NIH Investigator Manual for Human Subjects Research

Welcome to the online version of the NIH Investigator Manual for Human Subjects Research (MS Word document - 1.56 MB), published on September 6, 2022.

Please use the Table of Contents below, or links in the menu to navigate the manual.

Table of Contents

• Introduction

• Chapter 1 - Types of Research: Human Subjects Research Vs. Not Human Subjects Research
  
  • Overview
    • Key points
      • What does the term research mean?
      • What does the term human subject mean?
      • What does the term human subjects research mean given the explanations for research and human subjects above?
      • How do I know if my research is human subjects research?
      • Does secondary research with specimens and/or data need IRB review?
      • Where can I find additional information about secondary research and repositories?
  • Human subjects research that is exempt from IRB review
    • Key points
      • Can my human subjects research study be considered exempt from IRB review?
      • Does my QA/QI project require IRB review?
      • If I am planning a program evaluation, do I need to submit for an exemption or IRB approval?
      • How do I submit a request for exemption if I believe my research should be considered exempt human subjects research?
      • Where can I find resources about exempt research or information to help me submit a request for an exemption determination to the NIH IRB?
  • Types of IRB review of Non-exempt Human Subjects Research
    • Key points
      • If my human subjects research is not eligible for an exemption, is it eligible for expedited IRB review?
      • When does my human subjects research require review by the convened IRB?
      • What criteria must my non-exempt human subjects research meet to be approved by the IRB?
      • What options does the IRB have when deciding whether to approve my research when it is reviewed by the full Board?
• Chapter 2 - Roles and Responsibilities of the Principal Investigator
  • Overview
    
    • Key Points
      • What are the basic principles that inform the conduct of ethical human subjects research?
      • What is required to become a PI?
      • What are the general responsibilities of the PI?
      • What are the requirements for PI's regarding delegation of responsibilities?
      • Where can I find additional information about PI responsibilities?
• Chapter 3 – Obtaining and Preparing Required Documents for IRB Initial Review
  • Overview
    • Key points
      • Where can I locate a protocol template when writing my protocol for IRB submission?
      • What format should I use for my protocol when I submit to the IRB?
      • How do I name my protocol documents when submitting to the IRB?
      • Who is listed on the Study Personnel Page (SPP)?
      • What is my responsibility as PI to ensure only authorized study personnel obtain consent?
  • Recruitment Plan
    • Key points
      • What are the responsibilities of the PI for recruitment and subject correspondence?
      • What are my responsibilities for recruitment materials for FDA-regulated research?
      • What material may be used for recruitment?
      • What information should be included in recruitment material?
      • What must not be included as part of recruitment materials?
      • What is the NIH Office of Patient Recruitment?
      • What needs to be considered if 3rd party vendors will be used for recruitment or screening purposes?
  • Plan for Screening and Enrollment
    • Key points
      • What screening information should be included in my research protocol?
      • What screening activities can be conducted prior to obtaining informed consent from the prospective participant?
      • What screening activities are conducted after obtaining informed consent from the prospective participant?
  • Description of the research to be conducted
    • Key points
      • What information specific to my interventional research study needs to be included in the protocol?
      • What else should I include in my protocol if I am conducting a natural history or observational trial?
  • Collection and storage of data to preserve participant privacy and confidentiality
    • Key points
      • What information about data collection, storage and management should I include in my research protocol?
      • What should I know about information security requirements as they pertain to the collection and storage of study data?
  • Data and Safety Monitoring Plan
    • Key points
      • What is a Data and Safety Monitoring Plan?
      • What may be included in the written Data and Safety Monitoring Plan?
      • What is a Data and Safety Monitoring Entity?
  • Compensation for Research Participation
    • Key points
      • What are my responsibilities regarding compensation of research subjects?
  • Description of the consent process in the protocol
    • Key points
      • What information needs to be included in the protocol about the planned consent process?
      • What must be included in the protocol if an electronic platform will be used to document signature?
      • What information must be included in the protocol if a waiver or alteration of consent is being requested from the IRB?
      • Is waiver or alteration of consent permitted for FDA regulated research?
      • When can documentation of consent be waived, and what information must be included in the protocol if waiver of documentation of consent is being requested?
      • When is waiver of informed consent not permitted?
  • Additional reviews that may be required and resource information
    • Key points
      • What is a concept review?
      • How is the IRP Scientific Review conducted?
      • What is the PRIA?
      • What if my protocol will be a multisite study?
      • What do I need to do if my protocol involves an investigational test article (e.g., drug, biologic, or a device)?
      • What type of Ancillary Reviews may be needed?
      • Are there any other resources that provide helpful information about submitting my protocol to the NIH IRB?
• Chapter 4 - Writing Your Consent Document
  
  • Overview
    
    • Key points
      • What does informed consent mean and what is its purpose?
      • What ethical concerns should I think about when writing the informed consent document?
      • What information am I required to have in my consent form?
      • In addition to the information in the consent form that is required by regulation, what other information might need to be included?
      • What information must be included in the informed consent document for FDA-regulated research, as appropriate?
      • What is the key information section of the consent form, and what should be included in that section?
      • What is the reasonable person standard and how does it affect writing the consent form?
      • In what format do I submit my proposed consent in the electronic IRB system and what grade reading level should I target?
      • What should I know about the consent process if I will be enrolling children in my study?
      • Where can I find information about creating an assent form for use with minors who I hope to enroll on my study?
• Chapter 5 - Submitting Your Initial Review
  
  • Overview
    
    • Key Points
      • What forms and documentation do I need to provide with my submission for initial review of my protocol by the IRB?
      • Once I submit my Initial Review for non-exempt human subjects research in the electronic IRB submission system, what happens next with my submission?
• Chapter 6 - Things To Do After IRB Approval But Before Starting Enrollment
  
  • Overview
    
    • Key points
      • What forms or documents need to be ready before the start of enrollment?
      • What additional actions should be completed before beginning enrollment?
• Chapter 7 - Conducting Your Study
  
  • Overview
    • Key points
      • What do I need to know about the consent process?
      • What is the process for obtaining remote consent by phone or virtual platform?
      • For enrollment of subjects who do not read English, what is the difference between using a translated long form consent and using the short form consent process?
      • What else do I need to know about using a short form consent process?
      • How is the consent process conducted when a translated long form is used?
      • What do I do when the potential subject speaks and understands English but is blind or illiterate?
      • What should I do when conducting consent with a potential subject who does not speak English and for whom there is no written language?
  • Consent process when participants are considered a vulnerable population
    • Key points
      • What other considerations about the consent process exist when doing research with pregnant persons?
      • What other considerations about the consent process exist when doing research with prisoners?
      • What other considerations about the consent process exist when doing research with children?
      • What does it mean to obtain a child's assent to participate in my research study?
      • How should assent by the minor subject for research participation be documented?
      • What is the process regarding consent when minor participants on my study reach adulthood?
      • Can parental or guardian permission for research involving children be waived?
      • What considerations about the consent process exist when doing research with adults who lack capacity to consent to research participation?
      • What other considerations about the consent process exist when doing research with NIH Staff?
  • Documenting information in the medical and/or research records
    • Key points
  • Record retention
    • Key points
      • What are my overall responsibilities as an investigator for maintaining research records and for retaining them after study completion?
      • What are my responsibilities for maintaining records when my protocol is FDA regulated?
  • Data and Safety Monitoring
    • Key points
      • What are my responsibilities as a PI regarding the Data and Safety Monitoring Plan (DSMP) described in my non-exempt human subject research protocol?
  • Suspension or termination of research activities by the IRB
    • Key points
      • What does it mean if the IRB suspends or terminates my protocol?
  • Administrative hold or early study closures by other entities
    • Key points
      • What circumstances may warrant early closure of a research study (e.g., by the PI, the DSMB or the Sponsor)?
      • What happens if my research study is temporarily halted or prematurely terminated by an entity other than the IRB?
      • If my non-exempt human subjects research protocol is prematurely closed, what are the requirements for submission of study closure documents?
  • Maintaining your Regulatory Binder
    • Key points
      • What is a Regulatory Binder?
      • What forms should my Regulatory Binder contain?
      • Who is responsible for maintaining the Regulatory Binder?
      • What guidelines should I follow for maintaining my Regulatory Binder?
  • Subject complaints and communicating with subjects
    • Key points
      • How are subjects informed about who to contact if they have a research related complaint?
      • What should I do if I get a complaint from a subject participating in a study for which I am an investigator?
      • What if the subject tells me they want to keep the complaint confidential?
      • If I am the PI, to whom do I report the subject complaint?
      • In addition to the notifications above, what do I do if I think that the subject's complaint may result in a public relations concern?
      • What mechanisms can I use to electronically communicate with study participants?
• Chapter 8 - Subject Withdrawal from Research
  
  • Overview
    
    • Key points
      • What does it mean when a participant withdraws from all parts of my research study that is not FDA regulated?
      • What happens when a participant wants to withdraw from the primary intervention of the study but wishes to continue other research activities?
      • What happens if, as an investigator, I decide to terminate a participant's participation out of concern that the primary research intervention is exposing the participant to an unacceptable level of risk?
      • What should be documented when a participant withdraws from a research study?
      • May I retain and analyze date already collected about a participant who withdraws from my research study or whose participation is terminated by the investigator?
      • Can investigators honor participants' requests to have their data excluded from any analysis?
      • What are investigator responsibilities when a participant withdraws from a research study that is FDA regulated?
• Chapter 9 - Reporting Research Related Events or New Information to the IRB
  
  • Overview
    
    • Key points
      • Which research related events need to be reported to the IRB (Compliance and Training) in an expedited timeframe when NIH is the Reviewing IRB?
      • When NIH is the Reviewing IRB, which research related events should be reported to the IRB at the time of the continuing review submission?
      • If NIH is not the Reviewing IRB, what do NIH investigators need to report to the Reviewing IRB and what needs to still be reported in the NIH electronic IRB system?
      • Which research related events need to be reported to the FDA?
      • What happens once I have submitted an event report in the electronic IRB system within the required expedited time frame?
      • What is the RCRC?
      • Are there any specific considerations I should think about when completing an event report in the electronic IRB system?
      • Where can I find additional information about reporting research related events to the IRB?
• Chapter 10 - Protocol Modifications
  
  • Overview
    • Key points
      • What are my responsibilities as a Principal Investigator (PI) when submitting documents to the IRB for a modification?
      • What are the required materials that I must submit for modifications to my exempt human subjects research study?
      • What are the required materials that I must submit for an modification to my non-exempt human subjects research study?
      • What are the required materials that I must submit for modifications to my non-exempt human subjects research study when adding a participating site to initiate multi-site research or to expand any existing multi-site protocol?
      • If required Human Research Protection Program (HRPP) training is not up to date/current or if I am adding a new AI, will the modification undergo IRB review?
      • What format should I use for my protocol and/or consent form when submitting an modification?
      • What is the process when changes to the protocol require approval by other committee(s) as part of an modification submission?
      • What happens after the IRB receives my submission for an modification?
      • What determines whether my modification will get expedited review vs. full board review?
      • What happens when my modification to my non-exempt research study undergoes Full Board Review?
• Chapter 11 - Continuing Reviews (CR)
  
  • Overview
    
    • Key Points
      • What is a Continuing Review?
      • Why is Continuing Review required?
      • When does a protocol require a Continuing Review?
      • What protocols only require an Annual Progress Report instead of a full CR?
      • How often must my protocol go through Continuing Review?
      • What happens if the continuing review is not approved by the expiration date and there is a lapse in IRB approval?
      • What forms must be submitted in the electronic IRB system for a Continuing Review?
      • What happens after the IRB receives my CR submission?
• Chapter 12 - Study closures (routine)
  
  • Overview
    
    • Key points
      • What is Study Closure?
      • When can my non-exempt human subjects research study be closed?
      • What happens when studies are closed because all study activities are complete?
• Chapter 13 - Conducting Research With Special Populations
  
  • Pregnant women
    • Key points
      • What conditions must be met for enrollment of pregnant women, fetuses or neonates in trials supported or conducted by Health and Human Services (HHS)?
      • What should be considered when research involves pregnant women and has prospect of direct benefit?
      • What should be considered when research has no prospect of direct benefit to the mother or the fetus?
      • When the study does not enroll pregnant women but is greater than minimal risk, what do I need to include in the protocol about what will happen if a participant gets pregnant on study?
  • Prisoners
    • Key points
      • How do the regulations define prisoner?
      • What are the specified categories of research involving prisoners that are permitted under regulation?
      • Can exempt research involve prisoners?
      • What are my responsibilities as an Investigator when anticipating the enrollment and participation of prisoners on my research protocol?
      • What are my responsibilities as an Investigator when a subject becomes a prisoner after enrollment on my research protocol not previously reviewed and approved by the IRB for prisoner participation?
      • Can informed consent be waived or altered in research involving prisoners?
      • Where can I find additional information about conducting human subjects research with prisoners?
  • Children
    • Key points
      • How do the human subject research regulations define children?
      • What should I know about enrolling a child who is legally emancipated?
      • What is a ward and do special regulations apply to conducting human subjects research with children who are wards (of the state or other agency institution, or entity)?
      • What are the categories of research involving children and who can approve this research?
      • What are my responsibilities when enrolling a child on my research protocol?
      • What are my responsibilities for obtaining parental permission and assent from a minor subject when I will be enrolling children in my study?
      • Can children be enrolled in exempt research?
  • Adults who lack capacity to consent to research
    • Key points
      • What must be incorporated in my research study to allow for enrollment of adults who lack capacity to consent to research?
      • What are the categories of research for adults who lack capacity to consent to research participation?
      • What are my responsibilities as an investigator before enrolling a subject who may lack capacity to consent to my research protocol?
      • What should I do if my research study was not previously approved by the IRB for the participation of subjects without capacity, and a subject who was previously able to provide consent subsequently loses capacity to provide ongoing consent?
      • What resources are available at the Clinical Center to help guide me when enrolling potential subjects who may not have the capacity to consent?
  • NIH Staff
    • Key points
      • What must be done prior to enrolling NIH staff member on my research study?
• Chapter 14 - FDA Regulated Research
  
  • Overview
    • Key Points
      • What is FDA regulated research?
      • How does the FDA define research within the context of human subjects research?
      • What is a sponsor with regard to FDA regulated research?
      • What are my responsibilities if I am an investigator on an FDA regulated study?
    • Research with FDA regulated drugs or biologics
      • How do I know if my study includes an FDA regulated drug or biologic?
      • What is an Investigational New Drug Application (IND)?
      • What if my study is FDA regulated but I think my study should be considered IND Exempt?
      • What information must I provide to the IRB if I think use of the study drug or biologic is IND Exempt?
      • What is the FDA Form 1572 and why is it important?
      • As the investigator, what FDA-specific reports are required when my protocol is conducted under an IND?
      • If I am reporting an event to the sponsor, does the event also need to be reported to the IRB?
      • What are my responsibilities for maintaining records when my FDA regulated research protocol involves drugs?
    • Research with FDA regulated devices
      • What is a medical device?
      • How do I know if my study includes an FDA regulated investigational device?
      • What does the term IDE mean?
      • If my study includes an investigational device, what criteria need to be met to make use of the device in my study exempt from the Investigational Device Exemption (IDE) regulations?
      • What information must I provide to the IRB if I think my device is IDE Exempt?
      • If my study includes an investigational device, when does my device fall under IDE regulations?
      • What type of device information is required for my protocol?
      • As the investigator, what FDA specific reports are required when my protocol includes an IDE?
      • What are my responsibilities for maintaining records when my FDA regulated research protocol involves devices under IDE regulations (SR and NSR Devices)?
    • Expanded Access
      • What is Expanded Access and is this an option for patients who are not eligible for my trial?
      • What information must be documented in order for a patient to be eligible for expanded access use of a test article?
      • Do expanded access protocols, require prospective IRB review and approval?
      • If I am conducting an expanded access protocol, do I need to submit reports to FDA or the IRB?
      • Where can I get more information about Expanded Access?
• Chapter 15 - International Research
  
  • Overview
    • Key Points
      • What ethical considerations may exist when human subjects research is conducted internationally?
      • What is cultural competence and what cultural considerations exist when human subjects research is conducted internationally?
      • What are the regulatory requirements for international research, and where can I find information on these regulations?
      • When NIH is conducting international research, are the in-country review committees (Ethics Committees) subject to any specific regulations?
      • What if the NIH IRB is the Reviewing IRB?
      • What if the study is being completely conducted and overseen locally and I am only collaborating in the data analysis?
      • What if I am supporting international research but I am not actually engaged in human subjects research myself?
      • What approvals need to occur before NIH investigators engage in international research?
      • What information must be included a protocol and consent being submitted to the NIH IRB if any research will be conducted in another country?
      • What are the requirements for shipping test articles and biospecimens internationally?
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