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Protocol Authoring and Submission Guidelines Handbook

Version Date: June 6, 2007

NCI CTEP Protocol and Information Office

Telephone: (301) 496-1367

Fax: (301) 496-9384

**E-mail: <pio@ctep.nci.nih.gov>**

**Web site: http://ctep.cancer.gov**

Table of Contents

[**Protocol Authoring and Submitting - Introduction
1**](#__RefHeading___Toc164071332)

[1.1. LOI Submission Form 2](#__RefHeading___Toc164071333)

[1.2. LOI Funding Requests 3](#__RefHeading___Toc164071334)

[1.3. Mass Solicitations 3](#__RefHeading___Toc164071335)

[1.4. Unsolicited LOIs 4](#__RefHeading___Toc164071336)

[1.5. Components of a Competitive LOI 4](#__RefHeading___Toc164071337)

[1.6. CTEP Processing and Review of LOIs
6](#__RefHeading___Toc164071338)

[1.7. Withdrawal of an LOI 6](#__RefHeading___Toc164071339)

[1.8. LOI On-hold 6](#__RefHeading___Toc164071340)

[1.9. LOI Approval/Disapproval 7](#__RefHeading___Toc164071341)

[1.9.1. Pharmaceutical Collaborator Commitment
7](#__RefHeading___Toc164071342)

[1.9.2. Final LOI Approval 7](#__RefHeading___Toc164071343)

[1.9.3. LOI Disapproval 8](#__RefHeading___Toc164071344)

[2.1 Concept Submission Form 9](#__RefHeading___Toc164071345)

[2.1.1 Intergroup Concepts 10](#__RefHeading___Toc164071346)

[2.2 CTEP Processing and Review of Concepts
10](#__RefHeading___Toc164071347)

[2.3 Concept Approval 11](#__RefHeading___Toc164071348)

[3.1. Components of a Protocol Document
13](#__RefHeading___Toc164071349)

[3.2 Version Dating 15](#__RefHeading___Toc164071350)

[3.3 Use of Protocol Templates 15](#__RefHeading___Toc164071351)

[3.4 Protocol Submission Worksheet (PSW)
16](#__RefHeading___Toc164071352)

[3.5 Submitting Protocols -- General Policy
17](#__RefHeading___Toc164071353)

[3.5.1 Protocol Numbering 18](#__RefHeading___Toc164071354)

[3.6 How to Submit a Protocol to CTEP 18](#__RefHeading___Toc164071355)

[3.7 CTEP Review of New Protocols 19](#__RefHeading___Toc164071356)

[3.8 Review Types 19](#__RefHeading___Toc164071357)

[3.9 CTEP Reviewer Assignment 19](#__RefHeading___Toc164071358)

[3.10 Monitoring of Clinical Trials 20](#__RefHeading___Toc164071359)

[3.10.1 Clinical Trials Monitoring Service (CTMS)
21](#__RefHeading___Toc164071360)

[3.10.2 Cancer Trials Support Unit (CTSU)
21](#__RefHeading___Toc164071361)

[3.10.3 Clinical Data System (CDS) 21](#__RefHeading___Toc164071362)

[3.11 Adverse Events (AE) 22](#__RefHeading___Toc164071363)

[3.11.1. Action Letters 22](#__RefHeading___Toc164071364)

[3.11.2. Safety Reports 23](#__RefHeading___Toc164071365)

[3.11.3 Notice to Investigators 23](#__RefHeading___Toc164071366)

[3.11.4. Comprehensive Adverse Event and Potential Risk (CAEPR)
23](#__RefHeading___Toc164071367)

[3.12 Protocol Review Committee 24](#__RefHeading___Toc164071368)

[3.13 The Consensus Review 24](#__RefHeading___Toc164071369)

[3.14 Responding to the Consensus Review
24](#__RefHeading___Toc164071370)

[3.15 Institutional Review Board Approval
25](#__RefHeading___Toc164071371)

[3.15.1 Central Institutional Review Board (CIRB)
26](#__RefHeading___Toc164071372)

[3.16 Investigator Registration Status 26](#__RefHeading___Toc164071373)

[3.17 Regulatory Review 26](#__RefHeading___Toc164071374)

[3.17.1 Cooperative Research and Development Agreement and Clinical
Trials Agreement 26](#__RefHeading___Toc164071375)

[3.18 On hold and Approval On hold 27](#__RefHeading___Toc164071376)

[3.19 Expedited Protocols 27](#__RefHeading___Toc164071377)

[3.20 Withdrawing a study or document 27](#__RefHeading___Toc164071378)

[3.21 Final CTEP Approval 28](#__RefHeading___Toc164071379)

[3.22 Coding Letter 28](#__RefHeading___Toc164071380)

[3.23 Activating an Approved Protocol 28](#__RefHeading___Toc164071381)

[3.24 Submitting Amendments to CTEP 28](#__RefHeading___Toc164071382)

[3.25 Document Management Authoring and Review Tool (Docu-MART)
29](#__RefHeading___Toc164071383)

[Appendix A -- PIO Workflows by Document Type
30](#__RefHeading___Toc164071384)

[Appendix B - List of Resources 35](#__RefHeading___Toc164071385)

[Appendix C -- Definitions 37](#__RefHeading___Toc164071386)

[Appendix D -- Biotechnology 101 Glossary
39](#__RefHeading___Toc164071387)

[Appendix E - Principal Investigator Responsibilities
44](#__RefHeading___Toc164071388)

[Appendix F -- Common PIO Terms 45](#__RefHeading___Toc164071389)

**A Manual for Authoring and Submitting Letters of Intent, Concepts, and
Protocols Sponsored by DCTD, NCI**

[]{#__RefHeading___Toc164071332 .anchor}**Protocol Authoring and
Submitting - Introduction**

> The Protocol and Information Office (PIO) is the administrative arm of
> the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer
> Institute (NCI) and serves to support DCTD in the development of new
> anti-cancer therapies through the use of cancer clinical trials. PIO
> accomplishes this by serving as the liaison between sites submitting
> protocols and related documents, and the staff of the Cancer Therapy
> Evaluation Program (CTEP) that is part of DCTD. In addition, CTEP may
> review protocols sponsored by the NCI Division of Cancer Prevention
> (DCP) and the DCTD Cancer Imaging Program (CIP).
>
> As the liaison between CTEP and the submitting sites, all parties are
> encouraged to contact PIO via the main email address at
> <pio@ctep.nci.nih.gov>. PIO policies are developed in conjunction with
> CTEP policy but may also be the result of regulatory requirements set
> forth by the Food and Drug Administration (FDA), the Department of
> Health and Human Services (DHHS), and other Federal agencies.
>
> This handbook will describe the specific procedures required of
> submitting sites; the investigators, site coordinators, protocol
> specialists, etc. in order to author and submit a protocol to CTEP for
> review and decision. While specific policies and documents used will
> evolve, CTEP, DCTD, NCI will continue to provide a flexible and
> responsive environment to match the needs of the community.
>
> Throughout the handbook, references will be made to the CTEP
> Investigator's Handbook
> (<http://ctep.cancer.gov/handbook/index.html>), the CTEP Amendment
> Request Submission Policy, the CTEP web site, and other resources that
> can be used to supplement the information provided in this document. A
> complete listing of resources can be found in Appendix A. The CTEP web
> site and resources listed above can be found at
> [http://ctep.cancer.gov](http://ctep.cancer.gov/).
>
> We welcome the reader's comments on the content of this handbook and
> how to make it more useful. Please submit comments on this handbook to
> <info@ctep.nci.nih.gov>.
>
> **1.** **Letters of Intent - Introduction**
>
> A Letter of Intent (LOI) is a proposal submitted by an investigator
> interested in conducting phase 1 or 2 single or combination studies
> most often utilizing CTEP-held IND investigational agents. A protocol
> should not be submitted until the LOI has been approved. LOIs fall
> under the purview of the CTEP Investigational Drug Branch (IDB). LOIs
> that are submitted that don't utilize a CTEP-held IND investigational
> agent will have a CIB monitor as the lead reviewer. There are two
> mechanisms through which an LOI is submitted to CTEP: unsolicited LOIs
> and mass solicitations. The sections below describe the major sections
> of the LOI Submission form, components of a competitive LOI, and the
> LOI review process.
>
> Any investigator can submit an unsolicited LOI to CTEP for review at
> any time. However, all LOIs for Cooperative Group studies will be
> submitted by the Cooperative Group operations center or site
> coordinator will act as an agent of the Principal Investigator (PI) to
> submit the LOI to CTEP.
>
> Only the proposed PI may submit the LOI. Investigators that are
> proposed as a Co-Investigator on an LOI should not submit the LOI to
> CTEP for review.

1.  []{#__RefHeading___Toc164071333 .anchor}**LOI Submission Form**

> For an LOI to be considered by CTEP, an LOI submission form must be
> completed (if the investigator is seeking Translational Research
> Initiative (TRI) funding, a completed cost estimate worksheet must
> accompany the LOI Submission form, see section 1.2 below for more
> information on TRI funding).
>
> The LOI submission form is a tool that allows the investigator to
> document key elements of the proposal for CTEP to evaluate each
> proposal on scientific merit and determine that the proposed study is
> not duplicative of other ongoing efforts. LOI submission forms are
> located on the CTEP web site at:
> <http://ctep.cancer.gov/forms/LOI_form.doc>.
>
> All LOIs and related correspondence, including queries for information
> on the status of an LOI should be addressed to the PIO's main email
> address at: <PIO@ctep.nci.nih.gov>.
>
> The LOI submission form collects information in the following areas:

-   Group/Institution/Principal Investigator/Grant Holder information --
    For input into CTEP's database for tracking and demographic
    purposes.

-   Agents included in the proposal -- IDB has extensive experience with
    a large portfolio of investigational agents and will evaluate the
    known toxicities, adverse events, and agent to agent interactions
    which will in part determine if an LOI can be approved. This
    information will also be used to determine if the agent(s) is/are
    requested from CTEP under IND or will be provided by another
    source/mechanism.

-   Tumor type and specific disease included in the proposal -- In
    addition to adverse events, IDB can identify known response to the
    agents in the proposal as well as other studies underway using the
    agent-disease combination.

-   Performance measurement criteria/treatment plan/endpoint -- Allows
    CTEP to determine if reasonable criteria and an effective treatment
    plan is proposed.

-   Sample size/accrual rates/competing trial information -- The ability
    to successful accrue a statistically significant patient population
    in a reasonable timeframe is evaluated in conjunction with the type
    and experience of the lead organization submitting the proposal to
    ensure targets are met.

-   Funding information -- All parties involved deal with finite
    resources and CTEP evaluates requests for available funding as a
    part of the decision process. See below for more information on
    funding requests.

    1.  []{#__RefHeading___Toc164071334 .anchor}**LOI Funding Requests**

> Funding may be available through the Translational Research Initiative
> (TRI) on a competitive basis. Investigators can access the cost
> estimate worksheet through the CTEP web site at
> <http://ctep.cancer.gov/guidelines/> which allows funding for:

-   Personnel effort (appropriate and reasonable)

-   Consultants

-   Equipment maintenance/service costs if appropriately justified

-   Supplies

-   Shared resource costs

-   Patient care costs

> The request for funding should accompany the LOI. Funding is not
> available for the basic costs of running a clinical trial,
> administrative start-up fees, patient recruitment, IRB preparation,
> record keeping, travel, equipment, and the costs associated with
> setting up new labs or assays. Indirect costs may not be applied to
> patient care costs.
>
> Additional information about TRI funding can be found at:
> <http://ctep.cancer.gov/resources/trf-funding.html>.
>
> A completed worksheet should be submitted with the LOI submission form
> to be considered.

1.  []{#__RefHeading___Toc164071335 .anchor}**Mass Solicitations**

> A mass solicitation occurs when CTEP invites investigators to submit
> proposals for a clinical trial for a specific agent or for a
> combination of agents outlined in the letter of solicitations. The PIO
> will send out an email to investigators on behalf of IDB with the
> invitation/solicitation along with a LOI submission form and the
> applicable deadlines. PIO maintains a mailing list of investigators
> broken down in various categories to include; Cooperative Groups,
> Cancer Centers, Consortia, U01, N01, and SPORE grant holders as well
> as various tumor types such as breast, GI, GYN, lung, etc. If an
> investigator wishes to be included on the mass solicitation list,
> please send an email with name, email, institution/affiliation, and
> specialty to PIO at <PIO@ctep.nci.nih.gov>.
>
> Typically, investigators are given six weeks to submit the completed
> LOI submission form (and cost estimate worksheet if requesting TRI
> funds) back to the main PIO email address at <PIO@ctep.nci.nih.gov>. A
> single mass solicitation invitation can result in a large number of
> submissions so investigators are reminded to put the phrase "Mass
> Solicitation" and the name of the agent in the subject line of the
> submission email to distinguish it from other LOI emails.
>
> The cutoff for receipt of submissions is 5 PM ET on the designated
> last day of the solicitation (typically the deadlines are on
> Wednesdays) as specified in the solicitation letter. If the submission
> is received in PIO later than 5 PM ET, the LOI may not be reviewed
> with the mass solicitation. If CTEP elects to review the late LOI, it
> may not be included in the mass solicitation review and therefore
> would be placed at a competitive disadvantage. It will therefore be
> considered an unsolicited LOI. Therefore it is important to submit
> LOIs in response to a mass solicitation request by the deadline.
>
> The CTEP web site keeps a summary document of recent mass
> solicitations available for review at:
> <http://ctep.cancer.gov/forms/recentsol.doc>.

2.  []{#__RefHeading___Toc164071336 .anchor}**Unsolicited LOIs**

> An unsolicited LOI is one that is submitted for review to CTEP outside
> of a mass solicitation. Investigators must use the LOI submission form
> (and cost estimate worksheet if requesting TRI funding) or the PIO
> will not accept the submission. Unsolicited LOIs should be submitted
> to PIO at its main email address at <PIO@ctep.nci.nih.gov>.
>
> Once the PIO considers it to be a complete submission, an unsolicited
> LOI is assigned for review at the next IDB review. Typically, IDB
> review meetings are held on Wednesdays. Incomplete submissions are put
> on hold and PIO will request the missing information from the
> investigator. Incomplete LOIs will remain "on-hold" until the missing
> information is received by the PIO and the LOI specialists determine
> the request is fulfilled.
>
> IDB will evaluate unsolicited LOIs based on the scientific merit of
> the proposal as well as other well-defined criteria described below.

3.  []{#__RefHeading___Toc164071337 .anchor}**Components of a
    Competitive LOI**

> IDB will review the LOI on the basis of its scientific merit and other
> criteria (full
>
> listing of all criteria can be found at
> [http://ctep.cancer.go/forms/competitive
> \_loi.doc](http://ctep.cancer.go/forms/competitive _loi.doc))
> including:

-   Strong scientific hypothesis -- LOIs must provide specific
    information about the rationale/hypothesis, supportive data, trial
    design, patient population, treatment plan and statistical
    evaluation. The scientific sections critical to the CTEP review
    process include:

    -   Rationale/Hypothesis section -- The rationale for performing the
        trial should be explicitly stated including a specific reason
        for testing the agent. The hypothesis should be succinctly
        stated as a question to be asked as the primary endpoint of the
        study and the design of the study should answer that question.
        Supportive data that are relevant to the submission should be
        included. Examples include a summary, graphs and figures, and a
        grant progress report or application.

    -   Endpoints/Statistical considerations -- The primary endpoint
        must be explicitly stated and the statistics supporting the
        endpoint and trial design must be provided.

    -   Laboratory correlates -- The information included should be
        succinct but specific enough for CTEP to evaluate the merits of
        the correlates. The choice of targets and assays listed in the
        proposal should be explicitly justified as well as the reasons
        for not considering other targets and assays.

    -   Patient population -- As appropriate, note prior studies in this
        patient population and your accrual rate. If you project some
        very different and improved accrual rates, state why.

    -   Competing studies -- Note when competing trials are expected to
        be completed so CTEP can determine the priority of the proposed
        study.

-   Ability to meet regulatory reporting requirements

-   Not duplicative to another study already underway or proposal
    submitted for CTEP review

-   Agent availability regardless if the agent is to be supplied by CTEP
    or the drug company

-   Industry sponsor concurrence

> CTEP also considers if the Principal Investigator (PI) represents a
> Cooperative Group or CTEP contract awardee with peer-reviewed
> expertise in the conduct of early clinical trials.
>
> Clarity and brevity should be used when authoring the LOI. Typically,
> most LOIs range between 6-10 pages. LOIs that are exceedingly long may
> distract reviewers from the essence of the proposal. Investigators
> should not submit a fully written protocol as an LOI as it will not
> earn a higher score than a more succinctly and well written LOI.

1.  []{#__RefHeading___Toc164071338 .anchor}**CTEP Processing and Review
    of LOIs**

> All LOIs and correspondence regarding LOIs should be directed to the
> PIO at <PIO@ctep.nci.nih.gov>. In general, the review process for LOIs
> is the same for proposals submitted as part of a mass solicitation or
> that are unsolicited. In its role, the PIO will forward any questions
> or comments to the appropriate CTEP staff. Upon receipt of the LOI,
> PIO will begin abstracting key data elements into the CTEP Enterprise
> System module called the Protocol Authorization and Tracking System
> (PATS). PIO will send an acknowledgement email within 24 hours of
> receipt that will indicate that PIO received the submission back to
> the sender of the original email. Following abstraction of the LOI
> into the PATS database, PIO will send a second email to the
> investigator/site that includes the title of the LOI as well as the
> PATS generated LOI number (LOIs submitted by Cooperative Groups retain
> the number provided on the LOI submission form) within 48 hours of
> receipt.
>
> LOIs submitted as a part of a mass solicitation will be separated by
> phase of treatment and by disease. Mass Solicitation reviews will be
> scheduled for review based on the deadline for responses and the
> expected number of proposals that will be submitted. Typically, an
> unsolicited LOI will go to the IDB review meeting 2-3 weeks after the
> complete submission is received at the PIO.
>
> LOIs undergo a two part review process. First the proposal is reviewed
> by IDB who evaluates the LOI against the criteria listed above and
> assigns it a priority score. LOIs that are approved by IDB are
> scheduled for discussion at the CTEP Protocol Review Committee meeting
> (PRC) where they may receive preliminary CTEP approval with final
> approval pending response to CTEP comments, pharmaceutical
> collaborator commitment, or regulatory issues.
>
> In addition to CTEP review, LOIs may also be reviewed by the
> Investigational Drug Steering Committee.

2.  []{#__RefHeading___Toc164071339 .anchor}**Withdrawal of an LOI**

> If an LOI has a status of in-review, the LOI may be withdrawn from
> CTEP by the submitter at any time. In-review indicates that CTEP has
> not mad a final decision on the submission at the PRC meeting. Sites
> can withdraw an LOI by emailing the PIO at <PIO@ctep.nci.nih.gov>.

[]{#__RefHeading___Toc164071340 .anchor}**1.8. LOI On-hold**

> Following CTEP review, a consensus review (CR) will be developed based
> on the comments submitted by the CTEP reviewers. If the CR contains
> comments requiring a response, the LOI will be placed on-hold by PIO
> and sent to the site. The site will be required to make the changes to
> the LOI and resubmit it to PIO. The resubmitted LOI will again go
> through the CTEP review process. If all comments have been
> incorporated and CTEP can render a decision on the LOI then the LOI
> will follow the rest of the process stated below.

[]{#__RefHeading___Toc164071341 .anchor}**1.9. LOI
Approval/Disapproval**

> Following review of the LOI at PRC, the PIO will communicate the
> status of the LOI to the investigator via email. The LOI may receive
> final approval giving the PI the go-ahead to prepare a protocol for
> submission to CTEP. The LOI may also receive preliminary approval
> pending the commitment of the pharmaceutical collaborator to supply
> the agent under study. The LOI may also be disapproved.

[]{#__RefHeading___Toc164071342 .anchor}**1.9.1. Pharmaceutical
Collaborator Commitment**

> When an LOI is first approved by CTEP, the pharmaceutical collaborator
> supplying the agent is asked for a written commitment to provide the
> agent for the proposed trial. The company response may be an approval,
> approval with comments or disapproval.

[]{#__RefHeading___Toc164071343 .anchor}**1.9.2. Final LOI Approval**

> If the LOI is approved, the PIO will send out an LOI approval packet
> that will include:

-   CTEP review letter that will contain any comments generated by CTEP
    that the PI should incorporate into the protocol.

-   Comprehensive Adverse Events and Potential Risks List (CAEPR) for
    the agent being studied (see section 3.11.1 for more information).

-   LOI approval packages may also include a protocol template if a
    specific template was created for the agent that will be studied. If
    no agent specific template was developed, the PI can use the
    templates located on the CTEP web site
    ([http://ctep.cancer.gov](http://ctep.cancer.gov/)) and in Section
    4.1 and Appendix B of this guide.

> LOI approval packets get distributed to the grant holder (commonly
> referred to in CTEP as the Mail To contact), PI, site
> coordinator/Group operations contact, pharmaceutical collaborator (if
> applicable), CTEP Investigator Brochure Coordinator, as well as the
> CTEP Lead Reviewer, and other CTEP staff involved in the preparation
> of the review.
>
> Note: The Investigator Brochure (IB) Coordinator is copied on the
> approval packet emails which will trigger the coordinator to send the
> brochure if available. Otherwise the brochure will be sent once
> available. In addition, PMB will provide a data sheet for the
> CTEP-held IND agent(s) with the LOI approval letter.
>
> Once an LOI has been approved, Cooperative Groups, and Consortia have
> 60 days to submit a protocol and single institutions and cancer
> centers have 30 days. This timeframe is adhered to by CTEP in order to
> keep the clinical trial process moving forward. Sites can request an
> extension if circumstances prevent the timely submission of a
> protocol. However, if sites miss the protocol submission timeframe,
> CTEP may award the study to another institution that can more readily
> develop and conduct the protocol.

[]{#__RefHeading___Toc164071344 .anchor}**1.9.3. LOI Disapproval**

> If the LOI is disapproved, PIO will email the disapproval letter and
> the consensus review to the grant holder, the PI, and the site
> coordinator/Group operations contact.
>
> If the disapproved LOI was submitted by a Cooperative Group, only the
> contact person at the group operations office will receive the
> disapproval.
>
> If the PI has applied for and is awarded a National Institutes of
> Health grant, the PI may submit a protocol for review at CTEP even if
> the LOI has been disapproved.
>
> **2. Concepts -- Introduction**

Concepts represent the investigator's desire to conduct a phase 3 study.
As phase 3 studies typically focus on using an agent to treat a specific
disease, concept review is conducted by the CTEP Clinical Investigations
Branch (CIB) which serves as the disease experts for CTEP. Concepts are
typically submitted by Cooperative Groups and Consortiums due to the
target patient accrual needs for conducting phase 3 studies.

> Any investigator can submit a concept to CTEP for review. However, all
> concepts for Cooperative Group studies will be submitted by the
> Cooperative Group operations center or site coordinator who acts as an
> agent of the PI in submitting the proposal to CTEP
>
> Only the proposed PI may submit the concept. Investigators that are
> proposed as a Co-Investigator on a concept may not submit the concept
> to CTEP for review.

[]{#__RefHeading___Toc164071345 .anchor}**2.1 Concept Submission Form**

> For a concept to be considered and reviewed by CTEP, sites must
> complete a concept submission form. The concept submission form is
> available for download from the CTEP web site at:
> <http://ctep.cancer.gov/forms/Concept_Submission.doc> and is composed
> of five sections:

-   Administrative -- Includes the title of the concept, concept number,
    study chair, co-chair, and study personnel contact information. This
    section also asks for justification if the Cancer Trials Support
    Unit (CTSU**)** will not be participating in the study. See section
    3.10.2 for more information on the CTSU.

-   Science Section -- This is the section for declaring the specific
    hypothesis as well as primary and secondary objectives. The
    background section asks for critical information to be included such
    as:

    -   Rationale for selected approach and trial design

    -   Why the trial is important, including impact on overall
        survival, quality of life or advances in proof of biologic
        principles

    -   All relevant data including phase 1-3 trial results and any data
        that justify the use of the control and experimental arm

    -   Eligibility of targeted patient population as well as rationale
        for selecting certain cohorts

    -   Arms/Regimens including the schema

    -   Statistical design in detail including primary and secondary
        objectives, stratification, sample size with power
        justification, and the monthly accrual rate and total expected
        accrual

    -   Feasibility -- Submitted concepts must include competing phase 3
        trials for your Cooperative Group, other Groups (domestic and
        international), and pharmaceutical collaborator(s).

```{=html}
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-   Pharmaceutical Section -- CTEP has included a pre-formatted table in
    the submission form to list each agent in the proposal:

    -   Agent name

    -   Request for CTEP/PMB distribution

    -   Denoting if the agent is investigational or commercial as used
        in the proposed setting

    -   Identifying the IND sponsor (if applicable)

    -   List the NSC number, if available

    -   Denoting if the study is placebo-controlled

    -   Justifying CTEP distribution of agents not under a CTEP IND

-   Embedded Correlative Study Section - if applicable, including the
    title, study design, hypotheses, and statistical design. Identify if
    the study is blinded (single or double)

-   Information on person completing the submission form (typically the
    Cooperative Groups operations contact)

    []{#__RefHeading___Toc164071346 .anchor}**2.1.1 Intergroup
    Concepts**

> Tissue banks offer a unique opportunity to explore cancer biology
> correlated with information on the clinical presentation of the
> disease. To conserve this important resource and fairly disseminate
> specimens for research, all correlative science concepts proposing to
> use specimens from Intergroup studies will be reviewed and approved by
> the appropriate NCI Disease-Specific Intergroup Correlative Sciences
> Committee (CSC).
>
> Each Intergroup Coordinator will be responsible for coordinating the
> flow of information associated with the correlative study review
> process among the proposing investigator, Intergroup CSC, and CTEP's
> Protocol and Information Office (PIO).
>
> Additional information about the Intergroup process can be found at:
> <http://ctep.cancer.gov/resources/tbci/index.html>.

[]{#__RefHeading___Toc164071347 .anchor}**2.2 CTEP Processing and Review
of Concepts**

> All correspondence and materials regarding Concepts should go to the
> PIO at its main email address: <PIO@ctep.nci.nih.gov>. Sites will
> receive an acknowledgement email within 24 hours after PIO receives
> the submission. Once the completed Concept Submission form is
> received, PIO will begin the process of abstracting key data elements
> into the PATS database. PIO will complete the abstraction of Concepts
> within two business days of receipt and upon completion PIO will email
> the investigator as well as the respective Cooperative Group
> operations contact or site coordinator with an email that includes an
> acknowledgement letter which contains the Concept number and scheduled
> date of review.
>
> Part of the abstraction process is to schedule the Concept for CTEP
> review. Concepts are reviewed at the Concept Review Meeting (CRM) that
> occurs every Wednesday. The Concept review process now includes
> external reviewers, member of the public with an interest or other
> expertise in the disease listed to be studied. The main source for
> identifying and selecting external reviewers is through the Consumer
> Advocates in Research and Related Activities (CARRA) group. CARRA is
> an NCI initiative designed to get advocates more involved in NCI
> activities. More information about CARRA can be found at:
> <http://carra.cancer.gov/>. During the review process, CTEP will
> evaluate the Concept on its scientific merit to determine if approval
> can be granted. Reviewers will score the Concept based on the
> discussion which will be considered when deciding on the proposal.
>
> A Concept submitted for review at CTEP may go to PRC at the request of
> the Lead Reviewer for certain situations (e.g. inability to include
> external reviewers in the process).

[]{#__RefHeading___Toc164071348 .anchor}**2.3 Concept Approval**

> Concepts may be approved or approved on-hold pending pharmaceutical
> collaborator(s) commitment (if the agent to be used is under
> CTEP-sponsored IND). PIO will contact the pharmaceutical collaborator
> directly to secure commitment to supply the agent. Once the commitment
> has been secured or if the Concept does not utilize a CTEP-sponsored
> IND and has been approved, the approval letter and consensus review
> will be sent via email from the PIO to the PI, cooperative Group
> operations contact/site coordinator, and grant holder (aka mail to
> contact).
>
> If the approved Concept has as its lead disease, Genitourinary (GU
> i.e. bladder, prostate, etc.) or Lung cancers, CTEP's Expedited
> Protocol process will be used. The Expedited Protocol process puts
> approved concepts in the above mentioned disease groups through a fast
> track process (goal is to complete the process in 30 days) designed to
> review/approve the protocols enabling the sites to begin enrolling
> patients earlier than the conventional review process allows. The
> approval letter will contain information for the site to follow so the
> submission can seamlessly enter this process. While the process allows
> for rapid review and approval, the CTEP review process is essentially
> the same, however, communications regarding the protocol will take
> place via an email distribution group where comments can be rapidly
> disseminated to the site allowing for corrections to be made to the
> protocol and related documents in an expedited fashion.
>
> **2.4 Concept Disapproval**
>
> Concepts that are disapproved by CTEP can be resubmitted for further
> CTEP review provided that resubmission addresses the comments provided
> in the consensus review. The resubmission would go through the process
> as stated above. The resubmission would use the CTEP Concept number
> given to the original submission and PIO would notate the resubmission
> in PATS.
>
> **3 Protocols -- Introduction**
>
> The principal investigator has ultimate responsibility for the timely
> submission of a new protocol. This responsibility is usually delegated
> to the Group operations office for a Cooperative Group or Cancer
> Center operations center for a single institution with a site
> coordinator making the protocol submission to CTEP. Co-investigators
> can not submit a protocol to CTEP.
>
> Protocols are submitted following the approval of an LOI or Concept.
> Cooperative Groups and Consortia have 60 days from the date of
> approval to submit a protocol to CTEP, single institutions and cancer
> centers have 30 days. A site can request an extension to the
> timeframes stated by submitting the request by email to the PIO at
> <PIO@ctep.nci.nih.gov>. Sites should include the reason for the
> request for an extension. PIO will forward the request to the lead
> reviewer for consideration and will pass the decision back to the
> site.

[]{#__RefHeading___Toc164071349 .anchor}**3.1. Components of a Protocol
Document**

> Protocols that are submitted to CTEP for review contain complex
> scientific information that through the use of a CTEP protocol
> template expedite the review process. Using the CTEP protocol template
> as an example, the major components of a protocol are listed below:

-   Title Page -- lists the title of the study, version date, contact
    information of the principal investigator (PI), co-investigators,
    and other study personnel. Do not include the NSC or IND number(s)
    in the title but include them in the listing of NCI supplied agents
    on the title page.

-   Schema -- provides a summary of the proposed treatment plan.

-   Table of Contents -- include page numbers.

-   Objective(s) -- description of the primary protocol objectives and
    secondary objectives.

-   Background and Rationale -- background information on the
    investigational study agent(s) including the mechanism of action,
    summaries of clinical and nonclinical studies and pharmacokinetics,
    safety profile, the rationale for the proposed starting doses and
    dose escalation scheme, and the results of other clinical studies
    using a brief overview. Also included is background information on
    the study disease and background and the rationale for evaluating
    the study agent in the study disease.

-   Patient Eligibility Criteria -- specifically states the conditions
    under which a patient is eligible to join the study. Includes
    references to diagnosis, prior therapies, age, performance status,
    and organ and marrow function. This section will also include
    criteria that make a patient ineligible for the study such as
    treatment with other agents, allergies to the class of agent under
    study, pregnancy, brain metastasis, and HIV-positive patients. CTEP
    has developed guidelines that can be used during the protocol
    authoring process that outline the inclusion of various populations.
    These guidelines are posted on the web site at:
    <http://ctep.cancer.gov/guidelines/templates.html>.

-   Pharmaceutical Information -- The Pharmaceutical Management Branch
    (PMB) has posted a primer recommending how this section should be
    completed on the CTEP web site at:
    <http://ctep.cancer.gov/guidelines/pharm.html>. The PMB
    pharmaceutical data sheet for the CTEP-held IND agent(s) will be
    provided with the concept approval letter.

-   Treatment Plan -- a detailed description of the treatment enrolled
    patients will receive. CTEP uses the treatment plan to derive the
    Treatment Assignment Codes and Descriptors (TACs/TADs). CTEP has
    posted to the web site a guide for the development of TACs and TADs
    located at: <http://ctep.cancer.gov/forms/TreatmentAssignment.pdf>.
    More information about TACs and TADs can be found in section 3.22.

-   Procedures for Patient Entry on Study

-   Dose Modifications for Adverse Events - describes how the PI will
    modify the administration of the agent under study in the event an
    AE is experienced. This modification is specified by nature and
    grade of the AE.

-   Criteria for Response Assessment -- The CTEP web site contains
    information about the use of the Response Evaluation Criteria in
    Solid Tumors (RECIST) at:
    <http://ctep.cancer.gov/guidelines/recist.html>.

-   Monitoring of Patients -- See the section on Monitoring of Clinical
    Trials for more information

-   Off-Study Criteria -- Addresses how patients will be followed once
    off-study.

-   Adverse Event Reporting -- See section 3.11 on Adverse Events for
    more information.

-   Statistical Considerations

-   Multicenter Trials and Inclusion of Guidelines -- See the section on
    Monitoring of Clinical Trials for more information

-   Laboratory Approaches to be Used for Ancillary Studies

-   Informed Consent -- The informed consent form is a standard part of
    every protocol reviewed by CTEP. The informed consent is designed to
    educate and inform patients about the nature and objectives of the
    study as well as notify them of all potential risks associated with
    the study (as described in the CAEPR provided by CTEP for CTEP-held
    IND agents). The informed consent, once approved by CTEP should be
    presented to and signed by each study participant. The informed
    consent template can be found on the CTEP web site at:
    <http://ctep.cancer.gov/guidelines/consent.html>

-   CRADA/CTA -- The Cooperative Research and Development Agreement
    (CRADA) and the Clinical Trials Agreement (CTA) are agreements
    signed between CTEP and a pharmaceutical collaborator that may be
    supplying the agent in the study or otherwise collaborating on the
    clinical trial. This language is included in the regulatory section
    of the protocol, not as an appendix. The model CRADA and CTA forms
    are located on the CTEP web site at:
    <http://ctep.cancer.gov/forms/index.html>

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-   CRFs/CDEs -- Phase 3 Cooperative Group studies in gastrointestinal,
    genitourinary, gynecological, breast, lung, leukemia, and melanoma
    must submit Case Report Forms (CRF) using the Common Data Elements
    (CDE). While CRFs should be submitted with the original submission,
    the forms can be submitted at a later date to allow for scientific
    review of the protocol which may impact data points on the CRFs.
    CRFs are to be submitted to the PIO, who will route them for CDE
    review. Revisions to CRFs as a result of CDE reviews are submitted
    back through the PIO which are then communicated as part of the
    review process. Final approval will not be given until the protocol
    is CDE compliant and the CRFs are approved by CTEP. A CDE dictionary
    is available on the CTEP web site at:
    <http://ctep.cancer.gov/reporting/cde.html>

    []{#__RefHeading___Toc164071350 .anchor}**3.2 Version Dating**

> The Version Date is the day that reflects the most recent submission
> to CTEP. The Version Date shall approximate the date the submission
> was made to CTEP or the CIRB. The Version Date, though, may be
> assigned by some other mechanism as per local policy (i.e., the date
> the PI or Study Chair approved the version). CTEP will use the version
> date to identify the latest version of the protocol. Others outside of
> CTEP (i.e., Institutional Review Board \[IRB\], Central IRB \[CIRB\],
> Cancer Trials Support Unit \[CTSU\], local institutions) may use the
> Version Date to identify the latest edition of a protocol document or
> can use a local update date. The Version Date, including the month,
> day, and year (e.g., Version: ##/##/####), shall be clearly identified
> on the protocol title page. The Version Date is required on the
> protocol title page for all original protocol submissions, revisions,
> and amendments. If a protocol requires further modification based on
> comments received during the review process, then the Version Date
> shall be modified to reflect the most recent submission.

[]{#__RefHeading___Toc164071351 .anchor}**3.3 Use of Protocol
Templates**

> Protocol templates have been developed to assist sites in the
> authoring of phase 1 and 2 protocols and are specifically identified
> on the CTEP Web site in the following categories:

-   [Phase I Single Agent Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph1_sing_temp3.doc)

-   [Phase I Combination Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph1_comb_temp3.doc)

-   [Phase I Organ Dysfunction -- Renal Template Version 2.0 (MS Word
    document)](http://ctep.cancer.gov/forms/Renal_dysfunction_temp2.doc)

-   [Phase I Organ Dysfunction -- Hepatic Template Version 2.0 (MS Word
    document)](http://ctep.cancer.gov/forms/Hepatic_dysfunction_temp2.doc)

-   [Phase II Single Agent Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph2_sing_temp3.doc)

-   [Phase II Combination Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph2_comb_temp3.doc)

> The phase 1 and 2 templates may be used for the study of
> investigational agents first-in-human studies and to address agent
> activity, respectively. Typically, these templates are used following
> the review and approval of a Letter of Intent (LOI) that has been
> submitted, reviewed, and approved by CTEP. On occasion, CTEP will
> release to investigators, an agent-specific template. Typically, this
> is done following the approval of LOIs from a Mass Solicitation and is
> provided to investigators to ensure that language specific to the
> activity, side-effects, and interactions of the agent being studied
> are included for CTEP review.
>
> CTEP has developed a template for phase 0 studies. Phase 0 is a joint
> initiative of the Division of Cancer Therapy and Diagnosis (DCTD) and
> the Center for Cancer Research (CCR) to move biologic and molecular
> discovery to points earlier in the clinical development of new agents.
> Examples of studies that can be considered for phase 0 submission
> include: first-in-human and/or bioavailability trials of small
> molecules or antibodies or combinations of therapeutic with strong
> correlative laboratory and/or imaging support within CCR or DCTD;
> imaging of novel targeted agents for tumor localization and therapy;
> feasibility testing and biomarker assay development studies and
> pharmacologic studies to facilitate subsequent establishment of
> biologically effective dosing. Phase 0 study designs could include
> both single-agent and combination studies.
>
> Concurrently, the Food and Drug Administration (FDA) issued the
> Guidance for Industry, Investigators, and Reviewers on Exploratory IND
> Studies. These studies are intended to provide early information about
> candidate compounds' performance in humans, without compromising human
> subject protection. Exploratory studies will administer either
> subtherapeutic doses or doses intended to produce a pharmacologic but
> not an adverse effect reducing the risk to human participants. The
> complete guidance document can be found at:
> <http://www.fda.gov/cder/guidance/7086fnl.htm>.
>
> Phase 3 protocols are typically submitted following the review and
> approval of a concept. A phase 3 protocol template is currently under
> construction by CTEP.
>
> Use of the protocol templates can ensure that the submitted document
> addresses all of the essential areas for CTEP review. Please make
> certain to remove all inappropriate boilerplate language from the
> templates prior to submission.
>
> Sites may author a protocol as a Microsoft Word or PDF document.

[]{#__RefHeading___Toc164071352 .anchor}**3.4 Protocol Submission
Worksheet (PSW)**

> The Protocol Submission Worksheet (PSW) is a summary document that
> captures many of the key elements that PIO will abstract into the PATS
> database. The PSW is available on the CTEP web site at:
> <http://ctep.cancer.gov/guidelines/templates.html> as either a
> Microsoft Word of PDF document.
>
> The PSW is broken in seven main sections:

-   General Information -- Lead organization name, PI name and contact
    information, local protocol number, funding information and:

    -   Study Objectives (primary and secondary)

    -   List of agents (if applicable) to be used in the study including
        IND sponsor, IND number, NSC number, request for PMB
        distribution and if agent is investigational or commercial

    -   Type of Therapy

    -   Study Disease (by name and Simplified Disease Classification
        (SDC) number)

    -   Study Population Age Range

    -   Statistical Design

-   Embedded Correlative Studies -- listed by study code, title, grant
    number, anticipated number of samples to be analyzed and the
    estimated cost per sample

-   Subgroup Information -- includes subgroup number and description

-   Treatment Assignment Code Information -- see section 3.22 for more
    information

-   Gender and Minority Accrual Estimates -- required for all Phase 2
    and 3 as well as Pilot studies. If this information is missing or
    contradicts what is in the protocol, the submission will be
    considered incomplete and put on-hold by PIO.

-   Common Data Elements (CDE) -- outlines CTEP policy on the use of
    CDEs.

-   Person submitting PSW

> It is strongly recommended that the sections are completed with as
> much accuracy as possible, especially if the study is a multi-modality
> study, has multiple correlative studies and sub groups, or the site
> has specific system requirements for the coding of TACs and TADs.
>
> If changes are made in accrual goals or agents used a revised PSW
> needs to be submitted to PIO.

[]{#__RefHeading___Toc164071353 .anchor}**3.5 Submitting Protocols --
General Policy**

> All protocols, related documents (e.g. PSW), and correspondence should
> be submitted to the PIO via the mail email address at
> <PIO@ctep.nci.nih.gov>. CTEP will assign a protocol to a particular
> PRC meeting based upon when it was received in PIO and if the
> submission was complete. If a protocol is received in PIO before
> Tuesday 5PM ET and is complete and is not put on-hold for any reason,
> then it is expected to be reviewed at PRC three Thursdays later. That
> is a general policy for scheduling but a number of factors could
> change that review date. It is CTEP's goal to move complete,
> well-written protocols through the process and towards approval as
> quickly as possible.

[]{#__RefHeading___Toc164071354 .anchor}**3.5.1 Protocol Numbering**

> When PIO abstracts the protocol into the PATS database, a protocol
> number will be generated and communicated back to the submitting site
> in the acknowledgement letter. All future submissions of that study
> (including revisions and amendments) must include that number on the
> title page. If a local number is already assigned for the protocol at
> the time of the initial submission, it can be included on the title
> page. CTEP recommends that you clearly differentiate between local and
> NCI document numbers.

[]{#__RefHeading___Toc164071355 .anchor}**3.6 How to Submit a Protocol
to CTEP**

> Each new protocol should be sent directly to the PIO via email at
> <pio@ctep.nci.nih.gov>. Each new submission must include the
> following:

-   Completed Protocol Submission Worksheet (PSW),
    <http://ctep.cancer.gov/forms/index.html>

-   A clean (not highlighted or changes tracked) protocol document which
    addresses each of the components listed in section 3.1. Draft
    protocols will not be accepted for review.

-   An informed consent document which address the elements required by
    FDA regulations (see Appendix VII of the Investigator's Handbook) or
    the CTEP web site: <http://ctep.cancer.gov/guidelines/consent.html>.

> Within 24 hours of receipt of the submission, PIO will respond with an
> acknowledgement email and begin processing the submission. If the
> submission is incomplete, incorrect, or contradicts itself, the
> submission will be placed on hold until the information is corrected.
> PIO utilizes the Protocol Authorization and Tracking System (PATS) as
> the main database for entering and capturing protocol information.
> This process is known as abstraction and is done to provide CTEP
> personnel with a snap shot of information used during the review.
> During the abstraction process, the submission will be assigned an NCI
> protocol number which must be on the title page of the protocol and
> referenced in all future versions and communications with PIO. The
> assignment of the NCI protocol number does not signify final CTEP
> approval. Final CTEP approval will be communicated in a letter which
> also allows the participating site(s) to order investigational agents.
>
> Once the protocol is completely abstracted, is not on hold, and is
> prepared for distribution to CTEP reviewers, PIO will issue an
> acknowledgement letter that will contain the protocol title, NCI
> number, date received, and the PI on the study. The letter will be
> emailed to the site as verification that the protocol is ready for
> CTEP review.

[]{#__RefHeading___Toc164071356 .anchor}**3.7 CTEP Review of New
Protocols**

> Once the submission is complete, PIO will prepare the protocol for
> review by CTEP personnel. CTEP must review and approve every protocol
> involving DCTD investigational agents and/or studies that have NCI
> funding. Protocols are reviewed for completeness, scientific merit,
> duplication of existing studies, patient safety, and adequacy of
> regulatory and human subjects protective aspects. Assignment of CTEP
> reviewers is predicated by the "type" of review the protocol will
> undergo within CTEP, based on phase of study or disease.
>
> CTEP will also review protocols sponsored by the Division of Cancer
> Prevention (DCP) or the Cancer Imaging Program (CIP) upon request by
> those offices. CTEP may be asked to review those protocols in order to
> garner the clinical experience CTEP has working on agents or tumor
> types. If a DCP or CIP protocol is submitted to CTEP, it will follow
> the same procedures as a CTEP sponsored study.

[]{#__RefHeading___Toc164071357 .anchor}**3.8 Review Types**

> A complete description of review types is located on the CTEP web site
> at: <http://ctep.cancer.gov/forms/ReviewTree.doc>. Review types
> include:

-   *Full Review* -- Utilizes a CTEP IND, expected accrual \>100,
    includes phase 1, 2, and 3 studies as well as Pilot studies

-   *Safety Review* -- Cooperative Group phase 1 trials without a CTEP
    IND and expected accrual of \<100 patients

-   *Developmental Strategy Review* -- Cooperative Group phase 2 trials
    without a CTEP IND and expected accrual of \<100 patients

-   *File Only Review* -- All non-treatment trials with expected accrual
    of \<100 patients

    []{#__RefHeading___Toc164071358 .anchor}**3.9 CTEP Reviewer
    Assignment**

> Based on the review type, CTEP personnel are assigned to evaluate the
> protocol and informed consent document. Protocols may have between
> five to seven reviewers assigned to evaluate it.
>
> Most protocols will receive full review, thus the factor that will
> determine the reviewers assigned to the protocol will be phase,
> disease, and use of investigational or commercial agents. For example:

-   A phase 1 study utilizing investigational agents would have the
    following CTEP reviewers assigned:

    -   Drug Monitor (IDB) would be the Lead Reviewer

    -   A second IDB monitor

    -   Disease Monitor (CIB) only if required but not typical for a
        phase 1 study

    -   Cancer Diagnosis Reviewer (if there are embedded correlative
        studies)

    -   Statistical Reviewer

    -   Clinical Trials Monitoring Branch Reviewer

    -   Regulatory Affairs Branch (RAB)

    -   Pharmaceutical Management Branch Reviewer

    -   CTEP Coordinator

    -   If there is a surgical, radiation therapy, imaging, or quality
        of life component to the study, CTEP will add the appropriate
        reviewers

        -   A phase 3 study utilizing commercial agents would have a
            different set of reviewers:

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    -   Disease Monitor (CIB) would be the Lead Reviewer

    -   No Drug Monitor (IDB) would be assigned unless the agent
        utilized was under CTEP-held IND.

    -   All other reviewers would be the same as above

> CTEP uses a parallel review process for new protocols with reviewers
> submitting comments back to PIO prior to the PRC meeting.

[]{#__RefHeading___Toc164071359 .anchor}**3.10 Monitoring of Clinical
Trials**

> As a sponsor for investigational agents and/or the funding agency for
> cancer clinical trials, FDA regulations require the Division of Cancer
> Treatment and Diagnosis (DCTD) to maintain a monitoring program. The
> Clinical Trials Monitoring Branch (CTMB) of the Cancer Therapy
> Evaluation Program provides direct oversight of each Cooperative
> Group\'s monitoring program which includes auditing as one component.
> The purpose of an audit is to document the accuracy of data submitted
> to the Cooperative Groups and to verify investigator compliance with
> protocol and regulatory requirements. In addition, the monitoring
> program provides an opportunity for the audit team to share with the
> institution staff, information concerning data quality, data
> management, and other aspects of quality assurance.
>
> The major objective of the audit program used by the Cooperative
> Groups is to verify study data that could affect the interpretation of
> primary study endpoints. This corroboration is done through
> independent verification of study data with source documents. The
> NCI-CTMB Guidelines for On-Site Monitoring of Clinical Trials for
> Cooperative Groups, CCOP Research Bases, and Cancer Trials Support
> Unit (CTSU) require all institutions to be audited at least once every
> 36 months.
>
> In addition, CTMB conducts on-site audits for Cancer Centers. The CTEP
> on-site visit assesses protocol compliance as well as administrative
> review of central data management, protocol development, and data
> collection.
>
> Information about the CTMB audit process can be found on the CTEP web
> site at: <http://ctep.cancer.gov/monitoring/> as well as the
> Investigator's Handbook, page 48.

[]{#__RefHeading___Toc164071360 .anchor}**3.10.1 Clinical Trials
Monitoring Service (CTMS)**

> The objective of the CTMS is to review and audit the documentation of
> clinical observations made during phase 1 and limited phase 2 studies
> into a detailed patient database in order to provide reports to
> relevant parties. A centralized database was developed and a
> requirement for regular reporting of set data elements was created to
> meet this need. Another objective of the CTMS is to provide an on-site
> audit service at each phase 1 institution to help ensure that PIs and
> sites are meeting NCI policies and FDA regulations. Information about
> CTMS may be found at: <http://www.theradex.com/CTMS/ctmsmenu.htm>.

[]{#__RefHeading___Toc164071361 .anchor}**3.10.2 Cancer Trials Support
Unit (CTSU)**

> The primary goal of the CTSU is to increase participation in
> NCI-sponsored clinical trials. Several of the key functions of the
> CTSU are designed to streamline clinical trials through the
> development and operation of a comprehensive system for clinical
> trials management, including a regulatory support unit, an audit
> function, development of a clinical trials informatics support system,
> and the development and conduct of education and training in the CTSU
> system.
>
> The CTSU can be added as a participant on a study and if a
> participating organization would be added to the title page of the
> protocol. CTSU will also participate in the review of protocols by
> ensuring the CRFs have the correct enrollment information listed on
> the registration forms that will be used by the CTSU enrollment
> database. Complete information about the CTSU may be found at:
> <http://www.ctsu.org/>.

[]{#__RefHeading___Toc164071362 .anchor}**3.10.3 Clinical Data System
(CDS)**

> The CDS is the primary source of clinical trial data for all of DCTD
> (and DCP). CDS reports must be submitted for all phase 1, 2, and 3
> studies. The lead organization is responsible for submitting CDS data.
> There are two types of CDS data sets; Abbreviated (CDS-A) or Complete
> (CDS-C). Data can be reported to either a CTEP File Transfer Protocol
> (FTP) site or a CDS web site. Paper reports are not accepted. Phase I
> studies monitored by CTMS are also reported to the CDS database.
>
> A protocol is assigned to either CDS -- A or C at the PRC meeting but
> generally the following business rules apply:

-   Phase 1 studies will be assigned CDS Complete

-   Phase 2 and 3 studies will be assigned CDS Abbreviated. In some
    cases such as when a phase 2 study will use an investigational agent
    will the study be assigned CDS Complete.

> The complete set of CDUS Instructions and Guidelines can be found on
> the CTEP web site at: <http://ctep.cancer.gov/forms/CDUS_IG_3r3.pdf>.

[]{#__RefHeading___Toc164071363 .anchor}**3.11 Adverse Events (AE)**

> If a patient experiences an adverse event while on study, the
> investigator has the responsibility to report it through established
> CTEP mechanisms. The CTEP, NCI Common Toxicity Criteria (CTC) and
> Common Terminology Criteria for Adverse Events (CTCAE) are designed as
> instruments to be used to document AEs. CTEP has created the Adverse
> Event Expedited Reporting System (AdEERS) for PIs to use as the
> mechanism to report serious and/or expected AEs. The protocol
> submission must also include the proper table that outline AdEERS
> reporting requirements for AEs that occur within 30 days of the last
> dose of the investigational agent.
>
> The Adverse Event Reporting Requirements are located on the CTEP web
> site at: <http://ctep.cancer.gov/reporting/adeers.html>. The web site
> specifies the grades and attributions that must be reported via the
> expedited mechanism as well as those that are required to be reported
> via the routine mechanism based on the phase of study (phase 1 vs.
> phases 2 & 3).
>
> Additionally, CTEP will send out mailings based upon the need or level
> of severity to notify PIs of adverse events. The mailings will specify
> the steps the site is required to take (i.e. amend the protocol) and
> the timeframe for such actions. They various types of mailings are
> listed below:

[]{#__RefHeading___Toc164071364 .anchor}**3.11.1. Action Letters**

> The Food and Drug Administration (FDA) regulations \[21 CFR
> 312.32(c)\] require sponsors of clinical studies conducted under an
> IND to notify the FDA and all participating investigators of any
> serious and unexpected adverse events that are possibly related to the
> investigational agent. In compliance with these FDA regulations, CTEP
> will notify its investigators via IND AE Action Letter.
>
> The CTEP drug monitor may also determine that non CTEP-held IND
> protocols using the agent (i.e. commercially obtained agents or those
> under a company or investigator IND) should also receive the Action
> Letter.
>
> These letters are issued by CTEP for those serious adverse events,
> which warrant a change in the informed consent form and/or protocol.
> The investigators are sent a copy of the expedited adverse event sent
> to the FDA by CTEP with the requirement that the informed consent form
> and/or protocol be amended to include the new event. The investigators
> are provided a time frame for which to submit the amendment to the
> CTEP Protocol and Information Office. The letter will specify if
> accrual to the protocol is to be suspended until the revision is made
> and whether patients already on study require reconsenting.

[]{#__RefHeading___Toc164071365 .anchor}**3.11.2. Safety Reports**

The Food and Drug Administration (FDA) regulations \[21 CFR 312.32(c)\]
require sponsors of clinical studies conducted under an IND
(Investigative New Drug #) to notify the FDA and all participating
investigators of any serious and unexpected adverse events that are
possibly related to the investigational agent. In compliance with these
FDA regulations, CTEP will notify its investigators with Investigator
Safety Reports (ISRs) distributed via e-mail.

Pharmaceutical companies collaborating with CTEP will also send to CTEP
any Safety Reports that they send to the FDA. These reports, though not
on a CTEP held IND, still need to be sent to investigators on a CTEP
held IND for the same agent pending a determination by the IDB physician
responsible for the investigational agent.

The investigators are sent a copy of the expedited adverse event report
that is sent to the FDA by CTEP. The investigators are asked to file a
copy with their protocol file and to send a copy to their IRB according
to local IRB's policies and procedures. CTEP does not require a revision
to the protocol and/or informed consent documents.

[]{#__RefHeading___Toc164071366 .anchor}**3.11.3 Notice to
Investigators**

> In order for CTEP to communicate with its investigators about a
> variety of issues related either to protocols or agents, CTEP will
> issue a Notice to Investigators.
>
> If the Notice to Investigators contains information about changes to
> study agent supply/formulation and/or study agent safety issues, an
> amendment will be required of the PI. The Notice to Investigators will
> contain the time frame for submission of the amendment.
>
> If CTEP seeks to communicate with investigators about changes in
> status (such as administratively closed or temporarily closed), CTEP
> will issue a Notice to Investigators. In such cases, PIs are not
> required to submit and amendment.
>
> CTEP may issue an informational Notice to Investigators that seeks to
> inform PIs of relevant information but will not be required to submit
> an amendment.

[]{#__RefHeading___Toc164071367 .anchor}**3.11.4. Comprehensive Adverse
Event and Potential Risk (CAEPR) document**

> The protocol should include either the CAEPR provided by CTEP or list
> all of the reported and/or potential AEs associated with an agent if
> the CAEPR is not available. The Agent Specific Adverse Event List
> (ASAEL) which is a subset of the CAEPR, contains the list of AEs that
> are expected and is used for expedited reporting only.
>
> If a CAEPR for an investigational agent has been prepared by CTEP,
> then PIO will include the CAEPR as part of the LOI approval packet.
> Updated CAEPRs will be distributed to all sites that conduct CTEP
> sponsored trials utilizing the agent in question. CAEPRs are
> considered confidential documents as they reference adverse events
> associated with an investigational agent. If you are in need of an
> updated CAEPR for a particular agent, contact the PIO at
> <PIO@ctep.nci.nih.gov>.

[]{#__RefHeading___Toc164071368 .anchor}**3.12 Protocol Review
Committee**

> While this evaluation takes place, the protocol is scheduled for
> review by the CTEP Protocol Review Committee (PRC) approximately two
> weeks after a complete and correct protocol is received in PIO. The
> PRC meeting occurs after the assigned CTEP personnel have completed
> their evaluations. The PRC meeting includes CTEP personnel that
> reviewed the protocol, other CTEP personnel as well as other
> interested parties such as the FDA that wish to provide input on the
> scientific merit and regulatory concerns of the protocol and the
> informed consent document. The pharmaceutical collaborator, if there
> is one, also receives a copy and can provide comments. PRC will make a
> decision or put the protocol on-hold until more information is
> gathered.
>
> PRC decisions include:

-   Approved as written

-   Approved with Recommendations -- CTEP is requesting the investigator
    to consider the points raised at PRC but is not obligated to amend
    the study

-   Approved with Comments Requiring a Response -- CTEP is requesting
    the site to respond to the comments issued and amend the study based
    on the comments

-   Approved Deferred Pending Revisions -- CTEP has significant
    questions about the protocol. The investigator is being asked to
    make revisions to the protocol and resubmit for further CTEP review
    before it can be approved. The investigator has 30 days to submit a
    revision

-   Disapproved

    []{#__RefHeading___Toc164071369 .anchor}**3.13 The Consensus
    Review**

> Most approved protocols receive either Approved with Recommendations
> or Approved with Comments Requiring a Response. Therefore, following
> PRC, the lead reviewer will consolidate all of the reviewer comments
> into one document known as the consensus review. Once received by the
> lead reviewer PIO will send the consensus review by email to the
> Cooperative Group/submitting site once approved by the lead reviewer.

[]{#__RefHeading___Toc164071370 .anchor}**3.14 Responding to the
Consensus Review**

> If the consensus review requires changes to the protocol by the
> investigator, the investigator should submit a revised protocol back
> to PIO. The PI has up to 30 days to respond to the consensus review.
> When submitting the revision, the investigator should clearly address
> in a point-by-point fashion (i.e. Page 3, section 1.2, replace 'xyz'
> and insert 'abc'), the changes being made to the protocol. This
> document is known as the cover or change memo. Page numbers should
> reflect the clean, unmarked copy of the protocol document. When
> appropriate, a brief justification for the change should be included.
> Please note: All comments requiring a response to the consensus review
> must be addressed even if no changes were made to the protocol.
>
> When submitting a revision to PIO, the submitting site should include:

-   The change memo

-   A copy of the clean, revised protocol

-   A copy of a highlighted, revised protocol (optional)

> The revision submitted to PIO should include a current version date.
> The version date reflects the most recent submission to CTEP. The
> version date shall approximate the date the revision (or amendment)
> was submitted to CTEP and is required to be on the title page of the
> protocol. PIO personnel will not process a submission that does not
> include a correct version date. The revised submission should also
> include the NCI protocol number.
>
> It is permissible to also assign a local date to the protocol title
> page. A complete description of the use of NCI and local dates as well
> as version and update dates can be found in the "*CTEP Amendment
> Request Submission Policy*" located on the CTEP web site at:
> <http://ctep.cancer.gov/forms/RequestSubmissionPolicyFinal.pdf>.
>
> Once the revision is received and processed in PIO, the lead reviewer
> may choose to have the full PRC review the protocol or go to a
> modified set of reviewers depending on the changes addressed in the
> revision. Once reviewed, if there are any concerns that were not
> satisfactorily addressed by the investigator or new issues that are
> raised by CTEP reviewers, CTEP will issue a Follow Up Review letter
> with concerns for the investigator to address in the next revision.
> The PI has up to 30 days to responds to the follow up review. A PI can
> request an extension to this timeframe by emailing PIO at
> <PIO@ctep.nci.nih.gov>. If the PI fails to respond to either the
> consensus review or follow up review, CTEP can withdraw the study for
> administrative reasons. This process will continue until all concerns
> have been adequately addressed or the study is disapproved or
> withdrawn.
>
> Once CTEP provides final approval for a protocol, PIO will send out
> the approval to the submitting site and to other interested entities
> such as PDQ for posting on the
> [www.cancer.gov](http://www.cancer.gov/) web site.

[]{#__RefHeading___Toc164071371 .anchor}**3.15 Institutional Review
Board Approval**

> All protocols submitted by single institutions and cancer centers are
> required to obtain local IRB approval before CTEP grants final
> approval. Evidence of IRB approval should be sent to PIO for inclusion
> within the protocol file. See Section 8.3 in the Investigator's
> Handbook for a complete description of the documentation requirements.
>
> Cooperative Groups studies can receive CTEP approval and continue to
> secure local IRB approval.

[]{#__RefHeading___Toc164071372 .anchor}**3.15.1 Central Institutional
Review Board** **(CIRB)**

> The CIRB was created as a means of reducing the burden on local IRBs
> and to assist institutions without IRBs. The CIRB reviews phase 3
> Cooperative Group studies as well as phase 2 and 3 pediatric
> Cooperative Group studies. As a result, there is now an Adult CIRB and
> Pediatric CIRB to review the respective protocols. Once CTEP has
> approved the protocol, PIO will put it on-hold and submit the
> information to the CIRB. If the CIRB has no changes and approves the
> protocol, PIO will remove the on-hold designation and grant final CTEP
> approval. If the CIRB has changes or is conducting a continuing
> review, the CIRB will communicate directly with the site. Sites
> responding to CIRB requests should submit the revised protocol to the
> CIRB directly. Once the CIRB has provided approval, it will send the
> CIRB approved protocol back to CTEP. CTEP will review the changes
> prior to granting final approval.
>
> Information about the CIRB can be found at:
> [www.http://ncicirb.org](http://www.http://ncicirb.org).

[]{#__RefHeading___Toc164071373 .anchor}**3.16 Investigator Registration
Status**

> Before CTEP will grant final approval, the investigators on the study
> must have their registration status reconciled so all investigators
> listed on the title page who are providing treatment to patients have
> a registration status of "active". During the review process, CTEP
> will review the status of all investigators. Those investigators with
> a status other than "active" will be required to complete the
> necessary forms in order to have a status of active. Registration
> forms can be found on the CTEP web site at
> <http://ctep.cancer.gov/forms/index.html>.

[]{#__RefHeading___Toc164071374 .anchor}**3.17 Regulatory Review**

> CTEP also performs a regulatory review if the protocol utilizes a
> CTEP-sponsored IND, investigational agents, and is asking the
> Pharmaceutical Management Branch to distribute treatment agents.
> Regulatory review is conducted by the CTEP Regulatory Affairs Branch
> in conjunction with a review by the FDA, which reviews the protocol to
> ensure reporting requirements for adverse events are listed correctly
> and information pertaining to the standard protocol language is
> included if applicable. Final approval from CTEP for new protocols
> occurs after the FDA has provided its review and approval.

[]{#__RefHeading___Toc164071375 .anchor}**3.17.1 Cooperative Research
and Development Agreement and Clinical Trials Agreement**

> Both the CRADA and CTA represent agreements that CTEP enters into with
> the pharmaceutical industry that specifies the terms of collaboration
> in the development of a clinical trial or drug development. Both
> agreements are established with a pharmaceutical collaborator before
> CTEP will even send out a solicitation or be able to approve a
> proposal or protocol. The agreements are developed and maintained by
> the Regulatory Affairs Branch (RAB) at CTEP. RAB also acts as the main
> CTEP liaison with the FDA.

[]{#__RefHeading___Toc164071376 .anchor}**3.18 On hold and Approval On
hold**

> At any point in the protocol submission and review process, PIO may
> put a protocol "on-hold". This designation may reflect the
> identification of incomplete or conflicting information and the
> request by PIO to resubmit the correct information to CTEP. In some
> cases, placing a protocol in a status of on hold will pause CTEP's
> review until the new information is received. In other cases, CTEP
> review will continue but final approval won't be granted until the
> correct information is received.
>
> Once CTEP has approved a protocol, the study will be placed in a
> status of on hold (approval on hold) until the IRB or CIRB approval is
> received by PIO.

[]{#__RefHeading___Toc164071377 .anchor}**3.19 Expedited Protocols**

> The expedited protocol process was developed to speed up the time from
> Concept approval to Protocol approval for phase 3 studies that focus
> on GU or Lung cancers. Cooperative Groups can request directly to PIO
> that a non-GU or Lung phase 3 study go through the Expedited Protocol
> process, who will forward the request to the CTEP staff that would be
> the Lead Reviewer, for consideration. The Expedited Protocol process
> utilizes a focused discussion forum that incorporates CTEP and the
> Cooperative Group operations center/submitting site in an accelerated
> timeframe for review and response to comment to derive a 'final'
> version of the protocol. Typically, these protocols receive approval
> within the group of CTEP reviewers, primarily by the Lead Reviewer,
> but the Lead Reviewer can ask it to go to PRC for review and decision
> or for discussion only.
>
> Instructions for the specifics of working within the Expedited
> Protocol review process are included in the Concept approval letters
> for the GU and Lung cancer Concepts (see section 2.3).

[]{#__RefHeading___Toc164071378 .anchor}**3.20 Withdrawing a study or
document**

> Cooperative Group operations center/submitting sites may withdraw a
> study at any time prior to the study becoming activated. New protocols
> and revisions may be withdrawn by notifying PIO via email of this
> intention provided the study is either "in-review" or "approved". Once
> the study is activated, amendments that are submitted may be withdrawn
> while in-review. Once a study is activated, the site can't withdraw
> the study but would submit a protocol status update form to change the
> status to "Closed to Accrual", "Closed to Accrual and Treatment",
> "Administratively Complete", or "Complete".

[]{#__RefHeading___Toc164071379 .anchor}**3.21 Final CTEP Approval**

> Once all scientific and regulatory concerns have been addressed, all
> investigators have a status of active, and IRB approval is received
> (when applicable), and a supply of agent is available (if applicable),
> CTEP will grant final approval. This includes a two week period for
> the FDA to receive the protocol and for PMB to issue a final sign-off.
> PIO will email to the Cooperative Group operations center/submitting
> site the formal CTEP approval letter. The recipients of the letter
> include the PI, Grantholder, Group operations staff/site coordinator
> as well as PDQ so the PDQ contacts can post the study to the PDQ
> database.

[]{#__RefHeading___Toc164071380 .anchor}**3.22 Coding Letter**

> At the time of final approval, PIO will send out a Coding Letter. It
> is the responsibility of the site to ensure that the information
> contained in the coding letter is correct prior to activation. The
> coding letter lists the title and NCI protocol number. It also
> contains information regarding:

-   Monitoring Method -- If the protocol was assigned CTMS or CDS --
    Abbreviated or Complete

-   Correlative Studies -- The letter will contain the study code and
    descriptor based on the information provided in the PSW and
    protocol. A code and descriptor must be added for any laboratory,
    pharmacokinetic, or other correlative study embedded in a clinical
    trial

-   Subgroups -- A subgroup code and descriptor must be assigned when a
    subgroup (stratum) is used to uniformly group patients for separate
    analysis or treatment. Subgroups may be created by disease or other
    classification such as age, prior therapy, etc.

-   Treatment Assignment Codes and Descriptors (TACS/TADS)-- Treatment
    Assignment Codes and Descriptors are included for each arm and dose
    level of the protocol. The Treatment Assignment Instructions and
    Guidelines (<http://ctep.cancer.gov/forms/TreatmentAssignment.pdf>)
    provide a full description of TACs and TADs

-   Agents -- The letter will list all treatment agents in the study

    []{#__RefHeading___Toc164071381 .anchor}**3.23 Activating an
    Approved Protocol**

> Once the site is ready to activate an approved protocol, the site
> should complete and submit a protocol status update form to PIO. PIO
> will acknowledge and change the status of the protocol and inform
> other relevant parties to the change in status (i.e. PDQ). A status
> update form can be found on the CTEP web site at:
> <http://ctep.cancer.gov/forms/StatusUpdate.doc>. Completed protocol
> status update forms should be sent to the PIO at
> <PIO@ctep.nci.nih.gov>.

[]{#__RefHeading___Toc164071382 .anchor}**3.24 Submitting Amendments to
CTEP**

> Amendments represent changes to a protocol that has received CTEP
> approval. Sites are required to adhere to the information for
> submitting amendments as outlined in the CTEP Amendment Request
> Submission Policy located on the CTEP web site at:
> <http://ctep.cancer.gov/forms/RequestSubmissionPolicyFinal.pdf>

[]{#__RefHeading___Toc164071383 .anchor}**3.25 Document Management
Authoring and Review Tool (Docu-MART)**

> CTEP has developed and will be releasing over time, to submitting
> sites, a web-based tool to enhance the authoring, submission, and
> review of documents. The Document Management Authoring and Review Tool
> (Docu-MART) will allow users to develop a document (protocols,
> revisions and amendments) using web-based templates that can be
> populated with site and study specific information and submitted
> directly to CTEP. Docu-MART will then allow CTEP to review and comment
> on the document electronically to the submitting site. The objectives
> of Docu-MART include: reduce the time and errors in authoring a
> document, reduce the administrative burden associated with the process
> of authoring and reviewing a document, and increase efficiencies for
> both CTEP and the site. The end result should be the production of
> high-quality documents that receive rapid review and reduced time to
> final CTEP approval which will allow sites to enroll and treat
> patients who are depending on the benefits of these cancer clinical
> trials.
>
> Docu-MART will be introduced in a phased approach beginning with the
> Cooperative Groups phase 3 studies. With future releases based on user
> feedback, new sites and studies will begin utilizing the application.
> In time, all sites that submit documents for CTEP review and approval
> will utilize Docu-MART.

[]{#__RefHeading___Toc164071384 .anchor}**Appendix A -- PIO Workflows by
Document Type**

> LOI Process Review Tree

![](media/image2.wmf)

Concept Process Review Tree

![](media/image3.wmf)

New Protocol Process Review Tree

![](media/image4.wmf)

Revision Process Review Tree

![](media/image5.wmf)

Amendment Process Review Tree

![](media/image6.wmf)

[]{#__RefHeading___Toc164071385 .anchor}**Appendix B - List of
Resources**

> *Cooperative Research and Development Agreement (CRADA) and Clinical
> Trials Agreement (CTA) Model Forms* --
> <http://ctep.cancer.gov/forms/index.html>
>
> *Concept Submission Form* -
> <http://ctep.cancer.gov/forms/Concept_Submission.doc>
>
> *Criteria for Competitive Letters of Intent* --
> <http://ctep.cancer.go/forms/competitive_loi.doc>
>
> *CTEP Amendment Request Submission Policy* --
> <http://ctep.cancer.gov/forms/RequestSubmissionPolicyFinal.pdf>
>
> *CTEP PIO Main Email Address* - <PIO@ctep.nci.nih.gov>
>
> *CTEP Web Site* -- [http://ctep.cancer.gov](http://ctep.cancer.gov/)
>
> *Division of Cancer Prevention, Protocol Information Office (DCP PIO)
> Email Address* - <nci_dcp_pio@mail.nih.gov>
>
> *Informed Consent Template* --
> <http://ctep.cancer.gov/guidelines/consent.html>
>
> *Investigator's Handbook* -
> <http://ctep.cancer.gov/handbook/index.html>
>
> *Investigator Registration Information* --
> <http://ctep.cancer.gov/forms/index.html>
>
> *Listing of Recent Mass Solicitations* -
> <http://ctep.cancer.gov/forms/recentsol.doc>
>
> *LOI Submission Form* -- <http://ctep.cancer.gov/forms/LOI_form.doc>
>
> *Monitoring Methods Guide* --
> <http://ctep.cancer.gov/reporting/cdus.html> and
> <http://ctep.cancer.gov/monitoring/index.html>
>
> *National Cancer Institute Web Site* --
> [www.cancer.gov](http://www.cancer.gov/)
>
> *NCI Central IRB Initiative* -- <http://www.ncicirb.org/>
>
> *Pharmaceutical Section Guidelines* -
> <http://ctep.cancer.gov/forms/Concept_Submission.doc>
>
> *Protocol Status Update Form* --
> <http://ctep.cancer.gov/forms/StatusUpdate.doc>
>
> *Protocol Submission Worksheet (PSW)* --
> <http://ctep.cancer.gov/forms/index.html>
>
> *Protocol Templates* --

-   [Phase I Single Agent Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph1_sing_temp3.doc)

-   [Phase I Combination Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph1_comb_temp3.doc)

-   [Phase I Organ Dysfunction - Renal Template Version 2.0 (MS Word
    document)](http://ctep.cancer.gov/forms/Renal_dysfunction_temp2.doc)

-   [Phase I Organ Dysfunction - Hepatic Template Version 2.0 (MS Word
    document)](http://ctep.cancer.gov/forms/Hepatic_dysfunction_temp2.doc)

-   [Phase II Single Agent Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph2_sing_temp3.doc)

-   [Phase II Combination Template Version 3.0 (MS Word
    document)](http://ctep.cancer.gov/forms/ph2_comb_temp3.doc)

> *Response Evaluation Criteria in Solid Tumors* *(RECIST)* -
> <http://ctep.cancer.gov/guidelines/recist/html>
>
> *Review Types* -- <http://ctep.cancer.gov/forms/ReviewTree.doc>
>
> *Translational Research Initiative (TRI) Cost Estimate Worksheet* --
> <http://ctep.cancer.gov/guidelines/>
>
> *Translational Research Initiative (TRI) Additional Information --
> <http://ctep.cancer.gov/resources/trf-funding.html>*
>
> *Treatment Assignment Instructions and Guidelines* --
> <http://ctep.cancer.gov/forms/TreatmentAssignment.pdf>

[]{#__RefHeading___Toc164071386 .anchor}**Appendix C -- Definitions**

*Adverse Event*\" means an adverse clinical event as defined under 21
CFR 312.32 IND Safety Reports and other applicable Federal Regulations.
NCI shall establish and maintain records and make reports to the FDA for
the following Adverse Events: (1) all serious, unexpected adverse
events, (2) any significant increase in the frequency of serious
expected adverse events, and (3) any significant increase in the
frequency of therapeutic failures. Specific NIH and NCI guidelines and
policies for reporting Adverse Drug Experience, as well as common
toxicity criteria, have been developed. These guidelines and policies
appear in the \"Investigator\'s Handbook: A Manual for Participants in
Clinical Trials of Investigational Agents Sponsored by the Division of
Cancer Treatment, and Diagnosis, National Cancer Institute.\"

\"*Annual Report*\" means a brief report of the progress of an
IND-associated investigation which the IND sponsor is required to submit
to the FDA within 60 days of the anniversary date that the IND went into
effect (pursuant to 21 CFR 312.33

\"*BLA*\" means a Biologics License Application. The BLA is a formal
process by which the FDA approves a biologic for commercial
distribution.

\"*Clinical Trials Monitoring Service*\" or \"*CTMS*\" means a
non-governmental organization contracted by CTEP to receive, review, and
perform data management tasks on individual patient case report forms
for phase 1and selected phase 2 NCI investigational agent studies.
On-site audits are performed by the CTMS to assess data validity,
protocol compliance, and adherence to regulatory requirements. Data are
submitted to CTMS on a biweekly basis. On-site data audits are performed
thrice yearly. Data are reviewed by NCI staff on a monthly basis.

*"Concept"* refers to a proposal submitted to CTEP as a declaration of
interest by an investigator to conduct a phase 3 study.

\"*Cooperative Group*\" means the cancer cooperative group composed of
investigators who join together to develop and implement common
protocols, which have been approved by the Steering Committee (see
\"Steering Committee\"), and mutually agreed to by DCTD and
Collaborator. The distinguishing characteristic of cooperative groups is
the central operations and statistical offices which support the
administrative requirements of the research and perform central data
collection and analysis. Protocol compliance of cooperative groups is
verified by each group through its own quality assurance program and
through site visit auditing coordinated by CTMS. The Cancer Therapy
Evaluation Program of the DCTD has established guidelines, \"The
NCI-Cooperative Group-Industry Relationship Guidelines\", to explain the
policies and procedures of the NCI with respect to the Clinical Trials
Cooperative Groups and Industry. Some of these policies reflect DHHS's
requirements for Federally funded clinical research while others are the
result of a consensus among NCI staff and qualified extramural clinical
investigators.

*Cooperative Research and Development Agreement (CRADA) -* The CRADA is
a statutorily based mechanism created under the Federal Technology
Transfer Act of 1986 for the purpose of facilitating Government-Industry
collaboration and technology transfer.

\"*CTA*\" means Clinical Trials Agreement. CTA is an NCI-initiated
mechanism for the clinical co-development of an agent.

\"*CTEP*\" means the Cancer Therapy Evaluation Program, DCTD, NCI.

\"*DCTD*\" means the Division of Cancer Treatment and Diagnosis, NCI.

\"*DHHS*\" means the Department of Health and Human Services.

\"*FDA*\" means the Food and Drug Administration, DHHS.

\"*IND*\" means an Investigational New Drug Application. The IND is the
legal mechanism under which experimental drug research is performed in
the United States. An IND is submitted to the Food and Drug
Administration in order to conduct experimental clinical trials with
investigational agents. The FDA regulations require continual updates to
the IND including, but not limited to, annual reports, adverse event
drug experience reports, new protocols, protocol amendments and
pharmaceutical data.

\"*Investigator*\" means any physician who assumes full responsibility
for the treatment and evaluation of patients on research protocols as
well as the integrity of the research data.

*\"Investigator's Brochure*\" means a document containing all the
relevant information about the drug, including preclinical pharmacology,
preclinical toxicology, and detailed pharmaceutical data. Also included,
if available, is a summary of current knowledge about pharmacology and
mechanism of action and a full description of the clinical toxicities.

\"*Letter of Intent*\" or \"*LOI*\" means an investigator\'s declaration
of interest in conducting a Phase 1 or Phase 2 trial with a specific
investigational agent in a particular disease. Approval of the LOI by
CTEP commits an investigator to submit a protocol within a specified
time frame.

\"*NCI*\" means the National Cancer Institute, NIH, DHHS.

\"*NDA*\" means a New Drug Application. The NDA is the formal process by
which the FDA approves a drug for commercial distribution.

\"*NIH*\" means the National Institutes of Health, PHS, DHHS.

\"*PRC*\" means the CTEP Protocol Review Committee which reviews all
studies involving NCI investigational agents and/or activities supported
by NCI.

\"*Principal Investigator*\" means a physician who has organizational
and fiscal responsibility for the use of federal funds to conduct a plan
of research which frequently includes several clinical trials, e.g.,
Contract Principal Investigator or Grant Principal Investigator.

*"Protocol"* refers to the document submitted to CTEP following the
approval of either an LOI or Concept for the purposes of conducting a
cancer clinical trial sponsored by CTEP.

\"*Regulatory Affairs Branch*\" means the Regulatory Affairs Branch,
CTEP, DCTD, NCI.

\"*Sponsor*\" means an organization or individual who assumes legal
responsibility for overseeing clinical trials with investigational
drugs.

[]{#__RefHeading___Toc164071387 .anchor}**Appendix D -- Biotechnology
101 Glossary**

*Below is a list of scientific terms commonly included in protocols that
can possibly be abstracted by the PIO for example when used in
describing embedded correlative studies.*

**Amino acid**: The fundamental building blocks of a protein molecule. A
protein is composed of a chain of hundreds or thousands of amino acids.
Our bodies can synthesize most amino acids. However, eight amino acids
(called \"essential amino acids\") must be obtained from food.

**Antibody**: A protein produced in response to the presence of a
specific antigen.

**Antigen**: A foreign substance that elicits the production of
antibodies.

**Assay**: A method for determining the presence or quantity of a
component.

**B lymphocytes (B cells)**: A type of cell that produces antibodies.

**Baseline**: A measurement used as a basis for comparison. Usually
refers to a subject's condition at the start of a study, before they
have received study drug.

**Bacteriophage**: A virus that infects bacteria. Also called a phage.

**Bioassay**: A method of determining the effect of a compound by
quantifying its effect on living organisms or their component parts.

**Biocatalyst**: An enzyme that activates or speeds up a chemical
reaction.

**Biological control**: The use of one organism to control the
population size of another organism.

**Catalyst**: A substance that speeds up a chemical reaction, but is not
itself changed during the reaction.

**Cell**: The smallest structural unit of living organisms that is able
to grow and reproduce independently.

**Cell culture**: A technique for growing cells under laboratory
conditions.

**Chromosome**: Components in a cell that contain genetic information.
Each chromosome contains numerous genes. Chromosomes occur in pairs: one
obtained from the mother; the other from the father. Chromosomes of
different pairs are often visibly different from each other (see also
DNA).

**Clone**: A cell or collection of cells containing identical genetic
material. Clones are produced from a single parent cell.

**Complementary DNA**: A single strand of DNA synthesized in the lab to
complement the bases in a given strand of messenger RNA. Complementary
DNA represents the parts of a gene that are expressed in a cell to
produce a protein

**Culture**: To grow living organisms in a prepared medium or media.

**Culture medium**: A nutrient system for artificially growing bacteria
or other cells.

**DNA (deoxyribonucleic acid)**: The chemical molecule that is the basic
genetic material found in all cells. DNA is inherited. Because DNA is a
very long, thin molecule, it is packaged into units called chromosomes.
DNA belongs to a class of biological molecules called nucleic acids.

**DNA ligase**: An enzyme that rejoins cut pieces of DNA.

**DNA probe**: A molecule that has been labeled with a radioactive
isotope, dye or enzyme and is used to locate a particular portion of a
DNA molecule.

**DNA sequence**: The order of nucleotide bases in the DNA molecule.

**Double helix**: A term used to describe the configuration of a DNA
molecule. The helix consists of two spiraling strands of nucleotides
held together with chemical bonds.

**ELISA (enzyme-linked immunosorbent assay):** A rapid immunochemical
test that involves an enzyme (a protein that catalyzes a biochemical
reaction). It also involves an antibody or antigen (immunologic
molecules). ELISA tests are utilized to detect substances that have
antigenic properties, primarily proteins

**Enzyme**: A protein that accelerates the rate of chemical reactions.
Enzymes are catalysts that promote reactions repeatedly, without being
damaged by the reactions.

**FISH (fluorescent in situ hybridization)**; An important molecular
cytogenetic method for identifying chromosomes and parts of chromosomes,
deciphering chromosome rearrangements, and locating genes on
chromosomes. \"Fluorescent\" means emitting light. \"In situ\" refers to
the fact that this technique is done with the chromosomes, cells or
tissue in place (*in situ*) on a microscope slide.

**Gene**: A unit of hereditary information. A gene is a section of a DNA
molecule that specifies the production of a particular protein.

**Gene amplification**: The increase, within a cell, of the number of
copies of a given gene.

**Gene expression**: The physical manifestation of the information
contained in a gene.

**Gene mapping**: Determining the relative locations of genes on a
chromosome.

**Genetic code**: The way genetic information is stored in living
organisms.

**Genetics:** The branch of biology that deals with heredity, especially
the mechanisms of hereditary transmission and the variation of inherited
characteristics.

**Genome**: The total hereditary material of a cell.

**Genomics:** Branch of biotechnology concerned with applying the
techniques of genetics and molecular biology to the genetic mapping and
DNA sequencing of sets of genes or the complete genomes of selected
organisms using high-speed methods, organizing the results in databases,
and with applications of the data (as in medicine or biology)

**Genotype**: The specific genetic makeup of an organism, as contrasted
with the actual characteristics of an organism (see phenotype).

**Hybridization**: Production of offspring, or hybrids, from genetically
dissimilar parents. In selective breeding, it usually refers to the
offspring of two different species.

**Immunoassay**: A technique for identifying substances, based on the
use of antibodies.

**IHC (Immunohistochemistry):** A method of analyzing and identifying
cell types based on the binding of antibodies to specific components of
the cell. It is sometimes referred to as immunocytochemistry.

**In vitro**: Latin meaning performed in a test tube or other laboratory
apparatus.

**In vivo**: Latin meaning performed in the living organism.

**Interferon**: A protein produced naturally by the cells of our bodies.
It increases the resistance of surrounding cells to attacks by viruses.
One type of interferon, alpha interferon, is effective against certain
types of cancer. Others may prove effective in treating autoimmune
diseases.

**Interleukin**: A protein produced naturally by our bodies to stimulate
our immune systems. There are at least 18 known kinds of interleukins.

**Leukocyte**: A white blood cell, an important component of the body\'s
immune system.

**Lymphocyte**: A type of leukocyte found in the blood, lymph nodes and
certain organs. Lymphocytes are continuously made in the bone marrow
(see also B lymphocytes and T lymphocytes).

**Macrophage**: A type of white blood cell that ingests dead tissue and
cells and is involved in producing Interleukin 1.

**Marker gene**: Genes that identify which plants have been successfully
transformed.

**Microarray**: A 2D array, typically on a glass, filter, or silicon
wafer, upon which genes or gene fragments are deposited or synthesized
in a predetermined spatial order allowing them to be made available as
probes in a high-throughput, parallel manner.

**Molecular genetics**: The study of the molecular structure and
function of genes.

**Monoclonal antibody**: Highly specific, purified antibody that is
derived from only one clone of cells and recognizes only one antigen.

**Mutagen**: A substance that induces mutations.

**Mutant**: A cell microorganism that manifests new characteristics due
to a change in its genetic material.

**Mutation**: A change in the genetic information.

**Nucleic acid**: A biological molecule composed of a long chain of
nucleotides. DNA is made of thousands of patterns of four different
nucleotides repeated randomly.

**Nucleotide**: A compound made up of these three components: a sugar,
phosphate and a nitrogen-containing base. Found as individual molecules
(e.g., ATP, the \"energy molecule\"), or as many nucleotides linked
together in a chain (nucleic acid such as DNA).

**Oncogene**: A gene thought to be capable of producing cancer.

**Oncology**: The study of tumors.

**Phenotype**: The observable characteristics of an organism as opposed
to the set of genes it possesses (its genotype).The phenotype that an
organism manifests is a result of both genetic and environmental
factors. Therefore, organisms with the same genotype may display
different phenotypes due to environmental factors. Conversely, organisms
with the same phenotypes may have different genotypes.

**PCR (polymerase chain reaction)**: A technique for quickly making many
copies of a specific segment of DNA. A key technique in molecular
genetics that permits the analysis of any short sequence of DNA (or
RNA). PCR is used to reproduce (amplify) selected sections of
DNA. Previously, amplifying was done (by cloning) in bacteria, and took
weeks.

**PBMC (peripheral blood mononuclear cells)**: A mixture of monocytes
and lymphocytes; blood leukocytes from which granulocytes (RBCs) have
been separated and removed.

**Pharmacodynamics**: the study of the biochemical and physiological
effects of drugs and the mechanisms of drug action and the relationship
between drug concentration and effect. It is often summarily stated that
pharmacodynamics is the study of what a drug does to the body, whereas
pharmacokinetics is the study of what the body does to a drug.

**Pharmacokinetics**: the study of the time course of substances
(including drugs) and their relationship with an organism or system --
including absorption and disposition.

**Pharmacogenetics**: the study of the genetic factors that influence
individual responses to drugs and drug metabolism.

**Protein**: A complex biological molecule composed of a chain of units
called amino acids. Proteins have many different functions: structure
(collagen); movement (actin and myosin); catalysis (enzymes); transport
(hemoglobin); regulation of cellular processes (insulin); and response
to the stimuli (receptor proteins on surface of all cells). The
information for making proteins is stored in the sequence of nucleotides
in the DNA molecule.

**Protein engineering**: A technique used in the production of proteins
with new or artificial amino acid sequences.

**Proteomics** is the large-scale study of proteins, particularly their
structures and functions. This term was coined to make an analogy with
genomics, and while it is often viewed as the \"next step\", proteomics
is much more complicated than genomics. Most importantly, while the
genome is a rather constant entity, the proteome differs from cell to
cell and is constantly changing through its biochemical interactions
with the genome and the environment. One organism will have radically
different protein expression in different parts of its body, in
different stages of its life cycle and in different environmental
conditions.

**Real-time PCR:** (also known as Quantitative PCR, Real-time
Quantitative PCR, or RTQ-PCR \-- but not RT-PCR) is a method of
simultaneous DNA quantification and amplification. DNA is specifically
amplified by polymerase chain reaction (PCR). After each round of
amplification, the DNA is quantified. Frequently, real-time PCR is
combined with reverse transcription-polymerase chain reaction (RT-PCR)
to quantify low abundance messenger RNA, enabling a researcher to
quantify relative gene expression at a particular time, or in a
particular cell or tissue type. The combined technique is often called
quantitative RT-PCR.

**Recombinant DNA**: DNA that is formed through combining DNA from two
different sources. Humans direct the formation of recombinant DNA
through selective breeding and genetic engineering.

**Recombinant DNA (rDNA) technology**: The laboratory manipulation of
DNA in which DNA, or fragments of DNA from different sources, are cut
and recombined using enzymes. This recombinant DNA is then inserted into
a living organism. rDNA technology is usually used synonymously with
genetic engineering.

**Recombination**: The formation of new combinations of genes.
Recombination occurs naturally in plants and animals during the
production of sex cells (sperm, eggs, pollen) and their subsequent
joining in fertilization. In microbes, genetic material is recombined
naturally during conjugation.

**RT-PCR (reverse transcription-polymerase chain reaction):** a two-step
process. First, complementary DNA (cDNA) is made from an RNA template,
using a reverse transcriptase enzyme, and then some of it is used in a
PCR reaction to produce large quantities.

**Southern blot analysis**: A technique for identifying specific
sequences of DNA in which DNA fragments are separated by
electrophoresis, transferred to nitrocellulose, and identified with a
suitable probe.

**RNA (ribonucleic acid)**: Like DNA, a type of nucleic acid. There are
three major types: messenger RNA, transfer RNA, and ribosomal RNA. All
are involved in the synthesis of proteins from the information contained
in the DNA molecule.

**T lymphocytes (T cells)**: White blood cells, produced in the bone
marrow, which aid B cells in making antibodies to fight bacterial
infections. They also are instrumental in rejection of foreign tissue,
and may be important in the body\'s defense against cancer.

**Vector**: The agent used to carry new DNA into a cell. Viruses or
plasmids are often used as vectors.

**Virus**: An infectious agent composed of a single type of nucleic
acid, DNA or RNA, enclosed in a coat of protein. Viruses can multiply
only within living cells.

**Western blot analysis**: A technique for identifying specific
antibodies or proteins in which proteins are separated by
electrophoresis, transferred to nitrocellulose, and reacted with
antibody.

[]{#__RefHeading___Toc164071388 .anchor}**Appendix E - Principal
Investigator Responsibilities**

This section summarizes the primary responsibilities of the Principal
Investigator (PI) when conducting CTEP sponsored clinical trials.

1.  Investigator Registration -- The PI must ensure that the
    registration of the PI and all Co-Investigators is complete and up
    to date. Any investigator without a current 1572 form on file with
    CTEP will not be able to treat patients at that site or order drug
    at that site. In addition, any revision or amendment in-review at
    CTEP will not be able to obtain final approval until all
    registration issues have been resolved.

2.  Scientific Integrity of the Protocol -- The PI is the scientific and
    patient care leader of the study team and as such must lead the team
    with the highest level of integrity and ethics. Leadership includes
    reporting all adverse events and protocol deviations in a timely
    fashion using the correct mechanisms.

3.  Submissions to CTEP -- The PI has overall responsibility for the
    submission of documents to CTEP although that is typically delegated
    to the site coordinator or group operations office. Co-Investigators
    can not submit to CTEP. The PI is also ultimately responsible for
    meeting all CTEP and FDA deadlines.

4.  Compliance of Regulatory Affairs -- The PI is responsible for
    responding to CTEP concerning any FDA comments in a timely fashion.
    The PI is also responsible for the timely dissemination of Safety
    Letters, Notices to Investigators, and Action Letters to all sites
    participating on the study. CTEP should be copied on such
    dissemination.

5.  Changes in Study Status -- the PI as study leader is responsible for
    initiating a change in study status based upon goals and objectives
    met, protocol deviations, slow accrual, etc. The site coordinator or
    group operations office can act as the agent that submits the
    Protocol Status Update Form to the PIO.

6.  Analyzes, Reports and Publishes the Study Results -- CTEP does not
    bear any responsibility to analyze or report data. The PI is
    responsible for submitting annual report data and when the study is
    complete, final report data to CTEP. Any published data of a CTEP
    sponsored study should be sent to CTEP.

    []{#__RefHeading___Toc164071389 .anchor}**Appendix F -- Common PIO
    Terms**

  ------------- ---------------------------------- -------------------------
  **Acronym**   **Meaning**                        **Description**

  AdEERS        Adverse Event Expedited Reporting  
                System                             

  AE            Adverse Event                      

  ASAEL         Agent Specific AE List             

  BRB           Biometrics Research Branch         Statisticians

  CAEPR         Comprehensive AE and Potential     List of AEs for specific
                Risks                              drug

  CCOP          Community Clinical Oncology        
                Program                            

  CDE           Common Data Elements               Forms (CRF) reviewers

  CDP           Cancer Diagnosis Program           Correlative Reviewers

  CDS           Clinical Data System               

  CIB           Clinical Investigations Branch     Disease Monitors

  CIRB          Central Institutional Review Board 

  CRF           Case Report Form                   Forms for reporting trial
                                                   data

  CTCAE         Common Terminology Criteria for    
                Adverse Events                     

  CTEP          Cancer Therapy Evaluation Program  

  CTIS          Capital Technology Information     Off-site contractor
                Systems                            

  CTMB          Clinical Trials Monitoring Branch  Consent Reviewers

  CTMS          Clinical Trials Management Systems 

  CTSU          Cancer Trials Support Unit         

  DCP           Division of Cancer Prevention      

  DCTD          Division of Cancer Treatment and   
                Diagnosis                          

  DTP           Developmental Therapeutics Program 

  EMMES                                            Off-site contractors

  FDA           Food and Drug Administration       

  HHS           Health and Human Services          

  IDB           Investigational Drug Branch        Drug Monitors

  IND           Investigational New Drug           FDA authorization to
                Application                        study drug

  IRB           Institutional Review Board         

  LOI           Letter of Intent                   Preliminary design for
                                                   Phase I and II studies

  NCI           National Cancer Institute          

  NIH           National Institute of Health       

  NSC \#        National Service Center            Identification numbering
                (anachronism)                      system for study agents

  PATS          Protocol Authorization and         PIO's database
                Tracking System                    

  PDQ           Physician Data Query               NCI's clinical trial
                                                   database

  PIO           Protocol and Information Office    

  PMB           Pharmaceutical Management Branch   Pharmacists

  PRC           Protocol Review Committee          

  PSW           Protocol Submission Worksheet      

  QARC          Quality Assurance Review Center    

  QOL           Quality of Life                    

  RAB           Regulatory Affairs Branch          Adverse Event and FDA
                                                   issues

  RC            Resource Center                    Off-site storage facility

  TAC/TAD       Treatment Assignment               
                Code/Description                   

  TRI           Technical Resources International  Contractors assisting
                                                   CTEP
  ------------- ---------------------------------- -------------------------

  --------------- ------------------------------------------------------------
  **Cooperative   
  Groups**        

  ACOSOG          American College of Surgeons Oncology Group

  ACRIN           American College of Radiology Imaging Network

  AMC             AIDS Malignancy Consortium

  CALGB           Cancer and Leukemia Group B

  COG             Children's Oncology Group

  ECOG            Eastern Cooperative Oncology Group

  GOG             Gynecologic Oncology Group

  IBCSG           International Breast Cancer Study Group

  NABTC           North American Brain Tumor Coalition

  NABTT           New Approaches to Brain Tumor Therapy

  NCIC CTG        National Cancer Institute of Canada Clinical Trials Group

  NCCTG           North Central Cancer Treatment Group

  NSABP           National Surgical Adjuvant Breast and Bowel Project

  PBTC            Pediatric Brain Tumor Consortium

  RTOG            Radiation Therapy Oncology Group

  SWOG            Southwest Oncology Group
  --------------- ------------------------------------------------------------

Accrual *3*, *5*, *9*, *20*

acknowledgement email *6*, *19*

Action Letters 23

Adverse Events *7*, *14*, *39*

AE *23*

Approval On-hold *28*

Cancer Therapy and Evaluation Program

CTEP 1

Cancer Trials Support Unit

CTSU *9*, *15*, *21*, *22*

Case Report Forms

CRF *15*

Center for Cancer Research

CCR *16*

Central Institutional Review Board

CIRB *27*

change memo *26*

Clinical Data Update System

CDUS *22*

Clinical Trials Agreement

CTA *28*

Coding Letter *30*

Common Data Elements

CDE *15*, *18*

Comprehensive Adverse Event and Potential Risk (CAEPR) 25

Comprehensive Adverse Events and Potential Risks List

CAEPR *7*

Concept Review Meetings

CRM *11*

Concept submission form *9*

Concepts *1*, *9*, *10*

consensus review *26*

Consortiums *8*, *9*

Consumer Advocates in Research and Related Activities

CARRA *11*

Cooperative Groups 6, 8, 9, 10, 31

Cooperative Research and Development Agreement

CRADA *28*, *40*

*CTEP Amendment Request Submission Policy* *1*, *27*, *31*

CTEP Enterprise System *6*

CTEP web site *1*, *2*, *3*, *9*, *19*, *20*, *27*, *28*, *30*, *31*

Department of Health and Human Services

HHS 1

Division of Cancer Treatment and Diagnosis

DCTD 1

Document Management Authoring and Review Tool

Docu-MART 31

Expedited Protocol process *11*

external reviewers *11*

Final CTEP Approval *29*

Food and Drug Administration

FDA 1, 16

informed consent *19*, *20*

Institutional Review Board Approval

IRB *27*

Investigational Drug Branch

IDB *2*

Investigator Handbook 1

Investigator Registration *28*

Letter of Intent

LOI 2, 16

LOI submission form 2, *4*, *6*

mass solicitation *4*

mass solicitations *2*

Monitoring of Clinical Trials *14*, *15*, *21*

National Cancer Institute

NCI 1

Notice to Investigators 24

on-hold *5*, *11*, *19*, *28*, *29*

PATS *6*, *10*, *19*

Phase 0 studies *16*

PIO *1*, *2*, *4*, *6*, *7*, *10*, *19*, *25*, *26*, *27*, *28*, *29*,
*30*

Principal investigator

PI *13*

Principal Investigator

PI *2*

protocol review committee

PRC *6*

Protocol Review Committee 25

protocol status update form *30*

status update form *29*, *30*

Protocol Submission Worksheet

PSW *19*

Protocol templates *16*

revision *26*, *27*

Safety Reports 24

Simplified Disease Classification

SDC *17*

Translational Research Initiative

TRI *2*, *3*

Treatment Assignment Codes and Descriptors

TACs/TADs *14*

unsolicited LOI *4*

version date *13*, *26*

**withdrawal *29***