology is further advancing under the auspices of the Cancer Bioinformatics Grid (caBIG™), which is a major NCI initiative to bring all informatics systems in concert to utilize a uniform standard. In 2004 the Clinical http://ctep.info.nih.gov/reporting/

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Trials Working Group (CTWG) presented a report that included several informatics based objectives. This included the development of a database to serve as a central source of data for reporting and sharing information on all NCI sponsored clinical trials. The report also included the development and implementation of a plan that will enable all NCI supported internal and external clinical trials systems to seamlessly share standardized information that is interoperable with caBIG™. The caBIG™ endeavors relevant to this contract include but are not limited to establishing a comprehensive community-accessible NCI clinical trial database, promotion of information sharing between systems supporting NCI clinical trials, establishing a core library of standardized patient case report data forms through stakeholder consensus, and developing a credentialing system for investigators. Further information concerning the various initiatives of caBIG™ can be found at: https://cabig.nci.nih.gov/overview/.

The CTMB is responsible for on-site auditing of all clinical trials sponsored by the DCTD/CTEP as well as the monitoring of select trials sponsored by the Division of Cancer Prevention (DCP).

CTEP employs a centralized monitoring mechanism whereby data is submitted from sites participating in NCI sponsored clinical trials by electronic means via the Clinical Data System (CDS) for routine data submissions and via the AdEERS system for expedited reporting of adverse events. Data from CDS and AdEERS is reviewed by the Drug Monitors in the Investigational Drug Branch (IDB), CTEP. On-site monitoring is auditing and involves ensuring compliance with regulatory requirements, Good Clinical Practices, and NCI policies and procedures with the overarching goal of ensuring the integrity of data generated from NCI-sponsored clinical trials. CTMB accomplishes the goals of compliance and integrity through the auditing of all institutions (often referred to as sites in the Statement of Work). A site is a general term to describe the institution where the patient signed the Informed Consent. Each institution or site is assigned a unique NCI Institution Code. The institution may be an NCI designated Cancer Center, academic medical center, government-owned hospital (Veteran’s Administration Hospital, military hospital), community hospitals or physician/group practice office conducting DCTD sponsored IND clinical trials and the oversight of all Cooperative Groups, Community Clinical Oncology Program (CCOP) Research Bases and the Clinical Trials Support Unit (CTSU) quality assurance and audit programs. The CTMB is responsible for assuring that DCTD as a sponsor of clinical trials fulfills its obligations in regards to FDA regulations, Office for Human Research Protection (OHRP) regulations, Office of Research Integrity (ORI), and HHS/NIH/NCI policies, procedures, and regulations. One of three monitoring methods is employed and the decision as to which monitoring method is chosen is determined at the Protocol Review Committee at the time of initial approval of the study. The general requirements regarding the conduct of the audit remain the same, regardless of the monitoring method. A synopsis of the monitoring and auditing mechanisms is provided below:

https://cabig.nci.nih.gov/overview/

Attachment 3: Statement of Work Page 8 of 27

Phase of Study Study Monitoring Reporting Mechanism Auditing Phase 0, Phase 1 (early) and select Phase 2

CTMS + CTEP Bi-weekly CRFs to

CTMS

Monthly CTMS reports, downloads to

CDS

Real-time Expedited Adverse Event Reporting via AdEERS

CTMS

Pharm.D./M.D.

once per year

CTMS

CRA twice per year

Phase 2 and Phase 3 Cooperative Group Study

Cooperative Group +

CTEP

CDS Quarterly data submissions

Real-time Expedited Adverse Event Reporting via AdEERS

Group physicians, CRA’s nurses

Once every 36 months

Phase 2 and Phase 3 Cancer Center/Single Institution

CTEP CDS Quarterly data submissions

Real-time Adverse Event Reporting via AdEERS

CTEP + CTMS +

Outside Peer Physicians

Once every 36 months

To assist the CTEP in fulfilling its regulatory responsibilities as an IND sponsor and to assure protocol compliance and source data verification, the Clinical Trials Monitoring Service (CTMS) Contractor shall be responsible for the following tasks:

TASK I: To provide a protocol central patient registration, protocol patient data capture resource, and patient data quality control reviews for the Division of Cancer Treatment and Diagnosis (DCTD) for clinical investigators conducting phase 0 (exploratory IND), phase 1 and selected phase 2 clinical trials.

Option A: Integration and maintenance of NCI purchased Clinical Data Management System

(CDMS) into CTMS processes, workflow and IT infrastructure.

TASK II: To provide an on-site auditing resource for the DCTD to assure that contractors, grantees and other clinical investigators conducting phase 0, phase 1 and selected

Attachment 3: Statement of Work Page 9 of 27 phase 2 clinical trials are in compliance with federal regulations, Good Clinical Practices (GCP), and NCI policies and procedures in order to verify submitted protocol patient data, assure the quality of submitted data, assure protocol compliance, and assure patient safety through proper reporting.

TASK III: To assure the DCTD that the quality assurance programs of the Cooperative

Groups, Community Clinical Oncology Program (CCOP) Research Bases, the Clinical Trials Support Unit (CTSU), and other selected multi-institutional consortiums are actively monitoring their NCI sponsored clinical studies in compliance with the AGuidelines for Monitoring of Clinical Trials for Cooperative Groups, CCOP Research Bases, and CTSU@. This shall be accomplished by attending as co-site visitors, scheduled audits conducted by Cooperative Groups, Cancer Center CCOP Research Bases, and the CTSU or selected consortiums.

TASK IV: To assure the DCTD that all cancer centers, single institutions, multi-institutional consortiums and networks conducting clinical trials using DCTD sponsored trials are in compliance with Federal regulations, Good Clinical Practices (GCP), NCI policies and procedures. This oversight shall be accomplished by on site auditing at these institutions at least once every three years.

Option B: Expand capability for conducting on-site audits to encompass the expanded scope of trials conducted under the auspices of the Cancer Trials Support Unit (CTSU).

This expansion may also include clinical trials sponsored by other NCI Programs (SPORES, RAID and imaging).

TASK V: To assure the DCTD that international groups/institutions who are collaborators in DCTD sponsored clinical trials are conducting these trials in accordance with Good Clinical Practices (GCP) and International Conference on Harmonization (ICH) standards. This shall be accomplished through training and administrative support for quality assurance programs to ensure that GCP clinical trial and regulatory standards are met, particularly the protection of human subjects.

DETAILED TASK REQUIREMENTS:

The Contractor shall furnish services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government under the terms of this contract, as needed to provide a Clinical Trials Monitoring Service (CTMS) as set forth below:

A. Task I – Patient Registration, Protocol Patient Data Capture and Quality Control Reviews for Phase 0, Phase 1 and Selected Phase 2 Clinical Trials

1. The Contractor shall abstract approximately 25 new phase 0, phase 1 and selected phase 2 protocols per year for IND agents and other targeted agent protocols assigned by the Protocol Review Committee of CTEP for CTMS monitoring. The protocol abstraction process is undertaken to generate protocol-specific eligibility

Attachment 3: Statement of Work Page 10 of 27 checklists for the sites, to establish protocol-specific parameters for the database, to set-up a process for the computerized protocol patient data capture system, and to be utilized in the quality control review process as data is submitted from the sites. The number of protocols requiring abstraction for CTMS monitoring could increase or decrease depending on the number of IND filings; the Contractor shall be flexible in their approach to account for the possibility of fluctuations in number of IND filings.

2. The Contractor shall implement and maintain a 24 hour/day/week web-based protocol patient registry system, with back-up procedures in the form of telephone and facsimile available during the core hours of 8:30 a.m. to 5:00 p.m. ET Monday-Friday in the event of prolonged (greater than 3 hours) internet connectivity disruption. A log of down time shall be maintained and available for periodic review by the Contracting Officer’s Technical Representative. A 24 hour advanced notification (via email) shall be sent to the Contracting Officer’s Technical Representative as well as all system users announcing down time for routine maintenance. Unanticipated problems requiring emergency maintenance shall be announced via email to the Contracting Officer’s Technical Representative as well as all users prior to the system being taken off-line. Any other down time occurring without advance notification will be considered unscheduled down time.

3. The Contractor shall continuously maintain, enhance and revise as necessary a computerized protocol patient data capture system that is compatible with the CTEP-ESYS and can retrieve and review for quality control purposes medical information from electronic patient data capture systems. The electronic data capture system shall enable the automation of multi-user protocol patient data handling for single or multiple-site clinical research studies utilizing a web-based environment.

4. For the com puterized protocol patient da ta capture system , the Contractor shall utilize a system with software capabilities that at a minimum shall include:

a. Support for electronic data submission with a PC-based data entry system via internet connection through HTTP or FTP to a networked database.

The Contractor shall implement the use of electronic Case Report Forms (CRFs) developed by caBIG™. The Contractor shall utilize procedures for the electronic transfer of data that shall meet or exceed the data security guidelines as found in the HHS “Automated Information Systems Security Handbook” see:

http://www.hhs.gov/ocio/policy/index.html#Security.

b. Data submissions in the form of individual protocol patient electronic CRFs or in electronic batch-mode from existing commercially available database systems (FOCUS, Oracle, SAS, C3D, etc.) from study sites.

c. Compiled datasets electronically exported in batch-mode from the Contractor’s system to the CTEP Clinical Data Update System (CDUS).

http://www.hhs.gov/ocio/policy/index.html#Security

Attachment 3: Statement of Work Page 11 of 27

Data transfers from CTMS to CDUS shall be performed on a monthly basis.

NOTE: The CDUS is an Oracle based system created and supported by the CTEP Informatics Support Contractor and caBIG™.

d. Effective utilization of common data elements (CDEs) registered in the Cancer Data Standards Repository (caDSR) to enhance semantic operability. The contractor shall transition from CDE’s to standardized electronic case report forms developed by caBIG™.

e. An interface with the Enterprise Vocabulary System (EVS) developed by NCI and incorporate the utilization of appropriate models, such as Biomedical research Integrated Domain Group (BRIDG), Clinical Data Interchange Standards Consortium (CDISC), and Health Level 7 (HL7) for data transfer, and/or other models, as directed by the Contracting Officer’s Technical Representative.

5. The Contractor shall utilize electronic edit checks, which enables data fields to be reviewed for accuracy. Corrections shall be made before data is transferred to CTMS. The interface must be intuitive and user- friendly and utilize a range of expected values for data fields. Clinical data that does not meet the pre-defined expected range shall be flagged for review by the submitter and may be verified, edited or flagged for deletion. The Contractor shall employ a system to track all changes to data.

6. The Contractor shall monitor and promote timely data submission on a biweekly basis from the sites participating in CTMS monitored studies and shall monitor and send notifications via email to sites that are delinquent in data submissions.

7. The Contractor shall conduct quality control reviews of the submitted data as it is received from sites. When conducting the quality control reviews the Contractor shall check for accuracy, completeness, and compliance with protocol-specified requirements and cross-check laboratory data and other clinical data to ensure compliance with adverse event reporting requirements. The Contractor shall initiate clarifications requests to the site when data discrepancies are noted.

8. The Contractor shall participate in ongoing integration and harmonization efforts of informatics systems that may require changes to the CTMS systems and processes.

a. The Contractor shall inform the Contracting Officer’s Technical

Representative of system changes and processes.

b. The Contractor shall provide accurate project and cost status to developers, end users, and relevant stakeholders as identified by the Contracting Officer’s Technical Representative.

c. The Contractor shall provide impact analysis for all change requests including costs, personnel, and labor hours and affected CTEP-ESYS applications.

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d. The Contractor shall notify all relevant stakeholders prior to implementation of any changes to CTMS systems.

e. As systems become more integrated, the Contractor shall, at the request of the Contracting Officer’s Technical Representative, participate in CTEP- ESYS change management activities, including but not limited to participating in application stakeholder meetings and reviewing CTEP- ESYS change requests that may impact CTMS systems and processes.

9. The Contractor shall provide expert advice to the Contracting Officer’s Technical

Representative and participate fully in discussions regarding system integration and harmonization. The Contractor shall at a minimum perform the following tasks:

a. Harmonize CTMS systems with caBIG™ standards to promote interoperability among the systems.

b. The Contractor shall utilize an available information technology infrastructure that is interoperable with CTEP-ESYS and CTSU.

c. The Contractor shall perform analysis on all system-to-system harmonization and integration activities.

d. The Contractor shall attend appropriate caBIGTM and CTEP informatics meetings and seek input from the Government on new software purchases and conversions to meet specific internal or external technology needs.

e. If the Contractor is considering a COTS product for integration, the Contractor shall ensure that each vendor provides necessary and sufficient customized interfaces using database-to-database connectivity tools and XML-to-XML tools to streamline integration projects with CTEP’s legacy application. The Contractor shall provide a well documented and published set of Application Programmatic Interfaces (APIs) and/or web services to access (read, write, and update) underlying data in a transactional format to facilitate effective systems integration.

10. The Contractor shall provide on-line access to clinical reports as outlined in the

Statement of Work in section A.15. The reports shall be available to CTEP staff and designated supporting staff as directed by the Contracting Officer’s Technical Representative at any time. Data in the patient database shall be accessible to authorized users through a secure internet connection. Similar reports shall be available to authorized staff at the lead organization for multi-center trials. The database shall be Oracle or similar software based product and utilize Windows.

The database that supports these queries shall be updated monthly.

11. The Contractor shall provide technical support for the use of software capable of transmitting data in a format this is compatible with existing systems. As needed, the Contractor will provide training and help sessions for the use of the software for data collection, analysis and transmission to CTMS. The help system shall include, in addition to traditional protocol patient data capture transmission support messaging, the use of CTCAE toxicity criteria as well as the CTCAE

Attachment 3: Statement of Work Page 13 of 27 adverse event coding dictionary (MedDRA) as they apply to CTMS assigned clinical trial sites.

12. The Contractor shall maintain the existing patient data base in the format currently utilized (Oracle) by the incumbent CTMS Contractor or in a format that is transferable or convertible from the incumbent’s format. The Contractor shall provide the computer software and equipment to maintain the CTMS database for assessing this information in a flexible and convenient manner. The system must be flexible enough such that alternative report formats may be readily created and utilized as required.

NOTE: A typical set of data may be organized by investigational agent, institution, protocol number, dose level, patient and course.

13. The Contractor shall provide 24 hour on-line access to the data reception facility that shall be available to all users for direct data transmission. The Contractor shall assure the availability of access for data transmittal at all times. A log of any down time shall be maintained and available for periodic review by the Contracting Officer’s Technical Representative. A 24 hour advanced notification (via email) shall be sent to the Contracting Officer’s Technical Representative as well as all system users announcing down time for routine maintenance.

Unanticipated problems requiring emergency maintenance shall be announced via email to the Contracting Officer’s Technical Representative as well as all users prior to the system being taken off-line. Any other down time occurring without advanced notification will be considered unscheduled down time. Technical telephone support for direct data entry problems shall be available to users during normal working hours (Monday through Friday, 8:30 a.m. to 5:00 p.m. Eastern Time) or via e-mail.

14. The Contractor shall assure that clinical data is submitted to the CTMS with identifying numbers only. Patient names or unique identifiers, such as social security numbers shall never be used; all patient electronic records shall be treated as confidential material. If copies of source documents are obtained, any reference to name other than the patient's initials and/or identifying number shall be deleted.

The Contractor shall retain all patient/study records for a period of two years after the termination of an IND or after the approval of a New Drug Application (NDA) or Product Licensing Application (PLA), unless otherwise specified by the NCI during the performance period of this contract. Only upon written approval by the Contracting Officer may records be destroyed.

15. The Contractor shall prepare the following reports in accordance with Articles C.2., Reporting Requirements, and F.1., Deliveries.

a. Monitors Summary (MS) - summarizes the administrative conduct of studies, data submission status, protocol status, patient accrual and basic performance indicators.

Attachment 3: Statement of Work Page 14 of 27

b. Clinical Studies Summary (CSS) - summarizes dose levels and incidence of toxicity.

c. Monitors Detail (MD) Reports - detailed section display for each study.

d. Clinical Studies Detail (CSD) Reports - shall include the following types of reports: patient detail reports, patient summary reports, toxicity detail reports, study synopsis reports, toxicity cross tabulation, and response summary.

e. Special Ad Hoc reports (approximately 35/year) shall be generated as requested by the Contracting Officer’s Technical Representative (i.e. Organ Dysfunction Group).

16. The Contractor shall maintain separate financial accounting procedures for the cost of data collection in order for the Contracting Officer’s Technical Representative to perform cost analysis on the various cost categories and expeditiously respond to data requests. The financial accounting at a minimum shall be kept by institution, treatment, and phase of study.

17. The Contractor shall maintain and update on an annual basis, the monitoring plan for CTEP to submit as part of their Drug Master File on file with the FDA. The monitoring plan shall include procedures for the operation of the protocol patient data system and protocol patient data quality control reviews. The monitoring plan shall contain concise instructions for the handling of protocol patient data capture systems, quality control review storage procedures, and training of staff.

18. The Contractor shall maintain a duplicate copy of the database files and programs in a physically separate facility that meets industry standards for retrievable electronic data. The duplicate copy shall be on tape, disk, or other appropriate electronic medium and shall be updated at least once every week.

B. Option A: Clinical Data Management System (CDMS) Integration and Maintenance

1. If this option is exercised the Contractor shall integrate the CDMS into their processes, workflow and IT infrastructure.

2. The Contractor shall establish electronic linkages to accept data submissions from sites utilizing CDMS by developing, testing and deploying a set of Application Programmatic Interfaces (APIs) and/or web services to access (read, write, and update) underlying data in a transactional format to facilitate transmission and storage in the CTMS database.

3. In developing electronic linkages, the Contractor shall ensure flexibility in their approach so that sites utilizing other remote data capture systems may continue to do so without being adversely effected by any changes made to accommodate CDMS or the maintenance of legacy data.

4. The Contractor shall transition from the use of CDE’s to eCRFs as developed by caBIG™.

Attachment 3: Statement of Work Page 15 of 27

5. The Contractor shall, as directed by the Contracting Officer’s Technical Representative, provide training and support to Data Managers on the use of software to transmit patient data capture for CTMS monitored studies.

Note: The acquisition and deployment of the CDMS represents essential steps in realizing a primary NCI goal to facilitate development of a shared infrastructure that will support an integrated national cancer clinical trials network. This reflects a key recommendation of the National Cancer Advisory Board Clinical Trials Working Group 2005 report, Restructuring the National Cancer Clinical Trials Enterprise.

The NCI is purchasing perpetual licensing rights from a commercial vendor to distribute the Clinical Data Management System (CDMS) software package for free to NCI-supported institutions that elect to use it for cancer clinical trials. The CDMS will deliver a full-function clinical data management capability to the entire NCI-supported clinical research community, irrespective of a given organization’s ability to pay for such a system. The system will be made available free of charge to the CTMS contractor. It is an unlimited-user, perpetual license that can be used for all cancer trials, including industry. For additional background please refer to https://cabig.nci.nih.gov/vendor-cdms/vendor-tradename-clinical-data-management-system-cdms/?searchterm=cdms

C. Task II - Auditing for Phase 0, Phase 1 and Selected Phase 2 Clinical Trials

1. The Contractor shall conduct 60-80 on-site audits per year of investigators conducting phase 0, phase 1 and select phase 2 studies assigned by PRC, CTEP for CTMS monitoring.

a. The Contractor shall provide a Physician Monitor or Clinical Research

Coordinator (CRC)/Clinical Research Associate (CRA) with training and expertise to oversee the on-site auditing and to carry out certain aspects of the monitoring as described below.

b. New investigators/institutional sites, previously not participating in DCTD clinical trials, shall be visited by a Physician or CRC prior to initiation of a study at the discretion of the Contracting Officer’s Technical Representative. After the initial site visit, each investigator shall be audited at time points dependent upon accrual during the course of the clinical trial and the type of clinical trial (phase 0, phase 1 or phase 2) being conducted. Data audits shall be conducted by the Clinical Research Associate/Assistant (CRA). Audits shall be scheduled at a minimum of 4 weeks in advance of the anticipated audit date.

c. The minimum requirements for the initial audit or subsequent audits shall be:

1) A meeting between the Contractor Physician/CRC or CRA and the investigator to review his/her understanding of FDA regulations http://integratedtrials.nci.nih.gov/ http://integratedtrials.nci.nih.gov/ http://integratedtrials.nci.nih.gov/ict/CTWG_report_June2005.pdf http://integratedtrials.nci.nih.gov/ict/CTWG_report_June2005.pdf https://cabig.nci.nih.gov/vendor-cdms/vendor-tradename-clinical-data-management-system-cdms/?searchterm=cdms https://cabig.nci.nih.gov/vendor-cdms/vendor-tradename-clinical-data-management-system-cdms/?searchterm=cdms

Attachment 3: Statement of Work Page 16 of 27 and DCTD policies/procedures for conducting investigational agent trials. These include:

a) FDA regulations concerning GCP, Institutional Review

Board (IRB) obligations, Informed Consent Regulations and Obligations of Sponsors, Monitors, and Investigators.

b) DCTD, CTEP requirements for submission and review and approval of protocol and amendments prior to clinical trial activation at an institution.

c) DCTD's Expedited Adverse Event Reporting Requirements via AdEERS and procedures and the use of DCTD’s Common Terminology Criteria for Adverse Events v 3.0

(CTAE).

d) NCI Drug Accountability Record Forms (DARFs) and pharmacy procedures for proper drug accountability.

e) Review of DCTD required protocol patient data capture procedures and quality control reviews of submitted data.

2) A review of the scope of the investigator's research efforts and the adequacy of facilities for conducting the research. The Physician/CRC/CRA monitor shall collect the institution=s laboratory normal values.

3) A review of regulatory procedures and documentation of approval for:

a) Verification of initial IRB approval for each protocol and all amendments, as well as the required continuing annual IRB approvals and safety reports.

b) Review of the local consent form to assure that it is consistent with the informed consent form approved by the CTEP, PRC. Also, a review shall be conducted to determine if the consent form being used is the current IRB approved version.

4) A data verification audit encompasses the submitted patient data component of the audit for a random sample of protocol accrued cases estimated to be at least 10% and/or a minimum of 3 patient cases. The Contractor shall review protocol compliance to assure patient cases are treated in accordance with protocol specifications and that data has not been omitted from submission.

The Patient Case Review will include:

a) Comparison of source documents to the protocol patient data capture submissions electronically.

b) For all patient cases reviewed, verification of the presence of an IRB approved, properly signed and dated informed consent form.

c) Verification of patient eligibility.

d) Assessment of compliance with protocol treatment requirements including the presence of proper

Attachment 3: Statement of Work Page 17 of 27 documentation of treatment administration and adherence to dose/treatment modification requirements.

e) Verification that the response is assessed in accordance with the criteria described in the protocol.

f) Review of patient records to ensure the timely reporting of adverse events requiring expedited reporting via AdEERS.

The Contracting Officer’s Technical Representative is to be promptly notified of any unreported adverse event during the audit that required expedited reporting.

g) Verification that protocol required parameters (labs, exams, scans, etc.) were obtained in accordance with the protocol.

5) A review of the NCI Drug Accountability Record Forms (DARFs) and of procedures for storage, distribution, and the security of investigational agents to include:

a) A comparison of actual shelf inventory (vial count) versus the NCI DARFs.

b) For the patient cases selected for audit, a comparison of agent dispensed as recorded on the NCI DARFs, versus that recorded as administered in patient source records.

c) A comparison of the NCI DARFs with the protocol registration listing along with dates to assure all patients who received investigational agents were actually registered on the specified protocol.

2. The Contractor shall notify sites of any data discrepancies uncovered during the on-site review of source documentation and shall monitor and track the discrepancies to ensure that corrected data is submitted by the site. The Contractor shall immediately notify the Contracting Officer’s Technical Representative and the Contracting Officer by telephone with a follow-up email of any findings suspicious and/or suggestive of intentional misrepresentation of data and/or disregard for regulatory safeguards for any of the three (regulatory, pharmacy and patient case) components of an audit.

Similarly, any data irregularities identified through other quality control procedures suspicious and/or suggestive of intentional misrepresentation of data must be immediately reported to the Contracting Officer’s Technical Representative and Contracting Officer.

3. The Contractor shall prepare a report of the findings of the audit that will be submitted within 10 working days of the date of the audit. The report is to be transmitted electronically utilizing the Clinical Trials Monitoring Branch Audit Information System (CTMB-AIS). The audit report shall contain a narrative description of the interaction between the Contractor auditor and the investigator.

The audit report shall summarize the findings and be submitted via the CTMB- AIS in the AIS format. The Contractor’s report of the audit findings shall follow the parameter fields contained in the CTMB-AIS and shall:

Attachment 3: Statement of Work Page 18 of 27

a. Provide general information specific to the institution such as number of cases audited, average annual accrual, institutional staff present at the audit, and identification (title and affiliation) of members of the audit team.

b. Provide regulatory reviews of IRB documents and informed consent documents. Provide the title of each protocol audited and list the number of patients audited, the IND drugs, treatment modalities used and the disease(s) studied in each protocol. For each protocol, indicate whether OK, major or lesser deficiencies were found and describe each major and lesser deficiency. For informed consent reviews, identify any deficiencies.

Provide an overall assessment for this component and indicate if a re-audit is required and the time frame.

c. Describe accountability of Investigational Agents and pharmacy operations. Indicate Yes or No if INDs or NCI supplied agents were used at this site during the period covered by this audit following the CTMB- AIS parameters by selecting the appropriate descriptive term: [Compliant, Non-compliant, or NR (Not Reviewed)], for the items included in the pharmacy section of the report. Provide an overall assessment for this component and indicate if a re-audit is required and the time frame.

d. Provide protocol patient case review for each category (eligibility, treatment, response, toxicity and data quality), indicate if major or lesser deficiencies were found and describe otherwise, put OK or NR (Not Reviewed). Provide an overall assessment for this component and indicate if a re-audit is required and the time frame.

e. Describe the audit procedures as well as other pertinent information.

f. Provide additional comment in the General Comment Section indicating if any data or correspondence were submitted by the institution following the audit which affects the audit outcome.

g. Conduct an exit interview and provide a summary of the audit findings, clarifications by the staff, and any recommendations by the audit team and indicate who was present.

4. The Contractor shall maintain and update on an annual basis the monitoring plan monitoring plan shall include procedures for the conduct of phase 0, phase 1 and select phase 2 audits. The monitoring plan shall contain at least the following:

a. A short description of the points to be discussed at the meeting between the monitoring Physician/CRC/CRA and the investigator as described in C.1.c.1) – 3).

b. An outline of procedures for conducting the protocol patient data audit, regulatory reviews and pharmacy reviews as described in C.1.c.4).

5. The Contractor shall maintain separate financial accounting procedures for the cost of travel and auditing in order for the Contracting Officer’s Technical Representative to perform cost analysis on the various cost categories and

Attachment 3: Statement of Work Page 19 of 27 expeditiously respond to data requests. The financial accounting at a minimum shall be kept by institution and phase of study.

D. Task III - Co-Site Visit Monitoring of NCI Clinical Trials Cooperative Groups, Community Clinical Oncology Program (CCOP) Research Bases, Clinical Trials Support Unit (CTSU) and Selected Multi-institutional Consortiums with Quality Assurance Programs

1. The Contractor shall attend between 70 and 90 site audits per year (approximately

10% of scheduled site visits) conducted by the NCI Clinical Trials Cooperative Groups, Cancer Center CCOP Research Bases, the Cancer Trials Support Unit (CTSU), and selected multi-institutional consortiums with auditing programs. The site visits will be conducted at institutions/sites throughout the U.S. and occasionally abroad. The site visits may include treatment and prevention trials or other trials as assigned by the Contracting Officer’s Technical Representative.

The Contractor must be able to accommodate multiple scheduled audits on the same day. The Contractor shall assure that each Cooperative Group CCOP Research Base or select Consortium is conducting audits in compliance with the CTMB AGuidelines for Monitoring of Clinical Trials for Cooperative Groups, CCOP Research Bases and Clinical Trials Support Unit (CTSU)” dated August 2001. The specific Cooperative Group/CCOP Research Base/CTSU/Consortium audits to be co-site visited by the Contractor will be designated by the CTEP Contracting Officer’s Technical Representative. The Contractor shall receive the assignments electronically via the CTMB Audit Information System (CTMB-AIS).

Note: See http://ctep.info.nih.gov/monitoring/guidelines.html).

2. The co-site visits shall be structured as follows:

a. The Contractor shall appoint an experienced Clinical Research Associate

(CRA) to accompany the Cooperative Group/CCOP Research Base/CTSU audit team. The audit team generally consists of at least one physician and one or two CRAs from the Cooperative Group/CCOP/CTSU/Consortium.

b. The CTMS CRA shall participate as an impartial observer of the methods and results of the site visit and report these findings to the Contracting Officer’s Technical Representative. The CRA may prompt members of the team if the audit team fails to review key issues included in the CTMB Guidelines. The CTMS CRA may also provide information on regulations and procedures at the request of the audit team or the audit investigator.

The CRA shall review all checklists and forms generated by the audit team prior to leaving the site.

3. The Contractor’s co-site visitors shall:

a. Participate as observers of audit process and audit outcome.

b. Review the audit checklists as completed by the

Group/CCOP/CTSU/Consortium auditors. The Contractor shall assure that the flow sheets or data abstracts that have been centrally submitted are

Attachment 3: Statement of Work Page 20 of 27 verified with source documents. Protocol compliance shall also be reviewed.

c. Review the audit of IRB initial approvals, annual approvals and amendment approvals.

d. Check the on-site informed consent review performed by the auditors.

e. Accompany the auditor who performs the pharmacy inspection and the review of the NCI Drug Accountability Records Forms (DARF), observe and record any problems encountered during the NCI DARF review.

f. Observe the preparation for an exit interview, and the manner in which the exit interview is conducted.

4. The Contractor shall submit a Preliminary Report of audit findings within 24 hours of the end of the audit. The Preliminary Report will include a brief description of any major deficiency identified during the audit. The Preliminary Report will be faxed or submitted electronically to CTMB. The CTMB Contracting Officer’s Technical Representative and Contracting Officer must be notified by telephone with a follow-up email of any findings suspicious and/or suggestive of intentional misrepresentation of data and/or disregard for regulatory safeguards for any of the three (regulatory, pharmacy and patient case) components of an audit.

Similarly, any data irregularities identified through other quality control procedures suspicious and/ or suggestive of intentional misrepresentation of data must be immediately reported to Contracting Officer’s Technical Representative and Contracting Officer.

5. The Contractor shall submit to the Contracting Officer’s Technical Representative a co-site audit report in an electronic format to the CTMB-AIS within…