HEAL Policy for the Enrollment of Participants in Clinical Trials

The National Institutes of Health (NIH) launched the Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, in response to the public health emergency of opioid misuse, addiction, and overdose to speed new discoveries to prevent and treat opioid misuse and overdose and enhance pain management with non-addictive interventions.

HEAL-supported clinical trials expecting to enroll more than 75 participants or clinical studies deemed by the Program Official, regardless of enrollment size, to require enhanced oversight (e.g., interventions involving an invasive procedure with a high potential for serious adverse events) are subject to enrollment reporting minimally twice per year and will include a series of accrual goals for completing target enrollment. Continuation of the award will be conditional upon satisfactory progress, availability of funds, and scientific priorities of the NIH HEAL Initiative.

Purpose/Background

Clinical trials play a key role in identifying safe and effective treatments for opioid use disorder and unmanaged chronic pain. Effective clinical trial research relies on the ability of researchers to meet recruitment goals. The HEAL Policy for Recruitment of Participants in Clinical Trials outlines reporting, accrual, and achievement expectations to ensure the safe and efficient conduct of these studies while providing necessary stewardship of the public funds that support them.

Policy

HEAL-funded clinical trials that expect to enroll more than 75 participants or are deemed by the Program Official, regardless of size, to require enhanced oversight are subject to enrollment reporting minimally twice per year and will include a series of accrual goals for completing target enrollment. For the purposes of this policy, a participant is a human research subject who will contribute to the primary analyses (e.g., in the case of a randomized clinical trial, this number typically reflects the number of participants who are randomized and contribute to intention-to-treat analyses and does NOT include screened or consented participants who fail to meet full inclusion criteria or are otherwise not randomized). For individual research grant/contract/cooperative agreement awards that consist of multiple studies that do not involve pooled analysis across studies (i.e., the studies are independent and independently analyzed), the policy applies only to those independent studies that enroll 75 or more participants or are deemed to require enhanced oversight to mitigate risk.

This policy only applies to NIH-defined clinical trials.

  • Clinical Trial: A research study1 in which one or more human research subjects2 are prospectively assigned3 to one or more interventions4 (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.5

If participant enrollment remains below 50% of the expected enrollment for one year, a viable plan to recover should be negotiated with Program Official. If enrollment falls significantly below projected metrics, NIH may consider withholding future support and/or negotiating an orderly phase-out of a study. The NIH may also terminate or curtail the study in the event of (a) failure to obtain regulatory approval to start the trial/study, (b) failure to implement the study protocol, (c) a substantial shortfall in participant follow-up, quality control, or other major breach of the protocol, (d) substantive changes in the agreed-upon protocol with which the NIH does not concur, and (e) human subject safety and/or ethical issues.  Continuation of the award will be conditional upon satisfactory progress, availability of funds, and scientific priorities of the NIH HEAL Initiative.

Definitions

Expected enrollment accounts for the length of recruitment time at the time of enrollment reporting and is calculated as follows:

  • Total enrollment period (days): number of days between first participant enrollment date (Day 1) and projected recruitment end date.
  • Recruitment time elapsed (days): number of days of enrollment from first participant enrolled to date that current enrollment was reported.
  • Expected enrollment (participants): recruitment time elapsed/total planned enrollment period multiplied by the total target sample size.
    • Example: A study with a total enrollment time of 1,000 days that has been open for 500 days with a total sample of 400 participants should have enrolled 50% of the total sample or 200 participants.
  • % of expected enrollment (% participants): current enrollment/by the expected enrollment.
    • Using the example above, if the study has enrolled 200 participants at 500 days it has enrolled 100% of the expected enrollment. If only 100 participants were enrolled at 500 days, it has enrolled 50% of expected enrollment.

Responsibilities

  • Principal Investigator(s) (PI) determines the preliminary recruitment milestones for the recruitment phase of the study and ensures recruitment plans for appropriate representation of women, minorities and participants across the lifespan in accordance with the approved application and NIH policies. Reports participant enrollment according to the NIH Administrating Institute or Center policies and procedures as detailed in the Notice of Award. Upon request, provides additional information via the Authorized Organization Representative (AOR) to NIH officials regarding recruitment remediation efforts. The PI is also responsible for electronically reporting and updating their data on participants and clinical trials in the NIH Human Subjects System (HSS), and registering their study at ClinicalTrials.gov.
  • NIH Program Officials (POs) review the proposed recruitment milestones for appropriateness and feasibility, and request any additional information needed from the PI/AOR prior to award. The PO, together with Grants Management (GM)/Contracts Management (CM) staff, will discuss and determine the terms and conditions of the award and inform the PI/AOR. In coordination with GM/CM staff, the PO will monitor enrollment and determine whether the enrollment goals are being met in accordance with the terms and conditions in the Notice of Award. If changes to the enrollment targets are needed, the PI will work with the PO to establish appropriate revised targets.
  • NIH Grants Management Specialists (GMSs) and/or Contract Management Specialists (CMSs) ensure that NIH/HEAL actions comply with federal regulations and NIH policy. They receive documents for inclusion in the official grant or contract files and specify the appropriate terms and conditions for the award notice. Awards will not be issued without proper documentation, including:
    • Pre-determined enrollment milestones that are expected to be met.
    • Enrollment targets for inclusion based on gender, race, ethnicity, and lifespan, as described in NIH policies (see links below).
    • Any other identified requirements for completion of the approved research project.

Resources

1 See Common Rule definition of research at 45 CFR 46.102 (l).

2 See Common Rule definition of human subject at 45 CFR 46.102 (e)(1).

3 The term “prospectively assigned” refers to a pre-defined process (e.g., randomization) specified in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial.

4 An intervention is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints. Examples include drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and diagnostic strategies.;

5 Health-related biomedical or behavioral outcome is defined as the pre-specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life. Examples include positive or negative changes to physiological or biological parameters (e.g., improvement of lung capacity, gene expression); positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood management intervention for smokers; reading comprehension and /or information retention); positive or negative changes to disease processes; positive or negative changes to health-related behaviors; and positive or negative changes to quality of life.

Institute/Center specific details about reporting participant enrollment for HEAL clinical trials are available through the websites of the Institute or Center administering the individual HEAL award. Additional questions should be directed to your Program Officer and/or Grants Management Official.