adverse event reporting for clinical trials 9.23.05
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The Challenges of Safety Data Collection
Linda Messett RN BSN MA CCRP
Research Associate, Data ManagementAmerican College of Radiology
Radiation Therapy Oncology Group
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
How NOT to Ensure Accuracy in AE Reporting
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
RTOG
ACRIN EORTC GOG
CALGB
NSABP
ECOG
NCCTG
SWOGCOG
ACOSOG
NCI
National Cancer Institute Cooperative Groups
NCICNCIC
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
New Therapies, New Dilemmas
• Combined Therapeutic Modalities Are Proving Beneficial in Many Studies
• Concerns Are Growing Regarding the High Rate Adverse Events
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
The Delicate Balance
Efficacy
Toxicity
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Treatment Toxicity Timelines
End ofTreatment
180 days
Acute Toxicity Late Toxicity
Start ofTreatment
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Comparison of Survival and Toxicity
• 9003 Standard of Care (Radiotherapy 2 Gray/FX QD 5 Days/week 70 Gray)– Acute Grade 3+ 39%– Late Grade 3+ 27%– 4-Year Survival 33%
• 9914 72 Gray/42 FXs/6 Weeks AFX-CB Plus Cisplatin 100mg/M2 days 1 &22– Acute Grade 3+ 92%– Late Grade 3+ 42%– 4-year Survival 54%
– Feeding Tube Prior to Registration 24%
– Follow-up 83% One Year From Start of TX 41%, 4 Years From Start of TX 17%
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Our Challenge
• Solve the Dilemma of Poor AE Reporting
• Devise Methods to Improve Accuracy and More Complete Capture of AEs
• Continuously Improve Data Collection to Meet New Therapies
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Oncology Uses The Common Terminology Criteria for
Evaluating The Negative Effects of
Cancer Treatment
System # Terms # Organs Modality
WHO (1979) 28 9 ChemoCTC (1984) 48 13 ChemoRTOG-A (1984) 14 13 Acute RTRTOG-L (1984) 16 13 Late RTSOMA (1995) 152 22 Late RT CTC v 2.0 (1998) 260 24 Chemo/Acute RT
CTCAE v 3.0 (2003) 1058* Al All Acute & Late
The First Comprehensive Grading System for All Modalities
Evolution of Adverse Events Grading Systems
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Use Common Language
I can’t help you unless you are more specific. Do you feel “icky” or just “yucky?”
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
CTC GradingGeneral guidelines
1 2 3 4
Mild Moderate SevereLife
Threatening
A SymptomaticNo Interventions Indicated
Symptomatic: Interventions Such As Local Treatment or Meds May Be Indicated; Some Interference With Function, but No Impact on ADLs
Very Undesirable; Multiple, DisruptiveSymptoms; More SeriousInterventions, Including Surgery or Hospitalization May Be Indicated.
Life ThreateningCatastrophic, Disabling or Result inLoss of Organ, Organ Function, or Limb.
Low Grade High grade
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Adverse Event Terminology & Grading
Important Because It Provides:
• Recognition of the Injury
• Common Language for Communication
• Common Schema for Severity Grading
• Data for Toxicity/Safety Profiles
• Drives Interventions
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Interpret Subjective Symptoms in an Objective Manner
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
At Issue With the Grading System
Currently No Reporting Guidelines For:
• Data Collection
• Patient Screening
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Systematic Review of Variations in Safety Reporting In Phase III H&N Trials (1990-2003) Trotti A., Gwede C. (Submitted: ASTRO 3/2005)
The Negative Result
• Only 47% Reported on Late Events
• Late Organ Function:
– Only 3% Addressed Feeding Tube Dependence;
– Only 7% Discussed Tracheostomy Dependence
• Only 51% Reports Addressed Treatment Related Mortality
53 Papers From 41 Trials Show Wide Variations in Grading Systems and Reporting Methods:
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Identified Improvements for RTOG Head & Neck Studies
• Form Redesign for The Following Studies:
– 0421 (Revision pending January)
– 0234 (The forms will not be updated)
• Improve Directed Patient Assessments for Capturing AEs (RTOG 0522)
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
RT Summary
(Acute)
Follow-up (Late)
RTOG 0129Form
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
New AE Case ReportForm
Protocol-SpecificAE Form
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Eligibility: Squamous Cell Ca of the Oralpharyngeal (Tonsil, Base of Tongue or Palate)
• T1-T2, No-n1, Mo • No Prior Surgery to the Tumor or Nodal Disease• No Radiotherapy to the Head and Neck; • No Previous Chemotherapy, Etc.
Treatment Plan: • Conformal and or IMRT Techniques Utilized to Deliver a
Maximum of 66 GY/30 Fractions. • The Major Salivary Gland Will Be Spared According to Specific
Criteria.• Salivary Output Will Be Measured Before and Following
Therapy.
RTOG 0022 Phase I/II Study: Conformal & Intensity Mod. Radiation for Oropharyngeal Cancer
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
0022 Protocol Objectives • Assess the Feasibility of Adequate Target
Coverage and Major Salivary Gland Sparing in Patients With Oropharygeal Cancer Treated With IMRT Techniques.
• Determine the Rate and Pattern of Locoregional Tumor Recurrence.
• Determine the Nature and Prevalence of Acute and Late Side Effects (Using RTOG Scales) and Their Relationship to Local Dose.
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Dry Mouth Syndrome (Xerostomia)
• Determines Nature and Prevalence of Acute and Late Side Effects (Using RTOG Scales)
• Determines Relationship to Local Dose
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
RTOG Head & Neck Form 0022
• Form Design Weakness Identified: Dry Mouth/Xerostomia AE Not Captured on the Majority of CRFs Sent to RTOG
• Corrected Form Improves Data Collection
Revised FS Form for Study 0022
Form Now Includes Hard Coded Element: “Dry Mouth”
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Accurate Analysis of Adverse Effects Needed
Which Treatment(s) Might Provide the Best Outcome to Preserving Salivary Gland Function?
• 0022 IMRT • 0244 Salivary Gland Transfer• Radio-protectors: Pilocarpine/Amifostine
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
RTOG 0421 Phase III Trial for Locally Recurrent, Previously Irradiated Head and Neck Cancer:
Concurrent Re-irradiation and Chemo. vs. Chemo. Only
Eligibility
• Recurrent or Second Primary SCC of the Oral Cavity, Oropharynx, Hypopharynx, Larynx or Recurrent Neck Metastases With Unknown Primary
• Measurable Disease• Patients Must Be Surgically Inoperable• No Signs of Carotid Exposure• Must Have Had Prior Radiation to the Head and Neck 45 to 75 Gray
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
0421 Study Shows Why Baseline Data Is Important
Patients in 0421 Study Have Had at Least 45 and up to a Maximum of 75 Gray
Adverse Event Collection at Baseline & Careful Long Term Screening is Key for this Study
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Differentiating Between a Baseline Symptom and A New
One Can Be Challenging.
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Collect Baseline Dysphagia
Example:Study Form0421 I1 CRF
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
RTOG Head & Neck Study 0234
• Chemotherapy
• Radiotherapy
• C-225 (Cetuximab)
• Recognition and Grading of Erbitux Rash
Mild Moderate
Severe
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Criteria Problems RTOG Head & Neck Study 0234
• Proper Grading Needed to Capture Skin Rash
• Some Reports Suggest the More Severe the Rash, Perhaps the Better Outcome and Survival
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
1 2 3 4 Pruritus/itching* Mild of Localized Intense or Widespread Intense or Widespread
And Interfering With ADL -
Rash/desquamation* Macular or Papular Eruption or Erythema Without Associated Symptoms
Macular or Papular EruptioN or Erythema With Pruritus or Other Associated Symptoms; Localized Desquamation or Other Lesions Covering < 50% of Body Surface Area (Bsa)
Severe, Generalized Erythroderma or Macular, Papular or Vesicular Eruption; Desquamation Covering > 50% Bsa
Generalized,
Exfoliative,
Ulcerative, or
Bullous Dermatitis
Rash/acne/acneiform* Intervention Not
Indicated
Intervention Indicated Associated With Pain, Disfigurement, Ulceration, or Desquamation
-
Nail Changes*
Discoloration; Ridging (Koilonychias); Pitting
Partial or Complete Loss of Nail(s); Pain in Nail Bed(s)
Interfering With ADL
-
CTC Terms Relevant for Grading EGFRi Rash
1 2 3 4 Rash: Dermatitis Associated With Radiation: Select:
Chemo -Radiation
Radiation
Faint Erythema or Dry Desquamation
Moderate to Brisk Desquamation Erythema; Patchy Moist, Mostly Confined to S kin Folds And Creases; Moderate Edema
Moist Desquamation Other Than Skin Folds And Creases; Bleeding Induced by Minor Trauma or Abrasion
Skin Necrosis or Ulceration of Full Thickness Dermis; Spontaneous Bleeding From Involved Site
Mild Mod Severe Disabling
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Early And Late Effects Are Pivotal in Deciding New Standards of
Care • Randomized Trials Needed to Estimate the
Benefits of Combined or Single Therapies
• Accurate Data Can Answer Whether Added Toxicity Provides Additional Benefits
• Definitive Data Needed Before Therapies Become an Accepted Community Standard for a Patient Population
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
RTOG Plan of Action
Provide Clear Definitions for Grading AEs Not Clearly Defined in CTCAE 3.0
Provide a Check List to Use for Patient Assessments
Use More Hard Coded Elements on CRFs Provide Protocol Specific Instruction for
AssessmentsAdd Question to the Case Report Forms to
Capture Base Line Information. E.G. 0421 Forms
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
What You Can Do ...
• Review the Protocol Become Familiar With the Expected AEs for All Modalities Used
• Create a Checklist for Consistent Patient Assessment
• If Documentation is Lacking Ask the Person Assessing the Patient for More Information or an Addendum.
• Follow Your Patient After Treatment Is Over to Capture the Late Effects
Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
Thank You!