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NIAID Human Subjects Application and Grant Handbook

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.

Table of Contents

Are You Conducting Human Subjects Research?

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 or the PHS 398.

Determine if Your Study Involves Human Subjects

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 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.

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 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.

When Your Research Is Exempt

If your program officer agrees that an exemption applies, do the following:

  • Justify the exemption in the Protection of Human Subjects section of the 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.
    • 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/priority 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 Certifications: Training SOP.
  • Submit completed Planned Enrollment Report and Cumulative Inclusion Enrollment Report when appropriate.

Additional Resources

Overview of Requirements

Follow these NIAID policies and processes.

NIAID Requirements

  • Investigator-initiated clinical trials. When applying for an investigator-initiated clinical trial, you must go through our process (which does not apply if you are responding to a request for applications).
  • 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 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.
    • Paper applications—Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the PHS 398.
    • Electronic applications—Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the SF 424 Application Guide.
    • RFA or PA—If responding to a request for applications or program announcement, read the notice. If requirements differ from the application instructions, the RFA or PA takes precedence.
    • PHS 2590 Non-Competing Grant Progress Report.
  • 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. Consult the following resources:

Finding Help at NIAID

NIH staff play different roles each step of the way.

  • When planning the application, go to Communicating With NIAID—How to Get Help in the Strategy for NIH Funding 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 Communicating With NIAID—How to Get Help in the Strategy for NIH Funding.
  • 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 questions about your grant.

Additional Resources

Planning and Writing Your Application

Follow these NIAID policies and processes.

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 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.

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:

Investigator-Initiated Clinical Trials at NIAID

We summarized NIAID's required process at NIAID Requirements. For more information, go to Investigator-Initiated Clinical Trial Planning and Implementation Awards SOP.

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, 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

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 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.

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, 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.

Develop Your Human Subjects Research Plan

The human subjects section of your Research Plan has five sections.

Follow the instructions in the SF 424 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 application instructions.

Create a header for each section and subsection:

  1. Protection of Human Subjects
  2. Inclusion of Women and Minorities
  3. Phase III Clinical Trials
  4. Planned Enrollment Report
  5. 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 overall impact/priority 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. 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.

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.

Phase III

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.

Additional Resources

Special Populations: Women, Children, Minorities

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.

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 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.

Additional Resources

How Human Subjects Applications Are Reviewed

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—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 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:

  • 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.

Go to "Know the Top Reasons You May Get a Human Subjects Bar to Award" in the NIAID Funding Newsletter.

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.

Before You Enroll Patients

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. 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:

  • 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 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:

  • 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 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 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.

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 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 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 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 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.

Additional Resources

Register With ClinicalTrials.gov

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.

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 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 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:

  • 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 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.

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 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 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 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 Cumulative Inclusion Enrollment Report Form

As part of your reporting requirement, you must submit a Cumulative Inclusion Enrollment Report, which shows the cumulative accrual and demographic information of participants enrolled in your study.

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, send in the Cumulative Inclusion Enrollment Report semi-annually. For other clinical studies, send it with your progress report. Note: for progress reports with award dates after October 1, 2014, use the Cumulative Inclusion Enrollment Report. For progress reports with award dates before October 1, 2014, use the Cumulative Inclusion Enrollment Report (PHS 2590 forms).

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.

Send it with your annual progress report. For more detailed instructions, see the SF 424 Application Guide for your grant application package for electronic applications. For paper applications, see the PHS 398.

For more information on 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.

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

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?

Additional Resources

Clinical Terms of Award Checklist

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.

Additional Resources

More Human Subjects Links

In addition to reading the SF 424 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.​​​

Last Updated October 01, 2014

Last Reviewed April 04, 2012