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Protocol Performance and Resource Utilization from 16 Cancer Centers

Protocol Performance and Resource Utilization from 16 Cancer Centers. The Third Annual Clinical Research Management Workshop. Henry Durivage, Pharm.D. 06/22/2010. Yale School of Medicine. Protocol Performance and Resource Utilization: A Tale of Two Projects. Protocol Performance

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Protocol Performance and Resource Utilization from 16 Cancer Centers

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  1. Protocol Performance and Resource Utilization from 16 Cancer Centers The Third Annual Clinical Research Management Workshop Yale Center for Clinical InvestigationNew Haven, Connecticut Henry Durivage, Pharm.D. 06/22/2010

  2. Yale School of Medicine

  3. Protocol Performance and Resource Utilization: A Tale of Two Projects Protocol Performance Industry and cooperative oncology group trials1 Investigator-initiated oncology trials2 Impact Effort and estimated cost associated with study start-up, conduct and close out. Initiatives 1Durivage HJ, Bridges KD: Clinical Trial Metrics: Protocol Performance and Resource Utilization from 14 Cancer Centers, ASCO 2009 2Durivage HJ, Bridges KD, Sauers J, Baker L, Wellons M: Protocol Performance and Resource Utilization of Phase II Investigator-Initiated Trials, ASCO 2010

  4. Protocol PerformanceMetrics Framework What do we (think we) know? What do we hope to accomplish? identify challenges, areas for improvement Identify/measure factors that predict success Identify/measure impact identify initiatives to maximize success Identify best practices/benchmarks Measure impact of initiatives

  5. Investigator Initiated TrialsWhat do we (think we) know? Many trials are not completed Primarily due to not meeting target enrollment. Many are not implemented quickly Is the speed of activation predictive? Many are not completed quickly Over-estimates of accrual rate (centers + affiliates) are common. Impact is significant

  6. Investigator-Initiated Trials Investigator-initiated trials (IITs) are the backbone of cancer center clinical programs Highest priority Essential to early testing (e.g., dosing, safety, pharmacokinetics, pharmacodynamics, early indicators of efficacy, etc.) Little is known about cancer center IIT performance and associated resource use.

  7. Methods: Pre-Specified DataInvestigator-initiated trials, 8 cancer centers Phase I/II and II investigator-initiated trials Reason for closure and assessment Completed: accrual goal met, ineffective, too toxic Not completed: slow accrual, funding, etc. Life cycle months to from SRB/IRB approval to open to accrual, % open within benchmarks Accrual (target, actual, actual/month, % of target at 3 month intervals) Resources (usage and cost) Study activation activities, accrual, regulatory use, participating sites, etc.

  8. Results: Trials and Enrollment 170 phase II investigator-initiated trials median/center: 21 (range 3-37) 90 (53%) trials completed 58 (34%) trials not completed due to inadequate accrual 3320 patients enrolled median/center: 433 (range 51-964) 2369 (71%) patients enrolled to completed trials 684 (21%) patients enrolled to trials not completed due to inadequate accrual

  9. Protocol Performance(Investigator-initiated phase II trials, n= 170) 80 trials (47%) were not completed

  10. Enrollment(Investigator-initiated phase II trials, n= 3320 patients) Percentage of total enrollment to trials completed vs. not completed 951 patients were enrolled to studies not completed

  11. Reasons for Closure Investigator-initiated phase II trials, n= 170 90 (52.9%) completed accrual goal met, early toxicity 80 (47.1%) not completed 58 (34.1%) inadequate accrual 6 PI left institution 4 contracting/funding 3 replaced by another/competing trial 2 drug unavailable 2 eligibility/protocol compliance 5 other

  12. Protocol PerformanceInvestigator-initiated phase II trials, 2005-2009, n= 170

  13. Resource CalculationClinical Trials Office Resources 1Start-up: study tools, activation meetings, other local requirements: 80 hours 2Regulatory: IRB initial application (24 hrs), amendments (4 hrs), continuing reviews (6 hrs), IND safety reports (0.25 hrs) 1Center enrollment: 100 hrs/patient Multi-center management: 12 hrs/enrollment, 8 hrs/site start-up, 2 hrs/site amendment processing Cost assessment, salary + fringe: $60 per hour 1.C-Change Guidance Document for Implementing Effective Cancer Clinical Trials, www.c-changetogether.org/pubs/default.asp 2. Indiana University Simon Cancer Center-led regulatory metrics project

  14. Resource UseInvestigator-initiated phase II trials, 2005-2009, n= 170 Slow accruing trials 67,900 hours (8,500 hrs/center, ~ 1 FTE/center/yr), $4,075,000 ($509,000/center)

  15. Centers in the MedianCenters 5 and 6 Enrollment 983 patients enrolled to 41 phase II trials 761 patients at coordinating center, 222 at participating centers Resource Use 91,036 hrs @ $60/hr = $5,462,160 $5,556/patient enrolled (CTO cost, includes start-up and regulatory)

  16. Centers in the MedianCenters 5 and 6 41 phase I/II and II investigator-initiated trials 20 trials completed, 21 trials not completed 17 trials not completed due to inadequate enrollment 983 patients enrolled 589 patients to completed trials 394 (40%) patients to non-completed trials 322 (32.7%) patients to trials with inadequate accrual Resources and cost 37,133 hrs to trials not completed (3,713/center/year) 29,933 hrs ($1,795,980) to trials closed due to inadequate accrual(~3,000 hrs/center/year; $180,000/center/year)

  17. Protocol Performance PredictorsThe case for collaboration, phase II trials, n= 170 46 of 73 (63%) trials with collaboration were completed

  18. Predictor of Success: Activation Time No difference in time to activation: completed vs. slow accruing trials

  19. Predictor of Success: Activation Time Benchmarks? No difference in time to activation: completed vs. slow accruing trials

  20. Predictors of CompletionProgress at Early Time Points?

  21. Best PracticesThe Best vs. The Rest The Rest: 29% of total enrollment to slow accruing studies 7% of enrollment to slow accruing studies 9% of enrollment to slow accruing studies

  22. SummaryPhase II Investigator-Initiated Trials 170 therapeutic phase II investigator initiated trials from 8 cancer centers (median per center: 21) 58 (34%) were not completed due to slow accrual 3320 patients enrolled (median per center: 433) 684 patients (20.6%) enrolled to slow accruing trials Two centers enrolled 7.5% to slow accruing trials Cost of slow accruing trials is significant (> 1 FTE/year) Predictors of protocol completion: Time to activation: not predictive % enrollment at early time points: may matter Collaboration: 63% completed with affiliates vs. 45% without

  23. Industry & Cooperative Oncology Group TrialsWhat do we (think we) know? Enrollment per trial is low Many trials do not enroll any subjects Estimates of accrual are optimistic Many are not implemented quickly Is the speed of activation predictive? Impact is significant

  24. Methods: Pre-specified Data16 Cancer Centers Accrual data to industry- and cooperative oncology group-sponsored therapeutic clinical trials Protocols categorized into accrual levels Analyzed by phase and “rare diseases” Data: 4-year period from 2005 through 2008 Resources (usage and cost) Study activation activities, accrual, regulatory use Pediatric clinical trials were excluded.

  25. ResultsIndustry & Cooperative Oncology Group protocols, 2005-2008 3378 therapeutic clinical trials (1591 cooperative group and 1787 industry) 8977 patients enrolled (4012 cooperative group and 4965 to industry) 1802 (53.3%) did not enroll any patients 887 (55.7%) cooperative group 915 (51.2%) industry Only 936 (27.7%) trials enrolled > 2 patients and these trials accounted for 89.7% of the total enrollment. Excluding therapeutic clinical trials of hematologic malignancies did not significantly alter the results.

  26. Protocol Performance(Industry & Cooperative Group protocols, 2005-2008, n=3378) Protocol Enrollment Levels (e.g., 1 patient/protocol, etc.) 1802 of 3378 cooperative group and industry protocols did not enroll any patients. (56%) (51%) (24%) (31%)

  27. Protocol Enrollment Levels Effect on Overall Enrollment (8977 patients, 3378 protocols) 8055 of 8977 patients (89.7%) are enrolled to the protocols with >2 patients. Protocol Enrollment Levels

  28. Resource ImpactIndustry & Cooperative Group Trials with No Enrollment 915 industry trials and 887 cooperative group trials Clinical Trials Office (CTO) staff effort: 287,930 hrs, 16 centers, 4 years 4,500 hrs (2.9 FTE) per center per year 46 people per year across 16 centers Net Loss: $81,000 per center per year (assumes $6,000 start-up income to CTO for 915 industry trials)

  29. Follow-UpInitiatives of two cancer centers Rules governing selection of industry- and cooperative group-sponsored therapeutic clinical trials for activation were implemented at two cancer centers. One cancer center implemented “rules” in January 2008 the other in October 2008. Protocol selection rules are enforced by each center’s Protocol Review and Monitoring System.

  30. Protocol Submission PolicyImplemented by two cancer centers Industry-sponsored trials and cooperative group trials for adults must accrue at least 3 patients over the time-period that the trial will be open to enrollment. Principal investigators must demonstrate either: adequate accrual history to similar trial(s) or proof that they will see at least 12 potentially eligible patients over the time that the trial will be open to enrollment.

  31. Protocol Selection RulesEffect in Phase II-III Industry & Cooperative Group Trials, Center #5 Industry and adult cooperative group phase II-III trials. Trials approved in 2008-2010 and open to enrollment for > 6 months.

  32. ConclusionsPhase II-III Industry & Cooperative Oncology Group Trials 90% of the accrual to industry- and cooperative group-sponsored therapeutic clinical trials is from the 26% of the trials enrolling > 2 patients/trial. Significant resources are used on therapeutic clinical trials that do not contribute significantly to overall accrual. Effective rules governing selection of industry- and cooperative group-sponsored therapeutic clinical trials for activation are needed. Effective rules allow centers to re-direct valuable resources to useful activities without adverse effect on overall enrollment.

  33. Yale School of Medicine

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