ATT3FINALStatementofWork.pdf

ATTACHMENT 3

STATEMENT OF WORK

"Regulatory Support for Cancer Prevention Agent Development"

The Contractor shall furnish services, qualified personnel, material, equipment compatible with

NCI systems, and facilities, not otherwise provided by the Government under the terms of this contract, as needed to perform the support tasks set forth below.

TASK AREA 1: Regulatory Submissions

The Contractor shall be responsible for regulatory submissions to support the Division of Cancer

Prevention’s (DCP) chemoprevention agent development and clinical research program. The

Contactor shall develop and implement procedures for accessing, reviewing, and compiling safety, and clinical data for possible inclusion in Investigational New Drugs (IND) and other regulatory submissions. DCP will provide the background and current information on all of the chemopreventive agents. Regulatory submissions shall be made in accordance with Food and

Drug Administration (FDA) regulations (http://www.fda.gov), International Committee on

Harmonization (ICH) guidelines (http://www.ich.org/home.html), and National Institutes of

Health (NIH), National Cancer Institute (NCI), and DCP requirements and other relevant regulations, laws, and guidelines.

The Contractor shall prepare and submit Investigational New Drug Applications (IND) to the

U.S. Food and Drug Administration. Submissions shall also include Drug Master Files (DMFs), New Drug Applications (NDAs), providing adverse event data for development of the

Investigator's Brochures by the DCP Technical Support contractor, Common Technical

Documents, and other documents required by FDA regulations. For multinational research efforts supported by DCP, the Contractor may be directed to prepare submissions to international regulatory bodies. The DMFs will be updated yearly.

The Contractor shall plan and implement a transition to an electronic process for managing content and transmitting regulatory submissions to regulatory agencies. Content used for regulatory submissions comes in a variety of formats and from several sources and systems.

Data types and sources include: protocol information from the DCP Enterprise System

Knowledgebase (DESK), clinical data from research sites via Oracle Clinical Remote Data

Capture, preclinical data from the DCP's agent development program, and chemistry and manufacturing information from DCP's agent repository. Therefore, the Contractor shall interface with other systems and coordinate with DCP staff, DCP’s monitoring contractor, DCP’s information technical support contractor, DCP’s agent repository, pharmaceutical collaborators, and other organizations supporting DCP's chemoprevention program.

http://www.fda.gov/ http://www.ich.org/home.html

The Contractor shall perform the following activities under this task:

A. IND Submissions

1. The Contractor shall compile and submit IND applications as required by FDA. A portion of this information will come from the DCP databases. This includes protocols, protocol amendments, Serious Adverse Event (SAE) reports, Annual Reports, FDA forms 1571, additional chemistry and manufacturing information, and toxicology information.

2. The Contractor shall prepare all amendments to DCP-sponsored INDs, in addition to the initial IND submission.

3. The Contractor shall ensure the accuracy and completeness of supporting regulatory documents collected from the clinical institutions. These may include the FDA 1572, investigator biosketches, Investigational Review Board (IRB) approval documentation, and other documents required for submission to regulatory agencies and/or needed for

DCP to authorize the shipment of investigational agents to research sites. In addition, the

Contractor shall track Office for Human Research Protection (OHRP) assurances, human subjects protection training, certificates of confidentiality and other documentation for all investigators conducting clinical trials under contracts with DCP as required by

Department of Health and Human Services (HHS) Regulations and NIH policies.

4. The Contractor shall prepare and submit Annual Reports to the FDA in accordance with

21 CFR.312.33, “Investigational New Drug Application, Annual Reports”

(http://edocket.access.gpo.gov/cfr_2010/aprqtr/pdf/21cfr312.33.pdf). These Annual

Reports shall be provided to the FDA no later than 30 calendar days after the anniversary date of the IND submission to the FDA. The Contractor shall notify DCP if a delay in submitting the Annual Report to the FDA is anticipated.

5. In the instance where there is a collaborating pharmaceutical company, the Contractor may be requested to provide information regarding regulatory submissions to that company.

6. The Contractor shall coordinate IND cross-filing activities as needed.

B. Drug Master File (DMF)

Within 60 calendar days after award, the Contractor shall submit a draft DMF shall be submitted to DCP for review and approval. The Contractor shall review and update the DCP

Drug Master File (DMF) annually. Along with the standard required material, this file shall include Standard Operating Procedures (SOPs) for such areas as Protocol and Safety Review, Agent Development, and content of biomarker/assay methods validation.

http://edocket.access.gpo.gov/cfr_2010/aprqtr/pdf/21cfr312.33.pdf

The Contractor shall:

1. Edit, index, and format data in conformance with FDA requirements.

2. Prepare correspondence noting the DMF filing and withdrawals.

TASK AREA 2: Regulatory Correspondence and Administrative Tracking

1. As directed by the Contracting Officer’s Technical Representative (COTR), the Contractor shall prepare, review, maintain, and track correspondence related to regulatory submissions including:

a. Correspondence to accompany all IND filings, inactivations, and withdrawals.

b. Letters to investigators arising from FDA review of INDs and protocols.

c. Responses to FDA requests based on DCP and investigator comments.

d. All regulatory submissions and correspondence among the FDA, DCP, investigators, and pharmaceutical collaborators. These shall be tracked electronically within DESK.

2. In DESK, the Contractor shall maintain contact information on persons, organizations, and

FDA contacts, pharmaceutical collaborators, and other entities with which DCP interacts to carry out its regulatory activities.

TASK AREA 3: Safety Activities

The Contractor shall provide regulatory support for safety data (adverse event) review, processing, and submission to regulatory agencies and investigators. Specifically, the Contractor shall:

1. Establish a 24 hours/7 day notification system for the prompt reporting of serious adverse events (or other serious matters) to the study sites’ Medical Monitor. This system shall include the notification to the Contractor for tracking and monitoring purposes.

2. Receive, perform a regulatory review of and organize adverse event data to submit to FDA or other regulatory bodies in accordance with regulations and DCP instructions. The Contractor shall be able to collect adverse event data by several different mechanisms that include:

hardcopy reports from clinical investigators, legacy Access databases, the DESK (DCP

Enterprise System Knowledgebase) Investigator Technical Progress Reporting (ITPR)

System in DESK, Oracle Clinical Remote Data Capture, and the Chemoprevention Serious

Adverse Event Reporting System (CSAERS). The Contractor shall manage and integrate data from these sources as required for reporting adverse events.

3. Perform regulatory review of SAE reports using CSAERS. Research sites participating in new trials for which DCP has regulatory sponsorship will use CSAERS for serious and expedited adverse event reporting.

4. Provide support to DCP for adverse event coding. The Contractor shall have expertise in the use of Medical Dictionary for Regulatory Activities (MedDRA) and a working knowledge of other vocabularies used in regulatory activities, [including Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART), World Health Organization Adverse Reactions terminology (WhoART), and NCI's Common Toxicity Criteria (CTC)]. The Contractor shall obtain the appropriate licenses needed to use such vocabularies.

5. Provide adverse event data to collaborating pharmaceutical companies as directed by DCP.

6. Assist DCP staff and technical contractors in the development of expected adverse event lists for DCP-sponsored agents.

TASK AREA 4: Maintenance of Collaborating Research Agreement Records

To carry out its chemoprevention agent development and clinical research mission, DCP collaborates with pharmaceutical companies through the use of agreements such as Cooperative

Research and Development Agreement ( CRADAs), Clinical Trial Agreements (CTAs), Confidential Disclosure Agreements (CDAs), and Material Transfer Agreements (MTAs). In order to assist DCP, the Contractor shall:

1. Maintain electronic and paper files of agreement documents and other documents from pharmaceutical companies.

2. Create and maintain data about the status and nature of the collaborative agreement documents. This shall include correspondence between DCP and potential and actual collaborators, and tracking of special requirements for research activities conducted under collaborating research agreements. As directed by the COTR, these requirements may include sharing clinical data with the collaborator or restrictions on the type of trials for which a collaborator will supply drug. These data must be available to DCP so trials can be planned and conducted in accordance with the collaborative research agreements.

3. Establish appropriate security mechanisms to maintain confidentiality of data since data about collaborators and investigational agents may be sensitive and proprietary

TASK AREA 5: Coordination and Documentation of Regulatory Meetings

DCP meets with regulatory agencies, pharmaceutical companies, and preclinical and clinical researchers involved in the conduct of DCP- sponsored clinical trials to discuss study results, drug development plans, and data sharing. The Contractor shall assist in scheduling, facilitating, and attending meetings to support DCP's regulatory affairs, agent development, and clinical research programs. As directed by the COTR, the Contractor shall prepare detailed minutes and summaries of these meetings. These minutes may provide substantive content for future FDA correspondence.

TASK AREA 6: Document Management

The Contractor shall maintain regulatory documents (such as INDs and DMFs) in paper and electronic format in accordance with regulations, laws, and guidance. The Contractor shall develop and implement a document management system. The system shall:

1. Maintain, store, and provide to DCP all regulatory submissions, supporting documents, and collaborative research agreements. Documents may include: Annual Reports, active and inactive IND applications, amendments to the IND applications, and CTAs.

2. Handle document version control and review tracking.

3. Provide safe and secure electronic and physical storage conditions. Physical storage area for documents shall have an inert gas fire suppression system.

4. Provide daily back-up of electronic files with duplicate files maintained electronically at a secure, separate off-site facility.

5. Allow all active and archived materials to be readily retrievable and available to DCP staff within twenty-four hours from the time of a request.

6. Store electronic copies of reports prepared in mandated electronic formats and provide electronic delivery of these data upon request.

7. Archive records in accordance with regulatory and other requirements.

TASK AREA 7: Regulatory Review, Reporting, and Advisory Activities

The Contractor shall:

1. Perform regulatory and safety reviews of chemoprevention protocols and amendments as directed by DCP Protocol Information Office (PIO). The reviews shall be submitted to the

PIO within one (1) week of the request. The Contractor shall present comments at DCP's protocol review meetings.

2. Prepare slides and other briefing materials regarding DCP regulatory procedures and activities for presentation upon request of the COTR.

3. Participate as subject matter experts in DCP and NCI informatics design and development activities, as directed by the COTR. This may include attending knowledge acquisition sessions to define requirements and data model reviews, and participating in user testing efforts for DESK enhancements and other systems.

4. Participate in bi-weekly conference calls between DCP staff and the monitoring contractor to discuss protocol-specific issues, and be available for routine information sharing as needed.

5. Stay abreast of emerging regulatory guidelines and other developments that could affect DCP regulatory affairs.

6. Advise DCP on regulatory issues, as requested by the COTR. From a regulatory perspective, the Contractor shall review draft DCP guidelines and procedures for agent development and clinical research activities. The Contractor shall also assist in the development of DCP guidelines and procedures for activities governed by FDA and OHRP Regulations.

7. Provide information to the DCP, technical support contractor, and investigators that is relevant to agent development (e.g. Adverse event data) at the direction of the COTR.

TASK AREA 8: Process Quality Assurance (QA) and Quality Control (QC) Standard

Operating Procedures (SOPs)

The Contractor shall prepare and submit draft SOPs within 60 calendar days after award for all functions described in all Task Areas. The Contractor shall submit final SOPs to DCP for review and approval within 120 calendar days of contract award. SOPs shall be updated as needed and submitted to DCP.

The Contractor shall establish a written plan for quality assurance and quality control of all data and procedures described in all Task Areas. This plan shall:

1. Define parameters for the security of paper and electronic records;

2. Verify accuracy of data entry in information management systems, including the reconciliation of data discrepancies from different sources (such between legacy systems and current systems);

3. Ensure the accuracy of all information in the regulatory submissions including Annual

Reports, letters, and INDs;

4. Ensure documents and their copies are complete and free of grammatical and typographical errors.

TASK AREA 9: Information Management System

The Contractor shall maintain and enhance standard procedures for information management to support DCP's regulatory affairs.

1. The Contractor shall integrate the regulatory system with the DCP Enterprise System

Knowledgebase (DESK) and ensure that the regulatory system provides data to support

DESK users. The Contractor shall:

a. Ensure that the regulatory system is fully interfaced with the DCP Enterprise System

Knowledgebase (DESK) and has a remote access capability for DCP and its designees.

Data shall be shared between the system and DESK in an automated, labor-free process.

The process shall not involve duplicate storage of the same data in both systems. Data sharing with DESK shall not require a manual reconciliation process.

b. Ensure, to the extent possible, that the system uses the presentation layer and user interface that is standard across all new DESK applications.

c. Ensure that the regulatory system provide designated DCP personnel the capability to perform ad-hoc queries of information.

d. Maintain and update/upgrade/enhance standard procedures for information management for chemopreventive agents and test results. The Contractor shall ensure that regulatory system conforms and integrates with industry standards and NCI technology infrastructure.

e. Ensure that all messages between the regulatory system and external systems are based on HL7 messaging standards, specifically HL7 3.x (XML) version of standard.

f. Ensure that data used by the regulatory system complies with the National Cancer

Institute's Cancer Data Standards Repository (caDSR) metadata standards

(https://cabig.nci.nih.gov/concepts/caDSR), and that all data are represented as Common

Data Element approved by DCP. The data shall be integrated with the caDSR so that

Common Data Element metadata may be accessed directly wherever appropriate.

g. Ensure that the system is fully integrated with the NCI Enterprise Vocabulary Services

(EVS) (http://evs.nci.nih.gov/ ) and will use EVS as the source of terminology wherever possible. Specifically, the Contractor shall use the Cancer Bioinformatics Infrastructure

Objects Application Programming Interfaces (CaBIO API)

(http://cabioapi.nci.nih.gov/cabio42/Home.action) to access EVS services, and shall implement an e-mail-based mechanism for the regulatory system users to requests changes to EVS content.

2. The Contractor shall ensure that the regulatory system contain a complete audit trail of all changes to any data stored. Regular reporting of audit trail changes must be provided.

https://cabig.nci.nih.gov/concepts/caDSR http://evs.nci.nih.gov/ http://cabioapi.nci.nih.gov/cabio42/Home.action

3. The Contractor shall maintain experienced database management, programming and other technical personnel on its staff and shall provide support and maintenance of the system. The

Contractor shall also have appropriate Oracle licensure within 30 calendar days of contract award.

4. The Contractor shall utilize TestTrack Pro or a comparable tool to track bugs, issues and change requests. Remote web access to the tool and its contents should be provided to NCI representatives as designated by the COTR.

5. Changes to the system shall require approval by the DCP Change and Configuration Group

(CCG). The Contractor shall provide a representative to participate on the CCG. The

Contractor shall participate in other DCP IT status meetings and other activities as requested by the COTR.

6. The Contractor shall ensure that the system complies with 21 Code of Federal Regulations

Part 11, the FDA regulations regarding electronic records and signatures, as well as other applicable regulations and laws. 21 CFR 11 and current guidance are found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance s/UCM072322.pdf.

TASK AREA 10: Transition

The Contractor shall assist in the transition of the contract to a successor contract, if necessary.

The transition period shall consist of the final 60 calendar days of the contract.

1. As the start of the contract, the Contractor shall receive and store all paper and electronic documents.

2. The Contractor shall submit a plan for the transfer of all materials and data stored 90 calendar days before completion of the contract.

3. The Contractor shall provide instruction to the successor contractor in the policies and procedures utilized in the performance of the contract.

4. The Contractor shall provide the successor contractor with detailed briefing regarding the policies and procedures for managing all aspects of the project. As part of these detailed briefings, the Contractor shall provide the successor contractor with the SOP Manual for regulatory support. The Manual provided shall be complete, with all procedures detailed and current as of the date of the initial briefing.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072322.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072322.pdf