Here we offer 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 requirements.
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. This information supplements—it does not replace—the laws and regulations.
Table of Contents
- Are You Conducting Human Subjects Research?
- Requirements for Human Subjects Awards
- Plan and Write Your Human Subjects Application
- Federalwide Assurance
- Financial Conflicts of Interest
- IRB or IEC Approval
- International Research Requirements
- Write Your Application
- Review of Human Subjects Applications
- Before You Enroll Patients
- Manage Your Award
- Reporting Requirements
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 Form Instructions.
For help making the determination, see the NIAID index of Decision Trees for Human Subjects Requirements. Further, go to Does your human subjects research study meet the NIH Definition of a clinical trial? to know whether clinical trial rules and regulations will apply to your study.
- All NIH NOFOs list whether they allow, require, or disallow clinical trials in the NOFO’s title and in Section II. Award Information.
- You must select a NOFO that accepts the type of research you wish to propose.
You may also need the NIH Office for Human Research Protections (OHRP) Guidance on Research Involving Coded Private Information or Biological Specimens or NIH Stem Cell Information.
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.
Read definitions of these key terms:
- Human subjects. Legally defined term for living persons about whom an investigator obtains specimens or data through direct interaction or intervention or through identifiable, private information. Regulations include but are not limited to human organs, tissues, body fluids, and recorded information.
- Individually identifiable. Describes private information regarding the identity of human subjects that an investigator may ascertain directly or through a coding system. If identity is knowable, the study is considered to be human subjects research.
- Private information. Information for which a person can expect that observations or recordings are not taking place, and the information will not be made public. Information must be individually identifiable to constitute human subjects research.
- Research using human specimens or data. Human subjects research involving individually identifiable human specimens or data and subject to federal and state regulatory requirements. For example, this would include research on living persons using:
- Bodily materials such as cells, blood, urine, tissues, organs, hair or nail clippings, even if collected by others.
- Residual diagnostic specimens, including those from routine patient care, that are kept for research rather than discarded.
- Private information, such as medical or genetic information, even if collected for another study.
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.
If you still have questions about whether your application has human subjects, ask your institutional review board (IRB) or independent ethics committee (IEC) before writing your application. NIH recommends that you not determine whether research involves human subjects on your own.
When applying for a grant involving human subjects research, check "yes" for human subjects on the application face page.
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 on this page, 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.
If your program officer agrees that an exemption applies, do the following:
- Justify the exemption in the Protection of Human Subjects section of the PHS (Public Health Service) 398 Research Plan component of the grant application.
- Resolve any concerns for human subjects protections to NIH 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.
- Rarely, NIAID will return your application if you claim an exemption and it is incorrect or improperly justified; however, your justification may affect your overall impact 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 fact in your plan.
- For all exemptions, your Research Plan must state that you know the criteria for including or excluding any subpopulation.
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 Research Training SOP.
- Submit completed Planned Enrollment Report and Cumulative Inclusion Enrollment Report when appropriate. Learn more about Inclusion of Special Populations: Women, Minorities, and All Ages.
Follow these NIAID policies and processes.
- Investigator-initiated clinical trials (IICT). When applying for an IICT (not through a request for applications), you must follow our process. See the Investigator-Initiated Clinical Trials Resources and Clinical Trial Research page for more information.
- Opportunity-specific requirements. Opportunities often have unique requirements, so read the announcement carefully. The opportunity announcement’s 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 we require grantees to take when conducting clinical research.
NIH and Other 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.
- For applications, see Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the SF 424 Form Instructions.
- For progress reports, see NIH and Other PHS Agency Research Performance Progress Report (RPPR) Instruction Guide.
- Non-NIH rules. Other laws and regulations may apply to your application and award. Be familiar with the ones that apply to your situation.
- HHS regulations in 45 CFR 46, 45 CFR 74, and 45 CFR 92. Also see Food and Drug Administration (FDA) 21 CFR.
- 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. Consult the following resources:
- International Compilation of Human Subjects Research Protections.
- ClinRegs for country-specific clinical research regulatory information, including comparison information, presented in plain language.
Before NIAID can issue a human subjects award, your organization must do the following:
- Obtain a Federalwide Assurance (FWA) from the Office for Human Research Protections.
- Avoid financial conflicts of interest.
- Follow the NIAID process for investigator-initiated clinical trials. Learn more at Investigator-Initiated Clinical Trial Resources.
- 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 these items further 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.
- To register, update, or renew an FWA, go to Electronic Submission System for Federalwide Assurances and IRB/IEC Registrations.
- For help, read
- File a New Federalwide Assurance (FWA)
- Step-by-Step Instructions for Filing a Federalwide Assurance for International (Non-U.S.) Institutions
- Read the FWA descriptions of domestic and international institutions
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.
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:
- 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 Financial Conflict of Interest: HHS Guidance.
- 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. For details, read our Financial Conflicts of Interest for Awardees 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 must comply with the NIH Single IRB Policy for Multi-Site Research.
For international awards, see the section International Research Requirements below.
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 see the Informed Consent Frequently Asked Questions from the Office for Human Research Protections.
Note that for NIH-funded or supported clinical trials, you must post informed consent documents on a public federal website after recruitment closes and no later than 60 days after the last study visit. Learn more at Posting Clinical Trial Informed Consent Forms. For additional guidance, see Informed Consent Questions and Answers.
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 website 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 Guidance on IRB Review of Clinical Trial Websites.
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 are 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.
IRB and IEC Requirements
If you're applying from a foreign country, read the Get IRB or IEC Approval section of this page 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 Assurance Requirements
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.
Know Which Documents To Include
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 a clinical trial application, include all documentation needed to start the trial in the application. Attach a Dissemination Plan to the NIH Human Subjects and Clinical Trials Information form to address how you will meet the expectations of the NIH Policy on Dissemination of NIH-Funded Clinical Trial Information.
If you have questions, contact the program officer listed in the announcement.
Develop Your Human Subjects Research Plan
The human subjects section of your Research Plan has five sections.
Follow the instructions in the SF 424 Form Instructions, 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:
- Protection of Human Subjects
- Risks to Human Subjects
- Adequacy of Protection Against Risks
- Potential Benefits
- Importance of Knowledge to be Gained
- Data and Safety Monitoring Plan (See the Design Your Data and Safety Monitoring Plan section)
- ClinicalTrials.gov Requirements (See the Before You Enroll Patients section)
- If you are proposing a new applicable clinical trial, include a statement certifying you have registered with ClinicalTrials.gov. Follow the instructions on NIH's Requirements for Registering & Reporting NIH-funded Clinical Trials in ClinicalTrials.gov.
- Inclusion of Women and Minorities
- Phase III Clinical Trials
- Planned Enrollment Report
- Inclusion Across the Lifespan
- Explain why your proposed age range is appropriate in the context of the scientific question you propose. Provide a scientific or ethical rationale for the exclusion of children or any other age group.
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 overall impact score or result 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 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:
- 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. See DSMB information at NIAID Clinical Research Guidance, Policies, and Standard Operating Procedures.
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, 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 more information, see the NIAID Clinical Trial Monitoring SOP and Clinical Trial Safety Monitoring and Reporting Requirements flowchart.
Know reviewers' criteria and concerns.
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.
These assessments are independent of your IRB or IEC.
If Reviewers Have Concerns
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 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:
- Sources of materials, such as where data and specimens come from, are not specified.
- Human subjects section is missing or incomplete.
- Risks or protections are not adequately addressed.
- Informed consent issues are not fully addressed.
- Confidentiality and human genetic issues are not adequately addressed.
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 for Applications. 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.
Talk to your program officer about documents you will need to submit.
Submit Documents Just-in-Time
Before issuing your Notice of Award, we may require that you submit additional documents just-in-time, just before we make an award. Read more on that process at Responding to Pre-Award Requests ("Just-in-Time").
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:
- 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
- For domestic sites of multi-site studies where each site will conduct the same protocol involving non-exempt human subjects research funded by NIH, a single IRB carries out the IRB review requirements at 45 CFR Part 46 for participating sites of the multi-site study. See NIH Single IRB Policy for Multi-Site Research.
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 managing 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 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 FDA Good Clinical Practice and International Council for Harmonisation Guidelines. Use the FDA All Guidances for Drugs page and search for additional guidance under the “International Council for Harmonisation” topics.
Your protocol must 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
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 the sIRB or IEC approved the protocol and informed consent document.
Include the version number or date approved and dates for which these documents are valid.
Certificate of Confidentiality (CoC). A CoC 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.
NIH will automatically issue a Certificate of Confidentiality through a term and condition of award. For more information, go to the NIH Certificates of Confidentiality (CoC) website.
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 NIH's Data and Safety Monitoring of Clinical 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.
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 a Food and Drug Administration (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, the FDA IND or IDE number, any written comments from 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.
rDNA Institutional Review Board Approval
If your application transfers recombinant DNA, or DNA or RNA derived from recombinant DNA, into research participants, you'll need additional approvals from your institutional biosafety committee, FDA, and your IRB or IEC.
For more information, go to the NIH Guidelines for Research Involving Recombinant DNA Molecules website.
Document Training in the Protection of Human Subjects
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.
Check with your institution to see if it provides this training.
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.
Verify Your Federalwide Assurance
Before we can issue an award, your institution must file a human subjects Federalwide Assurance (FWA) with the OHRP. Go to the Obtain a Federalwide Assurance section of this page for details and see the OHRP list of approved assurances and registered IRBs/IECs.
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 Responding to Pre-Award Requests ("Just-in-Time").
Register With ClinicalTrials.gov
You must register applicable clinical trials on ClinicalTrials.gov and upload your data annually, in accordance with the NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information. Additional requirements are described below in the Manage Your Award section.
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 ICMJE’s Clinical Trial Registration policy.
IRBs and IECs Have Ongoing Responsibilities
The IRB and relevant 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 OHRP registration number, and FWA 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:
- OHRP Guidance on Continuing Review
- HHS regulations at 45 CFR 46.103(b)(4)
- Your institution's OHRP-approved FWA
For more, see NIAID Human Subjects Certifications: IRB or IEC SOP.
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 your program officer if 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
IRB or IEC Actions
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, the sIRB or IEC should review and approve the protocol. The sIRB 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 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.
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 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.
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 HHS 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 Science Policy 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 report 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 the sIRB 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 10 working days by email or fax, followed in 30 days by an official letter.
For more information, read OHRP guidance:
- Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events—review and reporting of unanticipated problems involving risks to subjects and adverse events
- Guidance on Reporting Incidents to OHRP—whether to report an incident, information to include, timelines, and other important items
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. Learn more about inclusion at Inclusion of Special Populations: Women, Minorities, and All Ages.
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:
- 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 Cumulative Inclusion Enrollment Report form to provide analyses showing the intervention differences among those groups.
Use the Human Subjects System (HSS) in the eRA Commons to complete these requirements. Note that you must update inclusion data records included with progress reports into the enrollment format supported by HSS, even if no new enrollment occurred in the past year.
For more information on HSS and how and when to use the Enrollment Report, read these NIH resources:
- NIH Inclusion of Women and Minorities as Participants in Research Involving Human Subjects
- NIH Inclusion Across the Lifespan
- eRA Human Subjects System (HSS)
- 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 Requirements for Registering & Reporting NIH-funded Clinical Trials in ClinicalTrials.gov.
To submit data annually or to register, go to FDAAA 801 and the Final Rule. 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 Requirements for Registering & Reporting NIH-funded Clinical Trials in ClinicalTrials.gov.