OEWG Timeline Analysis for CTEP Trials

Presentation to the Clinical Trials and Translational Research Advisory Committee

July 12, 2017

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1. Review of OEWG Report Goals and Timelines

2. Comparison of Reviews and Timelines Pre- and Post-OEWG

3. In-Depth Look at Recent Trials

4. Next Steps and Questions

Objectives

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Background: OEWG Report

Operational Efficiency Working Group (OEWG) established in December 2008 under CTAC

Established in response to issues identified in the 2005 Clinical Trials Working Group Report to the National Cancer Advisory Board

First objective: identify barriers to timely trial activation in the NCI system and solutions to improve timelines moving forward

Second objective: identify strategies to increase percentage of trials that reach their accrual targets in a timely fashion

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Background: Original OEWG Timelines

To reduce the time for CTEP Phase II early drug development trial activation, the OEWG set a target of 210 days to complete the steps under CTEP/IDB and extramural control – LOI review, protocol development, protocol review, and forms development. The timeline excludes industry negotiations, arranging drug supply, and IRB and

FDA approval.

However, the OEWG also set a “drop-dead” date of 18 months by which all external issues must be resolved.

If a protocol based upon an LOI submitted to CTEP is not activated within an 18-month period, it will be terminated.

Phase III trials: Target of 300 days for steps under CTEP and Group control

Drop-dead date of 24 months for resolution of all issues, including those controlled by industry partners or IRBs

Report of the CTAC Operational Efficiency Working Group. March 2010. https://www.cancer.gov/about-nci/organization/ccct/steering-committees/concept-submission-guidelines/OEWG-Report.pdf

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Background: 2010 and 2012 Timelines

OEWG tracking for Target Timelines began with all LOIs and Concepts received after 4/1/2010

Absolute Deadlines were decreased on 4/5/2012 Last protocol under the old timelines was activated March 21, 2014

Target 2010-2012

Absolute 2010-2012

Target 2012-Present

Absolute 2012-Present

Phase 1 and 2 LOIs 210 days 540 days 210 days 450 days

Phase 1/2 and 2 Concepts 240 days 540 days 210 days 450 days

Phase 3 Concepts 300 days 730 days 300 days 540 days

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OEWG Stages and Milestones

1) LOI/Concept Approval

• Initial LOI/Concept Consensus Evaluation

• LOI / Concept OEWG Start Date

• CTEP Program Review Committee (PRC) Review

• LOI / Concept Approved

• Follow-Up Consensus Evaluations and LOI/Concept Approval

• Revised LOI / Concept Submitted

• LOI / Concept Approved

2) Protocol Authoring

•Protocol Development

•Protocol Receipt

3) Protocol Development

• Initial Protocol Consensus Evaluation

• PRC Review• Revised Protocol

Submitted

• Follow-Up Protocol Consensus Evaluations

• Revised Protocol Submitted

4) Protocol Approval and

Activation

• Protocol Approved

• Amendment Receipt, Review, and Approval

• Protocol Active

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Key Question

How do trials after implementation of the OEWG timelines compare to trials before the OEWG timelines? Time to activation

Median days per stage of the trial development process

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Methods

Extracted data on OEWG stages and milestones for protocols with:

Timeline data tracked in CTEP systems, including data on LOI/concept

Activation dates 2012-2017, with two trial groupings by activation date:

Trials activated 7/1/2012 – 6/30/2014: post-OEWG but largely before the launch of the NCTN and ETCTN (2 years) Includes trials under both old and new deadlines

Last protocol under the old timelines was activated March 21, 2014

Trials activated 7/1/2014 – 6/30/2017: post-OEWG and after the launch of the NCTN and ETCTN (3 years) Only includes trials under the new deadlines

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Methods

407 protocols activated July 2012 – June 2017 with timeline data Removed 35 trials that were phase “other” / non-treatment (n=20) or

had no or inconsistent LOI or concept data (n=15)

Analyzed 372 protocols

For comparisons to pre-OEWG trials, used information from the March 2010 OEWG Report1

Conducted additional analyses of: More recently activated studies

Protocols that did not activate

1. Report of the CTAC Operational Efficiency Working Group. March 2010. https://www.cancer.gov/about-nci/organization/ccct/steering-committees/concept-submission-guidelines/OEWG-Report.pdf

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Comparison Results

Included Trials by Phase and Activation Time Period

Pilot I I/II II II/III III Total

July 2012 – June 2014 7 58 16 69 5 18 173

July 2014 – June 2017 5 57 9 91 9 28 199

Total 12 115 25 160 14 46 372

Included Trials by Lead Org and Activation Time Period

Group / NCTN

ETCTN / Related Program

Cancer Center /

Institution

Clinical Center

Consortia / Other

NetworkTotal

July 2012 – June 2014 74 4 59 12 24 173

July 2014 – June 2017 93 54 12 11 29 199

Total 167 58 71 23 53 372

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Comparing Time to Activation Pre- and Post-OEWG Phase 2 Trials

Pre-OEWG: Information from CTEP CDUS database on 137 CTEP Phase II trials activated 2006-2008 as reported in 2010 OEWG report. Post-OEWG: 160 phase II trials with complete OEWG information.

16%

61%

23%

16%

84%

0%

14%

81%

4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Less than 1 year 1-2 years More than 2 Years

Perc

enta

ge o

f Tria

ls

Time to Activation

Pre-OEWG: 2006-2008 (n=137) July 2012 - June 2014 (n=69) July 2014 - June 2017 (n=91)

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Comparing Time to Activation Pre- and Post-OEWG Phase 3 Trials

Pre-OEWG: Information from CTEP CDUS database on 70 Phase III trials activated 2006-2008 as reported in 2010 OEWG report. 67 were Cooperative Group trials, plus one study each from NCIC, PACCT, and BMTCTN. Post-OEWG: 46 Phase 3 trials.

2%

40%

58%

6%

89%

6%7%

93%

0%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Less than 1 year 1-2 years More than 2 years

Perc

enta

ge o

f Tria

ls

Time to Activation

Pre-OEWG: 2006-2008 (n=70) July 2012 - June 2014 (n=18) July 2014 - June 2017 (n=28)

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Comparing Median Days Per Step Pre- and Post-OEWG Phase 2 Trials

Pre-OEWG: Information from CTEP CDUS database on 137 CTEP Phase II trials activated 2006-2008 as reported in 2010 OEWG report. Post-OEWG: 160 phase II trials with complete OEWG information.

111 97 112

5960

65

259

178

210

44

28

13

0

50

100

150

200

250

300

350

400

450

500

Pre-OEWG: 2006-2008(n=137)

July 2012 - June 2014(n=69)

July 2014 - June 2017(n=91)

Median Days Per Step

Protocol Approval to Trial ActivationProtocol Receipt to Protocol ApprovalLOI Approval to Protocol ReceiptOEWG Start to LOI Approval

Median Overall: 447 Days

Median Overall: 448 Days

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Comparing Median Days Per Step Pre- and Post-OEWG Phase 3 Trials

Pre-OEWG: Information from CTEP CDUS database on 70 Phase III trials activated 2006-2008 as reported in 2010 OEWG report. Post-OEWG: 46 Phase 3 trials.

93 93 74.5

138.590.5 111

348.5

152.5224.5

94

129.535.5

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

Pre-OEWG: 2006-2008(n=70)

July 2012 - June 2014(n=18)

July 2014 - June 2017(n=28)

Median Days Per Step

Protocol Approval to Trial ActivationProtocol Receipt to Protocol ApprovalConcept Approval to Protocol ReceiptOEWG Start to Concept Approval

Median Overall: 545 Days Median Overall:

529.5 Days

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1%

26%

30%

23%

10% 11%

0%

23%

28%

25%

13%12%

0%

4%

24%

33%

23%

15%

0%

5%

10%

15%

20%

25%

30%

35%

0 1 2 3 4 5+

% o

f Tria

ls in

Tim

efra

me

Number of Revisions

Pre-OEWG: 2006-2008 (n=137) July 2012 - June 2014 (n=69) July 2014 - June 2017 (n=91)

Comparing Number of Revisions Pre- and Post-OEWG Phase 2 Trials

Pre-OEWG: Information from CTEP CDUS database on 137 CTEP Phase II trials activated 2006-2008 as reported in 2010 OEWG report. Post-OEWG: 160 phase II trials with complete OEWG information.

Median = 2 Median = 2 Median = 3

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0%3%

29%

33%

22%

13%

0%

33%

22%

11%

17% 17%

0% 0%

14%

57%

14% 14%

0%

10%

20%

30%

40%

50%

60%

0 1 2 3 4 5+

% o

f Tria

ls in

Tim

efra

me

Number of Revisions

Pre-OEWG: 2006-2008 (n=70) July 2012 - June 2014 (n=18) July 2014 - June 2017 (n=28)

Comparing Number of Revisions Pre- and Post-OEWG Phase 3 Trials

Pre-OEWG: Information from CTEP CDUS database on 70 Phase III trials activated 2006-2008 as reported in 2010 OEWG report. Post-OEWG: 46 Phase 3 trials.

Median = 3 Median = 2 Median = 3

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Overall ResultsJuly 2014 – June 2017

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Median Days for OEWG Stage by Lead Organization Type and Phase Grouping, 2014-2017

N=198; omitting 1 consortia phase III trial

108 92 89.5 113.582 75.5

6464 73.5

6185 116.5

271 300

140.5

259.5

188

239.582.5

5.5

25

28460.5 457

437.5 449.5 440

532

0

100

200

300

400

500

600

CancerCenter(n=12)

ClinicalCenter(n=11)

Consortia(n=28)

ETCTN(n=54)

NCTN - Early(n=57)

NCTN - Late(n=36)

Median Days Per Step

Protocol Approval to Trial ActivationProtocol Receipt to Protocol ApprovalLOI/Concept Approval to Protocol ReceiptOEWG Start to LOI/Concept ApprovalMedian Total Days

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Box and Whisker Plot: Total Time to Activation by Lead Org Grouping, 2014-2017

N=198; omitting 1 consortia phase III trial

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12 6

713 7 36

1

1

8

5

10 732

5

4

11

16

2111

68

8

44 16

1

3

3

11

6 529

2

42 2

1021 3 1 7

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

CancerCenter(n=12)

ClinicalCenter(n=11)

Consortia(n=28)

ETCTN(n=54)

NCTN -Early

(n=57)

NCTN -Late

(n=36)

Total(n=198)

Greater than 130%115% to 130%101% to 115%100%95% to 99%85% to 94%Less than 85%

Percent of Original OEWG Deadline* for Trials by Lead Organization Type and Phase Grouping, 2014-2017

*Automatic extension of 16 days for government shutdown added to 35 trialsN=198; omitting 1 consortia phase III trial, 97% of original deadline

77% of trials (n=152) activate within

original deadline

42% (n=84) take between 95% and

100% of allotted time

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Common Reasons for Deadline Extensions

Additional study component added or design changed

Delay in drug dosing decisions or production

NCI resource issues: Backup due to other studies in CIRB or steering committees

Change in CIRB and network systems requirements

Precision medicine study coordination

Regulatory issues, e.g. late decisions to try for registration or require an IND

Lead organization administrative issues

Combination of factors that contribute to a rush at the deadline

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Median Days for OEWG Stage by Number of Revisions, Early Phase Trials, 2014-2017

76.5115 113 99

74

73.5

67 62 68.562.5

143.5

217 249

324332

80

117

13.5

430.5 441 448467.5

453.5

0

50

100

150

200

250

300

350

400

450

500

1 to 2 (n=46) 3 (n=49) 4 (n=31) 5 (n=16) 6 or more (n=20)Median Days Per Step

Protocol Approval to Trial ActivationProtocol Receipt to Protocol ApprovalLOI Approval to Protocol ReceiptOEWG Start to LOI ApprovalMedian Total Days

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Limitations and Discussion

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Limitations

Potential bias due to studies withdrawn because they were expected to exceed OEWG deadline This analysis only includes protocols that have been activated – trials that

were withdrawn or disapproved are not included

Difficult to say conclusively why a study was withdrawn, but a brief review of LOIs, Concepts, and Protocols withdrawn after they are at least 100 days into their OEWG timeline suggests that the most common reasons for withdrawal are changes in the science

Potential timing bias If trials are grouped based on when their OEWG timeline started, then we

risk underrepresenting how long the process takes, unless we wait long enough to allow the trials that take the longest to activate This makes it harder to assess recent trials

This analysis grouped trials based on when they actually activated This allowed us to look at trials activated through 2017

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Next Steps and Questions for CTAC

Expect different reasons for trial activation delays based on trial design and lead organization Consortia & NCTN have centralized offices while ETCTN does not

Analysis of ETCTN trial activation times identified additional support for protocol development as a potential facilitator CTEP is developing a support mechanism to assist with the protocol

authoring and revision process for ETCTN trials

Plan to evaluate the effect on trial timelines

Strong tendency to work to the deadline across trials Should deadlines be shortened?

Are there other analyses we should conduct?

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Questions?

www.cancer.gov www.cancer.gov/espanol