Enrollment and Monitoring Procedures for NCI Supported Clinical Trials by r7Be86


									Enrollment and Monitoring
    Procedures for NCI
 Supported Clinical Trials

       Barry Anderson, MD, PhD
  Cancer Therapy Evaluation Program
      National Cancer Institute
          for FDA March 17, 2004
     Considerations for patients
         and clinical trials
Enrollment               Monitoring
 To assure that each      To monitor the
 child accrued to a       toxicity and
 clinical trial is        effectiveness of a
 receiving appropriate    treatment
 treatment                intervention within
                          each clinical trial
       Safe and Effective
Therapy for childhood cancer is often
successful, but it is always toxic and
carries risk of treatment related
morbidity or death
Proper Treatment is Essential
Compared with other serious childhood
diseases (asthma, cystic fibrosis),
childhood cancer includes many distinct
histologic diagnoses

Each tumor histology requires a distinct
treatment approach

The chances of cure diminish if the proper
therapy is not used at the outset
   Enrollment- Who should be
Within tumor histology, patient and tumor
characteristics establish a risk of relapse.

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

It is vital to treat the child, as best we can
ascertain, according to the appropriate
treatment regimen.
Enrollment- Eligibility Criteria
Protocol eligibility criteria must be
clear in regards to:
  1.   Clinical characteristics
  2.   Pathological characteristics
  3.   Biological characteristics

Pediatric oncologists must be
properly informed on how to apply
the eligibility criteria
 Enrollment- Eligibility Criteria

As histologic & biologic characteristics
of tumors are better defined and
refined, central input on pathology and
biology may be needed
     Enrollment- Central Review
     Central review of pathology and
     diagnostic biologic assays can improve
     the likelihood that a child receives the
     best available therapy for their specific
     tumor pathology and risk of relapse

1.   Alveolar vs Embryonal Rhabdomyosarcoma
2.   Neuroblastoma -biological characteristics
3.   Wilms tumor - favorable histology vs.
     focal/diffuse anaplasia
4.   Genetic studies for acute lymphoblastic
Phase 1 and Pilot Study Eligibility
For children with relapsed/resistant
disease or for child with newly-
diagnosed tumor of historically poor
therapeutic response
     important to assure that no treatment with a
      reasonable potential for cure or clinical benefit
     risk of treatment intervention balanced with
      likelihood of benefit in consideration of child’s
      prognosis and/or prior treatment history
 NCI Support for Childhood Cancer
        Clinical Research
1.   Children’s Oncology Group (COG)
2.   COG Phase 1/Pilot Consortium
3.   Pediatric Brain Tumor Consortium
4.   New Approaches to Neuroblastoma
     Therapy (NANT)
5.   Individual Grants to Investigators
     that may include clinical trial
         Pediatric Clinical Trials
      are usually Multi-Institutional
   Investigators committed to report toxicity,
    regimen delivery and response data in
    timely fashion (Remote Data Entry)
   Data center capable of readily receiving
    data, analyzing data and reporting
    important data trends to investigators
   Operations office able to communicate
    with investigators continuously throughout
    the clinical trial (email, Web site)
    Monitoring the individual child
   Laboratory results for tumor related or
    treatment related abnormalities
   Radiologic characterization of tumor and
    consequent organ dysfunction
   Interval evaluations to establish tumor
    response to treatment interventions

    Frequency consistent with or greater than
    good clinical practice, but dependent on
    intervention and specific tumor diagnosis
      Monitoring the clinical trial
   Submitting patient data at protocol-
    determined intervals
   Accumulating, analyzing & reporting
    the data
   Interpreting the data in regards to
    appropriate patient accrual,
    treatment toxicity & effectiveness of
    the treatment intervention
     Data and Safety Monitoring
         NIH 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
     NCI Essential Elements for Data
         and Safety Monitoring
1.   Monitoring the progress of trials
     and safety of participants

2.   Plans for assuring compliance with
     adverse event reporting

3.   Plans for assuring data accuracy
     and protocol compliance.
    Monitoring the progress of trials
      and safety of participants
   Reviewers outside of/in addition to
    the study committee evaluate trial
    data at regular intervals to monitor
    treatment toxicity and effectiveness

   Review determines whether
    continued accrual to trial is safe and
            Compliance with
         adverse event reporting
   NCI funded studies use the Adverse
    Event Expedited Reporting System
    (AdEERS) to report toxicities

   Institutional Principal Investigator is
    ultimately responsible to assure that
    all AEs are reported in a timely
      Assuring data accuracy and
         protocol compliance.

   Cooperative groups and consortia
    practice ongoing quality control and
    interval quality assessments
    (institutional audits) are conducted
1.   General Parameters
         enrollment appropriate to diagnosis & relapse risk, or
          availability of standard treatments for recurrent/relapsed
         laboratory & radiologic monitoring for toxicity and
          response to treatments

2.   Frequency of monitoring
         equal or greater than standard of care for individual
         continuous protocol monitoring by study committee
         interval protocol monitoring (monthly to biannually-based
          on risk, etc.) by group outside of study committee
3.   Who does the monitoring?
         daily monitoring by study committee
         interval monitoring including clinicians/statisticians not
          directly involved in the trial

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

Virtually always in peds oncology trials

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