WELCOME TO ATLANTA JANUARY 14, 1999

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Welcome to the RTOG Research Associate
Orientation Loews Philadelphia Hotel Philadelphia
June 23, 2005
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PROTOCOLS
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Protocol Design

• Types of Studies
• Protocol Format
• Protocol Development and Activation
• Preparation for Study Participation

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Types of Studies

• Phase I
• Phase II
• Phase I/II
• Randomized Phase II
• Phase III
• Lab Correlates
• Cancer Control
• Randomized vs. Non
• Intergroup

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Phase I, II, I/II, III Studies

• I determine the maximum tolerated dose.
  Investigational
• II response to treatment (extent of tumor
  reduction).
• I/II early and late endpoints, dose searching
  studies.
• III randomized prospective comparison of
  experimental regimens. Larger number of
  patients.

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• Laboratory correlates
• Cancer control
• Randomized
• Intergroup

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Study Classifications

• Single Blind
• Double Blind
• Single Arm
• Multiple Arm

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Protocol Format
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Sections of Protocol

• Schema
• Eligibility Check
• 1.0 Introduction
• 2.0 Objectives
• 3.0 Patient Selection
• 4.0 Pretreatment Evaluations
• 5.0 Registration Procedures
• 6.0 Radiation Therapy
• 7.0 Drug Therapy

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Sections of Protocol, Continued

• 8.0 Surgery
• 9.0 Other Therapy
• 10.0 Pathology/TRP Correlates
• 11.0 Patient Assessments
• 12.0 Data Collection
• 13.0 Statistical Considerations
• References
• Sample Consent
• Appendices

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Protocol Developmentand Activation
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Comprehensive Review Mechanism Group Strategy

• Concept review and feasibility survey
• Group review
• Internal review
• NCI review (generating a re-review by group and
  study chair)
• Activation
• Revisions

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RTOG Web Site

• http//www.rtog.org

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Preparation for Study Participation
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Preparation for Case Entry

• Review Eligibility Requirements (sect.3.0)
  -complete eligibility list
• -questions to RA at HQ prior to registration
• Review Required Studies Labs--did they occur
  within required time frame?
• Review Feasibility for Success--should this
  patient be entered on study?

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Registration Procedures

• Mandatory Web Registration Available 24 hours a
  day/7 days a week
• Intergroup Registration Fax Eligibilty
  Checklist to 215-574-0300
• IMPORTANT REMINDERS
• Complete Eligibility Checklist
• Signed and Dated Informed Consent
• Patients must be registered prior to the start
  of any protocol treatment

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Go to RA Corner for User Authorization Form
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Confirmation of Web Registration

• Following a successful Web Registration you will
  receive
• Treatment Assignment and Case Number
• E-Mail Confirmation
• A0
• Patient Calendar
• Check carefully for errors
• Patient Label Template is available on RTOG
  website/RA Corner

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Email Confirmation
From CONFIRMATION CONFIRMATION_at_rtog.org To
brenda_young Subject ACR New Case Registration
for Study No - 9998 and Case No
- 0034   Hello,   The Confirmation of New Case
Registration for the American College Of
Radiology Study 9998 Case 0034.Please Find the
attached A0 Patient Calendar HTML File.  
Thanks, ACR     Note This information E-mail
is Auto generated by the Clinical Server On Wed
Jan 14 124400 EST 2004 (Eastern Standard
Time).Replies will not be checked on this server,
so please send your Queries to HQ directly for
prompt response.  
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? QUESTIONS ?
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Calendars and Data Schedule

• Purpose
• Record / log forms
• Form description
• Changes to calendar
• Calendar extension

June 2005
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PURPOSE

• Verification of assignment
• case number
• Institution name / number
• Patient identification / number
• Calendar base date
• Timetable data / form submission
• Access to real-time calendars for all cases via
  RTOG Data Log In Center on website

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Example Hard Copy Calendar
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Example Web Calendar
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RECORD / LOG FORMS

• list of forms according to due date
• all forms are per section 12.0 of protocol
• each form requires a response

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ID / Description of Forms

• Form identification via two descriptors
  form title two letter ID code

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Changes / Due to Events

• Additional submission required per protocol upon
  occurrence of specific events
• Changes made due to a request to suppress a form
• Deletion of forms due to improper administration
  of pre-treatment or QOL tools
• Additional changes are as per the protocol
  section 12.0.

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Calendar Extension

• Headquarters revises calendar per case as needed
• Copies of updated calendars are sent to
  institutions by request

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Patient Status

• Alive
• Dead
• Lost

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Patient Status

• Lost Cannot obtain patient status / information
  for
• gt 3 years V5
• Need to document all efforts to establish
  patients status.

• Alive data submission is as per calendar
• Dead data due prior to date of death becomes
  due Z1 remains due until response is received

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? QUESTIONS ?
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Data Submission Overview

• Case Report Forms (CRF)
• Forms Due Report

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Case Report Forms

• Protocol Specific
• Forms Packet
• Source Documentation
• Investigator Obligations

Protocol Section 11.0 and 12.0
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Coding Reminders

• Write legibly
• Black or blue ink
• Signature/date required
• Single sided forms only
• Avoid post-its on forms
• Avoid blanks
• Avoid using highlighter

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Submission Reminders

• Affix Patient Label
• Complete Form
• All items have a response
• All pages are attached
• Quality of Life Cover Sheet
• Signature and Date
• Revision Box
• Comments

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Send All Data To

• Radiation Therapy Oncology Group
• (RTOG)
• C/O American College of Radiology
• 1818 Market Street
• Suite 1600
• Philadelphia, PA 19103

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Forms Due Report

• Institutional Report includes
• Past due data
• Projected data
• Frequency
• HQ established cut-off dates
• Mailed 3times per year monthly for Phase I and
  Phase II studies
• Purpose
• Encourage Prompt Data Submission
• Resolve Discrepancies

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A Useful Tool
The Memorandum Detailed explanation of
Report Run Date Date the report is
printed Voids all previously dated reports Cut
Off Date Report will include only data received
by the cut off Data received after the cut
off will be reflected on the next report DO NOT
resend data submitted after the cut off The
Printout Reinstatement of the case specific
calendar issued at registration
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? QUESTIONS ?
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Ongoing Evaluations and Reporting

• Disease Status
• Adverse Events

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Disease Status

• Objective assessment and evaluation of tumor
  response to protocol treatment as determined by
  the Principle Investigator or Attending Physician

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Reporting Tumor Response
Section 11.0 of the Protocol

• Recommended assessments
• Assessment timelines
• Response Criteria
• Site specific
• RECIST

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ADVERSE EVENTS EVALUATION AND REPORTING

• Adverse Event
• Common Terminology Criteria
• Evaluation and Reporting
• Special Reporting
• AdEERS

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National Cancer Institute (NCI) Definition of
Adverse Event (AE)

• Any unfavorable and unintended sign, symptom, or
  disease (including an abnormal laboratory
  finding) temporally associated with the use of a
  medical treatment or procedure regardless of
  whether it is considered related to the treatment
  or procedure (attribution of unrelated, unlikely,
  possible, probable, or definite). Each AE is a
  unique representation of a specific event used
  for medical documentation and scientific
  analysis.

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National Cancer Institute (NCI) Definition of
Serious Adverse Event(SAE)

• As defined in the FDA CFR 312, any adverse drug
  experience occurring at any dose that results in
  any of the following outcomes
• Death
• Life threatening adverse drug experience
• In patient hospitalization ( or gt 24 hours) or
  prolongation of an existing hospitalization
• Persistent or significant disability/incapacity
• Congenital anomaly/birth defect

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National Cancer Institute (NCI) Definition of
Attribution

• The determination of whether an AE is related to
  a medical treatment or procedure
• Clinical Investigators have the primary
  responsibility for AE
• Identification
• Documentation
• Grading
• Assignment of Attribution

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National Cancer Institute (NCI) Definition of AE
Attribution Categories

• Unrelated
• AE is clearly NOT related to the intervention
• Unlikely
• AE is doubtfully related to the intervention
• Possible
• AE may be related to the intervention
• Probable
• AE is likely related to the intervention
• Definite
• AE is clearly related to the intervention

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National Cancer Institute (NCI) Definition
ofExpected vs. Unexpected AEs

• Expected AE
• Determination is based on available literature
• Package Insert, Investigators Brochure
• Protocol Section 6.0, 7.0 and Informed Consent
• Unexpected AE
• Determination is based on available literature
• NOT in Package Insert, Investigators Brochure
• NOT in Protocol Section 6.0, 7.0 or Informed
  Consent

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ADVERSE EVENT SEVERITY GRADING CRITERIA Protocols
activated March 1998 through Feb 2003

• NCI Common Toxicity Criteria (CTC) version 2.0
• To evaluate AEs attributable to Systemic Agents
  and Radiation Therapy that occur between Day
  1and Day 90 of treatment
• RTOG/EORTC Late Radiation Morbidity
• Criteria
• To evaluate AEs attributable to Radiation
  Therapy ONLY that occur after Day 90 of treatment

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ADVERSE EVENTSEVERITY GRADING CRITERIAProtocols
activatedMarch 2003 through Present

• NCI Common Terminology Criteria for Adverse
  Events (CTCAE), version 3.0
• To evaluate all AEs during or after completion
  of ALL modalities of treatment including Systemic
  Agents, Radiation Therapy, and Surgery
• Adult and Pediatric trials

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What Criteria to Use and When??Use The
Protocol As Your Guide

• Protocol section 6.0 and 7.0
• Specific guidelines for AE Reporting
• Required criteria
• Special reporting requirements
• AE Report submission timelines

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ADVERSE EVENTEVALUATION

• Timelines
• Protocol Sections 6.0, 7.0, 11.0
• Pre-Treatment, During Treatment, Post Treatment
• Assessments
• Lab Values
• Normal Tissue/Organ
• Related to treatment modality
• Identified In Protocol and Informed Consent

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ADVERSE EVENTREPORTING

• Guidelines and Requirements
• Protocol Sections 6.0, 7.0, 11.0, and 12.0
• Routine AE Reporting
• Case Report Form (CRF)
• Treatment Summary Forms, Follow-Up Forms, Adverse
  Event Forms
• Expedited AE/SAE Reporting
• Via Phone to RTOG HQ
• AdEERS

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SERIOUS ADVERSE EVENTREPORTING

• Telephone RTOG within 24 hours of knowledge of
  event
• Contact RTOG HQ Primary Disease Site RA
• Information required at time of call
• Study , Case, Pt. Initials, treatment
  start/stop dates, description of event, severity
  grade, and attribution
• RTOG RA Coordinator will assist with additional
  reporting requirements
• AdEERS 24 hour notification (if applicable)
• MedWatch or AdEERS per FDA/NCI Guidelines

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MedWatch

• FDA required reporting form for SAEs R/T
  Systemic Therapy occurring during or within 30
  days of completing therapy
• Complete report due within 10 days of initial
  phone report
• Fax or mail to FDA (info on form)
• and
• Fax a copy to RTOG Regulatory Officer _at_
  215-717-0990
• Identify with RTOG Study/Case

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Adverse Event Expedited Reporting SystemAdEERS

• National Cancer Institute (NCI) mandated
  electronic SAE reporting system
• http//ctep.info.nih.gov/AdEERS/default.htm
• IMPORTANT UPDATED GUIDELINES DATED 12-15-2004,
• EFFECTIVE 2-1-2005
• SAE reports are submitted directly to NCI via the
  web application
• 24 Hour notification to AdEERS depending on Phase
  of trial, severity grade, and attribution of SAE
• Complete Report due within 5-10 calendar days of
  24 hour notification depending on Phase of trial,
  severity grade, and attribution of SAE
• NCI sends electronic notification to Coordinating
  Group
• RTOG requires AdEERS for all SAE reporting

• Computer based training program available

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AdEERSPreparing To Submit A Report

• Reporter I.D.
• Name, phone, fax, and email of RA and M.D.
• Patient I.D.
• RTOG Case Number
• i.e. 0099
• Mandatory Response Fields
• Text fields
• Description of Treatment
• Description of Event
• Dates, Doses, Lab Values, Ht, Wt, BSA
• List of Values
• Responses selected from drop down box
• AE Category, Severity Grade, Attribution Code

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?QUESTIONS?
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Quality Control/Assurance Procedures

• Medical Oncology

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Requirements for Participation

• Name of responsible Medical Oncologist
• Responsibilities of the Medical Oncologist
• Responsibilities of the Research Associates
  /Investigator

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Study Chair Review

• Every chemotherapy case is reviewed.
• Checked for
• documentation of wt.,
• ht., and BSA
• drug doses
• timing
• lab tests
• toxicity reporting

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Quality Control Guidelines for Chemotherapy

• Per Protocol
• Variation Acceptable (minor)
• Variation Acceptable (NOS)
• Deviation, Unacceptable
• Not Evaluable for Chemotherapy Review
• Incomplete Chemotherapy

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Quality Control/Assurance Procedures

• Surgical Oncology

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Surgical Study Chair Review

• Not done on every study
• The surgical section of the protocol will clearly
  specify the surgical technique to be followed.
• If the surgery is reviewed in a particular
  protocol you will receive a similar QC report to
  the chemotherapy QC review.

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?QUESTIONS?
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Intergroup Studies
Definition

• Two or more cooperative groups agree to
• Enroll their eligible patients
• Not conduct a competing study

Rationale

• Quick recruitment
• Decrease of protocols with same interests
• Uncommon tumors

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Structure
Coordinating Group (CG)

• Administration
• Randomization
• Data Processing
• Quality Assurance and Control
• Statistical Analysis

Participating Group

• Participates only
• Monitors data submission from its own institutions

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Patient Entry Procedures
Prior Process
Current Process
Complete eligibility/stratification checklist
Complete eligibility/stratification checklist
Contact Cancer Trials Support Unit (CTSU)
Call RTOG Headquarters
CTSU relays information to CG
RTOG relays information to CG
CG assigns treatment and intergroup case
CG assigns treatment and intergroup case
RTOG calls institution with information
CTSU relays information to Institution
Calendar and labels sent out to institution
Calendar and labels sent out to institution
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Data Submission

• Submit all data to RTOG unless otherwise
  specified in protocol (i.e., pathology,
  dosimetry, CTSU)
• All data must be labeled with RTOG Study/Case
  s and CG Study/Case s
• Labels are to be used for all data forms except
  for SWOG coordinated studies

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Request for Study Information (Z1)

• Queries generated from CG
• RTOG sends the CG query to the institution
  attached to a Z1
• Z1 reply is returned to RTOG, not CG

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REMINDER

• Eligibility
• Protocol Treatment
• Medical Issues

• Contact Protocol Coordinator at Coordinating
  Group Data Center

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QUESTIONS or COMMENTS
REMINDER Please Complete RA Orientation
Evaluation and return to the Registration Desk by
6PM Friday, June 25th.
Thank You ?