Accrual of Human Subjects (Milestones) Policy

Preamble

Regular monitoring of accrual and assessment of study feasibility is essential for the ethical conduct of human subjects research and the proper stewardship of public funds. All studies for which the success of the overall grant or contract depends on the timely recruitment of human subjects should have accrual monitoring plans. This includes, but is not limited to:

• clinical trials of equal to or greater than 150 subjects
• observational studies of equal to or greater than 1,000 subjects
• clinical research networks

NHLBI-funded ancillary studies in which 1,000 or more subjects are recruited from an existing parent study are also covered by this policy if they are funded separately from the parent study and have a separate informed consent.

This Policy includes principles and guidelines on monitoring and evaluating the adequacy of human subject accrual in NHLBI supported research and for establishing a study’s accrual monitoring plan.

Guidance

Establishing Recruitment Benchmarks
Before initiating any study covered by this policy, the investigators in collaboration with NHLBI staff and the monitoring entity, if applicable, shall agree on benchmarks for monitoring recruitment, which will include calendar time and subject numbers based upon a recruitment period initiation date, projected recruitment time duration, and final recruitment target. NHLBI staff will formally review human subject accrual during the study according to this agreed schedule.

For cause and with strong justification (for example, suspension of recruitment for a particular unforeseen circumstance), investigators may petition the NHLBI for changes in projected recruitment numbers and the recruitment timetable after study initiation. NHLBI’s decision to accept the revised targets as the milestones will depend on the maintenance of the study’s statistical power and study completion within the time and resources available. Final approval of revised benchmarks will be made by the Program Division Director, based upon advice from the Program Director, Branch Chief, the Grant or Contract Official, and the monitoring entity (if relevant).

Conduct of Accrual Reviews
Program staff and grants/contracts management staff are expected to monitor recruitment and budget. Formal reviews will normally occur at 25%, 50%, and 75% of the projected recruitment period, but may be more frequent.

At each scheduled interim review, actual enrollment will be compared to the benchmarks previously established for that time point.

Review Criteria

Suboptimal recruitment is classified as falling into one of three zones – green, yellow, and red. An example is provided in the Figure 1.

Green Zone: accrual is < 100% and ≥75% of the benchmark

• If study accrual is < 100% and ≥75% of the benchmark, Program staff may increase monitoring frequency and should ensure that the investigators are planning and implementing corrective actions to ensure full enrollment within the accrual period.

Yellow Zone: accrual is <75% of the benchmark, but still at or above the minimally acceptable levels (as defined in the Red Zone)

• If study accrual is <75% of the benchmark, but still at or above the minimally acceptable levels (as defined below in the Red Zone), the investigators shall be required to submit an analysis of recruitment barriers and a corrective recruitment action plan with budget for review by the NHLBI (Program Director, Branch Chief, the Grant or Contract Official) and the monitoring entity, and approval by the relevant Program Division Director. The corrective action plan may include restricting funds already awarded and/or withholding funds not yet awarded until such time as they are needed to support clinical costs.

Red Zone: accrual is below minimally acceptable levels

• Study accrual is below minimally acceptable levels as defined by:
  <25% of the benchmark at the 25% time point OR
  <25% of the benchmark at the 50% time point OR
  <50% of the benchmark at the 75% time point

In these cases, the NHLBI shall seriously consider temporarily restricting funds already awarded, withholding funds not yet awarded, or permanently discontinuing funding.

Figure 1: Cumulative target numbers are for illustrative purpose only; staff and investigators will agree/negotiate targets for individual studies

Funding Continuation Decisions

Studies in which recruitment falls below the minimally acceptable levels (red zone) and is deemed unlikely to improve sufficiently to bring the study to completion within an acceptable budget or time frame will be closed for lack of feasibility. Final support decisions will be made by the Institute Director based on the recommendations of the Director of the responsible Program Division and the Director of the Division of Extramural Research Activities, with the advice of program staff, grants/contracts staff, and the study monitoring entity, if indicated.

To be considered for continued funding despite not meeting minimally acceptable recruitment milestones, investigators must submit a corrective plan containing a compelling argument that the conditions leading to the poor accrual have changed and a clear description of how earlier challenges have been addressed and problems have been solved. Continued funding will be at the discretion of the NHLBI Director, based on the recommendations of the Director of the responsible Program Division and the Director of the Division of Extramural Research Activities, with the advice of program staff, grants/contracts staff, and the study monitoring entity, if indicated.

If a study is finally determined to lack feasibility and will no longer accrue subjects, investigators, in agreement with their business offices, must present to the NHLBI an acceptable closeout plan for review and approval within 30 days.

Before the Award is Issued (also see Figure 2):

1. For trials that fall under this policy, the Principal Investigator (PI) and Institution Business Official (BO) will receive communication reminding them of NHLBI’s milestone accrual policy, and the requirement that the accrual plan be submitted before award. The PI will submit an accrual plan with benchmarks that is countersigned by the Business Official.
2. NHLBI staff will review the proposed benchmarks for appropriateness and for compatibility with the budget and specific aims; and, if appropriate, invite the applicant organization to submit revised benchmarks and/or budget (same dollars, just reallocation between years) that more accurately reflect the recruitment timeline.
3. Funding actions may be withheld until the NHLBI and the awardee institution agree on accrual benchmarks. The only exception is for end of year activities when funds must be committed. Such awards will be issued with human subject and accrual restrictions.
4. Once all documentation is accepted, the award will be issued.
5. For trials that involve a Protocol Review Committee (PRC), a Data Safety Monitoring Board (DSMB), and/or FDA approval prior to recruitment, accrual benchmarks may need to be revised. NHLBI staff will make the decision to approve the revised benchmarks.
6. For clinical trial networks, accrual benchmarks will be established prior to initiation of recruitment for each protocol.
   • The Principal Investigator(s) and Institution Business Officials will receive a letter requesting recruitment milestones.
   • The awardee will have 30 days to provide a milestone plan.
   • NHLBI staff will review the proposed benchmarks for appropriateness and for compatibility with the budget and specific aims; and, if appropriate, invite the applicant organization to submit revised benchmarks and/or budget (same dollars, just reallocation between years) that more accurately reflect the recruitment timeline.
   • Once all documentation is accepted, the award will be issued.

Figure 2: Flow chart of activities prior to start of trial.

After the Trial is Implemented:

NHLBI staff will perform interim reviews by comparing established milestones with actual recruitment based upon established recruitment periods (25%, 50% and 75% or as appropriate). Both patient enrollment against established accrual benchmarks and expenditure of funds during the same period will be examined during the review. If warranted, additional information will be requested.

Clinical trials within Clinical Research Networks will have milestone reviews as above. However, the funding implications of a decision to discontinue a study will be evaluated in the context of the network activities as a whole and may not require signature of individual business offices or a revised award.

RED ZONE: applies to studies that are outside a clinical research network and have minimally acceptable recruitment or less (see also Figure 3).

REQUEST CORRECTIVE ACTION PLAN (CAP): If NHLBI staff believe that a study can meet its goals, investigators will receive a letter requesting that they submit a CAP within 30 days, countersigned by the Business Official, containing a clear description of how challenges have been addressed and how remaining issues will be addressed.

1. Upon receipt of the CAP, if NHLBI staff agree that continued funding is justified, they will work with the awardee on revised accrual benchmarks and a revised funding plan (if necessary).
2. When revised accrual benchmarks and revised budget (as appropriate) are approved, a revised award will be issued.
3. If after review of the CAP, NHLBI staff agree that continued funding is NOT justified,
   • The PI and Business Official will be asked to develop and submit within 30 days a close-out plan and corresponding budget.
   • NHLBI staff will review and, if necessary, discuss the closeout plan and budget with the PI and Business Official.
   • After the closeout plan and budget are approved, they are incorporated into a revised award.

DO NOT REQUEST CAP AND CLOSEOUT STUDY: If NHLBI staff decide that a CAP is not needed because the study cannot meet its goals, they will request a closeout plan and budget

1. The PI and Business Official will be asked to develop and submit within 30 days a close-out plan and corresponding budget.
2. NHLBI staff will review and, if necessary, discuss the closeout plan and budget with the PI and Business Official.
3. After the closeout plan and budget are approved, they are incorporated into a revised award.

Figure 3: Flow chart of activities for trials in the red zone

YELLOW ZONE: applies if accrual is <75% of the expected target, but still above the minimally acceptable level (see also Figure 4):

REQUEST RECRUITMENT ANALYSIS AND CORRECTIVE ACTION PLAN (CAP): NHLBI staff send a letter to the PI and Business Official requesting an analysis of recruitment barriers and a corrective action plan with budget.

1. If the proposed budget is equal to or is less than the current award and NHLBI staff agree that continued funding is justified, they will work with the awardee on revised accrual benchmarks and a revised funding plan. Once the revised accrual benchmarks and budget are approved, a revised award is issued.
2. If the proposed budget is greater than the current award and the NHLBI staff agree that continued funding is justified, they will work with the awardee on revised accrual benchmarks and a revised funding plan. Once the revised accrual benchmarks and budget are approved, a revised award is issued.
3. After several rounds of CAP negotiation, if the PO and GMS/CO agree that continued funding is NOT justified:
   • The PI and Business Official will be asked to develop and submit within 30 days a closeout plan and corresponding budget.
   • NHLBI staff will review and, if necessary, discuss the closeout plan and budget with the PI and Business Official.
   • After the closeout plan and budget are approved, they are incorporated into a revised award.

Figure 4: Flow chart of activities for trials in the yellow zone

Last update: [ August 29, 2017 ]

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