CCOP Cancer Prevention and Control Protocol Development and Approval
Process

1.  Overview

    After receiving approval for a concept from the Division of Cancer
    Prevention Cancer Prevention and Control Concept Review Committee,
    the Research Base should begin to formulate a protocol to conduct
    the proposed research. The protocol is a document that can be used
    by clinicians, nurses, CRAs, the Research Base, the NCI, and others
    associated with the research to conduct the study. Because most
    elements of the concept are incorporated in the protocol, there is a
    large degree of redundancy. The Cancer Prevention and Control
    Protocol Review Committee assigns credit for each study at the time
    of protocol approval. Because the utility of research and the
    scientific basis for conducting a study will change over time,
    concept approval expires 12 months after receipt of the approval
    letter. If the Research Base intends to submit a protocol that will
    be received later than 12 months after concept approval, they should
    contact their program director for guidance.

    In some circumstances investigators at Research Bases want to
    utilize the CCOP network for accrual to a study that has received
    approval through a peer review process and funding from a Government
    source other than the CCOP grant (e.g. R01). These studies need not
    be submitted as concepts but should be submitted directly as
    protocols, following the procedures below.

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1.  Submission Process

    The Research Base submits the final protocol document to the Program
    and Information Office (PIO) of DCP.

    2.1. How to submit a protocol

2.1.1. Research Bases should submit protocols electronically to
<NCI_DCP_PIO@mail.nih.gov>

2.1.2. Attachments that are difficult to send electronically may be sent
by mail:

US Mail Address:

Protocol Information Office

Division of Cancer Prevention

National Cancer Institute

Executive Plaza North, Room 2053

6130 Executive Blvd MSC 7323,

Bethesda MD 20892_7323

Commercial Delivery Address:

Protocol Information Office

Division of Cancer Prevention

National Cancer Institute

Executive Plaza North, Room 2053

6130 Executive Blvd.

Rockville, MD 20852

2.  Content of a Protocol

    3.1. Cancer Control Checklist and Protocol Submission Worksheet

    All new protocols must be accompanied by the Cancer Control
    Checklist and Protocol Submission Worksheet v4.0. All relevant
    sections of the PSW must be completed. These forms can be downloaded
    from <http://www.cancer.gov/prevention/pio/instructions.html> All
    subsequent submissions for the same protocol only require the Cancer
    Control Checklist.

    3.2. Cover Letter

    The cover letter includes point by point responses to issues raised
    by the Cancer Prevention and Control Concept Review Committee in its
    approval letter and specifies places in the protocol that include
    changes made since the concept. The cover letter should also
    indicate any other significant changes made to concept and provide
    reasons.

    If the protocol is for a study that will receive Government funding
    other than that in the CCOP grant and has received approval from a
    peer review panel, the cover letter should provide this information,
    and a copy of the grant application, budget pages, and summary
    review statement should be included as attachments.

    3.3. Title Page

    The title page of the protocol is the primary source of identifying
    information for the Protocol Information Office (PIO) of DCP, for
    the agent distribution system, for the IND file at the FDA, and for
    the listing of the protocol in the Physician Data Query (PDQ)
    system. Each protocol submitted, therefore, must have a title page
    that contains the following items:

-   Date of document

-   Local protocol number (i.e., institution or group number)

-   Title of study

-   A single protocol chair who will be responsible for the study,
    including his or her name, institution, address, phone and fax
    numbers, and e-mail address

-   Full name of institution or research base submitting the study

-   List of each participating institution or research base (can be
    summarized as open to all members)

-   For DCP-supplied agents, a listing of each agent by name and NSC
    number.

    3.4. Background

    The Background can largely be taken from the Background submitted
    with the concept for this protocol. It provides the reviewers the
    relevant arguments for conducting the proposed study. The Background
    section should be updated with recent relevant literature,
    information or discussion requested by the Concept Review Committee,
    or as appropriate based on changes to the protocol made after
    concept approval.

    3.4.1. Detailed rationale for study

    -What is the current state of knowledge or clinical practice?

    -What will this study contribute to cancer prevention or control?

    -Why is the study design the best way to make this contribution?
    (include information about the proposed study population and
    intervention)

    -How will this research affect subsequent research?

    -Why were the endpoints chosen? Justify choice of effect size.

    -Do data exist from a pilot study that supports conducting the
    proposed study?

    3.4.2. Literature Review

    -a focused review of relevant literature with citations, covering
    current knowledge, other studies that have contributed information
    applicable to the proposed study, information on drugs and
    procedures to be used, and information on nutrition, epidemiology,
    and related fields justifying the proposed research and its
    methodology.

    3.4.3. Feasibility

    -Provide data to support the anticipated accrual rate; specify
    procedures for recruitment and retention.

    -Level of participation and anticipated accrual from the CCOPs.
    State if CCOP members have been involved in developing or reviewing
    the concept. What is level of interest expressed by CCOPs?

    -If the study will involve costs in addition to data management,
    describe them and include a source of funding.

    3.5. Intervention Plan and Study Design

    3.5.1. Detailed Schema

    -This one page diagram provides an overview of the study design. To
    be most useful, it should include sample size, eligibility and
    ineligibility criteria; stratification factors; timing of informed
    consent, randomization, intervention(s), and data collection;
    specific intervention(s) with dose(s); and outcome(s)

    3.5.2.. Aims / Objectives

    3.5.3 Methodology

    3.5.3.1. Characteristics of study population

    -eligibility and ineligibility criteria

    -source of subjects

    3.5.3.2. Sampling, recruitment, and retention procedures

    -include estimates of minority recruitment and plans to increase
    minority recruitment, including participation of institutions
    intended to boost minority recruitment

    3.5.3.3. Procedures for randomization (include stratification
    factors with definitions and justification for stratifying by these
    factors)

    3.5.3.4. Plans for intervention

    -schedule for administration of intervention

    -schedule for adjustments to planned intervention related to side
    effects

    3.5.3.5. Plans for data collection

    -number and timing of contacts with subjects

    -data to be collected at each contact

    -rules for missed contacts

    -plan for missing data

    3.5.3.6. Definitions for primary and secondary endpoints

    3.6. Drug Distribution

    -plans for obtaining, storing, and distributing drugs and placebos

    -special instructions for the intervention

    3.7. Behavioral Intervention

    -describe the intervention in detail that will all implementation at
    sites conducting the study. Include requirements for special
    training, facilities, and equipment. A training or procedures manual
    may be included as an appendix.

    3.8. Statistics

    -defined stratification factors with justification

    -specific procedures to be used for randomizing subjects to
    treatment (or placebo) arms

    -full plans for analyzing and interpreting results regarding the
    primary and secondary endpoints for this study.

    -sample size calculation

    -information on the composition of the proposed study population
    (accrual targets) in terms of sex/gender and racial/ethnic group in
    the format as provided on the CTEP Protocol Submission Worksheet.

    -If the protocol is a NIH-defined Phase III trial (a broadly based
    prospective Phase III clinical investigation, usually involving
    several hundred or more human subjects, for the purpose of
    evaluating an experimental intervention in comparison with a
    standard or control intervention or comparing two or more existing
    treatments), the investigator must address whether he/she expects to
    find clinically important sex/gender and/or race/ethnicity
    differences in the intervention effect. The protocol must include
    one of the following plans:

    1\) plans to conduct valid analyses to detect significant
    differences in intervention effect among sex/gender and/or
    racial/ethnic subgroups when prior studies strongly support these
    significant differences among subgroups, OR

    2\) plans to include and analyze sex/gender and or racial/ethnic
    subgroups when prior studies strongly support NO significant
    differences in intervention effect between subgroups, OR

    3\) plans to conduct valid analyses of the intervention effect in
    sex/gender and/or race/ethnic subgroups (without requiring high
    statistical power for each subgroup) when the prior studies neither
    support nor negate significant differences in intervention effect
    between subgroups.

    3.9 Adverse Events Reporting

    -procedures to be used to report adverse events to the Research
    Base, NCI, and/or FDA

    -use current version of the CTC (currently CTCAE v3.0)

    3.10 Consent Form

    -Information on consent documents and templates are available at

    http://www.cancer.gov/clinicaltrials/understanding/simplification_of_informed_consent_docs/page2

3.  Protocol Review Process

    4.1. Receipt in DCP PIO

    -DCP conducts reviews within 4-6 weeks after receipt of protocol.
    This allows time to schedule reviewers and also gives reviewers
    adequate time to review the protocol.

    4.2. Review Group

    -The standing Cancer Prevention and Control Protocol Review
    Committee will be augmented as needed by invited reviewers inside
    and/or outside the NCI. The reviewers for the protocol often include
    the same reviewers as those for the concept, but this is not always
    the case.

    -The chair of the Cancer Prevention and Control Protocol Review
    Committee conducts the reviews and is the principal contact with
    investigators regarding protocols under review.

    4.3. Purpose of the Review

    -The protocol review will focus on the inclusion in the protocol of
    all information and procedures necessary for conducting a successful
    study. Specific attention is paid to responses to DCP's concerns
    conveyed to the Research Base at the time of concept approval. Since
    the rationale for the study and the broad study design have already
    received approval from the Cancer Prevention and Control Concept
    Review Committee, these are not generally the focus of a protocol
    review. However, if the protocol differs from the concept in
    significant ways (e.g. change in endpoint, change in eligibility
    criteria), the Protocol Review Committee will review all aspects of
    the protocol to determine that the study has scientific validity and
    is feasible to conduct in the CCOP network.

    -If the protocol is for a study that will receive Government funding
    other than that in the CCOP grant and has received approval from a
    peer review panel, the Division of Cancer Prevention considers the
    earlier peer review as a concept approval. Protocol review for these
    studies is similar to reviews for other CCOP protocols, but the
    Concept Review Committee will also evaluate feasibility and
    appropriateness of the study for use in the CCOP network.

    4.4. Outcome of the Review

    -DCP will send all correspondence by mail and/or email regarding
    protocol reviews to 1) Principal Investigator of the Research
    Base, 2) Study Chair, and 3) one other person designated by each
    Research Base to receive copies of correspondence related to all
    concepts and protocols under review at DCP. DCP sends results of
    protocol reviews within four weeks of the review meeting.

    Protocol review letters can take one of three forms:

    4.4.1. Protocol Approved

    -The Committee has determined that the protocol is ready for use in
    the CCOP network.

    -The approval letter includes the credit assignment for the
    protocol.

    4.4.2. Revise and Resubmit

    -The Committee has identified potentially remediable problems that
    the investigators should review and comment on. These problems
    usually require revisions to the protocol.

    -Investigator should respond to all the Committee's comments, change
    the protocol where necessary, and resubmit to the DCP Protocol
    Information Office as a revised protocol for further review.

    4.4.3 Protocol Rejected

    NOTE: Approval of the concept by the Cancer Prevention and Control
    Concept Review Committee indicates DCP's interest in conducting the
    proposed research, so protocol rejection is not common. However, the
    Cancer Prevention and Control Protocol Review Committee reserves the
    right to reject a protocol, particularly when the protocol differs
    significantly from the approved concept.

    4.5 After Approval

    4.5.1. Research Bases should submit activation date to PIO when
    study opens.