NIAID Human Subjects Application and Grant Handbook
Our Human Subjects Application and Grant Handbook gives you advice and information to help you understand and comply with regulations at all phases of application and award, including NIAID's requirements.
The handbook supplements -- it does not replace -- the laws and regulations cited below at Overview of NIAID Requirements.
Table of Contents
Overview of NIAID Requirements
Follow these NIAID policies and processes:
- Investigator-initiated clinical trials. When applying for an investigator-initiated clinical trial, you must go through a two-step process (it does not apply if you are responding to a request for applications).
- First, you apply for a planning grant (R34) and then, if approved, a cooperative agreement (U01).
- RFA requirements. Requests for applications often have unique requirements, so read the announcement carefully. RFA instructions take precedence over the general NIH application instructions. If you have questions, contact the program officer listed in the announcement.
- Award terms. We will attach the NIAID Clinical Terms of Award to your grant, which specify the actions the Institute requires grantees to take when conducting clinical research.
General Requirements
For a human subjects award, you must comply with all NIH guidelines and federal laws and regulations.
- Application instructions. NIH gives you detailed human subjects instructions in its application guides. Read this information and follow it explicitly.
- Non-NIH rules. Other laws and regulations may apply to your application and award.
Be familiar with the ones that apply to your situation. Many are listed at Laws and Regulations That Affect NIH's Programs.
- PHS and Office of Management and Budget guidelines.
- U.S. state and local regulations.
- Regulations of the host country, for international research. If regulations differ, the more restrictive one takes effect.
Are You Conducting Human Subjects Research?
Determine if Your Study Involves Human Subjects
To determine if NIH will consider your study to involve human subjects, read the information below, and find more detailed information in the Grant Application Guide or the PHS 398.
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:
- Human subjects.
- Individually identifiable.
- Private information.
- Research using human specimens or data.
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:
- You are not collecting samples by interacting or intervening with living people.
- None of the investigators or collaborators listed in the application can identify the subjects through coded private information or specimens (e.g., an investigator's access to identity is prohibited by a written agreement).
If any investigator involved in the research can determine a subject's identity or has access to identifiers, the research is considered to involve human subjects and human subjects requirements apply. Read more details in Office for Human Research Protections (OHRP)'s Guidance on Research Involving Coded Private Information or Biological Specimens.
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 investigators not be given the authority to determine whether research involves human subjects.
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 Instructions for Preparing a Multiproject Grant Application.
Additional Resources
Is Your Research Exempt?
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.
Almost all research at 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 think your research may be exempt, contact your program officer.
When Your Research Is Exempt
If your program officer agrees that an exemption applies, do the following:
- Justify the exemption in the human subjects section of your Research Plan, as follows:
- For electronic applications, include a justification in the PHS 398 Research Plan component of the Grant Application Package.
- For paper applications, create a section called Protection of Human Subjects in the narrative part of your application and include your justification there.
- Resolve any concerns for human subjects protections to NIH's satisfaction, keeping in mind:
- While you must justify the exemption, you don't need documentation from your IRB or IEC that your research is exempt.
- While it is rare that NIAID will return your application if you claim an exemption and it is incorrect or improperly justified, reviewers will assess your justification and it may affect your score.
- If your research is exempt but you still have access to basic characteristics about your subject population, you should include that information. If basic characteristics are unknown for exemption 4, indicate that in your plan.
- For all exemptions, if you know the criteria for including or excluding any subpopulation, you must identify that in your Research Plan.
For exemptions other than exemption 4:
- Provide certification of human subjects education for key personnel or send just-in-time (at the time of award). Read the Human Subjects Certifications: Training SOP.
- Submit completed Targeted/Planned Enrollment Tables and Inclusion Enrollment Report Tables when appropriate.
Additional Resources
Finding Help at NIAID
NIH staff play different roles at each step of the way.
- When planning the application, go to Contact Staff for Help to find an NIAID program officer to discuss your idea. Ask about meeting human subjects requirements before submitting an application.
- After submitting and before initial peer review, talk to review staff, either in our Scientific Review Program or in NIH's Center for Scientific Review, depending where the application is being reviewed. For more information, see Contact Staff for Help.
- After peer review, stay in close contact with your program officer, who's listed on your summary statement and Notice of Award and in the eRA Commons.
- Your program officer is your main contact for human subjects issues.
- He or she confirms the involvement of human subjects and looks at potential risks and proposed protection measures.
- You will work closely with that person to finalize the documentation we need before we can award your grant.
- If the peer review group had a human subjects concern and you have a bar to award, ask your program officer what documentation is needed for NIH to lift the bar.
- Before issuing a grant, our grants management staff make sure your institution has filed an OHRP assurance and we've received your IRB certifications and other required documentation.
- Call your grants management specialist for any business question about your grant.
Additional Resources
Planning and Writing Your Application
Know What to Do at the Planning Stage
Before NIAID can issue a human subjects award, your organization must do the following:
- Obtain a Federalwide Assurance (FWA) from the U.S. Office for Human Research Protections.
- Avoid financial conflicts of interest.
- Follow NIAID's two-step process for investigator-initiated clinical trials.
- Certify to NIAID that an IRB or IEC designated under your organization's FWA has reviewed and approved all human subjects research in the application.
We cover each of those items in the sections below.
Obtain a Federalwide Assurance
Whether you are performing research at a foreign or domestic site, your organization will need a 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.
Avoid Conflicts of Interest
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:
- Give your institutional official a list of your significant financial interests as well as those of your spouse and dependents. Include financial opportunities you expect to be affected by the proposed research.
- You, your IRB or IEC, and your institutional business official should read the Federal Register notice, Financial Relationships and Interests in Research Involving Human Subjects.
- If you think you may or could appear to have a financial conflict of interest, you must inform NIAID before spending any new NIH funds.
- Read our Financial Conflict of Interest for Awardees SOP.
Investigator-Initiated Clinical Trials at NIAID
NIAID uses a two-step approach to funding investigator-initiated clinical trials: a Clinical Trial Planning Grant (R34) followed by a Clinical Trial Implementation Cooperative Agreement (U01).
R34s provide funding to prepare 1) materials NIAID staff need to determine a project's feasibility and 2) documentation necessary for implementing the clinical trial in the U01.
This two-step process does not apply to applications responding to requests for applications (RFA). If you're applying for a clinical trial through an RFA, make sure you follow instructions in the announcement.
If you plan to apply for an investigator-initiated clinical trial, you'll need to consider many details in addition to the information we highlight on this page. We encourage you to contact appropriate NIAID program staff when planning your application.
For more information, go to Investigator-Initiated Clinical Trial Planning and Implementation Grants.
Additional Resources
Get IRB or IEC Approval
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.
What IRBs and IECs Do
Your organization's IRB or IEC performs many functions, which include the following:
- Reviews research to make sure human subjects are protected.
- Requires modifications to or disapproves research.
- Looks at privacy issues and informed consent.
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, the Research on Human Specimens NIH brochure, 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.
Additional Resources
Timing of Certifications
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.)
IRB, IEC, and FWA Requirements for International Research
Take care with IRB, IEC, and FWA processes when conducting international research.
IRB and IEC Requirements for 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:
- Start getting your approvals early since they often take a long time.
- If you're applying from a country that has a national IRB or IEC, find out if its approval is in addition to or in lieu of a local IRB or IEC. For countries with multiple levels of review, send us approvals from each IRB or IEC of the protocol and informed
consent document.
- To prevent delays, find out early on if IRB or IEC approval is required for each country, and what each country requires for clearance.
- Facilitate approvals through clear communication with all involved IRBs and IECs. It may help if you appear before each IRB or IEC in person to discuss issues and points of collaboration.
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.
Federalwide Assurances for International Research
Organizations need an FWA writing each 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.
Additional Resources
Writing Your Application
Know Which Documents to Include
While NIH requires some documentation in the application, whether to include other items, such as the protocol and informed consent document, varies by Institute. 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 or before you enroll patients.
If you are submitting an NIAID-approved clinical trials implementation (U01) application, include all the documentation you developed under your R34 planning grant 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 NIAID Points of Contact.
You may also want to read Submit Documents Before Enrollment in this handbook.
Develop Your Human Subjects Research Plan
The human subjects section of your Research Plan has five sections.
Follow the instructions in the Grant Application Guide or PHS 398, 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 NIH Grant Application Guides.
Create a header for each section and subsection:
- Protection of Human Subjects
- Inclusion of Women and Minorities
- Phase III Clinical Trials
- Targeted/Planned Enrollment Tables
- Inclusion of Children
See our Human Subjects Research Plan checklist for more information on creating the Research Plan.
Protection of Human Subjects
Risks to Human Subjects
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 score or resolved in a bar to award or both.
Design Your Data and Safety Monitoring Plan
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.
- Research Plan, including the protocol (if required by the division).
- Data and safety monitoring plan for clinical trials.
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.
Options for Safety and Monitoring
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 with your NIAID program officer.
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:
- Independent Safety Monitor -- a physician or other expert who is independent of the study and available to review and recommend actions regarding adverse events and other safety issues.
- Independent Monitoring Committee or Safety Monitoring Committee -- a small group of independent investigators and biostatisticians who review data.
- Data and safety monitoring board (DSMB) -- an independent committee that reviews interim safety and efficacy data and provides advice on continuing, modifying, or terminating the study.
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 Principles for Use of a Data and Safety Monitoring Board (DSMB) for Oversight of Clinical Trials Policy.
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.
Phase I and II
For phase I and II clinical trials, you must include a general description of your data and safety monitoring plan in your application.
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 NIAID for 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.
Phase III
All phase III clinical trials must have a DSMB and a detailed monitoring plan. NIH also requires DSMBs for other clinical trials, a DSMB if the studies have multiple clinical sites, are blinded, or use high-risk interventions or vulnerable populations.
Additional Resources
Special Populations: Women, Children, Minorities
For a new clinical study, provide information about the participants you plan to include in a Targeted/Planned Enrollment Table. 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 Inclusion Enrollment Report Table as part of your annual progress report. For more information, read Send NIAID the Inclusion Enrollment Form in this Handbook.
Investigating Foreign Populations
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 Targeted/Planned Enrollment Tables.
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 IND or 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.
Additional Resources
How Human Subjects Applications Are Reviewed
Reviewers Use Special Review Criteria
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:
- Risks to subjects.
- Adequacy of protection against risks.
- Potential benefits to the subjects and others.
- Importance of the knowledge to be gained.
- Data and safety monitoring.
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.
If Reviewers Have Concerns
Peer reviewers assess how well your application meets each requirement, judging its comprehensiveness and whether your plans to include special populations and protect subjects 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.
This creates a bar to award until you resolve it to the satisfaction of the NIH Office of Extramural Research. A human subjects involvement code or a human subjects inclusion code on the summary statement may indicate that NIAID is barred from issuing the award.
Before you start enrolling participants, you must resolve any concerns raised during the review of your application.
A bar to award can delay your grant. See If Reviewers Have Concerns and the Bars to Grant Awards -- Human Subjects SOP for more details.
Read our human subjects warning, and see NIAID Decision Trees for Human Subjects Requirements to learn how reviewers determine whether you meet requirements.
To learn how to avoid these negative results, read Writing Your Application in this Handbook.
When risks are serious and protections unacceptable, reviewers may also propose the application be not recommended for further consideration or suggest changes, such as limiting the scope of the work.
Before You Enroll Patients
Submit Documents Just-in-Time
Before issuing your Notice of Award, NIAID may require that you submit additional documents just-in-time, just before we make an award. For more on the 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 and submit a revised plan. You must resolve concerns from peer review before enrolling participants. See the Bars to Grant Awards SOP for details.
NIAID's grants management specialists will also check to see whether your organization has the following in place:
- A human subjects Federalwide Assurance on file with the Office for Human Research Protections.
- Certification to NIAID that an IRB or IEC, designated under your organization's Federalwide Assurance, reviewed and approved all nonexempt human subjects research proposed in your application.
Submit Documents Before Enrollment
Before enrolling, you will send NIAID any of the following items that are
applicable to your study:
- IRB- or IEC-approved protocol identified by version number, date, or both, including details of study design, proposed interventions, patient eligibility, and exclusion criteria.
- Documentation of IRB or IEC approval, including OHRP federalwide number, IRB or IEC registration number, and IRB or IEC name.
- IRB or IEC approved informed consent document, identified by version number, date, or both and dates it is valid.
- Plans for the management of side effects.
- Procedures for assessing and reporting adverse events.
- Plans for data and safety monitoring and monitoring of the study site, pharmacy, and laboratory.
- Documentation that the PI and all study staff responsible for the design or conduct of the research have received training in the protection of human subjects.
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 NIAID 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 Harmonization E6: Good Clinical Practice, Section 6, and address the following safety issues:
- Plans for managing side effects.
- Procedures for assessing and reporting adverse events.
- Plans for monitoring data and safety and the study site, pharmacy, and laboratory.
NIAID staff 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.
Additional Resources
We'll Discuss Data and Safety Monitoring
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.
Meet Requirements for IND or IDE
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 NIAID 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 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 NIAID written documentation from
it showing you are in compliance with local laws.
Additional Resources
Show rDNA Advisory Committee Approval
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.
Additional Resources
Document Training in Research Conduct
Your application must document mandatory training for investigators and key staff in the responsible conduct of clinical research.
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 training in research conduct. 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 research conduct 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 Certifications: Training SOP. For investigators who speak other languages, see the translations listed below.
Additional Resources
Verify Your Federalwide Assurance
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 you already have an assurance, include the number when you submit your application. If you don't or it has changed since your last submission, inform us of it 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 questions and answers.
Go to for more information..
Additional Resources
Register With ClinicalTrials.gov
You must register applicable clinical trials -- see the glossary term applicable clinical trial -- on ClinicalTrials.gov,
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.
Additional Resources
Managing Your Award
IRBs and IECs Have Ongoing Responsibilities
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 OHRP
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:
- Amendments to the protocol, identified by protocol version number, date, or both, and dates it is valid.
- Changes in informed consent documents, identified by version number, date, or both, and dates it is valid.
- Termination or temporary suspension of patient accrual.
- Termination or temporary suspension of the protocol.
- Any change in IRB approval.
- Any other problems or issues that could affect the participants in the studies.
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:
- IRB or IEC letter of renewal.
- Latest IRB- or IEC-approved protocol with the version number or date.
- Latest IRB- or IEC-approved informed consent document with the version number or date and dates it is valid.
To learn more about requirements for continuing IRB and IEC review, see the following:
Additional Resources
Comply with Reporting Requirements
Throughout the award, you must comply with the reporting requirements in this document, which stem from the references below:
You must notify NIAID 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:
- Protocol amendments.
- Protocol termination.
- Temporary suspension of the protocol.
- Change in informed consent or IRB or IEC approval status.
- Temporary suspension or permanent termination of patient accrual.
- Other problems or issues that could affect study participants.
- FDA communications.
Additional Resources
IRB or IEC Actions
Send NIAID 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.
Continuing review and approval
Send your program officer documentation of continuing IRB or IEC review and approval annually at a minimum. Include the following:
- A copy of the IRB or IEC letter of renewal.
- A copy of the current IRB or IEC approved protocol, identified by version number, date, or both (unless otherwise directed), and dates it is valid.
- A copy of the current IRB or IEC approved informed consent document, identified by version number, date, or both, and dates it is valid.
For countries with multiple levels of IRB review, written documentation of protocol review and approval from each IRB should be provided to NIAID, 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.
Amendments, Suspensions, Terminations, and Extensions
For interim changes to the trial, send your program officer documentation. For example:
- Amendments or changes to the protocol, with the version number or date. Unless participants are in imminent danger, your IRB or IEC must approve changes before you implement them.
- Changes in informed consent documents, with the version number or date. Your IRB or IEC must approve changes before you implement them.
- Temporary suspension or permanent termination of patient accrual.
- Temporary suspension or termination of the protocol.
- Change in IRB or IEC approval status.
- Other problems or issues that could affect participants.
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 a delay occurs due to circumstances beyond your control, 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:
- Research does not comply with human subjects regulations or IRB or IEC requirements.
- You have discovered unanticipated risks to human subjects.
- The IRB suspended or terminated its approval.
Go to Guidance on Reporting Incidents to OHRP.
Data and Safety Monitoring Reviews
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.
Report Adverse Events Promptly
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:
- Seven-Day IND Safety Report.
- Fifteen-Day IND Safety Report.
- Ten-Day IDE Reports of Unanticipated Adverse Device Effect.
For time-sensitive reports, submit the following to the program officer within 24 hours of notifying FDA:
- Expedited safety report of unexpected or life-threatening experience or death: a copy of any report of unexpected or life-threatening experience or death associated with the use of an IND drug. Report to FDA by telephone or fax as soon as
possible, no later than seven days after the IND sponsor receives the information.
- Expedited safety reports of serious and unexpected adverse experiences: a copy of any report of unexpected and serious adverse experience associated with an IND drug or finding from animal testing that suggests a significant risk
for human subjects. Report in writing to FDA as soon as possible, no later than 15 days after the IND sponsor receives the information.
- IDE reports of unanticipated adverse device effect: a copy of any report of unanticipated adverse device effect.
For these other reports do the following:
- Expedited safety reports: send to the NIH Office of Biotechnology Activities concurrently with the report to FDA.
- Other adverse events documented during the course of the trial: include in the annual IND or IDE report and reported to NIAID annually.
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:
- Go to OHRP for additional guidance.
Additional Resources
Send NIAID the Inclusion Enrollment Form
As part of your reporting requirement, you must send NIAID an Inclusion Enrollment Report form, which shows the cumulative accrual and demographic information of participants enrolled in your study.
If including foreign participants, clearly document this in your inclusion enrollment tables.
For clinical trials, send in the Inclusion Enrollment Report semiannually. For other clinical studies, send it with your progress report.
When conducting an NIH-defined phase III clinical trial, you have additional requirements:
- Report annual cumulative enrollment, as described above, and indicate if data analysis has begun. If it has, report progress made in conducting valid analyses for gender, ethnic, and racial differences.
- When you have completed the trial, use the Inclusion Enrollment Report form to provide analyses showing the intervention differences among those groups.
Send it with your annual progress report. For electronic applications, see the Grant Application Guide for your Grant Application Package. For paper applications, see the PHS 398 for more detailed instructions.
For more information on submitting a progress report, go to Send Us an Annual Progress Report in Part 11a. Managing Your Grant of the NIH Grant Cycle: Application to Renewal.
Other Reporting Requirements
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.
Additional Resources
ClinicalTrials.gov Registration
You must register applicable clinical trials -- see the glossary term applicable clinical trial -- on ClinicalTrials.gov, and NIH urges you to register all of them.
You submit the information to ClinicalTrials.gov. To register, go to the ClinicalTrials.gov Protocol Registration System. If you need help, contact your program officer.
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 trial type, ICMJE may require that you register before you enroll your first patient. To learn more, read Is This Clinical Trial Fully Registered?
Additional Resources
Clinical Terms of Award Checklist
The NIAID Clinical Terms of Award Checklist is at the end of the Guidance for Compliance with NIAID Clinical Terms of Award. Scroll to the bottom of that document to see the checklist. It serves as a reminder of all the different information that must be submitted to NIAID. You can complete the checklist and send it
to your program officer with any other submissions you need to make.
Additional Resources
More Human Subjects Links
In addition to reading the Grant Application Guide for electronic or PHS 398 for paper applications, go to these sites for more information:
You have reached the end of this tutorial. For more information, see All About Grants for tutorials and application tools. Help us improve our outreach to you by emailing deaweb@niaid.nih.gov.
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