Instructions for the Use of Protocol Templates for Organ Dysfunction Studies



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Specific Instructions for the Use of Protocol Templates for Organ Dysfunction Studies
The goal of an organ dysfunction study is to define the dose of an agent associated with an acceptable toxicity profile and measurable pharmacokinetic parameter(s) in patients whose impaired organ function may alter the absorption and disposition (pharmacokinetics) as well as the efficacy and safety (pharmacodynamics) of that agent. Ideally, the pharmacokinetic parameter(s) identified will correlate with the clinical effects of an agent. The target level of the chosen parameter(s) could thus serve to guide optimal dosing for a given patient. Organ dysfunction studies are designed to evaluate toxicity and to measure pharmacokinetic and pharmacodynamic parameters in each of five cohorts of patients with varying degrees of organ dysfunction at each dose of the agent administered.

Investigators planning to conduct studies in cancer patients with impaired hepatic or renal function should consider the following points:




  1. FDA Guidance

The investigator is advised to refer to the guidance provided by the Food and Drug Administration (FDA) on conducting studies in patients with organ dysfunction when planning their study. While not specifically written for neoplastic diseases, the following documents should be consulted:
Hepatic dysfunction: “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling” (posted 5/20/2003) is available as a PDF document (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf).
Renal dysfunction: “Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and Labeling” (posted 5/14/1998) is available as a PDF document (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072127.pdf).


  1. Extensive PK Sampling

Investigators planning to conduct studies in these special groups of patients should be prepared to conduct extensive pharmacokinetic (PK) sampling for the agent in question as well as its active metabolites to provide meaningful results that will lead to appropriate dosing recommendations. Identification of PK parameter(s) that correlate with an acceptable toxicity profile and which can then guide future dose recommendations (e.g., AUC when used as the target level for carboplatin dosing) is a goal of these studies. Because relatively small patient cohorts are indicated, detailed PK measurements become especially important. Once the PK parameter(s) and the target level have been identified in a small study cohort (6 patients), an expanded cohort of 12-15 patients should be treated using the selected parameter(s) and target level with extensive PK measurements to validate use of the parameter(s) to guide dosing.


  1. CYP450 Metabolic Interactions

The possibility that enzymatic activity of the CYP450 system may affect the agent of interest or its metabolites should be considered as well as the effect of concomitant medications. Investigators should also consider the possibility that these metabolic products could be excreted via an alternative route rather than the known primary route of elimination. The investigator should be prepared to exclude all medications that may affect the activity of CYP450 isoenzymes that interact with the study agent, as well as any other potential sources of drug-drug interactions (e.g., P-glycoprotein, etc.)


  1. Combination Regimens

If a study using a combination of agents is under consideration, the investigator is strongly advised to consult with the FDA on an appropriate design prior to drafting the protocol. Some of the relevant issues that must be addressed include (1) the choice of regimen and (2) the need for extensive sampling and PK measurements to isolate and identify any interactions between the agents administered.


  1. Data Capture

Investigators who conduct an organ dysfunction study should plan to make the raw data from their trial available to the FDA in the final study report. Data of interest include those data used to estimate hepatic function and to calculate the Child-Pugh Classification (CPC; hepatic studies) or data used to estimate the creatinine clearance using the Cockcroft-Gault formula and to estimate the glomerular filtration rate using the MDRD formula (renal studies). In addition, the final study report should contain all pharmacokinetic, pharmacodynamic, clinical, and laboratory data from the trial as well as the case report forms.

TEMPLATE INSTRUCTIONS
The protocol template is a tool to facilitate rapid protocol development. It is not intended to supersede the role of the Protocol Chair in the authoring and scientific development of the protocol. It contains the “boilerplate” language commonly required in protocols submitted to CTEP. Content may be modified as necessary to meet the scientific aims of the study and development of the protocol. Much of the formatting is needed for electronic submission of the protocol to the FDA and should not be changed unless necessary.
1. Each Protocol Template consists of two parts:
a. Protocol Submission Worksheet: available at

http://ctep.cancer.gov/forms/docs/psw.docx. This document contains prompts for required administrative information.
b. Main Body and Appendices of the protocol: attached below. This document provides standard language plus instructions and prompts for information.
Please note that the Informed Consent Template is provided as a separate document file.
2. The Protocol Submission Worksheet and Protocol/Informed Consent Template documents should be completed, and all documents (including the Appendices) should be submitted to CTEP for review. For protocol amendments a Summary of Changes should be provided as the first page (page i) of the document, as indicated in the template. The Summary of Changes must provide hyperlinks to the area referenced in the protocol or informed consent document.
3. All sections in the Protocol Template should be retained to facilitate rapid review. If not appropriate for a given study, please insert “Not Applicable” after the section number and delete unneeded text. Depending on the organ system of interest, include sections as follows:

  • No highlighting – for all protocols

  • Yellow highlighting – for hepatic dysfunction protocols

  • Blue highlighting – for renal dysfunction protocols

4. All Protocol Template instructions and prompts are in italics. As you complete the information requested, please delete the italicized text.


5. Please note that the Protocol Template has built-in styles for headings levels 1-4 (Level 1 Heading – Level 4 Heading; see image below).

These heading styles will automatically update the Table of Contents (TOC) and convert to Bookmarks in a final PDF protocol document. Please retain the heading styles.
6. Before updating the TOC, please ensure that the Title Page is page 1 of the protocol. For any pages preceding it (i.e., Summary of Changes) use alternative numbering (i, ii, iii, iv, … ). Use Section Breaks as necessary to preserve this numbering scheme.
7. To update the TOC in your protocol document:

2007 & 2010 MS Word

a. On the References tab, in the Table of Contents group, click Update Table.



b. Click Update entire table.

2003 MS Word

a. Click the table of contents.

b. Press F9.
Please do not edit the TOC manually.
8. Please redline, highlight or underline new or modified text as this will facilitate rapid review.
9. Note that CTEP cannot accept MS Word files that:


  • are read-only

  • are password protected

  • contain macros

  • are saved with a file extension other than .doc (Word 2003) or .docx (Word 2007/10)

10. For problems or questions encountered when using these documents (Protocol Submission Worksheet or Protocol/Informed Consent Template), please contact the CTEP Protocol and Information Office (PIO) by e-mail (pio@ctep.nci.nih.gov).


SUMMARY OF CHANGES – Protocol
For Protocol Amendment # to:
NCI Protocol #:

Local Protocol #:


NCI Version Date:

Protocol Date:


Please provide a list of changes from the previous CTEP approved version of the protocol. The list shall identify by page and section each change made to a protocol document with hyperlinks to the section in the protocol document. All changes shall be described in a point-by-point format (i.e., Page 3, section 1.2, replace ‘xyz’ and insert ‘abc’). When appropriate, a brief justification for the change should be included.
#SectionPage(s)Change1.2.3.4.5.

(Please retain the section break below, so that the Title Page is page “1” of the document.)

NCI Protocol #: Use the number assigned to the LOI by the NCI.
Local Protocol #: Please insert your local protocol # for this study.
ClinicalTrials.gov Identifier: [Insert ClinicalTrials.gov NCT#, if known, in the format “NCTxxxxxxxx; otherwise, “TBD”]
TITLE: A Phase 1 and Pharmacokinetic Single Agent Study of [CTEP IND Agent] in Patients with Advanced Malignancies and Varying Degrees of [Hepatic/Renal] Dysfunction
Use Simplified Disease Classification (SDC) terminology for study disease. Please refer to the CTEP Web site (http://ctep.cancer.gov/protocolDevelopment/codes_values.htm) for a complete list of SDC disease terms.
Corresponding Organization: Name of the corresponding grant or contract-level organization (Phase 1 Lead Academic Organization [LAO] or Phase 2 Consortium [P2C]). Please select from the table of LAOs and P2Cs below.
Principal Investigator: Name

Institution

Address

Address

Telephone

Fax

e-mail address
A study can have only one Principal Investigator. The Principal Investigator must be a physician and is responsible for all study conduct. Please refer to the Investigator's Handbook on the CTEP Web site for a complete description of the Principal Investigator's responsibilities (http://ctep.cancer.gov/investigatorResources/default.htm#Investigators_handbook).
The Principal Investigator and all physicians responsible for patient care must have a current FDA Form 1572, Supplemental Investigator Data Form (SIDF), Financial Disclosure Form (FDF), and CV on file with CTEP. Failure to register all appropriate individuals could delay protocol approval. If you are unsure of an investigator's status, please contact the Pharmaceutical Management Branch, CTEP at (240) 276-6575 or by e-mail at PMBRegPend@ctep.nci.nih.gov. Please indicate, on the title page, if an Associate Investigator is NOT responsible for patient care and therefore does not require a current 1572, SIDF, FDF, and CV on file.
The protocol title page of the ETCTN Rostered Model template lists all grantees and/or contractors that may potentially participate on an ETCTN protocol. It is the responsibility of the Corresponding Organization to delete the rows of the LAO (UM1) grantees (if phase 2 only) or P2C (N01) contractors (if phase 1 only) that will not be participating on this study from the table below. Individual LAOs or P2Cs (individual rows) should not be deleted without prior approval from CTEP. Additional Non-ETCTN single institution participants should be added under “Non-Member Collaborators” according to the formatted example. Additional Non-ETCTN rostered organization participants (e.g., ALLIANCE, ECOG-ACRIN, NRG, SWOG, COG, NCIC-CTG, CITN, BMTCTN, ABTC, PBTC, AMC, COGC) should be added under “Participating Organizations” as indicated below.
Participating Organizations (For trials involving LAOs, all LAOs must be included; for trials involving P2Cs, all P2Cs must be included.)

LAO-11030 / University Health Network Princess Margaret Cancer Center LAOLAO-CA043 / City of Hope Comprehensive Cancer Center LAOLAO-CT018 / Yale University Cancer Center LAOLAO-IL057 / University of Chicago Comprehensive Cancer Center LAOLAO-MA036 / Dana-Farber - Harvard Cancer Center LAOLAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAOLAO-MN026 / Mayo Clinic Cancer Center LAOLAO-NC010 / Duke University - Duke Cancer Institute LAOLAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAOLAO-OH007 / Ohio State University Comprehensive Cancer Center LAOLAO-PA015 / University of Pittsburgh Cancer Institute LAOLAO-TX035 / University of Texas MD Anderson Cancer Center LAOLAO-NCI / National Cancer Institute LAOP2C-11030 / University Health Network Princess Margaret Cancer Center P2CP2C-CA189 / University of California Davis Comprehensive Cancer Center P2CP2C-FL065 / H Lee Moffitt Cancer Center P2CP2C-IL057 / University of Chicago Comprehensive Cancer Center P2CP2C-MN026 / Mayo Clinic Cancer Center P2CP2C-OH007 / Ohio State University Comprehensive Cancer Center P2CP2C-TX035 / University of Texas M D Anderson Cancer Center P2COther Participating Rostered Organization #1 (e.g., ALLIANCE, ECOG-ACRIN, NRG, SWOG, COG, NCIC-CTG, CITN, BMTCTN, ABTC, PBTC, AMC, or COGC; list one organization per row; add more rows as necessary)

Non-Member Collaborators (individual treating sites that are not members of a participating rostered organization)

Institution #1 (non-rostered institution; insert more rows below as necessary for additional institutions; please include the CTEP Institution Code, which can be found at http://ctep.cancer.gov/protocolDevelopment/codes_values.htm)

Name

Address

Investigator #1

Name

Telephone

Fax

E-mail address

Investigator #2

Name

Telephone

Fax

E-mail address

Investigator #3

Name

Telephone

Fax

E-mail address
If this study includes an investigational agent supplied by the NCI Division of Cancer Treatment and Diagnosis and will involve a Canadian institution(s), a Clinical Trials Application (CTA) will need to be submitted to Health Canada for their participation in the study. A Canadian investigator should be designated to be responsible for preparing and submitting the CTA to Health Canada for the Canadian institution(s). Procedures and forms for preparing and submitting a CTA to the Canadian HPFB are available at http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/cta_application-eng.php. A copy of the “No Objection” letter must be forwarded to the Pharmaceutical Management Branch at PMBAfterHours@mail.nih.gov when available.
Statistician: Study Coordinator:

(if applicable) (if applicable)

Name Name

Address Address

Address Address

Telephone Telephone

Fax Fax

e-mail address e-mail address
Responsible Research Nurse: Responsible Data Manager:

Name Name

Address Address

Address Address

Telephone Telephone

Fax Fax

e-mail address e-mail address

Please list all agents and their suppliers in the fields below, including any imaging agents. “Supplier” is defined as the entity that provides the clinical supply of the agent.  If the agent is purchased through commercial sources, then please mark supplier as “commercial”.
NCI-Supplied Agent(s): [Agent Name and NSC #]

Other Agent(s): [Agent Name, NSC # (if applicable), and Supplier]
Below, please describe the IND Status of this study by choosing IND #/Sponsor OR Exemption from IND requirements, making sure to delete the inapplicable field(s).
IND #: [Enter the # of the IND under which this study will be performed. Enter “TBD” if an IND # is not yet available.]

IND Sponsor: [If this study is being conducted under an IND sponsored by CTEP, then enter “DCTD, NCI”. If this is solely an imaging study and is to be conducted under a CIP IND, then enter “Cancer Imaging Program, NCI”]
OR
Study Exempt from IND Requirements per 21 CFR 312.2(b).

If an IDE is not applicable to this study, then please delete the following fields (IDE #, IDE Sponsor, Device Name):

IDE #: [Investigational Device Exemption #]

IDE Sponsor:

Device Name: [This can include investigational in vitro diagnostics, which are regulated as devices]
Protocol Type / Version # / Version Date: [Type* / Version # / Version Date]
*Protocol types: Original, Revision, or Amendment


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