NIH Investigator Manual for Human Subjects Research

• Created by Swan, Jeremy (NIH/NICHD) [C], last modified by Pauly, Kelly (NIH/OD) [E] on Mar 20, 2024

Chapter 3 - Obtaining and Preparing Required Documents for IRB Initial Review

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Overview

Key points

• Investigators should use the protocol and consent templates that are available on the OHSRP website IRB Templates page.
  
  
• Some ancillary reviews must be completed prior to IRB review and/or approval of the protocol.

Where can I locate a protocol template when writing my protocol for IRB submission?

• Protocol templates can be accessed via this link to Protocol Templates and Forms on the OHSRP website. None of the templates are likely to be perfect for a given study without some modification. You should adapt the template to suit your needs.
  
  
• A protocol must contain a description of the research activities occurring at each site. If the study will be multi-site, see the section below regarding multi-site research. The IRBO website contains many different protocol templates for developing a variety of different new research protocols. The protocol templates available for use are listed below:
  • Interventional Drug and Device Clinical Trials Protocol Template
  • Behavioral and Social Science Research Protocol Template
  • Secondary Research Protocol Template
  • Repositories Protocol Template
  • Natural History and Observational Trials Protocol Template
  • Retrospective Data or Biospecimen Review (Request for Exemption) Protocol Template
  • Collecting Prospective Data from Humans (Request for Exemption) Protocol Template

What format should I use for my protocol when I submit to the IRB?

• The protocol must be submitted in Microsoft word. 
  
  
• When submitting documents to the IRB, each electronic regulatory file must have a consistent format, including naming of folders and files, to ensure required information is maintained and easily accessible.

How do I name my protocol documents when submitting to the IRB?

• For proper nomenclature study teams are required to use when submitting documents to the NIH IRB refer to the OHSRP webpage How to Name Documents for Submission which outlines protocol, consent and other study document nomenclature. 

What is my responsibility as PI to ensure only authorized study personnel obtain consent?

• You must ensure that investigators delegated to obtain informed consent are qualified to obtain informed consent (e.g., based on familiarity with the protocol, research, clinical experience, and qualifications) and have completed appropriate training per Policy 103, Education Program and other NIH requirements as applicable.
  
  
• Except as described below, Visiting Fellows, Intramural Research Training Awardees (IRTAs), and Cancer Research Training Awardee (CRTAs) serving as Associate Investigators may observe or participate in the informed consent process only if they are under direct and constant supervision by a qualified NIH federal employee investigator. These trainees may not sign the informed consent document. (See Policy 300 Investigator Responsibilities and  2300-320-7 – Intramural Research Training Award (IRTA) Program 
  • Post-doctoral IRTAs/CRTAs and post-doctoral VFs who are Associate Investigators may obtain the informed consent of a prospective subject without the presence of a qualified NIH federal employee investigator after sufficient training by the PI about the protocol. The post-doctoral IRTA/CRTA or post-doctoral VF must be knowledgeable, and be able to explain, about the protocol and all of the information contained the informed consent document and be capable of addressing all subject questions. In addition, to be eligible to obtain consent, the post-doctoral IRTA/CRTA or post-doctoral VF must have also completed Elements of a Successful Informed Consent course and the validated Objective Structured Clinical Examination (OSCE) for the Informed Consent Process offered by the NIMH Human Subjects Protection Unit (HSPU). 
    
    
• Those designated to obtain informed consent must be identified in the electronic IRB system prior to initiating informed consent.

Recruitment Plan

Key points

• Recruitment activities and materials are intended to provide prospective study subjects with their first introduction to the research study and are considered part of the process of informed consent.
  
  
• Recruitment of subjects will not commence prior to IRB approval of the research protocol.
  
  
• The plan for recruitment of subjects will promote the fair and equitable selection of subjects.
  
  
• The recruitment plan will be described in the protocol and the relevant recruitment material will be provided to the IRB for review.
  
  
• NIH investigators, or their supporting Institute or Center (IC), are not permitted to provide or receive finder's fees (e.g., payment in exchange for referrals of individual prospective research subjects, which are sometimes referred to as "recruitment incentives") from any source in connection with research conducted by the NIH.
  
  
• Additional information about subject recruitment can be found in the OHSRP Guideline for Recruitment and Screening of Participants listed under Policy 302, Recruitment and Compensation on the HRPP Policy and Guidelines page of the OHSRP website.

What are the responsibilities of the PI for recruitment and subject correspondence?

As PI, you must ensure the following are met for a protocol's recruitment plan:

• Benefits and burdens of research should be distributed fairly, and no specific population should be unfairly targeted or excluded.
  
  
• Include a description of a fair and equitable recruitment plan in your protocol (e.g., intended populations and cohorts, and methods for recruitment). Ensure that the recruitment plan is clearly described in the protocol so that the IRB can determine whether the proposed process respects potential subjects' autonomy, is not coercive, and does not subject the potential participant to undue influence.
  
  
• The recruitment plan should reflect the populations that have the disease or condition under study. For example, if the condition being studied is prevalent in African Americans, then the recruitment strategy must include efforts to enroll these persons.
  
  
• Prospectively submit all recruitment materials to the reviewing IRB via the electronic IRB system for review and approval (e.g., either at the time of initial submission or as an amendment if new materials are added).
  
  
• Verify that recruitment materials directed at prospective subjects are limited to the information needed to determine subject eligibility and interest in participation.

What are my responsibilities for recruitment materials for FDA-regulated research?

Ensure that recruitment materials for FDA-regulated research meet the following requirements:

• State that the test article (drug, biologic, or device) is investigational.
  
  
• Do not make claims, either explicitly or implicitly, that the test article is safe or effective.
  
  
• Do not make claims that the test article is known to be equivalent or superior to any other drug, biologic, or device.
  
  
• Do not promise "free medical treatment or care" when the intent is only to inform subjects that they will not be charged for participating in the study.
  
  
• Additional information regarding recruiting study subjects is described in the FDA information sheet, Recruiting Study Subjects - Guidance for Institutional Review Boards and Clinical Investigators.

What material may be used for recruitment?

Examples include:

• Publicly posted recruitment material: For example, advertisements, posters or flyers, or directed advertising such as posting study recruitment materials in a location where it will be seen by those possibly eligible for participation (e.g., flyer/poster placed in clinics where patients receive care specifically for the disease being studied in the research).
  
  
• Direct recruitment (e.g., physicians talk to their own patients about the study): In this case, it is preferable that a knowledgeable investigator from the study team who is not providing direct care for the patient approach the potential participant to discuss the study in order to prevent undue influence or pressure on the potential participant.
  
  
• Recruitment letters: Communications sent to prospective participants should indicate how the individual was identified and include study information and a contact person who can provide additional details.
  
  
• Referrals: Clinicians who are not part of the research can provide their patients who are potentially eligible for the protocol with IRB approved recruitment materials or letters that describe the study. The potential participant, if interested, can then contact the NIH investigator directly. Alternatively, after obtaining any required authorization, the clinician who initiated the discussion may share the potential participant's contact and relevant health information with investigators so that they can contact the individual directly. The referring clinician may not answer questions about the study nor obtain the informed consent of the participant, unless they are part of the study team (i.e., they must be included as an investigator on the IRB approved protocol, and if they will obtain consent, they must have IRB approval for this activity).
  
  
• Websites: Informed consent must be obtained for the collection of any information about the respondent unless the IRB has determined that the informed consent requirement can be waived. A mockup of the proposed website should be submitted for prospective IRB review. OHRP, in its guidance on IRB review of clinical trial websites, notes the following: "Some clinical trial websites ask viewers to answer questions regarding eligibility for a specific clinical trial. If identifiable private information is collected via the clinical trial website, the IRB should review plans for protecting the confidentiality of that information. The IRB should ensure that the website clearly explains how identifiable private information might be used."

What information should be included in recruitment material?

• You must ensure that the protocol and recruitment materials are consistent. For example, for a Phase 1 study, does the recruitment material(s) make it clear that the research is only intended to evaluate the safety and not the efficacy of the investigational product?
  
  
• Recruitment materials should be balanced and fair. These materials should include information that prospective participants need to determine interest and eligibility and should include all of the following:
  • A clear statement that the study is a research study.
  • Name of the investigator conducting the research and their affiliation such as the specific NIH IC (e.g., NIH National Cancer Institute).
  • The purpose of the research and/or condition under study.
  • Summary of eligibility criteria.
  • A brief discussion of what study participation involves (duration of the study, number of study visits/time commitment, study procedures).
  • Research location.
  • Person or office to contact for further information.
  • Materials may also include a brief list of significant risks, if any, and a brief list of possible benefits, if any, and payment information, if applicable.

What must not be included as part of recruitment materials?

Recruitment materials must not:

• State or imply a certainty of a favorable outcome or other benefits beyond what is described in the protocol consent.
  
  
• Include exculpatory language (language which has the general effect of freeing or appearing to free an individual or an entity from malpractice, negligence, blame, fault, or guilt).
  
  
• Emphasize payment or the amount to be paid (e.g., use of larger or bold type font).

What is the NIH Office of Patient Recruitment?

The NIH Clinical Center Office of Patient Recruitment serves to educate the public about clinical trial participation at the NIH Clinical Center in Bethesda, MD. Its mission is to support the research performed at the Clinical Center by coordinating the referral process as the primary point of contact between those seeking to volunteer in clinical studies and the researchers conducting them.

What needs to be considered if 3^rd party vendors will be used for recruitment or screening purposes?

If the study team plans to use a 3^rd party vendor for recruitment purposes (e.g., Buildclinical, Qualtrics) and that entity will be collecting personally identifiable information from potential participants, investigators must take the following steps:

1. Contact the IC Information Security Office and provide them with the relevant information so that they may determine that all NIH information security requirements are met.
   
   
2. Review the vendor's terms of service and privacy policy to ensure they are consistent with NIH policy and do not include terms that might place potential research participants at risk (such as disclosure of sensitive information to law enforcement).
   
   
3. Contact your IC Privacy Officer to determine whether a Privacy Impact Analysis is needed.
   
   
4. Provide a Privacy Act notification approved by your IC Privacy Office to the vendor to include on the webpage collecting participant information.
   • Additional information that participants may need to know with regard to the collection and storage of the data by a 3^rd party may also need to be included in this disclosure.
     
     
5. Ensure that any use of the NIH logo is permissible and consistent with NIH policies.
   
   
6. Plans to use a 3^rd party vendor for recruiting should be described in your protocol.

Plan for Screening and Enrollment

Key points

• Potential participants are screened using the inclusion and exclusion criteria in the protocol.
  
  
• Screening activities may include any interaction or intervention with participants that are used to determine eligibility. Screening procedures for research eligibility are considered part of the participant selection and recruitment process and, therefore, require IRB oversight and must be described in the protocol.
  
  
• Tests or procedures that are performed for clinical purposes can also be used for screening.
  
  
• Screening should include the fewest and least risky tests/interventions necessary to determine study eligibility and should minimize participant exposure to potential harm for those who fail screening.
  
  
• Screening activities specific to a protocol must be clearly defined in the protocol.
  
  
• The protocol should explain how consent for screening will be obtained.
  
  
• Unless the screening tests involve more than minimal risk or involve a procedure for which written consent is normally required outside the research context, the IRB may decide that prospective study participants need not sign a screening consent document.

What screening information should be included in my research protocol?

Your research protocol that is submitted via NIH electronic IRB system must contain a section titled "Screening Procedures" that is specific to your protocol, and this section must contain the following:

• The sequence of events that should occur during the screening process and any decision points regarding participant eligibility.
  
  
• The time frame prior to enrollment within which screening procedures/evaluations must be performed (e.g., within 28 days prior to enrollment).
  
  
• If a separate screening protocol is developed, describe how the screening protocol will be used to identify participants for this study.
  
  
• If a participant's medical chart or results of diagnostic tests performed as part of their regular medical care at a Health Insurance Portability and Accountability Act (HIPAA) covered entity are going to be used for screening or as a part of collection of trial data, HIPAA rules as well as other relevant federal or state laws, and local institutional requirements should be followed, as applicable. If this is the case, this section of your protocol should note which information is to be obtained through review of existing data. (NIH is not a HIPAA covered entity but is subject to the Privacy Act of 1974.)
  
  
• If 3rd party vendors will be used for screening purposes, review the requirements noted above in the section on use of 3^rd party vendors for recruitment?

What screening activities can be conducted prior to obtaining informed consent from the prospective participant?

• For research conducted under the 2018 Common Rule, the IRB may approve research in which an investigator will obtain information or biospecimens for the purpose of screening, recruiting or determining the eligibility of prospective subjects without the informed consent of the prospective subject or the subject's legally authorized representative (per section 46.116(g)), if either of the following conditions are met:
  • The investigator will obtain information through oral or written communication with the prospective subject or legally authorized representative. (e.g., email, written, in person or telephone communications with prospective subjects), or...
  • The investigator will obtain identifiable private information or identifiable biospecimens by accessing records or stored identifiable biospecimens. For example:
    • Review of existing medical records to include H&P, laboratory studies, etc.
    • Review of existing MRI, x-ray, or CT images
    • Review of existing photographs or videos
    • Review of existing pathology specimens/reports from a specimen obtained for diagnostic purposes
      
      
• These minimal risk activities that may be performed before the participant has signed a consent must be described in the protocol.

What screening activities are conducted after obtaining informed consent from the prospective participant?

• After consent has been signed, perform only those activities listed in your protocol that are used to determine eligibility. These may include procedures/evaluations such as:
  • Physical examination
  • Electrocardiograms
  • Radiographic or other imaging assessments
  • Biospecimen collection and laboratory evaluations
  • Special assays or procedures required (DNA sequencing, flow cytometry assays)
  • Administration of questionnaires or other instruments
    
    
• Assessments performed at outside facilities or on another NIH protocol within the timeframes specified in the protocol may also be used to determine eligibility once a participant has signed the consent.

Description of the research to be conducted

Key points

• The extent of the description in the protocol of the research plan will vary based on the type of research that is planned.
  
  
• Investigators should use the protocol templates that are specific to the type of study they will be conducting which are available on the OHSRP website. This will help ensure that all aspects of the description of the research in the protocol that are required for IRB review have been addressed.

What information specific to my interventional research study needs to be included in the protocol?

Please see the protocol template page for detailed information that must be included in each section below. In addition to other sections already discussed in this investigator manual, interventional protocols should include, but are not limited to, the following information:

• Protocol Summary
• Introduction
• Objectives And Endpoints
• Study Design
• Study Population
• Study Intervention
• Study Intervention Discontinuation and Participant Discontinuation/Withdrawal
• Study Assessments and Procedures
• Statistical Considerations

What else should I include in my protocol if I am conducting a natural history or observational trial?

• Be sure to use the protocol template on the OHSRP webpage that is intended for natural history and observational trials.
  
  
• In addition to including some of the same information as required for interventional studies, it is important that investigators distinguish between clinically driven care versus research (e.g., systematic research interventions or collection of secondary data during clinical care). Human subjects regulations apply only to research and not to the practice of medicine.
  • Research: means "an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships.)" (Belmont Report)
  • The practice of medicine: "refers to interventions that are designed solely to enhance the wellbeing of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individuals." (Belmont Report)
    
    
• For Natural History studies, please refer to the Guideline for Natural History Studies on the OHSRP Protocol Template webpage under the section labeled Observational Research Protocol Templates.

Collection and storage of data to preserve participant privacy and confidentiality

Key points

• Protocols that entail human subjects research must have a plan detailing how the privacy and confidentiality of research participants will be protected and must describe how the safety of the research data are being ensured both while the research study is being conducted and once it has been completed.
  
  
• Transfer and storage of data during the course of research must always be implemented using appropriate security measures.
  
  
• NIH is subject to the Privacy Act of 1974 which contains provisions for handling systems of records and investigators must comply with requirement of this Act.

What information about data collection, storage and management should I include in my research protocol?

• Describe whether participant identifiers will be attached to data/specimens, or whether they will be coded or unlinked.
  
  
• Describe any clinical/demographic information that will be collected (age, ethnicity, sex, diagnosis, stage, treatment, response to treatment).
  
  
• Explain in your protocol how this information might make specific individuals or families identifiable, and measures that will be taken to protect confidentiality of their data.
  
  
• If research data will be coded, explain how access to the "key" for the code will be limited. Include a list of security measures (password–protected database, locked drawer, other).
  
  
• Explain if pedigrees are to be published. Include a description of measures to minimize the chances of identifying specific families.
  
  
• Describe circumstances under which specimens and/or data (e.g., identifiable, coded, anonymized) will be shared with other researchers or third parties.
  
  
• Include information about plans for deposition in a genomic database (e.g., dbGaP).
  
  
• The protocol should specify what data capture system will be used.

What should I know about information security requirements as they pertain to the collection and storage of study data?

• Systems used to collect and store study data must meet NIH IT security requirements.
  
  
• If you will be using cloud-based systems, you should check with your IC Chief Information Officer or Information Security Officer (ISSO) to ensure that you will be engaging with a reputable cloud service provider.
  
  
• If the protocol is subject to FDA regulations, then the electronic data capture system that is used must be compliant with 21 CFR Part 11.

Data and Safety Monitoring Plan

Key points

• All non-exempt human subjects research protocols must include a data safety monitoring plan (DSMP) that is commensurate with size, the level of risk and the complexity of the research to monitor the data collected to ensure the safety of subjects, consistent with regulatory criteria for approval by an IRB at 45 CFR 46.111(a)(6) and [21 CFR 56.111(a)(6).
  
  
• Institutes and Centers (ICs) are required to ensure a system for appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of research subjects and the validity and integrity of the data.
  
  
• Depending on the level of risk, an independent Data and Safety Monitoring entity may be required to further safe and effective study conduct and to recommend conclusion of the trial when significant benefits or risks have been identified, or when the trial is unlikely to achieve its primary endpoint(s).

What is a Data and Safety Monitoring Plan?

• A Data and Safety Monitoring Plan (DSMP) prospectively identifies and documents monitoring activities that are required to protect the safety and welfare of the subjects, the validity of the data, and the integrity of the research study. The DSMP should be commensurate with the level of risk, nature and complexity of the research, and the population under study.
  
  
• Monitoring may be conducted in various ways or by various individuals or groups, depending on the size and scope of the research effort. These exist on a continuum from monitoring by the PI or NIH program staff in a small Phase I study to the establishment of an independent Data and Safety Monitoring Board (DSMB) for a large Phase III clinical trial.
  
  
• ICs are required to provide a system for appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of research subjects and the validity and integrity of the data.
  
  
• All non-exempt human subjects research protocols in the NIH Intramural Research Program must include a DSMP.
  
  
• The DSMP must be described in the written protocol and should be carefully considered and tailored to the individual protocol.

What may be included in the written Data and Safety Monitoring Plan?

• Procedures for communication between applicable groups such as the PI and research team members, the study sponsor, the data and safety monitoring entity, the IRB, the coordinating center, the FDA, and other study sites.
  
  
• Individual stopping rules and/or study stopping rules.
  
  
• Plans for interim and/or futility analyses.
  
  
• The frequency of any assessments or reviews of data and events.
  
  
• The identity and description of an independent Data and Safety Monitoring Entity.

What is a Data and Safety Monitoring Entity?

• A Data and Safety Monitoring Entity is an identified individual or group assigned to conduct interim monitoring of data from research activities. The NIH IC, the FDA, a Sponsor, or an IRB can require that a DSMP identify a data and safety monitoring entity that is independent from the PI and is chosen based on the risk of the research that is performed.
  
  
• Examples of Data and Safety Monitoring Entities commonly used at NIH:
  • Principal Investigator - At minimum, the PI must perform monitoring as part of their oversight duties as the study investigator per NIH HRPP Policy 300, Investigator Responsibilities and Policy 503, Data and Safety Monitoring. A Medical Advisory Investigator (MAI) must also be identified when the PI is not a member of the medical staff and the protocol requires direct medical care to protocol participants and consultation about clinical matters.
    
    
  • Independent Safety Monitor (ISM) - An ISM is an independent physician or other appropriate expert with relevant expertise whose primary responsibility is to provide independent monitoring of clinical trials in a timely fashion. The ISM must be independent from any professional or financial conflict of interest (COI) with the research project and/or study investigators. An ISM is typically used for small early phase trials that are considered lower risk but also can be used in higher risk studies together with a DSMB. ISMs are also used in studies where the PI is blinded to the treatment arm.
    
    
  • Safety Monitoring Committee (SMC) - An SMC provides a similar function as that of a DSMB but is convened by the NIH IC. Depending on the Institute, they may focus on the review of events related to safety concerns and may not perform any interim analyses or evaluations of clinical endpoint data. The specifications required by an IC should be referred to for details.
    
    
  • Data and Safety Monitoring Board (DSMB) – "A DSMB is a formal committee made up of independent experts, which reviews accumulating data and critical efficacy endpoints from one or more ongoing clinical trials, including multi-site research." (See NIH IRP Policy Glossary.) It may conduct interval assessments of clinical trial progress, safety data, and critical efficacy variables and recommend to the sponsor whether to continue, modify or terminate a trial. The DSMB should include clinical trial scientists/medical clinicians knowledgeable in the appropriate disciplines, including a biostatistician. DSMB members must be independent from any professional or financial conflict of interest (COI) with the research project and/or study investigators. In addition to multi-center clinical trials, a DSMB may be appropriate for high-risk interventional studies. They are also used in blinded studies or high-risk studies that involve certain vulnerable populations. For purposes of NIH Policy, the terms DSMB, Independent Data and Safety Monitoring Committee (DSMC), and Data Monitoring Committee (DMC) are considered synonymous.

Compensation for Research Participation

Key points

• As PI, when applicable, you must explain the compensation plan, including the method, timing of distribution, and amount for compensation of research subjects in your protocol and consent forms.
  
  
• Alternatively, both the protocol and the informed consent must describe that compensation will not be provided.
  
  
• Do not state or imply to subjects that compensation is a "benefit" of the research.

What are my responsibilities regarding compensation of research subjects?

As Principal Investigator (PI), ensure the following are met in your compensation plan:

• Eliminate or reduce, to the extent possible, undue influence or coercion, regarding the amount of payment, timing, and disbursement of compensation.
  
  
• Whenever possible, compensation must accrue over the course of the study and be provided to participants in a prorated manner, rather than being made in a single payment at the end of the study.
  
  
• Verify that any payment made for completing the study is reasonable and not so large so as to entice the subject to enroll or continue in the study when they might have otherwise withdrawn.
  
  
• Make certain that subjects who withdraw prior to completion of the study receive compensation for study activities that were completed.
  
  
• Compensation for NIH research should be based on time and inconvenience to the subject.
  
  
• Compensation of research subjects must be applied fairly to all study subjects in the same protocol. For example, when a study enrolls both affected individuals and healthy volunteers and there is no prospect of direct benefit to either cohort, the subjects will be offered compensation based on the same parameters, and compensation amounts will not be adjusted on an individual basis or due to cohort assignment.
  
  
• Ensure that individual subjects who decline to receive compensation for participation in research are permitted to participate in the study.

Description of the consent process in the protocol

Key points

• The protocol should have a detailed description of the consent process and, as applicable, the process for obtaining parental permission and assent, or how consent will be obtained by a subject's legally authorized representative if the subject lacks the capacity to consent to research participation.
  
  
• If a separate screening consent will be used, this should be stated in the protocol.
  
  
• If the PI is requesting a waiver or alteration of consent or assent or is requesting a waiver of documentation of consent from the IRB, the protocol should include an explanation of how the required waiver criteria have been met. Criteria for waiver of consent is discussed below.
  
  
• The IRB may only waive or alter elements of informed consent or documentation of informed consent when the IRB determines and documents that the specific requirements for waiver or alteration are met.
  
  
• When conducting remote informed consent using synchronous audio/video, only NIH-approved platforms may be used, and this process must be explained in detail in the protocol.
  
  
• For human subjects research determined to be exempt under the Common Rule, IRBO may require that the PI share certain consent information with the subject prior to beginning the research.

What information needs to be included in the protocol about the planned consent process?

The protocol should have a detailed description of the consent process and include this information, as applicable:

• Where and when consent will be obtained.
  
  
• Describe how the privacy of subjects will be protected during the informed consent procedure.
  
  
• How will the consent process be conducted? In person? By telephone/videoconference?
  
  
• Will the informed consent document be provided in advance either electronically or in hard copy in advance of the consent discussion?
  
  
• How much time will the potential subject be provided to consider their participation?
  
  
• Who will answer questions from the participant?
  
  
• Will the potential participant be provided the opportunity to consult with others (family, friends, private physician) prior to providing consent?

What must be included in the protocol if an electronic platform will be used to document signature?

• The name of the electronic platform.
  
  
• How signatures of the investigator and subject will be obtained.
  
  
• Use of true electronic signature or whether signature will be obtained using a stylus/mouse/finger. If you are obtaining a true electronic signature for your protocol, describe the process of how you will verify the identity of the subject prior to obtaining consent.
  
  
• If an electronic signature is to be used and the research is subject to FDA regulation:
  • The NIH Investigator must describe in the protocol the method by which identity of the participant will be verified prior to obtaining consent in accordance with applicable 21 CFR Part 11 and related FDA guidance, and
  • The platform must be certified as compliant with 21 CFR Part 11. See the FDA Guidance for Industry Part 11, Electronic Records; Electronic Signatures — Scope and Application.
    
    
• If you are conducting an FDA regulated protocol and using a stylus/mouse or finger to sign the consent form, the remainder of the document/record system must still be compliant with 21 CFR Part 11.

What information must be included in the protocol if a waiver or alteration of consent is being requested from the IRB?

The IRB may only waive or alter elements of informed consent or documentation of informed consent when the IRB determines and documents that the requirements for waiver or alteration are met. A waiver of consent occurs when an IRB waives the requirement to obtain informed consent for research, and alteration of consent means an IRB may approve a consent procedure that omits some, or alters some or all, of the elements of informed consent set forth in the regulations. An IRB may waive the requirement for documentation of consent in which case the investigator is not required to obtain a signed informed consent form for some or all subjects only if specific regulatory requirements are met.

The federal regulations require that certain criteria be met for the IRB to waive consent for study subjects. If you are going to request that the IRB approve a waiver of consent, you must provide an explanation and adequate justification for why waiver of consent is being requested.

Is waiver or alteration of consent permitted for FDA regulated research?

• While FDA permits IRB waiver or alteration of informed consent in some cases, the FDA regulations are not identical to the HHS regulations and, in some cases, FDA does not permit waivers or alterations that are now included in the HHS 2018 Common Rule requirements under 45 CFR 46.
  
  
• For FDA regulated research, the IRB may allow an exception from the requirements for informed consent for emergency research as specified in 21 CFR parts 50.23 or [50.24. |https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-50#50.54]
  
  
• For FDA regulated research, the IRB may also waive or alter elements of informed consent for non-emergency research in accordance with the July 2017 FDA guidance when:
  • Research involves no more that minimal risk;
  • Waiver or alteration will not adversely affect rights and welfare of subjects;
  • Research could not practicably be carried out without the waiver or alteration;
    and
  • Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

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?

• For research subject to the Common Rule only, An IRB may waive the requirement for the investigator to obtain a signed informed consent form for some or all subjects if it finds any of the following (45 CFR 46.117 (c)): 
  
  
• The only record linking the subject and the research would be the informed consent form, and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject (or legally authorized representative) will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern.
  
  
• The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.
  
  
• If the subjects or legally authorized representatives are members of a distinct cultural group or community in which signing forms is not the norm, that the research presents no more than minimal risk of harm to subjects and provided there is an appropriate alternative mechanism for documenting that informed consent was obtained.
  
  
• In cases in which the consent documentation requirement is waived, the IRB may require the investigator to provide subjects or legally authorized representatives with a written statement regarding the research.
  
  
• Examples of situations where the IRB may grant a waiver of documentation of consent might include:
  
  
• Research involving assessments, surveys or psychological tasks conducted over the phone or online
  
  
• Eligibility screening conducted via telephone
  
  
• Remote or in person benign behavioral interventions or assessments
  
  
• Mailed survey with a cover letter/information sheet with all elements of consent, and subject returning the survey indicates consent
  
  
• For FDA regulated research, the IRB may and waive documentation of informed consent if the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context.

When is waiver of informed consent not permitted?

Waiver or alteration of consent and waiver of documentation of informed consent are not permitted whenever any of the required criteria are not met (e.g., for research that includes procedures that are greater than minimal risk). Waiver of informed consent is not permitted for certain research with vulnerable populations. Per "Waiver of Informed Consent Requirements in Certain Emergency Research (61 FR 51531)," because of special regulatory limitations relating to research involving prisoners and research involving fetuses, pregnant women, and human in vitro fertilization, the waiver for emergency research (21 CFR parts 50.23 and 50.24) is not applicable to these categories of research.

Additional reviews that may be required and resource information

Key points

• Additional reviews may be required including, but are not limited to, Concept Review, Scientific Review, Protocol Resource Impact Assessment for protocols conducted at the Clinical Center, multisite research review, FDA review and ancillary reviews such as Radiation Safety Committee, Deputy Ethics Counselor Review, and other possible reviews as noted below.
  
  
• Investigators should be aware of the additional ancillary reviews that are required and ensure these are completed and documented in the electronic IRB system.

What is a concept review?

• Institutes/Centers (ICs) often conduct a protocol concept review via initial discussions by PIs with their laboratory/branch chief, Clinical Director and/or Scientific Director, or by a central IC concept review committee, for ICs that have such a committee.
  
  
• The purpose of concept review is to address feasibility, fit within the mission of the IC's intramural division, availability of resources both within and outside the lab/branch, and requirements for a CRADA or clinical trials agreement (CTA).
  
  
• Concept reviews can consider and modify objectives, design, eligibility, and statistical analysis.
  
  
• The concept review is not required in the official protocol record, although notation of whether it occurred will be recorded on the NIH Scientific Review of Clinical Protocols form in the electronic IRB system.
  
  
• The IRB does not review concept proposals.

How is the IRP Scientific Review conducted?

The NIH Policy for Scientific Review can be accessed here. Summary points include the following:

• ICs will conduct scientific review of complete protocols by a Scientific Review Committee within the office of the Clinical Director or Scientific Director unless waived by the IC leadership. All waivers of Scientific Review must be approved by the Chief Scientific Officer, Clinical Center (CC).
  
  
• Materials required for Scientific Review are outlined in the Policy for Scientific Review.
  
  
• Requests for Scientific Review are initiated in the electronic IRB (eIRB) system, and information about this process can be found in the NIH SRC Researcher's Guide.
  
  
• Scientific review must be completed in the eIRB system prior to IRB review of your submission.
  
  
• There is a prioritization process for protocols that require use of scarce resources at the Clinical Center.

What is the PRIA?

• For protocols conducted at the Clinical Center (CC), a Protocol Resource Impact Assessment (PRIA) must be completed and reviewed by the CC. 
  
  
• All protocols submitted through the PRIA process will receive a regulatory assessment from the Office of Research Support and Compliance (ORSC) Regulatory Support Section.  This review is done to point out regulatory items related to FDA (21 CFR 312 and 21 CFR 812) about which the IRB may need to make determinations during the its review.  The IRB administrator can access this regulatory assessment with the PRIA in the electronic IRB system.  Depending on the institute, PIs may receive the review as well or it may be sent to the IC's regulatory support office.

What if my protocol will be a multisite study?

• The 2018 Common Rule has specific requirements for cooperative multisite research as follows:
  • Per §46.114 (Cooperative Research), any institution located in the United States (US) that is engaged in cooperative research must rely upon approval by a single IRB for parts of the research conducted in the US. The reviewing IRB will be identified by the Federal department or agency supporting or conducting the research or proposed by the lead institution and which is accepted by the Federal department or agency supporting the research.
  • These requirements for review by a single IRB do not apply if the law requires that more than one IRB review the study (e.g., if tribal law requires local IRB review) or if the federal entity supporting/conducting the research determines that single IRB is not appropriate.
    
    
• For multi-site protocols conducted by NIH IRP investigators that were submitted for initial review after January 25th, 2018, the NIH Single IRB (sIRB) policy requires that there be only one Reviewing IRB. It does not apply to foreign sites or when it is prohibited by a federal, tribal, or state law, regulation, or policy. Any other requests for exception from the sIRB policy must be made through the NIH IRB Office.
  
  
• In the case of a PI who will be involved in a multisite study that is subject to the NIH sIRB policy, once it has been determined who will serve as the Reviewing IRB, it is likely that a reliance agreement between NIH and other participating site(s) will need to be executed. Please refer to Reliance and Single IRB (sIRB) Resources page on the OHSRP website. If it is determined that a reliance agreement is needed the link for the request form is here. (NIH login is required.)
  
  
• NIH investigators do not have the authority to sign or otherwise commit to any reliance agreement. The authority to execute reliance agreements on behalf of the NIH, is delegated to the OHSRP Director.
  
  
• If the NIH investigator is involved in a multi-site protocol that is being overseen by a non-NIH IRB, research related event reporting should be conducted according to the Reviewing IRB's policies. Additionally, if the event occurs at an NIH site and meets the NIH reporting criteria per Policy 801, Reporting Research Events, a reportable new information (RNI) form should also be submitted in the NIH electronic IRB system

What do I need to do if my protocol involves an investigational test article (e.g., drug, biologic, or a device)?

• When the research involves the clinical investigation of drugs or biologics as a test article, the PI must provide documentation in the protocol whether the test article(s) for use is under an IND or provide written justification for why the test article(s) is exempt from the requirement for an IND. Unless the PI is making the case that the test article is exempt from requirements for an IND, the IRBO will not further process the submitted IRB application until a determination has been reached by the FDA that either: 1) the test article does not require an IND; or 2) the research being conducted under IND is safe to proceed, or 3) 30 days has elapsed since submission of the IND application to the FDA, and no clinical hold has been placed on the clinical investigation. The IRB may require that the PI get a determination from the FDA about need for an IND even if the PI provides information as to why they believe the test article is exempt from the FDA IND requirements.
  
  
• When the research involves the study of the safety or efficacy of an investigational device, the PI needs to provide documentation in the electronic IRB system supporting the sponsor's assessment of whether the device is exempt (21 CFR 812.2(c)) from the IDE requirements, or that the use of the device in the specific protocol constitutes a non-significant risk (NSR) or significant risk (SR). If a determination by the FDA has already been made as to whether the device is exempt, NSR or SR, documentation from the FDA must be submitted in the electronic IRB system prior to full board review. If the IRB requires the PI to submit to the FDA for a determination prior to reviewing any device study, FDA is the final arbiter as to whether a device study is exempt, SR or NSR. This response provided from FDA needs to also be uploaded into the electronic IRB system. If the device has been determined to be a significant risk device in the context of the protocol under review, the investigator must upload documentation from FDA of the approved IDE for the device.
  
  
• For additional information, see the section of this manual related to FDA regulated research.

What type of Ancillary Reviews may be needed?

Ancillary reviews are reviews by additional committees or groups that may be required prior to IRB review and/or approval, and identification of the entities that need to provide a review will vary based on the protocol. Some of the more commonly required ancillary reviews are summarized below. Additional information is available in NIH Policy 106, Ancillary Reviews.

• IC Deputy Ethics Counselor (DEC) clearance for "covered research protocols", as applicable.
  
  • "Covered research protocols" include the following and need clearance by the IC Ethics Office (also referred to as "DEC Clearance"):
    • studies of investigational drugs and devices
    • studies with a research question about a commercially available drug or device
    • studies involving collaborations with a substantially affected organization (SAO) or another for-profit entity when the entity is receiving specimens and/or data from the NIH for the purpose of developing a product
      
      
  • Most interventional protocols will be covered research protocols unless the intervention does not involve the criteria listed above (e.g., a behavioral intervention might not meet the criteria for a covered research protocol or use of a device for physiological exploration where there is no intent to develop a commercial application).
    
    
  • Non-covered research protocols include NIH research protocols that are categorized as Natural History studies, unless these studies meet the criteria for covered research protocols listed above.
    
    
  • When the PI determines that the protocol meets the definition of a covered research protocol, the following steps occur. (See Policy 102, Investigator Conflict of Interest and Government Royalties for more detailed information on this process.)
    1. For covered research protocols, the PI must provide all investigators and individuals (including NIH employees, non-NIH federal employees, and individuals who are not federal employees) who will be engaged in activities as well as those involve in statistical analysis of primary endpoint data whose role has the potential to bias the research results, even if they are not otherwise engaged in human subjects research, with a copy of the Guide to Avoiding Financial and Non-Financial Conflicts or Perceived Conflicts of Interest in Clinical Research at the NIH found in the Reference section at the end of Policy 102, Investigator Conflict of Interest and Government Royalties.
    2. Relevant NIH federal employees and other federal employees within the Executive Branch must complete any public, confidential, or supplemental financial disclosure reports required by their employing agency.
    3.  NIH investigators who do not file public or confidential financial disclosure reports and non-NIH federal employees must sign a Conflict of Interest (COI) Certification Form. Most commonly, in the context of NIH study teams, it is the study statistician who is not otherwise required to file a financial disclosure report who needs to complete the COI Certification. 
    4. The PI must collect and submit the relevant COI Certification Forms in the eIRB system.
    5. The PI initiates DEC review in the eIRB system by going to the tab labeled Manage Ancillary Reviews.  Additional information can be found in the NIH DEC Researcher's Guide.  
    6. The PI's Ethics Office conducts an assessment of actual and apparent conflicts of interest for all investigators listed on the protocol and, if any federal employees have actual or apparent conflict of interest, the Ethics Office works with the employee, the NIH PI, NIH Ethics Official(s) and, as needed or appropriate, the NEO Director and/or the Office of the General Counsel, Ethics Division, to identify an appropriate remedy under applicable law.
    7. Upon completion of the COI review, approval of the IC DEC is noted in the eIRB system (also known as the DEC Clearance).
       
       

• Radiation Safety Committee (RSC):
  • Scans, tests and procedures that involve radiation that are specified in the protocol are considered by the IRB to be research procedures. If the scan, test or procedure is dictated solely by the clinical needs of the individual participant (and therefore vary for each participant), then this is considered a clinical procedure, and should not be included in the protocol or the consent documents. Dosimetry must be calculated for all radiation described in the protocol and the appropriate required radiation language from the Consent Library (under section of the library labeled "Radiation") must be included in the consent. See the link to the Consent Library on the Consent Templates and Guidance page of the OHSRP website.
    
    
  • Information about submission of RSC reviews in the eIRB system can be found in the RSC Researcher's Guide.
    
    
  • Protocols will only require review by the RSC if they meet the following criteria in which case the forms required by the RSC should be submitted in electronic IRB system. This review must be completed prior to review by the IRB.
    • Uses a radioactive research drug(s) regulated under the FDA requirements for review by the Radioactive Drug Research Committee (RDRC)
    • Involves use of any radiation in pediatric participants (<18 years old) with an annual effective dose > 0.5 rem or healthy pediatric volunteers (any dose level)
    • Uses any radiation in healthy adult volunteers, excluding DEXA and chest X-Ray
    • Uses therapeutic administration of radioactive materials (Examples include therapeutic use of I-131, Lu-177, Y-90, Th-227, Ra-223, or Ir-192 permanent seed implants. The following would be excluded from required RSC review: Use of linear accelerator such as total body irradiation or high dose-rate afterloader such as brachytherapy for breast or prostate cancer.)
    • Involves novel uses of radiation, including any radioactive Investigational New Drugs (IND) and radiation-producing investigational devices
    • The radiation itself is the research agent being studied in the protocol (For example: The protocol compares the effectiveness of 2 different doses of radiation therapy; comparison of the effectiveness of drug X vs drug X + radiation therapy; study of the uptake and biodistribution of a novel radioactive tracer.)
      
      
• Other reviews: As determined by the protocol, additional ancillary reviews may also be required prior to initial review of the protocol by the IRB (e.g., Institutional Biosafety Committee, NIH Office of Technology Transfer, Cooperative Research and Development Agreements (CRADAs) and/or review by the NIH Select Agent Program). Investigators should refer to NIH Policy 106, Ancillary Reviews for information about reviews by these specific entities.

Are there any other resources that provide helpful information about submitting my protocol to the NIH IRB?

See the following document that can be found on the OHSRP Other Additional Guidance Documents webpage: Tips & Tricks for When Submitting to the NIH IRB.

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