adverse event reporting for clinical trials 9.23.05

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

ACRIN EORTC GOG

SWOGCOG

ACOSOG

National Cancer Institute Cooperative Groups

NCICNCIC

New Therapies, New Dilemmas

• Combined Therapeutic Modalities Are Proving Beneficial in Many Studies

• Concerns Are Growing Regarding the High Rate Adverse Events

The Delicate Balance

Efficacy

Toxicity

Treatment Toxicity Timelines

End ofTreatment

180 days

Acute Toxicity Late Toxicity

Start ofTreatment

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%

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

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

Use Common Language

I can’t help you unless you are more specific. Do you feel “icky” or just “yucky?”

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

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

Interpret Subjective Symptoms in an Objective Manner

At Issue With the Grading System

Currently No Reporting Guidelines For:

• Data Collection

• Patient Screening

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:

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)

RT Summary

(Acute)

Follow-up (Late)

RTOG 0129Form

New AE Case ReportForm

Protocol-SpecificAE Form

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

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.

Dry Mouth Syndrome (Xerostomia)

• Determines Nature and Prevalence of Acute and Late Side Effects (Using RTOG Scales)

• Determines Relationship to Local Dose

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”

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

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

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

Differentiating Between a Baseline Symptom and A New

One Can Be Challenging.

Collect Baseline Dysphagia

Example:Study Form0421 I1 CRF

RTOG Head & Neck Study 0234

• Chemotherapy

• Radiotherapy

• C-225 (Cetuximab)

• Recognition and Grading of Erbitux Rash

Mild Moderate

Severe

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

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

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

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

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

Thank You!

adverse event reporting for clinical trials 9.23.05

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