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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

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



Protocol performance and resource utilization a tale of two projects
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


Protocol performance metrics framework
Protocol Performance ProjectsMetrics 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


Investigator initiated trials what do we think we know
Investigator Initiated Trials ProjectsWhat 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


Investigator initiated trials
Investigator-Initiated Trials Projects

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.


Methods pre specified data investigator initiated trials 8 cancer centers
Methods: Pre-Specified Data ProjectsInvestigator-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.


Results trials and enrollment
Results: Trials and Enrollment Projects

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


Protocol performance investigator initiated phase ii trials n 170
Protocol Performance Projects(Investigator-initiated phase II trials, n= 170)

80 trials (47%) were not completed


Enrollment investigator initiated phase ii trials n 3320 patients
Enrollment Projects(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


Reasons for closure investigator initiated phase ii trials n 17 0
Reasons for Closure Projects 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


Protocol performance investigator initiated phase ii trials 2005 2009 n 170
Protocol Performance ProjectsInvestigator-initiated phase II trials, 2005-2009, n= 170


Resource calculation clinical trials office resources
Resource Calculation ProjectsClinical 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


Resource use investigator initiated phase ii trials 2005 2009 n 170
Resource Use ProjectsInvestigator-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)


Centers in the median centers 5 and 6
Centers in the Median ProjectsCenters 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)


Centers in the median centers 5 and 61
Centers in the Median ProjectsCenters 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)


Protocol performance predictors the case for collaboration phase ii trials n 170
Protocol Performance Predictors ProjectsThe case for collaboration, phase II trials, n= 170

46 of 73 (63%) trials with collaboration were completed


Predictor of success activation time
Predictor of Success: ProjectsActivation Time

No difference in time to activation: completed vs. slow accruing trials


Predictor of success activation time benchmarks
Predictor of Success: ProjectsActivation Time Benchmarks?

No difference in time to activation: completed vs. slow accruing trials


Predictors of completion progress at early time points
Predictors of Completion ProjectsProgress at Early Time Points?


Best practices the best vs the rest
Best Practices ProjectsThe 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


Summary phase ii investigator initiated trials
Summary ProjectsPhase 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


Industry cooperative oncology group trials what do we think we know
Industry & Cooperative Oncology Group Trials ProjectsWhat 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


Methods pre specified data 16 cancer centers
Methods: Pre-specified Data Projects16 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.


Results industry cooperative oncology group protocols 2005 2008
Results ProjectsIndustry & 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.


Protocol performance industry cooperative group protocols 2005 2008 n 3378
Protocol Performance Projects(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%)


Protocol enrollment levels effect on overall enrollment 8977 patients 3378 protocols
Protocol Enrollment Levels ProjectsEffect on Overall Enrollment (8977 patients, 3378 protocols)

8055 of 8977

patients (89.7%)

are enrolled to

the protocols

with >2 patients.

Protocol Enrollment Levels


Resource impact industry cooperative group trials with no enrollment
Resource Impact ProjectsIndustry & 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)


Follow up initiatives of two cancer centers
Follow-Up ProjectsInitiatives 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.


Protocol submission policy implemented by two cancer centers
Protocol Submission Policy ProjectsImplemented 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.


Protocol selection rules effect in phase ii iii industry cooperative group trials center 5
Protocol Selection Rules ProjectsEffect 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.


Conclusions phase ii iii industry cooperative oncology group trials
Conclusions ProjectsPhase 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.