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Guidance and Implementation for
Monitoring Adequacy of Accrual of Participants to NHLBI Supported Human Subjects Research
October 9, 2009
On this page:
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.
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.
Review Criteria
Suboptimal recruitment is classified as falling into one of three zones
– yellow, amber, and red. An example is provided in the Figure 1.
Yellow 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.
Amber 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 Trial is Implemented (also see Figure
2):
- For trials that fall under this policy, the
Principal Investigator (PI) and Institution Business Official (BO)
will receive a letter reminding them of NHLBI’s milestone accrual
policy. The awardee will have 30 days to provide a milestone plan.
- The PI will submit an accrual plan with benchmarks
that is countersigned by the Business Official.
- 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.
- 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.
- Once all documentation is accepted, the award will
be issued.
- 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.
- 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.
- 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).
- When revised accrual benchmarks and revised budget
(as appropriate) are approved, a revised award will be issued.
- 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
- 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.
Figure 3: Flow chart of activities for trials
in the red zone
AMBER 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.
- 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.
- 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.
- 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 amber zone
Last update: [ February 2, 2012]
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