NCCIH Clinical Research Toolbox Frequently Asked Questions
Q: Do I need to use the NCCIH templates?
A: YES. To streamline the NCCIH review process, NCCIH requires the use of templates for the Study Accrual and Retention Plan (SARP), the Data and Safety Monitoring Plan (DSMP), and the Study Protocol (for studies assigned to Enhanced or Enhanced With Site Monitoring oversight levels ONLY). The SARP Electronic Template is sent directly to the principal investigator (PI) by the NCCIH program director (PD). Other required templates are available in the NCCIH Clinical Research Toolbox.
Q: My Institutional Review Board (IRB) requires a different protocol template. Do I need to prepare two study protocols?
A: YES. NCCIH requires the use of a template for the Study Protocol (for studies assigned to Enhanced and Enhanced With Site Monitoring Oversight Levels). We provide three different protocol templates in the NCCIH Clinical Research Toolbox for PIs to select the protocol template that best fits their planned study.
If the IRB of record requires an alternate format, NCCIH advises that the NCCIH Study Protocol document be updated each time the IRB-specific protocol document is updated to ensure consistency among all core study documents.
Q: Can I appoint an independent monitor instead of an independent monitoring committee?
A: MAYBE. Independent monitoring is required for all NCCIH-funded studies that involve human subjects. Independent monitoring should be commensurate with the nature, complexity, and risks to participants posed by the study.
For Routine and Routine Plus oversight levels, with agreement of the NCCIH PD, a single independent monitor may be appropriate. Studies that are observational, conducted remotely, have a simple design (no randomization or blinding), or are conducted by trainees with an assigned mentor may be candidates for oversight by an independent monitor instead of an independent monitoring committee (IMC).
Q: How often do I need to submit an accrual report?
A: Three times a year. NCCIH requests submission of an updated accrual report every 4 months while the study is actively recruiting or collecting participant data. The first accrual report request is sent approximately 4 months after the SARP start date.
Q: How often do I need to submit an independent monitoring report?
A: At least once a year, depending on your DSMP. NCCIH requests submission of an independent monitoring report on an annual basis. The PI will receive an email prompt to submit the independent monitoring report 1 year after the study begins participant enrollment. Submission should include the Open Session data report and signed IMC recommendations or letter from the IMC chair indicating the study may continue.
If an independent monitoring report is available before the email prompt is sent, the PI should send the data report and signed recommendation for study continuance to the assigned PD directly.
Q: What changes to NCCIH-approved study documents need to be reviewed by NCCIH prior to implementation?
A: Changes that require NCCIH prior approval: Protocol changes that affect the scientific intent, study design, patient risk, or human subject protection should be considered amendments and therefore must be submitted and approved by NCCIH prior to implementation. Both a track-changed and clean version of the revised protocol should be submitted to the NCCIH PD for NCCIH review.
All substantive revisions to the NCCIH approved SARP and DSMP should be submitted to the NCCIH PD for approval prior to implementation. Submission of all revised study documents should include both a clean copy and a track-changed version. If there is a request to add or substitute a member of the IMC, please also submit an updated CV or National Institutes of Health biosketch.
Changes that DO NOT require NCCIH prior approval: Editorial or administrative changes to the protocol do not need to be approved by NCCIH prior to implementation. Editorial or administrative changes do not affect the scientific intent, study design, patient risk, or human subject protection. As a courtesy, both a track-changed and clean version of the revised protocol should be submitted to the NCCIH PD after editorial or administrative changes have been approved by the IRB of record.
More information can be found at nccih.nih.gov/grants/toolbox/protocol-amendments.
Q: I would like to request changes that require prior approval. What’s the process?
A. Start with your PD. First email your NCCIH PD briefly outlining the proposed changes and rationale (See FAQS on changes to eligibility criteria and adding new sites for required information if relevant). Once you have discussed the proposed changes with your NCCIH PD, required study documents should be submitted via the NCCIH Document Submission Portal using your eRA Commons username and password.
Q: How do I know if I have approval to start recruitment?
A: Read your Notice of Award (NOA). For studies assigned to Routine and Routine Plus oversight, an unrestricted award will be issued following NCCIH approval of the SARP and the DSMP. If the award is issued with a human subject restriction, recruitment activities cannot begin until the restriction has formally been lifted.
For studies assigned to Enhanced oversight, a restricted award will be issued while NCCIH performs review of the required study documents. Once all required study documents have been reviewed and approved, an unrestricted award will be issued authorizing recruitment activities to begin.
For studies assigned to Enhanced With Site Monitoring oversight, the NCCIH contractor will schedule the site initiation visit within 1 month following both NCCIH and IRB approval of required study documents. After the site initiation visit occurs, the follow-up period consists of finalization of the site visit report (2 weeks) and completion of the action item process by the study team (up to 30 days). Revised study documents are sometimes required and will be reviewed by NCCIH within 2 weeks of submission.
A restricted award prevents the grant from using funds for activities related to human participants including screening, enrollment, randomization, and study conduct. If you are funded for an NCCIH grant, the NOA has terms and conditions that are specific to your grant. It is important to carefully review and fulfill the requirements that are outlined in your NOA.
Q: How do I add a recruitment site?
A: Start with your PD. NCCIH PDs routinely get requests from PIs to add a new study site. Often, these requests are precipitated by challenges to achieving expected rate of enrollment as detailed in the NCCIH-approved SARP. Additions or changes to the recruitment site(s) should be requested in writing and must be approved by the NCCIH PD prior to implementation. When making the initial request, please include the following information:
- If the new site is added, what would be the anticipated change to the current enrollment rate? Include information on the characteristics of the new site and the number of individuals seen at the site/portion expected to be eligible for study participation.
- Will the proposed new study site serve as a recruitment site only? A recruitment site promotes the study through the posting of flyers, orientating site staff to the study purpose, and designing and mailing of study advertisements. The recruitment site may also inform prospective participants about the availability of the research and can seek or obtain the individual’s permission for the study team to contact them. Please specify whether research-related activities, including delivery of the study intervention and completion of study assessments, will be performed at the parent site only or whether staff from the parent site will split their time between sites.
- Will staff at the new study site engage in research-related activities including, for example, consenting participants, performing protocol procedures, delivering the study intervention, or completing outcome assessments? Please refer to Office for Human Research Protections Guidance on Engagement of Institutions in Human Subject Research for a full description of activities that constitute engagement in the research (hhs.gov/ohrp/regulations-and-policy/guidance/guidance-on-engagement-of-institutions).
- Will staff at the new study site be trained and supported by the parent site? If staff at the proposed new site will engage in research activities, a formal budget modification, justification, and approval of a new subcontract to the award may be necessary. IRB approval is also required when site staff perform activities that engage the institution in the research.
- Will the new site seek approval from the IRB of record? If so, what is the status of the IRB approval process? Has the study’s independent monitoring committee reviewed and approved the suitability of the proposed new site?
- What implications would adding the proposed new site have on the original statistical analysis plan including treatment effect evaluation, variability, and the potential interpretation of study results? Is there a difference in the demographic composition of the proposed new site, such that there would be a need to adjust or stratify?
Your PD will review the information, may schedule a call to discuss, and will provide the formal NCCIH decision to approve or deny the request.
Q: How do I change eligibility criteria? When is it appropriate and who should approve?
A: Start with your PD. NCCIH PDs routinely get requests from PIs to change the study protocol, including participant eligibility criteria, subsequent to study initiation. Often, these requests are precipitated by challenges to achieving expected rate of enrollment as detailed in the NCCIH-approved SARP. However, it is important to think carefully about the scientific implications of changing your eligibility criteria. Changes to approved eligibility criteria should be requested in writing and approved by the NCCIH PD prior to implementation. Changes in eligibility criteria will also need to be reflected in the clinicaltrials.gov study record as a protocol change and may also impact the inclusion enrollment tables. When making the request, please include the following information:
- Provide a current enrollment update. How many participants have been enrolled/randomized/screen failures/excluded based on the study’s current inclusion and exclusion criteria?
- If a revision to the current inclusion and exclusion criteria is approved, what proportion of excluded individuals would subsequently meet eligibility criteria?
- What are the implications to participant safety based on the proposed protocol amendment(s)? Safety considerations include inclusion of individuals with more severe disease status, older or younger age, concomitant medication use, or exposure to prohibited interventions. The request should include a discussion of how the study will minimize risks to subjects posed by proposed protocol amendment(s).
- What implications would the proposed protocol amendment(s) have on the original statistical analysis plan?
- Provide status of the proposed protocol amendment(s) with respect to review and approval by the study’s IMC and IRB.
Your NCCIH PD will review the information, may schedule a call to discuss, and will provide the formal NCCIH decision to approve or deny the request.
Q: When should protocol deviations be reported to NCCIH?
A: Follow your DSMP. Protocol deviations are departures from the NCCIH-approved protocol, including changes in the schedule or procedure of data collection. Protocol deviations should be captured, documented and reported as described in the NCCIH-approved protocol and/or DSMP. Reporting of protocol deviations should occur at least annually to NCCIH, the IMC, and the IRB of record. Submission of protocol deviations in the annual IMC data report is sufficient for reporting to NCCIH.
Of note, any departure from planned data collection, either due to study factors or participant factors, must be recorded as a protocol deviation and reported according to the NCCIH-approved protocol/DSMP. In the case of studies with aims that include feasibility, acceptability, and adherence, protocol deviations may also be collected as endpoint data but must still be reported according to the NCCIH-approved protocol/DSMP.
Q. My study has been delayed. How do I update the SARP?
A. Please contact your NCCIH PD to discuss submission of a revised SARP. If your NCCIH PD agrees that a revised SARP is warranted, the NCCIH PD will initiate a request for an updated SARP submission. You must click on the link in the email you receive to complete your revised SARP directly in our electronic system.
Q. I collaborated with Dr. X 2 years ago. Can Dr. X be on my IMC?
A. NO. Please see guidance for independent monitoring associated with the study oversight level (nccih.nih.gov/grants/toolbox/clinical-study-oversight-levels).
NCCIH requires independent monitoring for all funded studies involving human subjects. NCCIH typically recommends at least three independent study monitors to serve on an IMC. It is strongly recommended that one of the independent monitors be a Ph.D.-prepared biostatistician. The independent monitors must not be supported financially or supervised by the PI, and there should be no publications or collaborations between IMC members and key study personnel within the last 3 years.
Q. How do I submit study documents for NCCIH review?
A. If your grant is selected for funding, you will receive additional instructions on the oversight level(s) associated with your planned study or studies in the NCCIH clarifications letter. Required study documents should be submitted via the NCCIH Document Submission Portal using your eRA Commons username and password.