Enrollment and Enrollment and Monitoring Procedures Monitoring Procedures

for NCI Supported for NCI Supported Clinical TrialsClinical Trials

Barry Anderson, MD, PhDBarry Anderson, MD, PhDCancer Therapy Evaluation Cancer Therapy Evaluation

ProgramProgramNational Cancer InstituteNational Cancer Institute

for FDA March 17, 2004for FDA March 17, 2004

Considerations for patientsConsiderations for patientsand clinical trials and clinical trials

EnrollmentEnrollment To assure that each To assure that each child accrued to a child accrued to a clinical trial is clinical trial is receiving receiving appropriate appropriate treatmenttreatment

MonitoringMonitoringTo monitor the To monitor the toxicity and toxicity and effectiveness of a effectiveness of a treatment treatment intervention within intervention within each clinical trialeach clinical trial

Safe and EffectiveSafe and Effective

Therapy for childhood cancer is often Therapy for childhood cancer is often successful, but it is successful, but it is alwaysalways toxic and toxic and carries risk of treatment related carries risk of treatment related morbidity or deathmorbidity or death

Proper Treatment is EssentialProper Treatment is Essential

Compared with other serious childhood Compared with other serious childhood diseases (asthma, cystic fibrosis), diseases (asthma, cystic fibrosis), childhood cancer includes many distinct childhood cancer includes many distinct histologic diagnoseshistologic diagnoses

Each tumor histology requires a distinct Each tumor histology requires a distinct treatment approachtreatment approach

The chances of cure diminish if the proper The chances of cure diminish if the proper therapy is not used at the outset therapy is not used at the outset

Enrollment- Who should be Enrollment- Who should be enrolled?enrolled?

Within tumor histology, patient and tumor Within tumor histology, patient and tumor characteristics establish a characteristics establish a risk of relapserisk of relapse. .

The relapse risk is used to stratify The relapse risk is used to stratify treatment assignment (intensity) to best treatment assignment (intensity) to best fit the child’s cancer.fit the child’s cancer.

It is vital to treat the child, as best we can It is vital to treat the child, as best we can ascertain, according to the appropriate ascertain, according to the appropriate treatment regimen. treatment regimen.

Enrollment- Eligibility CriteriaEnrollment- Eligibility Criteria

Protocol eligibility criteriaProtocol eligibility criteria must be must be clear in regards to:clear in regards to:

1.1. Clinical characteristicsClinical characteristics2.2. Pathological characteristicsPathological characteristics3.3. Biological characteristicsBiological characteristics

Pediatric oncologists must be Pediatric oncologists must be properly informed on how to apply properly informed on how to apply the eligibility criteriathe eligibility criteria

Enrollment- Eligibility CriteriaEnrollment- Eligibility Criteria

As histologic & biologic characteristics As histologic & biologic characteristics of tumors are better defined and of tumors are better defined and refined, refined, central inputcentral input on pathology and on pathology and biology may be neededbiology may be needed

Enrollment- Central ReviewEnrollment- Central Review

Central reviewCentral review of pathology and of pathology and diagnostic biologic assays can improve diagnostic biologic assays can improve the likelihood that a child receives the the likelihood that a child receives the best available therapy for their specific best available therapy for their specific tumor pathology and risk of relapsetumor pathology and risk of relapse

1.1. Alveolar vs Embryonal RhabdomyosarcomaAlveolar vs Embryonal Rhabdomyosarcoma2.2. Neuroblastoma -biological characteristicsNeuroblastoma -biological characteristics3.3. Wilms tumor - favorable histology vs. Wilms tumor - favorable histology vs.

focal/diffuse anaplasiafocal/diffuse anaplasia4.4. Genetic studies for acute lymphoblastic Genetic studies for acute lymphoblastic

leukemialeukemia

Phase 1 and Pilot Study EligibilityPhase 1 and Pilot Study Eligibility

For children with relapsed/resistant For children with relapsed/resistant disease or for child with newly-disease or for child with newly-diagnosed tumor of historically poor diagnosed tumor of historically poor therapeutic responsetherapeutic response

important to assure that no treatment with a important to assure that no treatment with a reasonable potential for cure or clinical benefit reasonable potential for cure or clinical benefit existsexists

risk of treatment intervention balanced with risk of treatment intervention balanced with likelihood of benefit in consideration of child’s likelihood of benefit in consideration of child’s prognosis and/or prior treatment historyprognosis and/or prior treatment history

NCI Support for Childhood Cancer NCI Support for Childhood Cancer Clinical ResearchClinical Research

1.1. Children’s Oncology Group (COG)Children’s Oncology Group (COG)

2.2. COG Phase 1/Pilot ConsortiumCOG Phase 1/Pilot Consortium

3.3. Pediatric Brain Tumor Consortium Pediatric Brain Tumor Consortium (PBTC)(PBTC)

4.4. New Approaches to Neuroblastoma New Approaches to Neuroblastoma Therapy (NANT)Therapy (NANT)

5.5. Individual Grants to Investigators that Individual Grants to Investigators that may include clinical trial researchmay include clinical trial research

Pediatric Clinical Trials Pediatric Clinical Trials are usually Multi-Institutionalare usually Multi-Institutional

InvestigatorsInvestigators committed to report toxicity, committed to report toxicity, regimen delivery and response data in regimen delivery and response data in timely fashion (Remote Data Entry)timely fashion (Remote Data Entry)

Data centerData center capable of readily receiving capable of readily receiving data, analyzing data and reporting data, analyzing data and reporting important data trends to investigators important data trends to investigators

Operations officeOperations office able to communicate able to communicate with investigators continuously throughout with investigators continuously throughout the clinical trial (email, Web site)the clinical trial (email, Web site)

Monitoring the individual childMonitoring the individual child

LaboratoryLaboratory results for tumor related or results for tumor related or treatment related abnormalitiestreatment related abnormalities

RadiologicRadiologic characterization of tumor and characterization of tumor and consequent organ dysfunctionconsequent organ dysfunction

Interval evaluationsInterval evaluations to establish tumor to establish tumor response to treatment interventionsresponse to treatment interventions

Frequency consistent with or greater than Frequency consistent with or greater than good clinical practice, but dependent on good clinical practice, but dependent on intervention and specific tumor diagnosis intervention and specific tumor diagnosis

Monitoring the clinical trialMonitoring the clinical trial

Submitting patient data at protocol-Submitting patient data at protocol-determined intervalsdetermined intervals

Accumulating, analyzing & reporting Accumulating, analyzing & reporting the datathe data

Interpreting the data in regards to Interpreting the data in regards to appropriate patient accrual, appropriate patient accrual, treatment toxicity & effectiveness of treatment toxicity & effectiveness of the treatment interventionthe treatment intervention

Data and Safety MonitoringData and Safety MonitoringNIH RequirementsNIH Requirements

1. Oversight and monitoring of all human intervention studies to ensure the safety of participants and the validity and integrity of the data.

2. Level of monitoring should be commensurate with the risks and the size and complexity of the clinical trial.

3. Oversight and monitoring under Phase III clinical trials should be in the form of Data Safety Monitoring Boards (DSMBs).

4. A DSMB also may be appropriate for Phase I and II clinical trials if the studies have multiple clinical sites, are blinded (masked), or employ particularly high-risk or vulnerable populations.

NCI Essential Elements for Data NCI Essential Elements for Data and Safety Monitoringand Safety Monitoring

1.1. Monitoring the progress of trials and Monitoring the progress of trials and safety of participantssafety of participants

2.2. Plans for assuring compliance with Plans for assuring compliance with adverse event reportingadverse event reporting

3.3. Plans for assuring data accuracy Plans for assuring data accuracy and protocol compliance.and protocol compliance.

Monitoring the progress of trials Monitoring the progress of trials and safety of participantsand safety of participants

Reviewers outside of/in addition to Reviewers outside of/in addition to the study committee evaluate trial the study committee evaluate trial data at regular intervals to monitor data at regular intervals to monitor treatment toxicity and effectivenesstreatment toxicity and effectiveness

Review determines whether Review determines whether continued accrual to trial is safe and continued accrual to trial is safe and appropriateappropriate

Compliance with Compliance with adverse event reportingadverse event reporting

NCI funded studies use the Adverse NCI funded studies use the Adverse Event Expedited Reporting System Event Expedited Reporting System (AdEERS) to report toxicities(AdEERS) to report toxicities

Institutional Principal Investigator is Institutional Principal Investigator is ultimately responsible to assure that ultimately responsible to assure that all AEs are reported in a timely all AEs are reported in a timely mannermanner

Assuring data accuracy and Assuring data accuracy and protocol compliance.protocol compliance.

Cooperative groups and consortia Cooperative groups and consortia practice ongoing quality control and practice ongoing quality control and interval quality assessments interval quality assessments (institutional audits) are conducted(institutional audits) are conducted

SummarySummary

1.1. General ParametersGeneral Parameters enrollment appropriate to diagnosis & relapse risk, or enrollment appropriate to diagnosis & relapse risk, or

availability of standard treatments for recurrent/relapsed availability of standard treatments for recurrent/relapsed diseasedisease

laboratory & radiologic monitoring for toxicity and laboratory & radiologic monitoring for toxicity and response to treatmentsresponse to treatments

2.2. Frequency of monitoringFrequency of monitoring equal or greater than standard of care for individual equal or greater than standard of care for individual

patientpatient continuous protocol monitoring by study committeecontinuous protocol monitoring by study committee interval protocol monitoring (monthly to biannually-based interval protocol monitoring (monthly to biannually-based

on risk, etc.) by group outside of study committee on risk, etc.) by group outside of study committee

SummarySummary

3.3. Who does the monitoring?Who does the monitoring? daily monitoring by study committeedaily monitoring by study committee interval monitoring including clinicians/statisticians not interval monitoring including clinicians/statisticians not

directly involved in the trialdirectly involved in the trial

4.4. When is Data Monitoring Committee needed?When is Data Monitoring Committee needed? phase III studies (DSMB)phase III studies (DSMB) multi-institutional trialsmulti-institutional trials high-risk population or treatment high-risk population or treatment complex treatmentcomplex treatment early stopping rulesearly stopping rules conflicts of interestconflicts of interest

Virtually always in peds oncology trialsVirtually always in peds oncology trials