1. 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

2. Considerations for patients and clinical trials Enrollment To assure that each child accrued to a clinical trial is receiving appropriate treatment Monitoring To monitor the toxicity and effectiveness of a treatment intervention within each clinical trial

3. Safe and Effective Therapy for childhood cancer is often successful, but it is always toxic and carries risk of treatment related morbidity or death

4. 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

5. Enrollment- Who should be enrolled? 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.

6. 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

7. Enrollment- Eligibility Criteria As histologic & biologic characteristics of tumors are better defined and refined, central input on pathology and biology may be needed

8. 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 leukemia

9. 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 exists important to assure that no treatment with a reasonable potential for cure or clinical benefit exists risk of treatment intervention balanced with likelihood of benefit in consideration of child’s prognosis and/or prior treatment history risk of treatment intervention balanced with likelihood of benefit in consideration of child’s prognosis and/or prior treatment history

10. NCI Support for Childhood Cancer Clinical Research 1. Children’s Oncology Group (COG) 2. COG Phase 1/Pilot Consortium 3. Pediatric Brain Tumor Consortium (PBTC) 4. New Approaches to Neuroblastoma Therapy (NANT) 5. Individual Grants to Investigators that may include clinical trial research

11. Pediatric Clinical Trials are usually Multi-Institutional Investigators committed to report toxicity, regimen delivery and response data in timely fashion (Remote Data Entry) 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 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) Operations office able to communicate with investigators continuously throughout the clinical trial (email, Web site)

12. Monitoring the individual child Laboratory results for tumor related or treatment related abnormalities Laboratory results for tumor related or treatment related abnormalities Radiologic characterization of tumor and consequent organ dysfunction Radiologic characterization of tumor and consequent organ dysfunction Interval evaluations to establish tumor response to treatment interventions 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

13. Monitoring the clinical trial Submitting patient data at protocol- determined intervals Submitting patient data at protocol- determined intervals Accumulating, analyzing & reporting the data Accumulating, analyzing & reporting the data Interpreting the data in regards to appropriate patient accrual, treatment toxicity & effectiveness of the treatment intervention Interpreting the data in regards to appropriate patient accrual, treatment toxicity & effectiveness of the treatment intervention

14. 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 populations.

15. 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.

16. 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 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 appropriate Review determines whether continued accrual to trial is safe and appropriate

17. Compliance with adverse event reporting NCI funded studies use the Adverse Event Expedited Reporting System (AdEERS) to report toxicities 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 manner Institutional Principal Investigator is ultimately responsible to assure that all AEs are reported in a timely manner

18. Assuring data accuracy and protocol compliance. Cooperative groups and consortia practice ongoing quality control and interval quality assessments (institutional audits) are conducted Cooperative groups and consortia practice ongoing quality control and interval quality assessments (institutional audits) are conducted

19. Summary 1. General Parameters enrollment appropriate to diagnosis & relapse risk, or availability of standard treatments for recurrent/relapsed disease enrollment appropriate to diagnosis & relapse risk, or availability of standard treatments for recurrent/relapsed disease laboratory & radiologic monitoring for toxicity and response to treatments laboratory & radiologic monitoring for toxicity and response to treatments 2. Frequency of monitoring equal or greater than standard of care for individual patient equal or greater than standard of care for individual patient continuous protocol monitoring by study committee continuous protocol monitoring by study committee interval protocol monitoring (monthly to biannually-based on risk, etc.) by group outside of study committee interval protocol monitoring (monthly to biannually-based on risk, etc.) by group outside of study committee

20. Summary 3. Who does the monitoring? daily monitoring by study committee daily monitoring by study committee interval monitoring including clinicians/statisticians not directly involved in the trial interval monitoring including clinicians/statisticians not directly involved in the trial 4. When is Data Monitoring Committee needed? phase III studies (DSMB) phase III studies (DSMB) multi-institutional trials multi-institutional trials high-risk population or treatment high-risk population or treatment complex treatment complex treatment early stopping rules early stopping rules conflicts of interest conflicts of interest Virtually always in peds oncology trials