See the Glossary for more terms.
Our Human Subjects Application and Grant Handbook gives you advice and information to help you determine whether your research is considered human subjects, and if it is, how to understand and comply with regulations at all phases of application and award, including NIAID's requirements. We also describe special requirements for clinical trial applications and awards.
After you determine your research qualifies as human subjects, it will help you decide what to include in your application and what other items to comply with before and during the application process. The handbook supplements—it does not replace—the laws and regulations cited below at Overview of NIAID Requirements.
For grants that contain a clinical trial, we'll let you know how to manage your award.
For general information on application and award, see the Strategy for NIH Funding.
Your research may fall under the umbrella of human subjects even if you aren't working on humans directly. For example, some basic research on samples would be considered human subjects, while research taking a different approach would not. This is a complicated topic with many rules and regulations, so tread carefully and read on to learn more.
To determine if NIH will consider your study to involve human subjects, read the next section. You can find more detailed information in the SF 424 Application Guide.
HHS' Protection of Human Subjects in 45 CFR Part 46 defines a human subject as a living person about whom an investigator obtains either 1) data through intervening or interacting with the person or 2) identifiable, private information.
Before you decide whether your research involves human subjects, make sure you understand NIH's Guidance on Research Involving Coded Private Information or Biological Specimens. Go to the glossary links in the right column for definitions of these key terms:
In general if you're using coded private information, data, or specimens, NIH will consider your research to involve human subjects unless it meets both of the following conditions:
Also see the HHS Human Subjects Regulations Decision Charts and NIH's flow chart for Research Involving Private Information or Biological Specimens.
If you still have questions about whether your application has human subjects, ask your IRB or IEC before writing your application. NIH recommends that you not determine whether research involves human subjects on your own.
When applying for human subjects research, check "yes" for human subjects on the application face page.
For more help, go to the following on NIAID's Web site:
Most requirements for protecting human subjects are codified in the law, 45 CFR Part 46.
Multiproject applications. If you are submitting a multiproject application, you are applying for human subjects research even if only one component includes human subjects. Complete human subjects requirements for each component of the application. Go to our Guidance for Preparing a Multiproject Research Application.
When we refer to human subjects research in this document, we are referring to nonexempt research. The six human subjects exemptions rarely apply to NIAID because almost all research supported by NIAID is either human subjects or not human subjects. To determine whether you are conducting human subjects research, see the section Determine if Your Study Involves Human Subjects.
To determine whether your research is exempt, go to OHRP's Is an Activity Research Involving Human Subjects? If you still think your research may be exempt, contact your program officer.
If your program officer agrees that an exemption applies, do the following:
For exemptions other than exemption 4:
Follow these NIAID policies and processes.
For a human subjects award, you must comply with all NIH guidelines and federal laws and regulations.
NIH staff play different roles each step of the way.
Before NIAID can issue a human subjects award, your organization must do the following:
We cover each of those items in the sections below.
Whether you are performing research at a foreign or domestic site, your organization will need to File a New Federalwide Assurance before we can fund your research.
Check with your organization to determine whether it has an FWA. If it does not, allow plenty of time to apply.
Generally, each institution conducting human subjects research has its own FWA. Your institution needs an FWA even if you're not studying human subjects but your collaborators are.
If you're applying for a multiproject application, reviewers check that each project has an assurance. One exception is when a collaborator or institution does not need a separate FWA because the research is conducted under the direction of a PI from an assured institution.
For details, see Guidance on Extension of an FWA to Cover Collaborating Individual Investigators and Introduction of the Individual Investigator Agreement.
If you have an assurance, include the number in your application. If you don't or it has changed, you can inform us of the FWA number after you receive a just-in-time notification.
NIH takes financial conflicts of interest very seriously.
By law, institutions must manage, reduce, or eliminate financial conflicts of interests (FCOI) for any person—including subawardees and collaborators—responsible for the design, conduct, or reporting of funded research.
When planning your project, avoid conflicts of interest stemming from a financial relationship (including the appearance of a conflict) that can negatively affect the rights and welfare of your subjects.
Here's what to do:
We summarized NIAID's required process at NIAID Requirements. For more information, go to Investigator-Initiated Clinical Trial Planning and Implementation Awards SOP.
You will need to get IRB or IEC approval of your human subjects research, including the protocol, informed consent document, and possibly other documents.
Where other institutions are involved in the research, e.g., a multicenter study, you will provide documentation that each institution's IRB or IEC approved these documents.
For international awards, see the section IRB, IEC, and FWA Requirements for International Research.
Your organization's IRB or IEC performs many functions, which include the following:
If the IRB or IEC determines that you need informed consent, it must approve the informed consent form. For details, read 45 CFR 46.116, 45 CFR 46.117, and 45 CFR 46.115. Also visit the Informed Consent section of Human Research questions and answers from the Office for Human Research Protections.
IRBs and IECs perform two types of review: full board and expedited. For more information, see 46.107, 46.110, and 46.111 of 45 CFR Part 46, and NIAID's Human Subjects Certifications: IRB or IEC SOP.
To register an IRB or IEC for the first time or to update or renew an existing IRB or IEC registration online, go to Electronic Submission System for Federalwide Assurances and IRB/IEC Registrations.
If you plan to use a clinical trials Web site to advertise for subjects, you may also need IRB or IEC approval, for example, if the site has more than basic descriptive information. For details, go to OHRP's Guidance on IRB Review of Clinical Trial Web sites.
Start getting approvals early—well before the application's due date.
Certification of IRB or IEC approval of your protocol, informed consent document, and possibly other documents is due just-in-time, just before we issue an award. But if ready when you apply, include in the application.
(A few grants, such as training grants, do not require IRB or IEC approval until before you begin research.)
Take care with IRB, IEC, and FWA processes when conducting international research.
If you're applying from a foreign country, read Get IRB or IEC Approval in this Handbook for information about submitting certification of IRB or IEC approval.
Then follow these suggestions:
If you have multiple levels of review, you must send NIAID the full documentation from all the IRBs or IECs. Check with your program officer for advice.
Organizations need an FWA if they are 1) domestic with foreign research sites or 2) foreign engaged in clinical research funded by NIAID.
Some collaborators may not be required to obtain their own FWA. See Guidance on Extension of an FWA to Cover Collaborating Individual Investigators and Introduction of the Individual Investigator Agreement.
Also read more on these topics at Get IRB or IEC Approval.
While NIH requires some documentation in the application, it varies by institute as to whether to include other items, such as the protocol and informed consent document. At NIAID, requirements also vary by division, so talk to a program officer to find out when you must submit required documents.
When responding to a request for applications, read the announcement to see what documentation it requires in the application and which items you are supposed to submit before we are ready to make an award.
If you are submitting an NIAID-approved clinical trials implementation (U01 or R01) application, include all the documentation needed to start the trial in the application. See the NIAID Clinical Trial Implementation (U01) Cooperative Agreement program announcement for details.
If you have questions, contact the program officer listed in the announcement—see Communicating With NIAID—How to Get Help in the Strategy for NIH Funding.
You may also want to read Submit Documents Before Enrollment in this handbook.
The human subjects section of your Research Plan has five sections.
Follow the instructions in the SF 424 Application Guide, and complete the required information. Use the guidance below to supplement that information.
To make it easy for reviewers to access your application, organize your research plan in the same order as the human subjects section of the application instructions.
Create a header for each section and subsection:
See our Human Subjects Research Plan checklist for more information on creating the Research Plan.
Show peer reviewers how you will protect subjects from research risk. Leave no questions about what you propose to do. Clearly state how you will include diverse groups and protect subjects from study-related risks.
Failing to show how you will protect participants from risk can negatively affect your overall impact/priority score or result in a bar to award or both.
Data and safety monitoring provides an independent review of the research, interim safety and efficacy data, and progress towards achieving the goals of the study.
To enable NIAID to properly monitor studies, clinical investigators must submit the following information in the application.
At the time of award, a program officer will ask you to submit the items described above. Submit these items electronically or by mail, following the processes of the awarding division.
Though your application will propose monitoring, you and NIAID will jointly make the final decision about the type of monitoring before you enroll patients. Discuss this topic with your program officer before patient enrollment begins.
Clinical trials require independent monitoring for research that puts participants at more than minimal risk when involving investigational drugs, devices, biologics, or other studies, including licensed products.
The PI and IRB or IEC oversee data and safety monitoring using one of these types of independent monitoring:
Type of monitoring depends on the risks, and the size and complexity of a clinical trial. A study whose interventions pose a potential risk to participants must have a DSMB. Go to NIAID Policy on Data and Safety Monitoring Board (DBMB) Operations (PDF).
In your monitoring plan, describe how you will report adverse events to the IRB or IEC, FDA, and NIH. Your peer review group will review your plan, and its comments or concerns will appear in your summary statement.
For phase I and II clinical trials, your application must include a general description of your data and safety monitoring plan.
After award but before you begin the clinical trial, you need to submit a detailed monitoring plan as part of your protocol, first to your IRB or IEC and then to your program officer for our review and approval.
Phase I and II clinical trials have more leeway in the type of monitoring they may use. If you're planning a clinical trial that involves potentially high risks or special populations, you must consider additional monitoring safeguards, which could include a DSMB.
All phase III clinical trials must have a DSMB and a detailed monitoring plan. NIH also requires DSMBs for other clinical trials, e.g., a DSMB if the studies have multiple clinical sites, are blinded, or use high-risk interventions or vulnerable populations.
For a new clinical study, provide information about the participants you plan to include in a Planned Enrollment Report. Show peer reviewers how you will include required populations.
You must justify including or excluding children, both genders, and minority populations. Find more information in OHRP's Special Protections for Children as Research Subjects.
Also see NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research.
After you get the award, you will submit updated information in the Cumulative Inclusion Enrollment Report as part of your annual progress report. For more information, read Send NIAID the Cumulative Inclusion Enrollment Report Form in this Handbook.
For foreign awards, the NIH policy on inclusion of women and minority groups in research is the same as that for the U.S., and the tables are based on U.S. minority populations.
For both foreign awards and domestic awards with foreign components, report on planned study populations using the Planned Enrollment Report.
If there is scientific rationale for examining subpopulation group differences in a foreign population, consider designing your study to accommodate those differences, and discuss this in your application.
Outreach plan. You will need a culturally sensitive outreach plan. Build trust by involving relevant parties, such as family, religious organizations, and community leaders, when developing the plan.
In some cases, conducting a community consultation may benefit potential participants and your study. Although not required, NIH supports and encourages community consultations for many types of research. To learn more, read Points to Consider When Planning a Genetic Study That Involves Members of Named Populations.
For more details, see NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research.
Regulatory oversight. You must obtain regulatory oversight by either FDA (under an investigational new drug (IND) or investigational device exemption (IDE)) or the regulatory body of the country where the research is to be conducted. Send NIAID written documentation from a foreign regulatory body showing you are in compliance with local laws.
Know reviewers' criteria and concerns.
In addition to the regular review criteria, reviewers evaluate the justification for involving human subjects and proposed protections from research risk according to five criteria:
Although your institution determines whether your research is considered human subjects, the scientific review officer and peer reviewers assess this determination—see Are You Conducting Human Subjects Research? in this Handbook.
These assessments are independent of your IRB's or IEC's.
Peer reviewers assess how well your application meets each requirement, judging its comprehensiveness and whether your plans to protect subjects and include special populations are acceptable.
You will see their comments and concerns in your summary statement.
Any problems, such as inadequate protection of human subjects or inclusion of special populations, may negatively affect your overall impact/priority score, causing reviewers to designate a human subjects concern.
The concern creates a bar to award until you resolve it to the satisfaction of the NIH Office of Extramural Research. Certain human subjects involvement codes or human subjects inclusion codes on the summary statement indicate that NIAID is barred from issuing the award. NIAID applicants most commonly receive bars to award for the following reasons:
Go to "Top Ways to Prevent a Human Subjects Bar to Award" in the NIAID Funding News.
Before you start enrolling participants, you must resolve any concerns raised during the review of your application. See the Bars to Grant Awards—Human Subjects SOP for more details.
Also read our Human Subjects—Warning, and see NIAID Decision Trees for Human Subjects Requirements to learn how reviewers determine whether you meet requirements.
When risks are serious and protections unacceptable, reviewers may also propose the application not be recommended for further consideration or suggest changes, such as limiting the scope of the work.
To learn how to avoid reviewer concerns, read Writing Your Application, above.
Talk to your program officer about documents you will need to submit.
Before issuing your Notice of Award, we may require that you submit additional documents just-in-time, just before we make an award. For more on that process, see How do I submit just-in-time information? in our Just-in-Time questions and answers.
If you have a bar to award from peer reviewers, work with your program officer to resolve it. The bar must be lifted before you may enroll participants. See the Bars to Grant Awards SOP for details.
Our grants management specialists will also check to see whether your organization has the following in place:
Before enrolling, you will send NIAID any of the following items that are applicable to your study:
You must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NIAID staff to our satisfaction.
Send documents to your program officer for approval. Your program officer will review the documents and send you comments within three weeks. Contact him or her to find out the submission process, which varies by division.
You can begin to enroll participants once program and grants staff have received, reviewed, and approved all amended or missing documentation.
Protocol. Submit the IRB- or IEC-approved protocol identified by version number, date, or both. It must detail the study design, proposed interventions, patient eligibility, and exclusion criteria.
Protocols must adhere to International Conference on Harmonisation, Good Clinical Practice, Section E6, and address the following safety issues:
We will send you their comments within three weeks. Then you must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NIAID staff to our satisfaction before enrolling participants.
Your IRB or IEC must review and approve any changes to the protocol before you may enroll participants.
IRB or IEC approvals. If several institutions are involved, submit to the program officer written documentation that each institution's IRB or IEC approved the protocol and informed consent document.
Include the version number or date approved, and dates for which these documents are valid.
Get a Certificate of Confidentiality from NIH. You can protect your subjects from forced disclosure of personal information with an NIH Certificate of Confidentiality.
A certificate can encourage participants to take part in your study by assuring them that their privacy will be protected. It allows you to refuse to disclose identifying information in a civil, criminal, or other proceeding.
Learn how to apply at NIH's Certificates of Confidentiality Kiosk and NIAID's Certificates of Confidentiality SOP.
Though your monitoring plans go through peer review, you will work with NIAID to make the final decision about safety monitoring before you begin the study. Discuss this topic with your program officer early on.
We may require you to use an NIAID DSMB if your study poses sufficient risk to subjects. Your program officer can answer your questions.
Each NIAID division oversees and monitors clinical trials to ensure participants' safety and the validity and integrity of data. That oversight is separate from your study's data and safety monitoring.
For more information see the NIH Policy for Data and Safety Monitoring and Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials.
After organizing a monitor or monitoring board, submit a description of the monitor or board, its charter or operating procedures, proposed meeting schedule, plan for review of adverse events, roster, and curriculum vitae from all members. NIAID must approve all documents before you enroll patients.
For details on monitoring plans, go to Design Your Data and Safety Monitoring Plan in this Handbook.
Clinical research that involves investigational therapeutics, vaccines, or other medical interventions (including licensed products or devices used for a new purpose) should be performed under an FDA IND or IDE. FDA must grant exceptions in writing.
For clinical trials performed under an IND or IDE, provide NIAID the name and institution of the IND or IDE sponsor, date it was filed with FDA, FDA's IND or IDE number, any written comments from the FDA, and written responses to those comments.
Also submit risk information, e.g., product development plan, investigator's brochure, or information obtained through published literature review or other venue.
You must wait 30 days from FDA receipt of initial IND or IDE application before enrolling patients.
If FDA places the study on clinical hold, notify your program officer and send us any written comments from FDA, written responses to the comments, and documentation in writing that the hold has been lifted. You may not use grant or contract funds during a clinical hold.
International research. For intervention studies, you must obtain regulatory oversight by either FDA (under an IND or IDE) or the regulatory body of the country where the research is to be conducted. For a foreign regulatory body, send us written documentation from it showing you are in compliance with local laws.
If your application transfers recombinant DNA, or DNA or RNA derived from recombinant DNA, into research participants, you'll need additional approvals.
The NIH Recombinant DNA Advisory Committee must review your application before review by your institutional biosafety committee, FDA, and your IRB or IEC. Send NIAID written documentation, including comments, of those reviews and approvals.
For more information, go to the NIH Office of Biotechnology Activities Web site and the NIH Guidelines for Research Involving Recombinant DNA Molecules.
Your application must document mandatory training for investigators and key staff in the protection of human subjects.
Include a list of key personnel, the title, and a one-sentence description of the training. See our Sample Letter to Document Training in the Protection of Human Subjects and Just-in-Time questions and answers.
Check with your institution to see if it provides this training. Alternatively, key personnel may take the Protecting Human Research Participants course from NIH's Office of Extramural Research.
When you're being considered for an award, you must submit documentation that the investigators involved in the human subjects research have completed the training. You can send it just-in-time when we request it, or if it's ready, you can submit it in the application.
To learn more, read our Human Subjects Research Training SOP. For investigators who speak other languages, see the translations listed below.
Before we can issue an award, your institution must file a human subjects Federalwide Assurance (FWA) with the Office for Human Research Protections (OHRP)—go to Obtain a Federalwide Assurance for details.
If it already has an assurance, include the number when you submit your application. If it does not or the assurance has changed since your last submission, inform your grants management specialist, copying your program officer, after you receive a just-in-time notification.
Just-in-time means we ask you to send the information just before we make an award. See our Just-in-Time SOP and Just-in-Time questions and answers for details.
You must register applicable clinical trials—see the glossary term applicable clinical trial in the right column—on ClinicalTrials.gov and upload your data annually.
Know that depending on trial type, the International Committee of Medical Journal Editors' (ICMJE) policy may require that you register before you enroll your first patient. To learn more, read Is This Clinical Trial Fully Registered?
For more information on this requirement, go to ClinicalTrials.gov Registration in this Handbook.
All relevant IRBs and IECs must review the protocol and analysis plans at intervals appropriate to the degree of risk, at least once a year and whenever changes occur in your procedures.
Submit all IRB or IEC notifications of protocol approval to your program officer, including the name of the IRB or IEC, its Office of Human Research Protection (OHRP) registration number, and Federalwide Assurance number.
If your protocol changes at any time, you must get IRB or IEC approval for the changes. Work with your program officer throughout to make sure you take all necessary steps.
Send your program officer copies of documents related to major changes in the status of protocols, including the following:
In addition, you must report changes in informed consent or IRB or IEC approval status to NIAID. Send your program officer a copy of the following:
To learn more about requirements for continuing IRB and IEC review, see the following:
Throughout the award, you must comply with the reporting requirements in this document, which stem from the references below:
You must notify your program officer if the FDA puts your study on clinical hold and send in copies of all correspondence with FDA, including documentation that the hold has been lifted.
Always promptly inform your program officer of major changes to the protocol and any reports to FDA, including:
Send your program officer all IRB or IEC notifications of protocol renewal, amendment, suspension, and termination.
If other institutions are involved in the research, e.g., in a multicenter study, each institution's IRB or IEC should review and approve the protocol. The IRB for each site conducts continuing reviews at intervals appropriate to the degree of risk, but not less than annually—see 45 CFR 46.109.
Send your program officer documentation of continuing IRB or IEC review and approval annually at a minimum. Include the following:
For countries with multiple levels of IRB review, written documentation of protocol review and approval from each IRB should be provided to the program officer, along with a copy of the IRB- or IEC-approved informed consent document, identified by version number, date, or both, and dates it is valid.
For interim changes to the trial, send your program officer documentation. For example:
Talk to your program officer to confirm what documentation is required.
Notify your program officer by fax or email within three working days of an event; then follow up with a detailed letter signed by you and your institutional business official, and include copies of relevant communications with the IRB or IEC.
If you can't complete a clinical trial by the end of the award, you may be eligible for an administrative extension. See our Investigator-Initiated Clinical Trial Administrative Extensions SOP and Investigator-Initiated Clinical Trial Administrative Extensions questions and answers.
For the following incidents, you need to file an incident report with OHRP:
Go to Guidance on Reporting Incidents to OHRP.
Submit written summaries of all reviews conducted by the monitoring group to your program officer within 30 days of reviews or meetings. When reviews are frequent, semiannual or quarterly reports are sufficient.
You must notify NIAID in writing if the FDA places your study on clinical hold if your research is under an IND or IDE. If not, you and NIAID jointly determine safety reporting requirements.
IND and IDE sponsors must notify FDA about serious adverse events through safety reports and provide copies to the NIAID program officer within 24 hours of FDA notification. These include:
For time-sensitive reports, submit the following to the program officer within 24 hours of notifying FDA:
For these other reports do the following:
Report other adverse events you document during the trial in the annual IND or IDE report.
If you are conducting a multisite phase I or II clinical trial, send timely summary reports of adverse events to all sites and IRBs or IECs, whichever monitoring type you use. The frequency of the summary reports depends on the nature of the clinical trials.
If we have an issue, your program officer will let you know within ten working days by email or fax, followed in 30 days by an official letter.
For more information, read:
As part of your reporting requirement, you must submit the cumulative accrual and demographic information of participants enrolled in your study following the Cumulative Inclusion Enrollment Report format.
If including foreign participants, clearly document this in your Cumulative Inclusion Enrollment Reports. Specify the study title and use two separate tables if part domestic and part foreign.
For clinical trials, complete the Cumulative Inclusion Enrollment Report semi-annually. For other clinical studies, complete it with your progress report.
When conducting an NIH-defined phase III clinical trial, you have additional requirements:
Use the Inclusion Management System (IMS) in the eRA Commons to complete these requirements. Note that you must update inclusion data records included with progress reports submitted on or after March 5, 2015, into the enrollment format supported by IMS, even if no new enrollment occurred in the past year.
For more information on IMS and how and when to use the Enrollment Report, read these NIH resources:
For more information on submitting a progress report, go to Understanding the Annual Progress Report in Strategy for Your Grant in the Strategy for NIH Funding.
You have two other reporting requirements.
Recombinant DNA Advisory Committee Reports—Send your program officer a copy of the adverse event and annual reports required by NIH's Office of Biotechnology Activities.
Research Conduct Training—If you hire new staff, include documentation in your progress report of their training in the protection of human subjects. You can use our Sample Letter to Document Training in the Protection of Human Subjects.
The following are legal requirements described in your Notice of Award.
Registering and submitting data. You must register applicable clinical trials—see the glossary term applicable clinical trial in the right column—on ClinicalTrials.gov, and NIH urges you to register all of them.
Not registering your trial or submitting annual data is a criminal offense that could have repercussions to your award. For additional information, read What NIH Grantees Need to Know About FDAAA.
To submit data annually or to register, go to the ClinicalTrials.gov Protocol Registration System. If you have questions, contact your program officer.
Progress report. In the human subjects section of your progress report, create a ClinicalTrials.gov heading. Certify you've completed required submissions by following the instructions on NIH's What NIH Grantees Need to Know About FDAAA.
For additional information, read:
Make sure you understand the International Committee of Medical Journal Editors' (ICMJE) registration policy if you want your study published by a journal using ICMJE's standards.
Depending on the trial type, ICMJE may require that you register before you enroll your first patient. To learn more, read Is This Clinical Trial Fully Registered?
Use the NIAID Clinical Terms of Award Checklist at the end of the Guidance for Complying with NIAID Clinical Terms of Award as a reminder of all the information you must submit to NIAID. You can complete the checklist and send it to your program officer with any other required submissions.
In addition to reading the SF 424 Application Guide, go to these sites for more information:
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Last Updated February 18, 2015
Last Reviewed April 04, 2012