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2	PROTOCOLS
3	Protocol Design Types of Studies Protocol Format Protocol Development and Activation Preparation for Study Participation
4	Types of Studies Phase I Phase II Phase I/II Randomized Phase II Phase III Lab Correlates Cancer Control Randomized vs. Non Intergroup
5	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.
6	"Laboratory correlates" Laboratory correlates Cancer control Randomized Intergroup
7	Study Classifications Single Blind Double Blind Single Arm Multiple Arm
8	Protocol Format
9	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
10	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
11	Protocol Development and Activation
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13	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
14	RTOG Web Site http://www.rtog.org
15	Preparation for Study Participation
16	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?
17	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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23	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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27	Calendars and Data Schedule Purpose Record / log forms Form description Changes to calendar Calendar extension
28	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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31	RECORD / LOG FORMS list of forms according to due date all forms are per section 12.0 of protocol each form requires a response
32	ID / Description of Forms Form identification via two descriptors * form title * two letter ID code
33	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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35	Calendar Extension Headquarters revises calendar per case as needed Copies of updated calendars are sent to institutions by request
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38	Patient Status Alive Dead Lost
39	Patient 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 Lost * Cannot obtain patient status / information for > 3 years * V5 Need to document all efforts to establish patient’s status.
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41	Data Submission Overview Case Report Forms (CRF) Forms Due Report
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43	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
44	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
45	Send All Data To: Radiation Therapy Oncology Group (RTOG) C/O American College of Radiology 1818 Market Street Suite 1600 Philadelphia, PA 19103
46	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
47	A Useful Tool
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50	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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54	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 > 24 hours) or prolongation of an existing hospitalization Persistent or significant disability/incapacity Congenital anomaly/birth defect
55	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
56	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
57	National Cancer Institute (NCI) Definition of Expected vs. Unexpected AE’s Expected AE Determination is based on available literature Package Insert, Investigator’s Brochure Protocol Section 6.0, 7.0 and Informed Consent Unexpected AE Determination is based on available literature NOT in Package Insert, Investigator’s Brochure NOT in Protocol Section 6.0, 7.0 or Informed Consent
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59	ADVERSE EVENT SEVERITY GRADING CRITERIA Protocols activated March 2003 through Present NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 To evaluate all AE’s during or after completion of ALL modalities of treatment including Systemic Agents, Radiation Therapy, and Surgery Adult and Pediatric trials
60	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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65	ADVERSE EVENT EVALUATION 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
66	ADVERSE EVENT REPORTING 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
67	SERIOUS ADVERSE EVENT REPORTING 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
68	MedWatch
69	Adverse Event Expedited Reporting System AdEERS 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
70	AdEERS Preparing 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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72	Quality Control/Assurance Procedures Medical Oncology
73	Requirements for Participation Name of responsible Medical Oncologist Responsibilities of the Medical Oncologist Responsibilities of the Research Associates /Investigator
74	Study Chair Review Every chemotherapy case is reviewed. Checked for: documentation of wt., ht., and BSA drug doses timing lab tests toxicity reporting
75	Quality Control Guidelines for Chemotherapy Per Protocol Variation Acceptable (minor) Variation Acceptable (NOS) Deviation, Unacceptable Not Evaluable for Chemotherapy Review Incomplete Chemotherapy
76	Quality Control/Assurance Procedures Surgical Oncology
77	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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