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:
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.
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.
These formal reviews, when actual enrollment is compared to previously established benchmarks, serve as the minimum number of time points at which action will be taken. However, the NHLBI may take action at any point in the conduct of the study. The frequency and exact timing for additional formal interim reviews will depend upon the characteristics of the study, including such factors as the total length of time for recruitment and the level of risk.
At each scheduled interim review, actual enrollment will be compared to the benchmarks previously established for that time point.
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
Yellow Zone: accrual is <75% of the benchmark, but still at or above the minimally acceptable levels (as defined in the Red Zone)
Red Zone: accrual is below minimally acceptable levels
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
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.
Figure 2: Flow chart of activities prior to start of trial.
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.
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
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.
Figure 4: Flow chart of activities for trials in the yellow zone
Last update: [ August 29, 2017 ]
For questions and/or concerns regarding the content of this page, please contact the Clinical Research Policy Manager