Virginia Commonwealth University Massey Cancer Center

Virginia Commonwealth University
Massey Cancer Center

Investigator-Initiated TherapeuticClinical ProtocolTemplate

(For Use with Protocols Requiring an IND)

Version 2

TEMPLATE INSTRUCTIONS

This template is meant to serve as a tool to help you through the process of writing a clinical trial protocol. Although the template contains typical sections and language that can be used as a starting point for your protocol, you will need to tailor it to best suit the objectives of your protocol.

Comments and instructions are in blue italics and should be removed from the final document.

Underlined words represent place holders that should be replaced with protocol-specific information.

The Virginia Commonwealth University (VCU) Internal Review Board(IRB) Informed Consent Template is appended at the end of this document.

Sections 6.02-6.15 of ICH Guideline for Good Clinical Practice (E6)are provided throughout the template on a blue background. These are meant to serve as a ready reference for you when writing the protocol, and they should be deleted from the final document.

References to other protocol sections are highlighted in greento facilitate finding these references and making sure that the appropriate section number is cited. The highlights should be removed from the final document.

To facilitate the development of consistently formatted Massey Cancer Center (MCC) investigator-initiated protocols, please do not modify or delete major protocol headings (1, 2, 3, etc.) when they are NOT used. Instead, please indicate that they are “notapplicable.”

This document is designed using the “style” feature of Microsoft Word. By following a few simple instructions you will get consistent formatting throughout the document, an outline structure that is easy to apply and does not “break”, and a table of contents that automatically updates with a couple of mouse clicks. Please review the MCC Protocol Template Guide for this information before you begin editing.

Completion of the title page is best done with the “show gridlines” feature turned on for tables.

If you need help with the templates or have any questions, please contact:

Kevin T. Hogan, Ph.D.
Senior Scientific Writer
Massey Cancer Center
Office:804-628-4915
E-mail: / Heidi Sankala Bauer, Ph.D.
Scientific Writer
Massey Cancer Center
Office:804-628-3028
E-mail:

Delete this page prior to submission.

Title:Insert title here.
MCC Protocol #:To be assigned by the PRMC Coordinator. / FDA IND #:To be assigned by the FDA.
Principal Investigator/Study Chair/Coordinating Center/Sponsor-Investigator:(Use one as appropriate)
Name
Address
Address
Telephone
Fax
E-mail address / IND Sponsor:(If not sponsor-investigator)
Name
Address
Address
Telephone
Fax
E-mail address
Subinvestigator/Responsible Investigator:(Use one as appropriate)
Same information as per PI
A Responsible Investigator must be listed for each participating site in a multi-institutional study) / Subinvestigator/Responsible Investigator:(Use one as appropriate)
Same information as per PI
Subinvestigator/Responsible Investigator:(Use one as appropriate)
Same information as per PI / Subinvestigator/Responsible Investigator:(Use one as appropriate)
Same information as per PI
Subinvestigator/Responsible Investigator:(Use one as appropriate)
Same information as per PI / Subinvestigator/Responsible Investigator:(Use one as appropriate)
Same information as per PI
Subinvestigator/Responsible Investigator:(Use one as appropriate)
Same information as per PI / Subinvestigator / Responsible Investigator:(Use one as appropriate)
Same information as per PI
Biostatistician:
Same information as per PI / Responsible Research Nurse:
Same information as per PI
Funding Sponsor: (or other designation as appropriate; delete if not needed)
Name
Contact information / Funding Sponsor: (or other designation as appropriate; delete if not needed)
Name
Contact information
Investigational Agent(s):Provide each agent name and indicate if its use is “commercial” or “investigational use” stock.
Version #:### / Version Date:MM/DD/YYYY

Protocol Summary

• A description of the type/design of the trial to be conducted (e.g.,double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages. [6.4.2] (See also section 3, STUDY DESIGN.)

Limit the length of the Protocol Summary to no more than 2 pages.

Title:
Protocol Number:
IND Sponsor: / If applicable
Principal Investigator /Study Chair/‌Coordinating Center/Sponsor-Investigator:
Study Sites:
Clinical Trial Phase: / I, II, III, or IV
Study Disease:
Main Eligibility Criteria:
Primary Objectives:
Secondary Objectives:
Endpoints:
Study Design:
Study Agent/‌Intervention Description: / Name, dose, frequency, duration, and route of administration
Number of Subjects:
Subject Participation Duration:
Estimated Time to Complete Enrollment:
Statistical Methodology:

SCHEMA

Insert a schema (figure or table) that concisely describes the study.

Revision History

Revision history is presented in reverse order so that the information pertaining to the most current version of the protocol is presented first in this section.

Version 1, Version Date MM/DD/YYYY

Initial submission of the protocol.

TABLE OF CONTENTS

Protocol Summary

SCHEMA

Revision History

TABLE OF CONTENTS

List of Abbreviations

1background

1.1Study Disease (replace header with study disease)

1.2Investigational Agent(s) (replace header with investigational agent; use additional headers if more than one investigational agent is used)

1.3Other Agents (replace header with other agents used in the study)

1.4Correlative Studies Background

2objectives

2.1Primary Objectives

2.2Secondary Objectives

3STUDY DESIGN

3.1General Description

3.2Primary Outcome Measure(s) (Primary Endpoint[s])

3.3Secondary Outcome Measure(s) (Secondary Endpoint[s])

4patient selection

4.1Inclusion Criteria

4.2Exclusion Criteria

5study entry and withdrawal procedures

5.1Study Entry Procedures

5.2Study Withdrawal Procedures

6Treatment plan

6.1Baseline Tests and Procedures (if applicable)

6.2Investigational Agent Administration (or other appropriate title; “Radiation Therapy” might be appropriate for a radiation oncology protocol)

6.3Definition of DLT (applicable only for phase 1 trials)

6.4Additional Treatment Modalities (if applicable)

6.5General Concomitant Medication and Supportive Care Guidelines (if applicable)

6.6Duration of Therapy

6.7Monitoring Subject Compliance (if applicable)

6.8Follow-Up Period

7dosing delays/dose modifications

8adverse events: Definitions and reporting requirements

8.1Definitions

8.2Known AEs List

8.3Time Period and Grade of AE Capture

8.4Procedures for Recording AEs, SAEs, and UPs

8.5Routine Reporting Procedures for AEs

8.6Expedited Reporting Procedures for SAEs, SARs, UPs, and DLTs

9pharmaceutical information

9.1Agent #1 (replace header with appropriate information; repeat this section as needed for each investigational or commercial agent)

10measurement of effect

10.1Anti-tumor Effect (Solid Tumors or Hematologic Malignancies as Appropriate)

10.2Other Response Parameters

11correlative studies/Special Studies

11.1Laboratory Correlative #1

11.2Laboratory Correlative #1

11.3Shipping Instructions

12study calendar

13statistical considerations

13.1Study Design and Analysis

13.2Sample Size/Accrual Rates

13.3Stratification Factors

13.4Analysis of Secondary Endpoints

14data and safety monitoring plan (dsmp)

14.1Study Team

14.2Audit Committee

14.3DSMB

15regulatory compliance and ethics

15.1Ethical Standard

15.2Regulatory Compliance

15.3Institutional Review Board

15.4Informed Consent Process

15.5Subject Confidentiality and Access to Source Documents/Data

16data handling and record keeping

16.1Data Management Responsibilities

16.2Source Documents

16.3Case Report Forms (or other appropriate title to reflect the study-specific manner in which protocol-specific data will be recorded)

16.4Study Record Retention

17references

18appendix 1. Insert title here.

19informed consent template

MCC Protocol #:1Version #:

IND #: Version Date: MM/DD/YYY

List of Abbreviations

1background

• Name and description of the investigational product(s). [GCP 6.2.1]
• A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial. [GCP 6.2.2]
• Summary of the known and potential risks and benefits, if any, to human subjects. [GCP 6.2.3]
• Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s). [GCP 6.2.4]
• Description of the population to be studied. [GCP 6.2.6]
• References to literature and data that are relevant to the trial, and that provide background for the trial. [GCP 6.2.7]

The outline below illustrates one way in which the background information can be organized in this section. However this information is organized, it is important to include each of the items required by Good Clinical Practice (GCP) guidance.

1.1Study Disease(replace header with study disease)

Provide background information related to the disease to be studied.

1.2Investigational Agent(s)(replace header with investigational agent; use additional headers if more than one investigational agent is used)

Provide the name and description of each investigational agent to be used in the study. Include background information on the agent, including the mechanism of action, summaries of nonclinical and clinical studies, nonclinical and clinical pharmacokinetics, major route of elimination, safety profile, and the rationale for the proposed dose or dose escalation scheme, as well as the route of administration, dosage regimen, and treatment period. Include information on the metabolism of the agent in humans and its potential for drug interactions, if available. The “Preclinical Data” and “Clinical Data” sections below may be useful in organizing this information. They may be used or deleted as appropriate.

1.2.1Preclinical Data

1.2.2Clinical Data

1.2.3Known and Potential Risks and Benefits

Provide a summary of the known and potential risks and benefits to the study subjects.

1.2.4Rationale

Provide the overall rationale for evaluating this agent in this disease.

1.3Other Agents(replace header with other agents used in the study)

1.4Correlative Studies Background

Provide background information for each of the planned correlative studies.

2objectives

• A detailed description of the objectives and the purpose of the trial. [GCP 6.3]

The objectives should state the scientific question(s) that the study seeks to answer. The objectives should indicate why the study is being done and differ from the study endpoints which are theparameters used to evaluate the objectives.The primary objectives are generally therapeutic in nature (to assess the safety of…, to determine the efficacy of…, to determine the DLT [Dose-limiting toxicity] of…) while the secondary objectives are frequently related to correlative studies.

2.1Primary Objectives

2.1.1Insert primary objectives here.

2.2Secondary Objectives

2.2.1Insert secondary objectives, if any, here.

3STUDY DESIGN

• A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial. [6.4.1]
• A description of the type/design of the trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages. [6.4.2] (See also the SCHEMA section.)
• A description of the measures taken to minimize/avoid bias, including: (a) randomization; (b) blinding. [6.4.3]

3.1General Description

Provide a description of the type/design of the trial to be conducted including any measures such as randomization or blinding to be taken to avoid bias (e.g.,double-blind, placebo-controlled, parallel design).

3.2Primary Endpoint(s)

The primary endpoints are the clinical, chemical, biological, etc. parameters that are being measured to evaluate the primary objective(s).

3.2.1

3.3Secondary Endpoint(s)

The secondary endpoints, if any, are the clinical, chemical, biological, etc. parameters that are being measured to evaluate the secondary objective(s).

3.3.1

4patient selection

• Subject inclusion criteria. [GCP 6.5.1]
• Subject exclusion criteria. [GCP 6.5.2]
• Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial. [GCP 6.6.2] (See also the TREATMENT PLAN section.)

The following prompts are suggestions for inclusion and exclusion criteria. The promptsshould be replaced with the actual criteria or deleted as is appropriate for the study. See “Inclusion and Exclusion Criteria Guidelines” for additional suggestions.

4.1Inclusion Criteria

A potential subject must meet all of the following inclusion criteria to be eligible to participate in the study.

Criteria which might be included include: (i) disease including histological or cytological confirmation and stage; (ii) allowable type and amount of prior therapy; time since last treatment; (iii) age restriction, if any; (iv) performance status and scale; (v) life expectancy; (vi) any organ or marrow function requirements; (vii) any laboratory parameter requirements; (viii) willingness to use contraception as required; (ix) any additional inclusion criteria that are appropriate to the study.

4.1.1

4.1.2Ability to understand and the willingness to sign a written informed consent document.

4.2Exclusion Criteria

A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.

Criteria which might be included include: (i) receiving any other investigational agents; (ii) brain metastases, if a factor; (iii) history of allergic reactions to any of the required agents on the study; (iv) concomitant medications or substances that have the potential to affect the activity or pharmacokinetics of the study agent; (v) uncontrolled or intercurrent illness that would interfere with achieving the study objectives;(vi) pregnant; (vii) HIV-positive; (viii) any additional exclusion criteria that are appropriate to the study.

4.2.1

5study entry and withdrawal procedures

• Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment)and procedures for specifying: (a) when and how to withdraw subjects from the trial/investigational product treatment; (b) the type and timing of the data to be collected for withdrawn subjects; (c) whether and how subjects are to be replaced; and (d) the follow-up for subjects withdrawn from investigational product treatment/trial treatment. [GCP 6.5.3] (See alsosection 6, TREATMENT PLAN; section 13, STATISTICAL CONSIDERATIONS.)

5.1Study Entry Procedures

5.1.1Required Pre-Registration Screening Tests and Procedures

Refer to section 11, STUDY CALENDAR, for the screening tests and procedures that are required prior to registration, and for the timing of these events relative to the start of treatment. (sample language)

5.1.2Registration Process

Describe the process to be used. Who should be contacted and how? What information is required (ICF, HIPAA authorization form, copy of required laboratory tests, eligibility screening worksheet, registration form, etc.)? How soon after registration must the subject begin treatment? What are the procedures to be followed if this is a multicenter trial?

5.2Study Withdrawal Procedures

5.2.1A patient may decide to withdraw from the study at any time.

5.2.2A patient may be removed from treatment for one of the following criteria:(The 2 broad categories are as follows, although the first is frequently made more specific as indicated below.)

5.2.2.1If in the opinion of the treating physician, it is in the best interest of the patient to do so. (This is a generic statement that some investigators prefer. You may want to include more specific criteria such as (i) unwillingness or inability of the patient to comply with the protocol requirements; (ii) disease progression; (iii) intercurrent illness that prevents further administration of treatment; (iv) unacceptable adverse events (AE[s]); and (v) general or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.)

5.2.2.2Sponsor’s decision to discontinue the study.

5.2.3The reason for withdraw from the study and the date the patient was removed from the study must be documented in the case report form (eCRF/CRF[choose one]).

6Treatment plan

• A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s).Also include a description of the dosage form, packing, and labeling of the investigational product(s). [GCP 6.4.4] (See also section 9,PHARMACEUTICAL INFORMATION.)
• The expected duration of the subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any. [GCP 6.4.5]
• The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial. [GCP 6.6.1]
• Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial. [GCP 6.6.2] (See also section 4, PATIENT SELECTION.)
• Procedures for monitoring subject compliance. [GCP 6.6.3]
• Specification of safety parameters. [GCP 6.8.1] (See also section 7, DOSING DELAYS/DOSE MODIFICATIONS; section 8, ADVERSE EVENTS.)
• The methods and timing for assessing, recording, and analyzing safety parameters. [GCP 6.8.2] (See also section 8, ADVERSE EVENTS; section 12, STUDY CALENDAR; section 13, STATISTICAL CONSIDERATIONS; section 14, DATA AND SAFETY MONITORING PLAN.)
• The type and duration of the follow-up of subjects after adverse events. [GCP 6.8.4]

6.1Baseline Tests and Procedures(if applicable)

Indicate any tests or procedures that are necessary to confirm that a subject still meets the eligibility requirements, or that are required at baseline for later outcome comparison after study intervention. Alternatively, indicate that this information is located in section 11, STUDY CALENDAR.

6.2Investigational Agent Administration(or other appropriate title; “Radiation Therapy” might be appropriate for a radiation oncology protocol)

**’*PHASE 1 STUDIES***

State the starting dose of the investigational agent and describe the dose escalation scheme and treatment regimen (dose, route, duration of infusion for intravenous drugs, and schedule). Use exact dose rather than percentages. State any special precautions or warnings relevant for agent administration (e.g., incompatibility of agent with commonly used intravenous solutions, necessity of administering agent with food, pre-medications, etc.). A table may be used to describe the regimen.

***PHASE 2 STUDIES***

Describe the regimen (agent, dose, route, duration of infusion for intravenous drugs, and schedule) and state any special precautions or warnings relevant for investigational study agent administration (e.g., incompatibility of the agent with commonly used intravenous solutions, necessity of administering agent with food, pre-medications, etc.). Inclusion of a treatment table may be useful in clarifying the regimen.

***INTERVENTIONAL STUDIES INVOLVING OTHER THAN A STUDY DRUG***

If the primary intervention involves something other than a study drug, a different header will most likely be more appropriate for this section. As an example, Radiation Therapy”may more accurately reflect the intervention. The “Additional Treatment Modalities” section below might then be used to describe the concomitant use of other treatment modalities.

6.3Definition of DLT and MTD(applicable only for phase 1 trials)

Please provide explicit definitions of the types, grades, and durations of all AEs that will be considered dose-limiting, or provide definitions of other endpoints that will be used to determine dose escalations. A classical 3+3 design is illustrated below, but other designs may be used at the discretion of the Investigator. What follows is sample language that can be included in addition to that indicated in this paragraph.