Terminologies and Definitions

What is the difference between clinical research and clinical trials?

Clinical trials are a subset of clinical research studies. When you conduct clinical trials, you are doing clinical research.

Clinical research includes all research involving human subjects, or human specimens and data for which an investigator (or colleague) directly interacts with human subjects. It can include observational or interventional studies. It does not include secondary studies using existing biological specimens, data collected without identifiers or data that are publicly available.

Clinical trials are research studies that must include an intervention. According to the National Institutes of Health (NIH) definition, it is a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

What is a mechanistic trial?

Clinical trials designed to understand a biological process, the pathophysiology of a disease, or the mechanism of action of an intervention are considered mechanistic clinical trials. Trials with mechanistic outcomes differ from those with clinical outcomes that are designed to determine the clinical safety, tolerability, efficacy or effectiveness of an intervention. For more information about NIAMS policy for acceptance of mechanistic clinical trials, see NOT-AR-21-009.

What is the difference between a NIH clinical trial defined as Basic Experimental Studies with Human (BESH) and a Mechanistic Clinical Trial?

NIH classifies BESH studies as a subset of mechanistic trials. BESH studies are considered clinical trials whose primary purpose is the pursuit of basic science. These studies, in addition to meeting the definition of a clinical trial, must also meet the definition of basic research: the systematic study directed toward greater knowledge or understanding of the fundamental aspects of phenomena or of observable facts without specific applications towards processes or products in mind. BESH studies use an experimental manipulation/probe or intervention to understand a basic phenomenon in contrast to mechanistic trials which uses an intervention to understand disease process or treatment effect so that treatment target can be modified- these studies have a translational/applied process in mind, BESH studies do not. 

More information about BESH and Mechanistic Clinical Trials can be found here: https://grants.nih.gov/policy/clinical-trials/besh.htm.

What are single-blind and double-blind studies?

Blinded studies are designed to prevent anyone (doctors, nurses, or participants) from influencing the outcome. This allows scientifically accurate conclusions. In single-blind ("single-masked") studies, only the participant is not told what intervention is being given and they can describe what they experience without bias. In a double-blind study, participant as well as doctors, nurses, and other health care staff are not informed of the intervention and similarly can describe what happens without bias.
 

What is randomization?

Randomization is when two or more alternative treatments are selected by chance, not by choice. The treatment assigned is given with the highest level of professional care and expertise, and the results of each treatment are compared. Analyses are done at intervals during a trial, which may last years. As soon as one treatment is found to be definitely superior or non-inferior, the trial is stopped. In this way, the fewest number of participant receive the less beneficial treatment.
 

What is a “single-site” (as opposed to a “multi-site”) clinical trial?

A single-site clinical trial utilizes one investigational site to conduct and coordinate the study protocol. While a single-site clinical trial may enroll participants from multiple locations, participants will receive an intervention and/or undergo outcome assessments under the direction and oversight of one research team located at one investigational site.

A multi-site clinical trial involves the implementation of the same study protocol at two or more independent investigational sites where participants are seen for an intervention and/or for outcome assessments. In a multi-site clinical trial, investigational sites are typically administratively distinct from each other.

General

Why are detailed milestones and metrics important for single-site trials, which are typically less complex and easier to manage than multi-site clinical trials?

Although single-site clinical trials are, in general, operationally less complex than multi-site clinical trials, they still benefit from careful planning, including the identification of milestones and metrics that promote the successful conduct of the trial. These milestones help the NIAMS and the monitoring body (if applicable) track progress and any deviations from the study timeline that may impact the successful completion of the trial.
 

What if unanticipated delays/changes occur after I am funded that necessitate changing the timing or nature of my clinical trial milestones? Is that allowed? If so, what should I do?


In general, the NIAMS does not expect changes will be made to NIAMS approved milestones. It is expected that the final negotiated milestones at the time of funding are included in the Notice of Grant Award (NoA) and will be completed as planned.  However, if an unanticipated event necessitates changing any of your milestones or impacts the study timeline, then you should contact the NIAMS Program Official and Grants Management Specialist as soon as possible to discuss. They will work with you to determine whether changes are warranted and, if so, how they may be implemented.
 

Are blinded and de-identified samples that are grouped as best and worst responders considered prospectively assigned to an intervention in terms of the NIH definition of a clinical trial?

Grouping de-identified biological samples is not prospective assignment to an intervention because there is no intervention. De-identified biological samples are not human subjects based on current Federal regulations in Federal Regulation 45 CFR 46. A study that does not involve human subjects nor has prospective assignment to an intervention is not a clinical trial.
 

What is the role of a NIAMS Project Scientist on a cooperative agreement clinical trial?

A Project Scientist (PS) has substantial scientific involvement in project activities and generally is not involved in normal programmatic stewardship of the award.  A PS has a collaborative relationship with the investigator(s) and participates/collaborates on the work being done. Such activities may include:

  • Participating as a voting member on committees, such as steering committees and sub-committees, central to the research activity
  • Participating in protocol design or development
  • Helping to select contractors or other project staff
  • Coordinating or participating in data collection, analysis, and interpretation
  • Coordinating or providing training of project staff in awardee institutions
  • Participating in selection and approval of data analysis mechanisms
  • Co-authoring papers

Data and Safety Monitoring and Oversight

Who determines level of risk for my clinical research study?

Your IRB has primary responsibility for determination of the level of risk to study participants and ensuring proper procedures are in place to minimize harm and maximize potential benefits. However, if the NIAMS funds your clinical research grant or contract, it will also assess risk to determine the appropriate data and safety monitoring oversight that should be in place for your study. 

How does the NIAMS assess risk for clinical trials and determine the type of data and safety oversight?

The NIAMS has developed internal guidance to evaluate risk to aid in determining the appropriate level of data and safety monitoring oversight for a given study. The NIAMS determines study risk based on factors beyond human subjects risk, including but not limited to operational risks, financial risks, and other risks related to the population and intervention(s). Together, these critical pieces of information help guide the NIAMS on the risk level assigned (e.g., low, moderate, high) and what level of data and safety monitoring oversight is needed.
 

When does a clinical study require an independent monitoring body, also referred to as a NIAMS-appointed monitoring body?

Monitoring is commensurate with risk and with the size and complexity of the trial. All intervention studies (clinical trials), regardless of the phase, must have ongoing data and safety monitoring oversight. The NIAMS requires independent data and safety monitoring boards (DSMBs) for all phase III clinical trials. For phase I and II clinical trials or other applicable clinical research studies, the approach to data and safety monitoring will depend on several factors. For example, the NIAMS may determine that independent DSMBs may be appropriate if the studies have multiple clinical sites, are blinded, employ particularly high-risk interventions or invasive or risky procedures, or are conducted in especially vulnerable populations. In other cases, the NIAMS may determine an independent DSMB is appropriate for a small, first-in-human trial at a single-site. The NIAMS also considers operational and financial risk when making a determination for data and safety monitoring oversight.

The determination for the type of data and safety monitoring oversight is made by the NIAMS and shared with the investigator once a study is awarded. An independent monitoring body includes but is not limited to a NIAMS-appointed DSMB/Observational Study Monitoring Board (OSMB), or NIAMS-appointed Safety Officer (SO)/Safety Officers (SOs).

Do low risk clinical trials also need to be monitored?

Yes. All clinical trials require some level of monitoring. Lower risk clinical research and/or clinical trials that do not utilize a vulnerable population, are not blinded or randomized, or are conducted at a single-site may be suitable for data and safety oversight that does not include a NIAMS-appointed monitoring body. These types of studies could have oversight conducted by the Principal Investigator in coordination with the Institutional Review Board (IRB), or an internally appointed monitoring body which consist of experts selected by the Principal Investigator.
 

What are the main responsibilities of an independent, NIAMS-appointed Data and Safety Monitoring Board (DSMB)?

The DSMB is an independent advisory body to the NIAMS. Some responsibilities of the DSMB include but are not limited to routinely monitor data from the clinical trial, review and assess the safety and performance of its operations, safeguard the interests of study participants, and make recommendations to the NIAMS with respect to:

  • Participant safety
  • Efficacy of the study intervention
  • Benefit/risk ratio of procedures and participant burden
  • Selection, recruitment, and retention of participants
  • Adherence to the study protocol requirements
  • Data and statistical analysis plan
  • Adequacy of measured and collected data
  • Possible amendments to the study protocol and other study materials
  • Performance of individual centers and core laboratories
  • Study continuation or termination

What are the main responsibilities of an independent, NIAMS-appointed Observational Study Monitoring Board (OSMB)?

The OSMB is an independent advisory body to the NIAMS. Some responsibilities of the OSMB include but are not limited to routinely monitor data from the observational study, review and assess the performance of its operations, and make recommendations to the NIAMS with respect to:

  • Issues related to participant safety, confidentiality, and informed consent, including notification of and referral for abnormal findings
  • Adequacy of study progress in terms of recruitment, quality control, data analysis, and publications
  • Issues pertaining to participant burden
  • Impact of proposed ancillary studies and sub-studies on participant burden and overall achievement of the main study goals
  • Overall scientific directions of the study
  • Study continuation or termination

What are the main responsibilities of an independent, NIAMS-appointed Safety Officer or Dual Safety Officer?

The Safety Officer (SO)/dual SO is an independent advisory body to the NIAMS. Some responsibilities of the SO/dual SO include but are not limited to routine monitoring of data from the clinical trial, reviewing and assessing the safety and performance of its operations, safeguarding the interests of study participants, and making recommendations to the NIAMS with respect to:

  • Participant safety
  • Efficacy of the study intervention
  • Benefit/risk ratio of procedures and participant burden
  • Selection, recruitment, and retention of participant
  • Adherence to the study protocol requirements
  • Data and statistical analysis plan
  • Adequacy of measured and collected data
  • Possible amendments to the study protocol and other study materials
  • Study continuation or termination

What are the responsibilities of the NIAMS Executive Secretary in data and safety monitoring?

The responsibilities of the NIAMS Executive Secretary include but are not limited to:

  • Assisting the NIAMS with the assembly of NIAMS-appointed independent monitoring bodies
  • Inviting the Board (DSMB or OSMB) members, Chairperson and Safety Officer to meetings
  • Reviewing of potential conflicts of interest (initial and annual) of Board members
  • Assisting the Chairperson in setting the agenda of each meeting
  • Coordinating email polls and other correspondence among the monitoring body between meetings
  • Liaising between the Study Team, the Board, and the NIAMS
  • Preparing and distributing minutes of all meetings and ensuring their timeliness and accuracy
  • Facilitating meetings and safety reports
  • Coordinating all meeting logistics (web-conference/ in-person) and honoraria payments/reimbursements to Board members

What is the role of the NIAMS Program Officer (PO) with respect to participation in the DSMB or OSMB meetings?

The PO, as well as any other invited NIH staff, should be easily accessible should questions related to NIH policies or process arise during DSMB or OSMB meetings. NIAMS staff are not to influence DSMB discussions or recommendations and are never voting members. The NIAMS PO attends all sessions of the DSMB or OSMB meetings.
 

Does the Principal Investigator (PI) determine if his or her clinical trial requires a NIAMS-appointed Data and Safety Monitoring Board or Observational Study Monitoring Board or Safety Officer(s)?

The final determination of whether a clinical trial requires a NIAMS-appointed monitoring body is made by the NIAMS. Investigators may propose a monitoring entity as required by the Data and Safety Monitoring Plan (DSMP; Section 3.3 of G.500 PHS Human Subjects and Clinical Trials Information Form), but this subject is  to change based on the NIAMS evaluation pre-award. The NIAMS will conduct a risk assessment to determine which level of monitoring oversight is needed for a study. Once a determination has been made, the NIAMS will notify the contact PI in writing.
 

Can a single person serve on multiple NIAMS-appointed monitoring bodies at any given time?

The oversight of research being conducted is best served by a diverse board of members. In general, individuals may serve on no more than two boards at any one time and may not serve as the Chairperson or Safety Officer of more than one NIAMS-appointed monitoring body (e.g. DSMB, OSMB, SO, SOs) at a time. Any exceptions must be explicitly approved by the NIAMS.
 

What is the typical time commitment for serving on a NIAMS-appointed DSMB?

The term of service is on average about five years (a typical 5-year grant period) but may last longer, such as 5-7 years if the study is extended or if it is more than a 5-year award. Alternatively, there are 3-year clinical trial awards that may only be monitored for a shorter duration such as 3-4 years. 

Typically, more time from DSMB members is required up front when a new study is launched because it requires reviewing the full set of study materials (e.g., study protocol, informed consent form, manual of operating procedures, data and safety monitoring plan, and data and safety monitoring report templates). Members should plan to attend a 3-hour introductory meeting held prior to study start. The estimated time required for an introductory DSMB meeting may range between 6-8 hours, inclusive of pre-review of study materials, meeting attendance, post meeting review of recommendations/minutes, and other follow-up items. Once the study is ongoing, the DSMB members periodically review reports with aggregated safety and enrollment data and participate in routine DSMB meetings (generally held semi-annually via web-conferences and lasting approximately 2-hours). The NIAMS estimate 3-5 hours per meeting, inclusive of pre-review of study documents, meeting attendance, post meeting review of recommendations/minutes, and other follow-up items. Please note that these are general estimates and will vary from study-to-study.
 

What is the typical time commitment for serving as a NIAMS-appointed Safety Officer (SO)?

The term of service is on average about five years (a typical 5-year grant period) but may last longer, such as 5-7 years if the study is extended or if it is more than a 5-year award. Alternatively, there are 3-year clinical trial awards that may only be monitored for a shorter duration such as 3-4 years.

Typically, more time from the SO is required when a new study is launched because it requires reviewing the full set of study materials (e.g., study protocol, informed consent form, manual of operating procedures, data and safety monitoring plan, and data and safety monitoring report templates). Unlike membership on a NIAMS-appointed DSMB, studies with a NIAMS-appointed SO only have a 2-hour introductory web-conference prior to the study start and no routine meetings. Once the study is ongoing, the SO conducts an electronic review of routine safety reports, generally submitted on a semi-annual basis. The SO will also need to review safety-related events (such as serious adverse events or unanticipated problems) that are reported in an expedited manner by the study team. The estimated time required for an introductory SO meeting may range between 3-4 hours, inclusive of pre-review of study materials, meeting attendance, post meeting review of recommendations/minutes, and other follow-up items. Subsequent and ongoing time commitment once the study begins is estimated to be 1-3 hours semi-annually. Please note that these are general estimates and will vary from study-to-study.
 

Will DSMB meetings be held in person, and require travel or via web-conferences?

Introductory DSMB meetings are encouraged to be held in-person* by the NIAMS and typically held at the NIAMS location based in Bethesda, Maryland. The subsequent routine DSMB meetings are typically held via web-conferences. *All in-person meetings are on hold until after the COVID-19 pandemic or until further notice.
 

Is there someone with whom the NIAMS-appointed DSMB Safety Officer (SO) can consult when making the judgement on the association between a serious adverse event and the study?

If the SO encounters a serious adverse event for which they would like additional input/guidance, they may request input from other members of the DSMB as needed (the NIAMS Executive Secretary would facilitate this process). In order to maintain the confidentiality of the study data, the SO should not share study data with colleagues from their own institution or anyone outside of the DSMB.
 

What type of information should be included in the Principal Investigator’s (PI’s) PowerPoint presentation for routine DSMB meetings?

Routine DSMB meetings are intended to provide the latest update about the study so the DSMB members can evaluate progress and assess safety in order to provide advice to the NIAMS on study continuation/termination or any potential issues. This presentation may include but is not limited to a brief overview of the study design and aims/objectives, an update on the plans for recruitment and retention numbers, listing of safety events/incidents, the overall study status and timeline, and any roadblocks or setbacks that have occurred. It may also include any additional information that the study team feels is important for the DSMB to know, as well as any concerns or questions which they would like to discuss with the DSMB. Presentations should be limited to 20-30 minutes and are required to be provided by a PI.
 

Is a medical monitor appointed by the NIAMS?

The NIAMS does not appoint medical monitors. NIAMS-appointed safety oversight consists of either a Data and Safety Monitoring Board (DSMB), an Observational Study Monitoring Board (OSMB), or a single or dual Safety Officer, which is separate and distinct from the safety oversight a medical monitor provides. If a study wishes to have a separate medical monitor, this individual should be selected by the investigator and would be considered part of the study team.
 

What should I do if there are changes in human subjects research risk or changes to the Data and Safety Monitoring Plan (DSMP)?

The Principal Investigator should notify the NIAMS Program Official and Grants Management Specialist as this may have several implications for the study which should be discussed right away. Generally, modifications that impact human subjects risk or the DSMP will also need to be vetted through the monitoring body (if applicable) and approve by the Institutional Review Board (IRB) prior to implementation of any change in the study.
 

Does the NIAMS have any requirements or guidance on reportable events for clinical research studies/trials?

Yes. See the NIAMS Reportable Events Requirements and Guidelines for Investigators Conducting NIAMS-Funded Clinical Research Studies.
The NIAMS requires reporting of adverse events (AEs), serious adverse events (SAEs), Unanticipated Problems (UPs) and Protocol Deviations, Serious or Continuing Noncompliance, and Suspension or Termination of IRB Approval. In general, the NIAMS reporting timelines are as follows:

Event Reporting Timeline
AES All AES regardless of their relatedness or expectedness are reported in aggregate as part of the routine Data and Safety and Monitoring Report to the NIAMS and monitoring body; typically, twice per year for NIAMS-appointed monitoring bodies.
SAEs/UPs and Protocol deviations that impacts the participant safety within 48 hours of the investigator becoming aware of the event
Serious or Continuing Noncompliance within 3 business days of IRB determination
Suspension or Termination of IRB Approval within 3 business days of receipt


 

What happens in cases where there is a difference of opinion between the investigator and the NIAMS-appointed monitoring body regarding the assessment or management of a Serious Adverse Event (SAE) reported to the NIAMS and monitoring body?

The NIAMS has detailed internal guidance that is used for the SAE Review Process and Adjudication. The monitoring body Chairperson (if applicable) and NIAMS Program Official(s) may need to weigh in on the SAE report and the investigator’s and Safety Officer’s assessments and provide their feedback. The process is outlined in the NIAMS Reportable Events Requirements and Guidelines for Investigators Conducting NIAMS-Funded Clinical Research Studies document.
 

My research is classified as a mechanistic clinical trial by the NIH definition. Unlike a traditional treatment-based trial, it is not studying the safety or efficacy, and does not pose high-risk. Why does NIAMS require additional data and safety monitoring oversight beyond what the Principal Investigator (PI) and Institutional Review Board (IRB) are providing?

While it is required for a clinical trial to at a minimum be monitored by the PI and IRB, the NIAMS policy for all trials is to require additional monitoring oversight that is commensurate with the risks involved; even trials that do not pose high-risk require monitoring. The NIAMS considers risk beyond human participants safety when deciding the level of oversight. For clinical trials that do not pose high risk a trial may be allowed to implement monitoring that is managed by the investigator. See question “How does the NIAMS assess risk for clinical trials and determine the type of data and safety oversight?” and “Do low risk clinical trials also need to be monitored?”.

The NIH policy requires each Institute and Center (IC) to have a system for the appropriate oversight and monitoring of the conduct of all clinical trials to ensure the safety of participants and the validity and integrity of the data generated from these studies. Therefore, the NIAMS has flexibility to implement the requirement for data and safety monitoring as appropriate for its clinical research activities. For more information about the NIH policy, see: https://grants.nih.gov/grants/guide/notice-files/not98-084.html

The NIAMS Data and Safety Monitoring (DSM) Guidelines further elaborates on the NIAMS requirements for implementing data and safety monitoring.

Why do I need to submit all of my study materials for my clinical study and get the NIAMS’ approval if they have already been vetted by NIH peer review and the Institutional Review Board (IRB)?

Study materials submitted for peer review and IRB review still require an additional level of review prior to study commencement if funded by the NIAMS.

If your study is monitored by a NIAMS-appointed monitoring body (e.g., a NIAMS-appointed OSMB/DSMB or NIAMS-appointed Safety Officer(s)), the study materials must be reviewed by the NIAMS and the appointed monitoring body prior to the commencement of recruitment to ensure they are adequate to implement the study. In addition, if changes are made to the study materials after the study has been granted approval, they should be reviewed by the monitoring body, the NIAMS, and the IRB prior to implementing the changes.

If your study is monitored by an internal monitoring body, where the Principal Investigator (PI) selects, assembles, and manages the data and safety monitoring oversight process, the NIAMS still requests all study materials be submitted for review prior to study initiation. The NIAMS conducts an administrative review of the study materials focused on quality to ensure all aspects pertaining to the data and safety monitoring oversight process are outlined clearly and consistently across all study materials. This review will not focus on the scientific or methodological aspects of the study.

I am funded to conduct a clinical research study that does not include a clinical trial. The NIAMS is requesting that I submit a Data and Safety Monitoring Plan (DSMP). I thought a DSMP was only required if conducting a clinical trial. Why is the NIAMS requesting a DSMP?

The NIAMS has its own policy for requesting a DSMP for its clinical research studies. If the NIAMS funds your clinical research study, it may require you to put together a DSMP, dependent upon the risks of the study. This ensures the safety of participants enrolled in the study. Please note that this DSMP is slightly different and is a shorter version of the DSMP required for a clinical trial. 

Information about what must be included in a DSMP for a clinical study can be accessed on the NIAMS website at https://www.niams.nih.gov/grants-funding/conducting-clinical-trials/clinical-trial-policies-guidelines-and-templates/data-and

I am conducting an observational study funded by the NIAMS and it will be monitored by an Observational Study Monitoring Board (OSMB). Since my study does not involve an intervention, we do not plan to collect or report any adverse events/serious adverse events. Is this acceptable to the NIAMS?

No. The NIAMS understands there are differences in events observed in studies testing an intervention versus those that are not. However, it is not acceptable for observational studies to not collect or report any adverse events/serious adverse events when monitored by a NIAMS-appointed OSMB. You should discuss with the NIAMS what type of collection and reporting of events is appropriate for your study and will not cause undue burden. In general, the NIAMS requires reporting of Adverse Events, Serious Adverse Events, Unanticipated Problems and Protocol Deviations, Serious or Continuing Noncompliance, and Suspension or Termination of IRB Approval for observational studies. 

See the NIAMS Reportable Events Requirements and Guidelines for Investigators Conducting NIAMS-Funded Clinical Research Studies for more details.

Study Documents

My clinical trial is getting funded by the NIAMS. The Data and Safety Monitoring Plan (DSMP) is part of my grant application and has been peer reviewed. Is this sufficient, or am I required to send something else?

The DSMP in your grant application is sufficient if it contains the essential elements listed in the NIAMS DSMP template. Typically, grantees revise some parts of this document to reflect the NIAMS safety reporting process and other details that may not have been addressed in the DSMP submitted with the grant.  A review of the DSMP by the NIAMS and the independent monitoring body is required before enrollment can commence.
 

Does the NIAMS have templates that can help with developing study materials for my clinical trial?

Yes. The NIAMS provides templates that can assist investigators with the development of their specific study materials. The Clinical Study Tools and Templates are available and can be accessed on the NIAMS Clinical Trials webpage.
 

Do protocol amendments need to be submitted to the Institutional Review Board (IRB) before they are submitted to the NIAMS and NIAMS-appointed monitoring body for their review?

The timing of the submission of protocol amendments to the IRB and to the NIAMS and the monitoring body (via the NIAMS Executive Secretary) is up to the discretion of the study team. If the materials are submitted to the IRB and the NIAMS or monitoring body concurrently, an amendment may need to be re-submitted to the IRB if any additional changes are requested by the NIAMS or monitoring body. In order to minimize the administrative burden for the investigators, it is generally recommended that any substantial amendments be submitted to the NIAMS or monitoring body prior to IRB submission.
 

NIAMS Clinical Funding Opportunities, Review and Award

What NIAMS clinical trial funding opportunities are available? Where can I find this information?

There are a variety of clinical trial opportunities for a wide range of studies offered by the NIAMS. See: https://www.niams.nih.gov/grants-funding/conducting-clinical-research/investigator-clinical-trial-policies.
Note that the NIAMS also participates in some trans-NIH initiatives sponsored by other Institutes/Centers (ICs) that solicit clinical trials. Please read those funding opportunity announcements carefully to learn if any exceptions apply.
 

Does the NIAMS fund mechanistic trials? How do I apply for funding for a mechanistic clinical trial?

Yes. The NIAMS supports and funds mechanistic trials. Mechanistic clinical trials must be submitted through the NIH Parent R01 and R21 (Clinical Trial Required) funding opportunity announcements. If you would like to learn more about the NIAMS clinical trials funding announcements, you can access them at https://www.niams.nih.gov/grants-funding/conducting-clinical-research/investigator-clinical-trial-policies  [Scroll down to NIAMS Participation in other Clinical Trial Funding Opportunity Announcements (FOAs)].
 

Which Scientific Review Group (SRG) will review my NIAMS U01 clinical trial application?

NIAMS U01 clinical trial applications are reviewed by the NIAMS Arthritis and Musculoskeletal and Skin Diseases Clinical Trials Review Committee (AMSC). This is a standing study section convened by the NIAMS with expertise in NIAMS disease areas and in clinical trial methodology.
 

I have funding from the NIAMS for a R21, multi-site, pilot and feasibility trial. I would like to conduct a larger, definitive trial and would like to know if a U01 is the right mechanism. Also, since I have completed some clinical trial planning activities under the R21, am I exempt from the R34 planning requirements?

First, please schedule a consultation with your Program Director and complete a NIAMS clinical trial planning milestone checklist found on the NIAMS website. A U01 is the appropriate mechanism for conducting a larger, definitive trial, but whether a planning grant is needed should be determined in consultation with a Program Director after the review of the milestone checklist.
 

Would the NIAMS accept an U01 application for a clinical trial if the necessary materials/activities for trial planning were demonstrably complete through funding resulting from a foundation grant or other private source of funding?

Yes. The planning milestones expected to be in place are included in the NIAMS clinical trial planning milestone checklist. If these required elements have been completed using another funding source, the NIAMS will take this into consideration when advising on the readiness of the U01 application to be submitted. However, you are strongly advised to first engage in a discussion with a NIAMS Program Director to discuss the planning milestones that have already been accomplished and if any further planning is advised.
 

Is the study protocol and Manual of Operating Procedures (MOP) required to be submitted as attachments to the U01 application?


A study protocol and MOP are not required to be submitted as attachments to the U01 application. Please only submit what is specified in the Funding Opportunity Announcement (FOA) or the NIH Appendix Policy at https://grants.nih.gov/grants/guide/notice-files/not-od-17-098.html. If you do not, your application will be withdrawn.
 

I am submitting a U01 clinical trial application. In which section of the application should I provide information about the Statistical Analysis Plan (SAP)?

This information should now be submitted through the new FORMS-F (PHS Human Subjects and Clinicals Trial Information). Once you answer “Yes” to Human Subjects on the R&R Other Project Information Form, you will be prompted to add a study record and all the additional information related to the trial. This will include the Study Population and Characteristics (Section 2); Protections and Monitoring Plans (Section 3); Protocol Synopsis (Section 4); and Other Clinical Trial- related Attachments (Section 5- required if specified in the Funding Opportunity Announcement (FOA)). The statistical analysis plan is an attachment in Section 4, 4.3 of the form.
 

Is there a limit on the number of Principal Investigators (PIs) on an U01 application?

There is no limit on the number of PIs on an U01 application. A single applicant organization may designate multiple PIs from the applicant organization or may designate multiple PIs from multiple institutions. Multiple organizations may not submit the same multiple PI application. However, decisions should be consistent with the scientific goals of the project. For institutions/organizations proposing multiple PIs, see the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
 

Are foreign institutions eligible to submit an application to the NIAMS U01 Clinical Trial Implementation Funding Opportunity Announcement (FOA) or the NIAMS R21 Exploratory Clinical Trial FOA?

No. See eligibility information listed in the FOAs.

  • Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply
  • Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply
  • Foreign components, as defined in the NIH Grants Policy Statement, are allowed

Can other trial-related documents, such as the IRB-approved informed consent form and study-specific case report forms, be included in the Appendix with my clinical trial application?

Yes. Blank informed consent/assent and case report forms may be included in the Appendix. Please see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-126.html for more information.
 

We are submitting a clinical trial application to the NIAMS. In preparing our budget, we are unsure of whether to include fees for the Data and Safety Monitoring Board (DSMB). Should this be included in our budget, or will this be administered by the NIAMS?

For most clinical trials, the NIAMS typically appoints an independent monitoring body (it may be a DSMB/OSMB or a Safety Officer) and covers the costs associated with paying Board members for their time and any travel to in-person meetings (if required). However, you should budget for time required by your study team (e.g., biostatistician) to prepare materials and reports for the monitoring body as well as any in-person DSMB meetings that may require travel by your study team members.
 

I am submitting a R34 application and I was not sure if we needed to submit the Protection of Human Subjects, Planned Enrollment Forms, and Inclusion of Women, Children, and Minorities etc. sections, since this application is not conducting a clinical trial.

These sections do not apply if there are no human subjects being enrolled in the R34 planning grant. If you are proposing any type of model recruitment (which is allowable), then you will need to complete the sections (answer ‘Yes’ to “are human subjects involved?”). If you are not doing any model recruitment, then you can answer ‘No’ to the question and ‘No’ (presumably) to the question about human specimens and/or data.
 

Can I submit the clinical trial application and then send in updated information on the IND or IDE as Post-Submission Material?

No. An IND or IDE as post-submission material is not allowed. The allowable post-submission materials can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-19-083.html.
 

Do I have to submit both a Letter of Intent (LOI) and a Letter of Request (LOR) when applying for a NIAMS R34 planning grant or a U01 clinical trial?

No. A Letter of Intent (LOI) is not required but is strongly encouraged for R34 applications. A LOI is also strongly encouraged for U01 applications that have budgets under $500K in direct costs/year. For more information of what should be included in the LOI, please refer to https://www.niams.nih.gov/grants-funding/clinical-research/grants/letters-intent-less-than-500k.

A Letter of Request (LOR) is only required for U01 applications that will have budgets of $500K or greater in direct costs/year. R34 applications never require a LOR. A LOR requires substantially more detail and is required to be submitted for the NIAMS’ consideration at least 6-weeks (10-weeks is preferred) in advance of the application due date. You will be notified by the NIAMS if your LOR is accepted and you are allowed to proceed to submit a U01 application. For more information of what should be included in the LOR, please refer to https://www.niams.nih.gov/grants-funding/applying-grant/niams-large-grant-policy.
 

How do I submit a LOR to the NIAMS?

LOR submissions are done electronically. The Principal Investigator (PI) initiates the process by sending a request (via email) to the Program Officer (PO) listed in the Funding Opportunity Announcement (FOA) under Scientific/Research Contacts, who can advise the PI on the feasibility of successfully competing for an award. The NIAMS will then initiate the request electronically, in the eRA Commons, after which the PI will receive an invitation to submit the required materials through the Prior Approval Module.
Please consult the Prior Approval User Guide for additional information about the Prior Approval Module.
 

I am a trainee planning to submit a clinical trial. Does the NIAMS accept clinical trials under any K funding opportunities? If so, where can I find more information?

Yes. The NIAMS accepts clinical trials under some K funding opportunities. See a list of FOAs for clinical trials at: https://www.niams.nih.gov/grants-funding/conducting-clinical-research/investigator-clinical-trial-policies.

Can I submit a clinical trial to a career development funding opportunity (i.e., K01, K23, K99/R00, K24) that proposes to test feasibility and acceptability of an intervention?

The effect of the intervention being evaluated on the participant must be a health-related biomedical or behavioral outcome in order to meet the NIH definition of a clinical trial. 

Feasibility and acceptability are not health-related biomedical outcomes and applications proposing these as standalone outcomes are not considered a clinical trial. However, if you include a health-related outcome in addition to feasibility and acceptability that may qualify as a clinical trial per the NIH definition. Studies only testing feasibility and acceptability must be submitted under a “Clinical Trial Not Allowed” FOA. Feel free to reach out to a NIAMS Program Official for further guidance. See case #29 which helps illustrate this point: https://grants.nih.gov/policy/clinical-trials/case-studies.htm#accordionFilterTerms.

My clinical research study has three Aims and the clinical trial component of my research begins in Aim 3 (the third year of my grant), after Aims 1 and 2 have been completed. What does the NIAMS require from me in order for the clinical trial to begin?

The NIAMS Program Official will check-in with you periodically regarding the progress of your Aims to receive a status update on whether you are on track for staring Aim 3 in year 3. This may include submitting semi-annual updates to the NIAMS so progress toward Aim 3 can be closely monitored. Although the NIAMS will be in close communication with you, you should plan on having your study protocol, Data and Safety Monitoring Plan, Manual of Operating Procedures, Informed Consent Form, Data and Safety Monitoring Report Templates ready for the NIAMS review prior to year 3 (Aim 3). However, the NIAMS will let you know when to submit. Typically, with clinical trials, some level of data and safety monitoring oversight is required, and so this will need to be established. See the terms and conditions of the award for further information.

I am in the process of assembling the information for my NIAMS U01 clinical trial grant application in response to PAR-21-036 but I am a bit confused regarding the specific instructions in Section 5 that state two additional attachments are required, including a Clinical Monitoring (Part A) and Data Management Plan (Part B). Should I include these in addition to the Protection and Monitoring Plans, Section 3?

The two attachments (Clinical Monitoring and Data Management Plan) are separate from Section 3- Protection and Monitoring Plans. They are part of Section 5- Other Clinical Trial-related Attachments. The information in these attachments are distinct from what is included in Section 3. If you have further questions about what should be included in Section 5 attachments, please reach out to NIAMSclinicaltrials@mail.nih.gov.

I just received a supplement to my ongoing multi-site clinical study, which was funded prior to the NIH single Institutional Review Board (sIRB) policy (i.e., prior to January 25, 2018). Am I required to establish a sIRB for the study supported by the supplement since it is also a multi-site study?

It depends on the type of supplement you receive.

  • A competing supplement to an ongoing multi-site non-exempt human subjects research study is required to establish a sIRB under the revised Common Rule cooperative research provision (45CFR46.114(b)).  
  • For a non-competing supplement (i.e., administrative supplement) to an ongoing parent study which is not subject to the NIH sIRB policy (i.e., the grant was submitted prior to January 25, 2018) involving (1) the addition of a new domestic multi-site non-exempt human subjects protocol that will require IRB approval on or after January 20, 2020, the new protocol will require a sIRB or (2) if the administrative supplement to the parent study does not involve the addition of a new protocol, but is an amendment to the existing parent study protocol, it is not required to use a sIRB until the parent study is submitted for a competitive renewal.

I am conducting a study where my site is responsible for all human subjects research activities except for delivering the study intervention. Participants will receive the intervention at various community sites. I will train local health professionals on how to perform the intervention. Federal funds will not be used to pay sites to participate. Is my study considered a multi-site study and required to have a single IRB?

It depends. The revised Common Rule single IRB requirement (45 CFR 46.101(a)) applies to all sites that are engaged in the non-exempt human subjects research activities, even if some of the sites are not receiving NIH funds for this research. The Principal Investigator (PI) should consult with the reviewing IRB to help determine which sites are engaged in non-exempt human subjects research.  If the sites are considered engaged, then the study is considered a multi-site study, and the PI should establish a single IRB regardless of the use of federal funds on those sites.

Ancillary Studies

My ancillary study is not a clinical trial. Is a recruitment and retention plan required as part of my ancillary study application?

Yes. A recruitment and retention plan is required for all human subjects studies, not just clinical trials. The application should include the recruitment strategy for the ancillary study. If the participants of the ancillary study will be a subset of the Parent Clinical Trial (CT) participants, then the application should specify the recruitment and retention strategy of the Parent CT, being very careful to distinguish between the Parent CT and the ancillary study. Information about the Parent CT can be included for context.

Is an ancillary study to an ongoing clinical trial also considered to be a clinical trial?

No. An ancillary study using data/participants from the Parent clinical trial is not automatically considered a clinical trial. In order to be a clinical trial, the ancillary study must also include prospective assignment and an intervention, two of four elements that characterize a NIH-defined clinical trial.

I have an ongoing multi-site clinical study (i.e., parent study) and will be adding an ancillary study. My clinical study grant was funded prior to January 25, 2018 and I am not using a single Institutional Review Board (sIRB) for this study. Is my ancillary study required to comply with the NIH sIRB policy that allowed time limited exceptions for ancillary studies or should I comply with the revised Common Rule?

You must comply with the revised Common Rule. The revised Common Rule cooperative research provision (45CFR46.114(b)) is effective as of January 20, 2020.  For protocols initially approved on or after this date, there are no longer any  NIH “Time Limited Exceptions” (NOT-OD-18-003) granted under the NIH sIRB policy. Therefore, any newly added ancillary study to an ongoing parent study (that was previously not required to comply with the NIH sIRB policy), is required to use a sIRB if it involves domestic multi-site non-exempt human subjects research and any of the following apply: 1) the ancillary study protocol is initially IRB approved on or after January 20, 2020, or 2) the last competing application for the parent study was submitted on January 25, 2018 or later.

Human Subjects and Clinical Trials Information Form

Will the “PHS Human Subjects and Clinical Trials Information” form (FORMS-F) capture all the details of the clinical trial (e.g., inclusion and exclusion criteria; drug administration; schedule of follow-up visits, forms completion, and laboratory tests; storage of biological samples; statistical evaluation of trial data), or should I include the (modified) clinical trial protocol as an Appendix?

All pertinent clinical trial information is captured in the PHS Human Subjects and Clinical Trials Information Form. Please refer to Research Instructions for NIH and other PHS Agencies SF424 (R&R Application Packages). A clinical trial protocol may not be submitted as part of the Appendix. See https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-126.html.
 

Question # 3.4 on FORMS-F asks, "Will a Data and Safety Monitoring Board be appointed for this study?" It is my understanding that the NIAMS will determine that either a Data and Safety Monitoring Board (DSMB) or Safety Officer (SO) is required. How should this question be answered for my clinical trial grant application?

For the purposes of completing the form, the NIAMS advise that you select “Yes” for question 3.4, and then in your data and safety monitoring plan (3.3), you can elaborate further to explain that the monitoring entity would be appointed by the NIAMS and refer to the data and safety monitoring (DSM) policies on the NIAMS website to further describe the data and safety monitoring plan. If you think an independent SO, rather than a DSMB, would be more appropriate, you can state that in your DSMP, but you should also provide a statement that it will be at the NIAMS discretion to select the appropriate level of monitoring.
 

If my study will require an Investigational New Drug (IND) or Investigational Device Exemption (IDE), is an FDA approval or exemption needed prior to submitting my clinical trial application?

Applicants are required to complete section 4.6 of the Human Subjects and Clinical Trials Information Form (FORMS-F). It asks for information regarding the IND or IDE status of the study agent and also to indicate whether applicants have had any interaction with the FDA. As long as you fully explain the information in the application, you should be covered. If the IND number or status of exemption is not available at the time of the application, this is OK. The current NIAMS Exploratory R21 and U01 Implementation clinical trial Funding Opportunity Announcements (FOAs) do not require any specific FDA documentation to be included with the application. However, if your study will be funded by the NIAMS, FDA documentation may be required prior to the award.
 

I am conducting a non-exempt clinical research study. What sections of PHS Human Subjects and Clinical Trials Information Form (FORMS-F) are required to be submitted?

For studies that involve non-exempt human subjects research, the following sections are required:

  • Section 1 - Basic Information
  • Section 2 - Study Population Characteristics
  • Section 3 - Protection and Monitoring Plans- questions 3.1 and 3.2 only. Questions 3.3, 3.4, and 3.5 of Section 3 are optional for clinical research that does not involve a clinical trial. However, please note that while question 3.3- Data and Safety Monitoring Plan is required only for a clinical trial, it may be appropriate to include for your clinical study if your study has significant risks to participants.

Non-exempt human subjects research that involve a clinical trial require submission of Sections 1-5 of the Human Subjects and Clinical Trials Information Form (FORMS-F). They include:

  • Section 1 - Basic Information
  • Section 2 - Study Population Characteristics
  • Section 3 - Protection and Monitoring Plans
  • Section 4 - Protocol Synopsis
  • Section 5 - Other Clinical Trial-related Attachments

Please be sure not to include information that is redundant with your research strategy.

I am conducting an exempt clinical research study. What sections of PHS Human Subjects and Clinical Trials Information Form (FORMS-F) are required to be submitted?

Studies that claim exemption 1, 2, 3, 5, 6, 7 or 8 from Federal Regulations for the Protection of Human Subjects, require the following sections:

  • Section 1 - Basic Information
  • Section 2 - Study Population Characteristics
  • Section 3 - Protection and Monitoring Plans- questions 3.1 and 3.2 only. Please note that for question 3.1- Protection of Human Subjects, a justification for why the research meets the criteria for the exemption(s) that the study claims must be provided and should not merely repeat the criteria or definitions themselves.

If conducting an exempt clinical trial, in addition to the above, the following are required:

  • Section 3 - Protection and Monitoring Plans- questions 3.3, 3.4, and 3.5
  • Section 4 - Protocol Synopsis
  • Section 5 - Other Clinical Trial-related Attachments

Studies that claim exemption 4 from Federal Regulations for the Protection of Human Subjects, require the following sections:

  • Section 1 - Basic Information
  • Section 3 - Protection and Monitoring Plans- questions 3.1 and 3.2 only.  Please note that for question 3.1- Protection of Human Subjects, a justification for why the research meets the criteria for exemption 4 must be provided and should not merely repeat the criteria or definitions themselves.

ClinicalTrials.Gov

Do I need to register my NIAMS-funded clinical trial and report study results on ClinicalTrials.gov?

Yes. Per the NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information and Final Rule for Clinical Trials Registration and Results Information Submission  (42 CFR Part 11), all NIH-funded clinical trials must be registered on ClinicalTrials.gov by the sponsor or responsible party no later than 21 days after the first participant is enrolled. The study record must be updated at least once every 12 months.

Results should be submitted to ClinicalTrials.gov no later than 12 months after the trial’s primary completion date. Elements to be reported include participant flow, demographic and baseline characteristics, outcomes and statistical analyses, adverse events, the protocol and statistical analysis plan, and administrative information. 
For more information please see the NIH Policy and Regulation on ClinicalTrials.gov Registration and Reporting.

How do I determine if my clinical trial is an applicable clinical trial (ACT)?

The Final Rule for Clinical Trials Registration and Results Information Submission  (42 CFR Part 11) outlines which clinical trials of FDA-regulated drug products (including biological products) and device products and which pediatric post-market surveillances of a device product are ACTs and what information must be submitted to ClinicalTrials.gov. The Checklist for Evaluating Whether a Clinical Trial or Study is an Applicable Clinical Trial (ACT) can help you determine whether or not your trial is an ACT.
 

Training Requirements for Clinical Trials

Is Good Clinical Practice (GCP) training required for investigators and other study personnel conducting clinical trials at international sites?

GCP training is required for all study personnel involved in a clinical trial receiving funding from the NIH; this includes trials that have international sites.
 

Is GCP training required for study staff who are part of a clinical trial but will not be coming into direct contact with human subjects (e.g., staff processing de-identified data samples)?

Every member of the study team for a clinical trial is required to complete GCP training regardless of their direct contact with human subjects. The policy indicates that all NIH-funded investigators and staff who are involved in the conduct, oversight, or management of clinical trials should be trained in GCP (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html). Management of clinical trial data, even if de-identified, falls under this policy.  Please note: The Grantee institution provides assurance to NIH that GCP training has occurred by signing the grant application. The NIAMS staff are permitted to request verification of GCP training if needed.
 

Does IRB-required Collaborative Institutional Training Initiative (CITI) training cover the GCP requirement?

Yes. CITI training is accepted as GCP training.

Last Updated: February 2022