Frequently Asked Questions

Start at your Institute and find out if you have protocol navigator services available to assist you in submitting ot IRBO. If you do not, please contact Dr. Gini Guptill in the ORSC: orscprotocolsupport@nih.gov.

Work with your protocol navigator to submit a change in PI to the IRB.

All submissions to the IRBO will occur via NIH PROTECT. Your protocol navigator can assist you.

We are adding materials to the website as they are being developed.  All available NIH Policies, Procedures, and SOPs can be found here: Policies & Guidance .

New studies submitted to the IRBO after January 21, 2019 are affected by the changes to the Common Rule. The IRBO will review your submission and ensure the required information is there. Mostly the IC is affected and a template is posted for use: IRB Templates.

Federal and state Right to Try laws generally permit the use of unapproved, experimental drugs and biological products by individuals diagnosed with a life-threatening condition who (1) have exhausted approved treatment options, and (2) are unable to participate in clinical trials involving the product.

However, NIH is a federal research agency. Therefore, it cannot provide an unapproved drug or biological product to an individual unless the subject is enrolled in an NIH protocol. Further, Right to Try laws do not establish a “right” to participate in a clinical trial or protocol, i.e., the laws do not entitle patients to participate in an NIH-sponsored clinical trial.

If you are unable to enroll in an NIH protocol involving an unapproved drug or biological product, the Right to Try Act may provide another option. Interested individuals should speak to their home-based treating physician about the possibility of receiving an unapproved drug or biological product from a source other than the NIH through the Right to Try pathway. The federal Right to Try Act became law on May 30, 2018. More information is available at https://www.congress.gov/bill/115th-congress/senate-bill/204/text.

Please discuss this at the IC level. There is an NIH requirement that the IC hold the IND. Usually there is a regulatory expert that can assist with this. If your IC does not have this expertise, please contact Dr. Gini Guptill in the ORSC: orscprotocolsupport@nih.gov. 

Protocol templates can be found on the Templates & Forms page.

Consent templates can be found on the Templates & Forms page.

The Clinical Center has Recruitment Services available: Recruitment Services.

Please email: IRB@od.nih.gov or call 301-402-3713.

Under the pre-2018 Common Rule regulation (45 CFR 46), unless the research qualified for specific exemptions, prospective consent from the potential subject for recording of their identifiable private information being obtained for recruitment was required, unless waived by the IRB.   For protocols subject to the revised (2018) Common Rule only, an IRB may approve certain screening or recruitment activities, or activities to determine eligibility, prior to obtaining informed consent.  These include:

• Obtaining information through oral or written communication with the prospective subject, OR
• Obtaining identifiable private information of identifiable biospecimens by accessing records or stored identifiable biospecimens.

In this event, the PI does not need to request a waiver of consent, but these activities that will occur prior to obtaining informed consent must be clearly described in the IRB approved protocol.  The solicited information should be limited to the minimum necessary for screening, or to determine study eligibility.

For minimal risk research being conducted remotely, the IRB may approve a web-based consent form or approve waiver of documentation of consent with no requirement for oral consent.  When a research study is subject to the Privacy Act, (i.e., will collect identifiable private information about a subject), the prospective subject must be provided with written Privacy Act notification. If an investigator wishes to conduct an oral consent process and receive a waiver of documentation of consent, they must still at least offer to provide the Privacy Act notification in writing. A description of the plan should be included in the consent section of the protocol. When the subject will not be registered as a patient at Clinical Center, please refer to the section labeled Privacy Language for Studies Conducted Outside of the Clinical Center in the  Consent Library. The Consent Library can be accessed on the OHSRP webpage titled Consent Templates and Guidance.

If the protocol will include use of a remote consent procedure (e.g., by phone or videoconferencing), the process must be described in the protocol, and IRB approval must be obtained. Otherwise, if the plan to use the remote consent process is only temporary and for a few subjects (e.g., due to the pandemic), a single patient planned deviation request form may be submitted rather than a protocol amendment. If the investigator will be conducting such a process via telehealth, use only an approved synchronous video platform that meets required NIH security and privacy standards. For additional information, please refer to Policy 303 Intramural Program Telehealth Requirements which can be found here. 

The subject should be provided with the consent form in advance of the consent conversation.  After the consent process has been conducted and the investigator has responded to the subject’s questions, the subject signs the consent form noting the current date. The investigator documents the process in CRIS/medical record (or the research record if there is no medical record) in real time on the day of the consent conversation. When the signed/dated consent form is returned to the investigator who conducted the consent discussion, the investigator signs and dates the consent form with the date s/he received the signed the consent from the subject.  The investigator should then record another note in CRIS/research record indicating the updated status and send a copy to medical records (or research record if there is no medical record) and provide a copy of the completed consent form to the subject. The date that the subject signs the consent form is considered their “date on study.” If, after the subject has signed the consent form, specimens and/or data are collected locally for research purposes, no analyses of these specimens and/or data may occur until the investigator has verified that the subject has returned a signed and dated informed consent document, unless the IRB has granted a waiver of documentation of consent.  

NIH investigators should document the consent process in the subject’s record, and describe the method used for communication with the subject and the specific means by which the subject communicated agreement to participate in the study (e.g., their verbal response and signing of the informed consent document).  Additional FAQs related to documentation of consent in CRIS are available at this internal  link.

The short form consent process is used when the subject is unable to read the long form version of the consent due to a language barrier. An interpreter is utilized for subjects who are unable to understand the language in which the long form consent is written.

Whenever possible, a professional interpreter, who is in-person, should be used or, alternatively, a professional interpreter can be utilized via a telephone interpretation service. Use of a family member for interpretation is not permitted unless a professional medical interpreter cannot be located.  The reasons for using a family member and the attempts made to locate a professional interpreter must be documented in the research record. Family members may not have adequate medical knowledge and are not trained as professional medical interpreters.  Additionally, family members may not be impartial or may try to speak for the subject which can limit the subject’s decision-making process. (Also see Question 20 for more information about when an investigator may server as the interpreter.)

 When the subject speaks and understands English but is illiterate or blind, the English long form should be used to obtain consent from the subject. The short form consent document should not be used. The subject may use assistive technology (such as screen readers for sight-impaired individuals) to read the consent, or the consent form should be read to the subject. There must be a witness to the entire oral presentation of the consent. The witness then signs the witness line on the English long form consent. See the screenshot below. Subjects who are unable to sign their name can make their mark on the signature line. (e.g., They may make an “X,” or provide a fingerprint.) The consent notes in Clinical Records Information System (CRIS) or the research record should document the process and include a statement that there was a witness to the entire consent process and any special circumstances regarding documentation of consent.

When conducting the consent process with a subject for whom no written language exists, the process is similar to that used with a blind or illiterate subject.  There should be an oral presentation of the English long-form consent by the interpreter.  There must be a witness (who can be the interpreter if they are willing to act as the witness) at the location of the investigator, who is present during the entire oral presentation.  The subject must sign or make their mark on the consent, and the investigator and witness both sign the consent. The administrative block for interpreters must be completed, and there must be a note in CRIS or the research record documenting the consent process used in this circumstance.

Even though the subject is illiterate or blind, written documentation of consent is still required, unless waived by the IRB.  This is a requirement of the regulations and in addition, it is respectful of the participant.  They may want to share the consent form with family members or health care providers who can read the consent form written in the subject’s language. Alternatively, they may have access to assistive technology (e.g., screen reader) that can “read” the consent form to them in the language they understand.  When conducting the consent process in this situation, there must be a witness who is present during the entire oral presentation. The witness can be the interpreter if they are willing to act as the witness. Interpreters scheduled by the CC Language Interpreter Program (LIP) must sign as the witness (See FAQ #12 below.) 

The English long form consent is used as the basis for discussion, whether or not there is a translated long form. The investigator obtaining consent reads the consent in English and the interpreter orally interprets the English words of the investigator and will facilitate the question-and-answer phase of the informed consent process between the non-English speaking potential subject and the investigator.  The interpreter’s role is to facilitate verbal discussions between parties that do not speak the same language.  Having the subject know what is in the translated long form, even if they are illiterate or blind, is optimal because the required information about the study is contained in the consent form.

If there is a translated long form consent in the subject’s language, the subject, the investigator obtaining consent, and the witness sign the translated long form consent.  Subjects who are unable to sign their name can make their mark on the signature line. (e.g., They may make an “X,” or provide a fingerprint.  The administrative block for interpreters must be completed.  The subject is provided with a copy of the signed translated long form that is in their language.

If there is no translated long form in the language of the subject, the English long form consent is used as the basis for discussion, and the short form process is used.  In this case, the subject and witness sign the short form consent that is written in the subject’s language (or, if applicable, the subject makes their mark as noted above), and the investigator obtaining consent and the witness sign the English long form consent. The administrative block for interpreters must be completed. The subject is provided with copies of both the signed English long form and  translated short form consents.

If there is no translated long form or short form in the language of the subject, the subject cannot be enrolled until the consent form (preferably the long form consent, but at the least, the short form consent document) is translated into the language of the subject and submitted to the IRB along with the certificate of translation and is approved by the IRB prior to use.

In all cases, the consent note in Clinical Records Information System (CRIS), or the research record should document the process and include a statement that there was a witness to the entire consent process and any special circumstances regarding documentation of consent.

While the above scenarios provide an acceptable path to document informed consent, OHSRP expects investigators to carefully consider whether it is appropriate to enroll an individual in the study in the situations described above.  In particular, enrolling an illiterate non-English speaking person when the only document we can provide is the translated short form, which they cannot read without assistance, provides that person with no study specific information to use for future reference.  The challenges with effective and meaningful communication to assure there is adequate understanding of the risks of the study and the requirements of study participation will continue to be present throughout the study.  In such circumstances, investigators must be able to justify that the potential benefits outweigh the risks for that individual participant.

For the English long form consent: the investigator obtaining consent and the witness sign the English long form consent document. The interpreter may also act as the witness.

Alt Text: Image title is English long form consent.  Image shows the signature page of the English long form consent.  There is an arrow pointing to the Signature of Investigator line.  The arrow text indicates that the Investigator obtaining consent needs to sign on this line.  Image then shows the signature page of the English long form consent.  There is an arrow pointing to the Signature of Witness line.  The arrow text indicates that the Interpreter or separate witness to the entire consent process needs to sign on this line.

For the short form consent that is in the language that can be read by the subject:  The subject and the witness sign the short form consent document.  

Alt Text: Image title is Required signatures on the short form consent.  Image shows the Spanish short form consent.  There is an arrow pointing to the participant line.  The arrow text indicates that the participant needs to sign on this line.  Image then shows an arrow pointing to the Signature of Witness line.  The arrow text indicates that the Interpreter or separate witness to the entire consent process needs to sign on this line.

Confirm that the witness has signed both the short form in the language of the subject and the English long form used as the summary of what is to be said to the subject.

Alt Text: Image title is Required signatures when using the short form process.  Image shows the Spanish short form consent as an example.  There is an arrow pointing to the participant line.  The arrow text indicates that the participant needs to sign on this line.  Image then shows an arrow pointing to the Signature of Witness line.  The arrow text indicates that the Interpreter or separate witness to the entire consent process needs to sign on this line.

Yes. Interpreters in the CC scheduled by the CC Language Interpreter Program (LIP) are either NIH staff members who are federal employees or contract employees whose job is to provide medical interpretation. Interpreters scheduled by the CC LIP must sign the short and long form consent as the witness when facilitating the short form consent process, because they speak both languages. In all cases, the identity of the interpreter will be noted as indicated in Questions 14 and 17 below. The witness must be present for the entire oral presentation.

Before starting the consent process, confirm with the interpreter if they are willing to witness the consent. If the interpreter declines to act as the witness, please contact the CC LIP immediately at 301-496-2792 and they will assist.

A telephone service interpreter cannot act as a witness since they are not physically present to observe the consent process. Another individual, fluent in the language of the subject and in English, must observe the entire consent process at the site of the investigator and sign as the witness. Information regarding the interpreter should be included in the administrative sections of the long form and short form consent documents as described in Question 14.

In the vary rare instance that a witness who is fluent in both English and the language of the subject cannot be located, then the witness should verify with the interpreter that the subject understands the information presented, that all questions have been satisfactorily addressed, and that the subject agrees to participate. The witness, or investigator, obtaining informed consent should document this as a note in the record documenting the short form consent procedure.

Both the English long form and the translated short form includes a section titled NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN INTERPRETER which must to be completed when the short form consent process is used. (Note: On the translated short form, this section will be in the subjects preferred language.) This section allows NIH staff to attest that an individual speaking both English and the subject’s preferred language facilitated the consent process and also indicates whether the individual acting as the interpreter also served as the witness to the short form consent process.

If the individual providing interpretation services did not serve as a witness, the interpreter’s name (for on-site interpreters), or ID number (for telephone-based interpreters), should be entered in the designated 2^nd field below.

English long form administrative block

Examples of scenarios

• Interpreters in the CC scheduled by the CC Language Interpreter Program (LIP) who are either NIH staff members who are federal employees or contract employees whose job is to provide medical interpretation:  The first option is checked, and these interpreters sign as the witness.

• A telephone translation service (trans-telephonic interpreter service, e.g. “blue phone” service) is used and the consent is obtained in person (person obtaining consent and the subject are co-located):  Since the interpreter is not physically present and cannot serve as witness, the second option is selected, and the name or ID of the interpreter is entered.  In such cases there must be a separate individual present with the investigator to observe the entire consent process and who signs as the witness.

The difference from the earlier examples relates to the location of the individual who will serve  as the witness, and timing of the investigator and witness signatures.

• The subject should be provided with both the short form consent and the long-form English consent prior to the phone discussion.
• The investigator who is obtaining consent is in the same place as the witness (this may/may not   be the interpreter).
• The investigator, interpreter, and witness (if the interpreter will not/cannot serve as the witness) must all be involved for the duration of the consent process conducted via phone.
• After completion of the consent process, the following should be completed in real time:
  • The subject signs and dates the short form consent and returns it to the investigator.
  • At the time of the consent process, the investigator and the witness sign and date the long form English consent that was used as the basis of translation.
  • The administrative section on the last page of the long form English consent is completed.
  • The investigator documents the process in a consent note in the subject’s medical chart or research record (in real time after the consent discussion).
• Upon receipt of the signed and dated short form consent from the subject, the investigator completes the administrative section of the short form, and the same witness signs and dates the short form consent using the current date. (It is not backdated to the date that the consent process was conducted by phone.)
• The subject is provided with copies of the signed short and long form consent
• The investigator adds a note to the medical/research record regarding the date the signed short form was received and signed by the witness and indicates when the copies were returned to the subject.

The short form consent process requires that the witness attest, by signature, to the validity of the consent process and the subject’s agreement to participate.  If the witness is unable to sign the required documents, it is not acceptable for the PI to make a notation in the research record on behalf of the witness.

In such scenarios, the acceptable options for obtaining informed consent are to either: 1) translate the full consent into the language of the subject, or 2) if it is urgent to enroll the subject, the short and long form consents could be provided electronically to the witness, who will then sign and return the documents electronically.  Note, that such signatures must be “wet” signatures using a pen, mouse or stylus and not electronic signatures.

If these options are not feasible, then it may not be possible to enroll the subject.

The CRIS documentation of the Informed Consent Progress Note has been updated to include the required fields related to use of interpreters and witnessing the consent process. Whenever an interpreter facilitates the informed consent process, the PI or investigator who is obtaining consent should complete the check box fields in the progress note and include the name or ID number of the interpreter in the designated field.

If investigators anticipate enrolling subjects who speak a specific language other than English, the English long form consent should be fully translated into that language and submitted to the IRB for approval.  In this case, an interpreter is also used to facilitate the discussion and answer the subject’s questions, and the investigator obtaining consent and the subject both sign the fully translated long form consent (as they would if the long form was in English).

In this case, since an interpreter is used but a witness is not required on the long form consent, the second box in the administrative section should be checked to indicate that the interpreter facilitated the consent process but did not serve as the witness.

Check “yes” to the question, “Interpreter used during the consent process?” Fill in the name or ID code of the person providing interpretive support. Under additional notes, include a statement that a translated consent long form was used.  See below.

If the investigator is truly fluent in English and the language of the subject, consent may be obtained using the IRB approved translated long form if it exists, and no witness is needed. When the short form process is used because the long form has not been translated into the subject’s language, the bilingual investigator conducts the consent process in the language of the subject and explains all applicable elements of consent using the English long form as the summary of what is said to the subject.  The investigator obtaining consent cannot act as the witness, so the second option in the administrative block noted in FAQ question 9 above is checked, and the investigator’s name is noted on the provided line.  In such cases, there must be a separate individual present to observe the entire consent process who signs as the witness.

If the long form has not been translated into the language of the proposed subject, the subject should not be enrolled until a short form in their language is available. If you need a short form that is in a language which is not available on the IRB website, then you must obtain a translation of the appropriate English short form version.  A resource for obtaining a translation is the NIH Library.   Once you receive the translation, submit the translated short form and the certificate of accuracy to the IRB via PROTECT using a modification form.

The interpreter should ask the subject the embedded question and convey their response to the investigator obtaining consent. The investigator indicates the subject’s response on the long form ICF. Neither the interpreter nor the subject should record the response. This process should also be described in the consent note in CRIS or the research record.

Verbal assent should be obtained from the minor, and the process should be documented in the consent note. NIH does not have translated short form assent documents.

When obtaining assent from a non-English speaking older minor, if there is a translated long form and the IRB has   approved a process that allows older minors to provide their assent on the long form, then the older minor may read and indicate their assent on the translated long form. Otherwise, verbal assent should be  obtained and documented as above.

Submit the updated long form English consent document for translation. (A resource for obtaining a translation is the NIH Library.) Upon receipt, submit the newly translated long form, along with the certificate of translation, to the IRB for approval. If the IRB requires reconsent prior to translation and IRB approval of the updated consent in the subject’s language, the short form process should be used with the approved English long form (that has the updated information) as the basis for consent.  When the updated translated long form has received IRB approval, provide it to the subject.  Document each of these activities in the subject’s medical or research record.

Except as described below, VFs, IRTAs, and CRTAs serving as Associate Investigators may observe or participate in the informed consent process only if they are under the direct and constant supervision by a qualified NIH federal employee investigator. These trainees may not sign the informed consent document.

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 only if they have completed the expanded training requirements listed in MC 3014-301 Informed Consent that include the following:

• They must have received 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 the protocol and all the information contained the informed consent document and be capable of addressing all subject questions.
• They 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).

The policy permitting post-doctoral IRTAs/CRTAs and Visiting Fellows (VFs) to obtain informed consent so long as they meet expanded training and policy requirements is specific to these trainees. IC staff should NOT confuse IRTAs/CRTAs and VFs with Clinical  Fellows and Research Fellows who are federal employee investigators who can independently obtain informed consent. For more information, you can look up various types of fellows including helpful information about fellow hiring authorities here: https://oir.nih.gov/sourcebook/personnel/ipds-appointment-mechanisms/official-list-approved-intramural-professional-designations-ipds

If the IRB has determined that signature of both parents is required, permission must be obtained from both parents unless one is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.  However, for research taking place at an NIH site when the IRB has approved the study as needing permission from only one parent, in cases where parents share joint legal custody for medical decision-making of a child (e.g., by a custody agreement or court order), both parents must give their permission regardless of the risk level of the research. Exceptions may include if one parent has since died, become incompetent, or is not reasonably available. However, in such cases, if one of the parents wants to give the decision-making responsibility to the other parent, they can do so.  In this situation, the parent who wants to give up such responsibility must write and sign a letter to the study PI stating they want the other parent to make decisions about the child as they relate to their study participation at NIH. It can indicate the parent’s willingness to give up this responsibility for a specific duration of time, or they can indicate that they are doing so indefinitely or until they decide otherwise.  This letter does not need to be notarized.

If the potential subject is able to speak, verbal consent may be obtained.  If the individual is unable to speak, they can be entered into a study if they are competent and able to indicate approval by other means. However, if the protocol states that written documentation of consent is required, the alternative procedure that will be used to indicate the subject’s consent (including verbal consent) must be prospectively reviewed and approved by the IRB.  This should be done by submitting a Single Patient Modification Request in the electronic IRB system.

When a method of obtaining consent other than written documentation is utilized (for example, verbal consent for a subject who does not have the ability to provide written consent), investigators must document the method used for communication with the subject and the specific means by which the subject communicated agreement to participate in the study in the documentation of consent note in the subject’s medical or research record.  When feasible, it is advisable to have a witness present.

The OHSRP office of Compliance and Training is responsible for the following:

• Coordinating review and management of events that occur during the conduct of Intramural Research Program (IRP) human subjects research (HSR) activities that are reported by study investigators via a Reportable New information (RNI) Smart Form in PROTECT. The process is described in this flow diagram.
• Responding to questions from investigators, study staff members about event reporting
• Addressing administrative aspects of monthly meetings of the Research Compliance Review Committee (RCRC), which is a duly convened NIH IRB with nine specific members who review research related events that rise to the level of possible serious and/or continuing noncompliance
• Conducting investigations of alleged noncompliance with federal regulations and NIH policy related to protection of human subjects that are/were under the jurisdiction of an NIH IRB or that may involve additional alleged noncompliance within the NIH HRPP
• Providing follow-up and as needed, additional investigation related to participants who contact Compliance and Training with concerns related to their participation in NIH HSR
• Reporting to the Health & Human Services (HHS) Office for Human Research Protections (OHRP) and, as applicable, FDA, all NIH IRB/RCRC IRB determinations of serious and/or continuing non-compliance, Unanticipated Problems (UPs), or NIH IRB suspension or termination of IRB approval within 30 days of the determination.
• Facilitating Quality Assurance (QA)/Quality Improvement (QI) reviews of NIH IRB activities
• Responding to questions related to the training required for investigators who conduct HSR overseen by the NIH IRB
• Creating HSR related educational materials for NIH investigators, staff and IRB members and coordinating monthly OHSRP Education Series sessions and the OHSRP Investigator Seminar Series

You can contact the office of Compliance & Training email for questions and information.

A RNI Smart  Form is the communication method used to submit specific protocol-related events that require expedited reporting in PROTECT.

Reportable events, from an NIH HRPP perspective, are those that occur during the course of human subjects research that require notification to the NIH IRB. For the purposes of NIH policy, reportable events that require expedited reporting include non-compliance, unanticipated problems involving risks to participants or others (also referred to as UPs), major deviations, deaths related or possibly related to research activities, new information that might affect the willingness of participants to enroll or continue participation in the study, and suspension or termination of research activities, , including holds on new enrollment, placed upon the research by the Study Sponsor, NIH or IC leadership, or any regulatory agency. Additional information about these events that require expedited reporting using the RNI Smart Form in PROTECT, is provided below.

• Deaths that are at least possibly related to research need to be reported in the electronic IRB system within 24 hours of the investigator becoming aware.
• The following research-related events need to be reported using the RNI Smart Form in PROTECT within 7 calendar days of the investigator becoming aware:
  • Major Deviation: Major deviations from the IRB-approved protocol are those that have, or may have the potential to negatively impact, the rights, welfare, or safety of the participant, or to substantially negatively impact the scientific integrity or validity of the study.
  • Unanticipated Problem (UP): An Unanticipated Problem is any incident, experience, or outcome that meets all three of the following criteria:

1. 1. 1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the participant population being studied; and
      2. Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
      3. Suggests that the research places participants or others (which may include research staff, family members or other individuals not directly participating in the research) at a greater risk of harm (including physical, psychological, economic, or social harm) related to the research than was previously known or expected.

• • New information that might affect the willingness of a participant to enroll or remain in the study
  • Non-compliance: Noncompliance means failure of an investigator to follow the applicable laws, regulations, or institutional policies governing the protection of human subjects in research, or the requirements or determinations of the Institutional Review Board (IRB), whether the failure is intentional or not.
  • Any suspension or termination of research activities including holds on new enrollment placed upon the research by the study sponsor, NIH or IC leadership, or any regulatory agency
  • FDA Form 483 or any other official communication regarding an inspection issued regarding an NIH research protocol and/or investigator within 7 calendar days of receipt of the communication. This should be submitted as an attachment to the RNI Smart Form in PROTECT using the section on the PROTECT Smart Form titled “Attach files containing supporting information.”
• Information is also available in Policy 801, Reporting Research Events and the accompanying Guidance-Reporting Research Events and Non-compliance found under policies 801 and 802 on the OHSRP webpage HRPP Policies & Guidelines.

• Major Deviations are deviations from the IRB-approved protocol that have, or may have the potential to, negatively impact, the rights, welfare or safety of the participant, or to substantially negatively impact the scientific integrity or validity of the study.
• Minor Deviations are deviations that do not have the potential to negatively impact the rights, safety, or welfare of participants or others, or the scientific integrity or validity of the study.

• Enrollment of a participant who did not meet all inclusion/exclusion criteria
• Performing a study procedure that has not been approved by the IRB 
• Failure to report an Unanticipated Problem to IRB and/or sponsor of the study 
• Study visit conducted outside the required timeframe that, in the opinion of the investigator, may impact the safety of the participant
• Failing to obtain legally effective consent prior to initiating research procedures-this includes failure to obtained signed consent when required 
• Medication errors, such as administering the wrong study drug to a participant or the wrong dose of the right study drug 
• Implementation of recruitment procedures that have not been IRB-approved

• Receiving completed questionnaires back from participants where items are missing
• Completing a study visit outside of the required timeframe when, in the opinion of the investigator, there are no safety implications.
• Use of an expired consent form in which the information contained is not substantively different than the currently approved consent unless the deviation occurs repeatedly
• Minimal over-enrollment
• A signed copy of the consent form was not given to the participant
• Documentation deficiencies in the consent form such as: 
  • A missing investigator signature 
  • The participant signs the consent form but does not print their name in the signature block
• Note: When a participant does not sign and date the consent form prior to the initiation of research, the event is considered a major deviation.

• When NIH is not the Reviewing IRB, the NIH Site PI/Lead Investigator must report research related events to the Reviewing IRB in accordance with that IRB’s Additionally, when the Reviewing IRB is an external IRB, and the reportable event occurred at an NIH site, or directly impacts the NIH site, the NIH PI must also report to the OHSRP office of Compliance and Training using the RNI Smart Form in PROTECT within 7 calendar days of the NIH PI becoming aware of the event.
• When the Reviewing IRB is an external IRB, and the event occurred at a non-NIH site, the NIH PI/Lead Investigator is required to ensure that the reporting requirements of the Reviewing IRB are The investigator does not also report these events to the OHSRP office of Compliance and Training, except as follows:
  
  • External IRB determinations of serious and/or continuing non-compliance about an NIH investigator: If the NIH is relying on an external IRB and the Reviewing IRB makes a determination of serious and/or continuing non-compliance regarding an NIH investigator, the NIH PI/designee must report this using the RNI Smart Form in PROTECT within 7 calendar days of any member of the NIH research team being notified of the determination by the Reviewing IRB. The NIH PI must provide the OHSRP office of Compliance and Training with documentation from the Reviewing IRB.
  • Suspension or termination of research activities at NIH by an external IRB: If the NIH is relying on an external IRB and the Reviewing IRB suspends or terminates NIH research activities, this must be reported within 7 calendar days of any NIH member of the research team being notified.

Investigators must provide the following information to the IRB in summary format at the time of continuing review, or when otherwise specifically requested by the IRB. Investigators should provide a high-level summary of these events that have occurred since the time of the last IRB review and not a line-item listing:

• The  Modification/Continuing Review Form in PROTECT requires investigators to check off boxes about the occurrence of various events since the initial review or the last continuing review such as the following examples: NO subjects experienced unexpected harm; Anticipated adverse events have NOT taken place with greater frequency or severity than expected; NO unanticipated problems involving risks to subjects or others, NO other relevant information regarding this study, especially information about risks; NO non-compliance has occurred (including minor or major deviations) etc. 
• For any items that are unchecked the PI must provide an explanation.

• All RNI Smart Forms submitted in PROTECT are reviewed  by a Compliance Analyst  at the OHSRP office of Compliance and Training
• Upon receipt of the RNI form, a Compliance Analyst reviews the form and determines if the form has been filled out correctly and includes all information required to fully understand the event(s).
• If there is information in the RNI Smart Form that needs to be added/corrected or if there are questions, the Compliance Analyst will send a “Request Pre-Review Clarification” to the study team.  The “Add Comment” function can also be used.
• The RNI Smart Forms are presented for consideration at the weekly meeting attended by OHSRP leadership and staff from OHSRP Compliance and Training.
• After the weekly review meeting, documentation indicating OHSRP leadership’s decision about the event is sent via PROTECT in an “Acknowledgement” letter to the PI and the study team within 24-48 hours of the meeting.
  
  • Events that are possible UPs on protocols overseen by the NIH IRB are forwarded to the NIH IRB for review, and the NIH IRB will subsequently provide the PI with an outcome letter.
  • Events that represent noncompliance that is considered possible serious and/or continuing noncompliance are forwarded to the Research Compliance Review Committee (RCRC) for review, and the office of Compliance and Training will subsequently provide the PI with an outcome letter.
  • Events that are not referred for review by the IRB or the RCRC are acknowledged in a letter sent to the team and include, as needed, any request for additional action.

• This flow diagram will help determine whether the event needs to be reported via a Reportable New Event Form in an expedited
• For additional information, please refer to Policy 801, Reporting Research Events and the accompanying Guidance-Reporting Research Events and Non-compliance found under policies 801 and 802 on the OHSRP webpage HRPP Policies & Guidelines.

Any questions about an event form can be sent via e-mail to OHSRPCompliance@od.nih.gov.  You will be provided a response within 24 hours, Monday-Friday except for federal holidays.

Refer to the section titled “Create and Submit Reportable New Information” in the PROTECT NIH Researcher’s Guide.

• Provide complete and comprehensive answers to the required questions on the RNI Smart Form and to follow-up questions posed by the Compliance Analysts after their review of your submission.
• If the event is being reported outside of the required reporting window, an explanation of the delay must be provided on the RNI Smart Form in the section where the event is described.
• If the event form being submitted reports that consent was not obtained prior to the start of research, list all of the research procedures that occurred prior to obtaining the participant’s consent.
• Compliance and Training as well as members of OHSRP leadership who initially review the RNI Smart Forms as well as the IRB or RCRC members who review event(s) referred to the board, pay particular attention to what corrective action has been taken or will be taken to mitigate the problem and prevent it from recurring. In most cases, a robust explanation in this regard is required.
• Electronically attach any relevant supporting documents when you submit the RNI Smart Form, for example:
  • If the event was reviewed by the DSMB, attach the DSMB’s follow-up report of its review.
  • If an autopsy is available, attach it with the submission.

• For FDA regulated studies, investigators are required to report events to the study sponsor as described in the protocol.
• For studies FDA regulated device studies, investigators are also required to immediately report (i.e., no longer than 10 days) report Serious Adverse Events (SAE)s or Unanticipated Adverse Device Effect (UADEs) to the study sponsor.
• If the event is also an actual or suspected UP that occurred on your study, you should also submit a RNI Smart Form in PROTECT to the IRB within 7 calendar days of becoming aware of the event.
• OHSRP office of Compliance and Training must be provided a copy of any official FDA communication regarding an inspection (e.g., FDA Form 483) issued regarding an NIH research protocol and/or investigator. This must occur within 7 calendar days of receipt of the FDA communication and should be reported in PROTECT using an RNI Smart Form.  

Information regarding when IND Safety Reports should be submitted with a RNI Smart Form.  Information about how Safety Reports should be classified in the RNI Smart Form (UP vs. New Information) can be found in the OHSRP website FAQs related to IND Safety Report Submissions.

• The RCRC is responsible for reviewing possible serious or continuing non-compliance in human subjects research for which the NIH IRB is the Reviewing IRB (whether the protocol is currently open or closed), or for human subjects research conducted by NIH Investigators without IRB approval.
• The RCRC has the final authority to determine whether there is non-compliance that is serious and/or continuing and to determine corrective action.
• As a duly convened committee, the RCRC may exercise the full authority of an IRB including suspension or termination of IRB approval of research.
• The determination by the RCRC is provided in writing to the Principal Investigator and study contacts.

• When the reported event is referred for RCRC review, you (as the PI) will be notified in PROTECT by the Compliance Analyst. You will also receive an email noting the date and time of the RCRC meeting at which the event will be reviewed. This email also explains that, if you choose to do so, you may attend the meeting to address the RCRC and answer any questions posed by the Committee You should respond to this email.
• You are also invited to provide, in advance of the meeting, any additional written information that you believe will be helpful to the RCRC members in their review of the event. You should provide any supplemental written information 7-10 days in advance of the scheduled RCRC meeting.
• After the meeting, an Analyst from the Office of Compliance & Training will send you an outcome letter in PROTECT notifying you about the RCRC determination of the event and informing you of any required follow-up action items.

• Investigators are expected to comply with NIH HRPP Policy 104, Managing Research-Related Complaints from Subjects
• You should communicate respectfully with the participant who has the concern/complaint.
• You should report the participant’s research-related complaint to the study PI.
• The PI will address the complaint as soon as feasible, and/or refer the matter to other NIH or IC offices, as appropriate.
• If the investigator is unable to resolve the participant’s complaint, the OHSRP office of Compliance and Training should be contacted to provide assistance in handling and responding to complaints.
• You should document the participant’s concern in the medical (e.g., CRIS) or research record.
• Unresolved participant complaints should be reported at the time of the CR.

• While designated contacts are identified in the consent form and include the PI and any other study investigator specifically listed on the form, if the participant wants to speak with a non-study team member about a concern, they can contact the IRB Office as listed in the consent form. Participants seen at the Clinical Center (CC) may also contact the NIH CC Patient Representative.
• Institutes/Centers (ICs) who have investigators who conduct human subjects research at other locations that do not have a designated Patient Representative may also have specific individuals or offices within the IC listed on the ICF who participants can contact about their study related concerns.
• Participants may also bring their concerns or complaints to OHSRP.
• To the extent that the participant has explained their concern, you should document the participant’s concern in the medical (e.g., CRIS) or research record.
• Unresolved participant complaints should be reported at the time of the CR.

• You can find these requirements in NIH Policy 103, Education Program, and additional information can be found in the accompanying Guideline for Investigator HSR Training.
• See additional information about this topic on the OHSRP website CITI training FAQs. You can also send questions to the OHSRP office of Compliance & Training via email.

Information on how to check required training records can be found at the Training FAQs link on the OHSRP website.

If the investigator is covered by the NIH FWA, they should click on the green box labeled “CITI Training” on the NIH CITI Training page to gain entry to the NIH CITI portal and complete the required CITI course/refresher. 

• NIH HRPP Policy 301, Informed Consent, describes the requirements for informed consent when human subjects research is conducted.  
• Additional information about how to handle situations such as use of the short form process when you have an unexpected enrollment of a participant who is non-English speaking and who cannot read the English long form as well as other situations (e.g., consent obtained via telephone and how to document such a process) can be found under the OHSRP website FAQs General and short form consent processes.

You can find these requirements in Policy 103, and additional information can be found in the accompanying guidance on Policy 103.

Log into your CITI account via the NIH portal by clicking here, and then scroll down to Required Training and then click on CITI Training.

After accessing the portal as described in question 1, click on “Records” along the banner at the top of the page.

A list of your completed courses will be displayed.  The list is easiest to view in full screen mode.

You must be sure that the email used for this account matches your NED AD email in order for your training records to download to PROTECT. To find your NED AD email, go to the NIH directory on the NIH home page and click on Staff Directory in the upper right.

Enter your name

Towards the bottom of the page that then opens, locate your NIH AD Email and be sure this is the email you use in your NIH CITI portal account.

Log into your CITI account via the NIH portal by clicking here, and then scroll down to Required Training and then click on CITI Training.

When you open the NIH CITI Portal, do NOT click on Add Institutional Affiliation. (You are all ready affiliated with the correct NIH affiliation since you logged on via this portal.)  Instead, click on “View Courses” to the right of National Institutes of Health

Click on the button that says “View Courses” to the right of National Institutes of Health

You will see either a screen with courses listed, or you will see this:

If the course you need to complete (e.g. Biomedical 101, Social & Behavioral Educational Modules or Good Clinical Practice Course (US FDA focus)) is not listed, scroll to the bottom of the screen and click on Add a Course.

Pick the course you want to complete.

When you click on a course, it is added under your Active Courses so that you can access the content

Once you complete the course, save your certificate in case a non-NIH sponsor needs to see it. Additionally, you may need to provide if a non-NIH IRB is overseeing your protocol since these entities will not have access to either the NIH CITI portal or to training records in PROTECT.

If you have a completion certificate that shows that your training has not expired, but it does not have “National Institutes of Health” at the bottom left (see below), this means that you took the course through an alternate CITI portal that will not download records into PROTECT, and you will need to transfer your training records into the correct NIH CITI portal in order to download into PROTECT.  (See Q6 for instructions to transfer records)

First you need to establish an account in the correct NIH CITI portal. See instructions in Question 3 above.

Note that your CITI user ID will appear at the top right in the banner section. If you need to transfer records from another CITI account into the NIH CITI account, you will need this number. Do not confuse this with the numbers that are assigned to specific courses.

You will need to call CITI at 888-529-5929 and provide them with your NIH CITI portal ID and ask them to transfer them in from the non-NIH portal. E.g. If you are new to NIH, you may have completed GCP (US FDA focus) at your prior site, and you can transfer that completion record into the NIH CITI portal.

Log into your CITI account using the NIH CITI portal and follow the instructions in Questions 1 and 2 above.  By the following day, your records should have transferred from the NIH CITI database to PROTECT. 

You can check to see if training has downloaded in PROTECT after 6 hours by clicking here and signing into PROTECT. 

After you log into PROTECT, follow the instructions in the screenshots below.

In the upper right corner, click on the drop-down arrow, and then click on “My Profile".

Once your profile opens, scroll to the bottom of the page where you will find your training courses listed with both the date completed and the expiration date.

If you still have questions, feel free to email Peg Sanders at margaret.sanders@nih.gov

IND Safety Reports are communications from a Sponsor that relay information about adverse events possibly related to an Investigational New Drug (IND) and do not necessarily reflect an event that occurred at an NIH site or as part of an NIH protocol. These reports are usually sent by email or through a web-based portal and may lack full context of the event. 

The event may have occurred on a different protocol that is using the same investigational product. This may mean that the participants on your trial may also be at risk of experiencing the same adverse event.  The FDA requires Sponsors to notify all participating investigators in a written IND Safety Report of “any adverse experience associated with the use of the drug that is both serious and unexpected” and “any finding from tests in laboratory animals that suggests a significant risk for human subjects.”¹  Sponsors are required to “keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use.”²  Additional helpful information can be found in Section II of the 2009 FDA Guidance titled “Adverse Event Reporting to IRBs — Improving Human Subject Protection: Guidance for Clinical Investigators, Sponsors, and IRBs.”

¹ 21 CFR 312.32(c)(1)(i)(A),(B)

² § 312.55(b

• In some cases, NIH PIs will receive an IND Safety Report from a study that is not under oversight by the NIH IRB but that is using the same investigational product being used in the NIH study. The event may have occurred on an unrelated study or on the same multisite protocol being conducted at a non-NIH site that is being overseen by a non-NIH IRB.  The NIH PI must evaluate the Safety Report and determine if the event is a possible unanticipated problem (UP) or new information that might affect the willingness of subjects on the NIH study to enroll or remain in the study. If so, the event should be reported in PROTECT for the NIH study via a Reportable New Information (RNI) submission. The PI should also consider if a protocol modification and an updated consent need to be submitted to the IRB for the NIH study based on the circumstances of the event being reported.  Note that the IRB will not provide a UP determination for an event that occurred on a protocol for which they are not the IRB of record.  However, they will review the submission and determine whether your proposed corrective actions regarding the event are sufficient.  For the full definition of an Unanticipated Problem, please refer to OHSRP Policy 801 Reporting Research Events Section 4.10 “Unanticipated Problem Involving Risks to Subjects or Others.” (Refer to Question 5 for details on reporting in PROTECT.) 
• If the event in the IND Safety Report occurred on a protocol for which the NIH IRB has oversight, and it meets the definition of a UP or represents new information that might affect the willingness of a subject to enroll or remain in the study, the event should have been previously reported to the NIH IRB within 7 calendar days of an investigator becoming aware of the event. Only if there is new information from the Sponsor contained in the subsequent Safety Report that would change the PI’s determination of the event or if it has not previously been reported, should the IND Safety report be submitted to the NIH IRB via a follow-up RNI submission.  At the time of the original RNI submission, the PI should consider if a protocol modification and an updated consent should also be submitted to the IRB based on the circumstances of the event being reported.  In most cases, when the NIH IRB is the IRB of Record, the modification will be reviewed concomitantly with the RNI submission at the same IRB meeting. (Refer to Question 5 for details on reporting in PROTECT.)

• For the full definition of an Unanticipated Problem, please refer to the OHSRP Policy 801 Section 4.10: “Unanticipated Problem Involving Risks to Subjects or Others.”
• If the sponsor is requiring a protocol modification or changes to the consent form as a result of the event, it is likely that the event meets the definition of an Unanticipated Problem or New Information.
• The FDA Guidance referenced in question 2 above specifically addresses the burden of the increasing number of IND Safety Reports and contains examples of when events meet the definition of a UP and when they should be reported to the local IRB.
• Section IIIA of the FDA Guidance provides information regarding whether an adverse event is an Unanticipated Problem and is titled, “How to Determine If an AE is an Unanticipated Problem that Needs to Be Reported.” This section includes full guidance and examples of events that would be considered Unanticipated Problems.

• If the event occurred at a site under the oversight of the NIH IRB and is a possible UP or new information that might affect the willingness of subjects to enroll or remain in the study, the event should have been reported in PROTECT within seven calendar days of the event per OHSRP Policy 801 and before the Sponsor would have issued an IND Safety report.  The subsequent IND Safety report would only need to be submitted to the NIH IRB if the information provided by the Sponsor in the report changes the PI’s previous determination of the event or if the event had not been previously reported to the IRB.
• If the event occurred on a protocol under the oversight of a non-NIH IRB, “New Information” should be selected in in the identify the categories section of the RNI Smart Form even if the PI determined that the event is a UP (See Question 4).You should not select "Unanticipated Problem" since the NIH IRB cannot make a UP determination for a study overseen by a non-NIH IRB. In these cases, submission of the RNI to the NIH IRB serves to provide the Board with the new relevant information in order to determine if the new information (e.g. a new risk was discovered with the investigational product being used on a different protocol) should be added to the NIH consent form and protocol that uses the same investigational product. The NIH IRBB will review the submission and determine whether your proposed corrective actions regarding the event are sufficient.  

• If the event occurred on a study overseen by a non-NIH IRB, only submit the IND Safety Report to the NIH IRB if the event meets the definition of a UP or represents new information that might affect the willingness of a subject to enroll or remain in the study. In that case, the event should be reported to the NIH IRB as New Information. Note that the IRB will not provide an UP determination for an event that occurred on a non-NIH IRB study. (See question 5 for details on how to submit a RNI in PROTECT.)
• If the event occurred on a protocol overseen by the NIH IRB, the event should have already been submitted to the IRB within 7 calendar days if it is a possible UP or relevant new information. The subsequent IND Safety report would only need to be submitted to the NIH IRB if the information provided by the Sponsor in the report changes the PI’s previous determination of the event or if the event had not been previously reported to the IRB.
• In either case, OHSRP Policy 801 can be provided to the Sponsor if they have questions, and you may also reference the FDA Guidance. The Sponsor may request that investigators keep a log of the PI’s review and subsequent written assessment of IND Safety Reports provided by the Sponsor.

The guidelines for an IDE are the same, and the report should be submitted to the IRB if the event is a UP or New Information. (FDA Guidance Section IV: Reporting AEs To IRBs in Clinical Trials of Devices Under the IDE Regulations)

The GDPR, which became effective May 25, 2018, is an EU regulation that relates to personal data that is collected in the European Economic Area (EEA), which includes 28 EU states as well as Norway, Iceland, Liechtenstein, and Switzerland.  It describes requirements for entities that collect, use and store personal data in the EEA (including study sponsors located in the EEA who will obtain personal data about study subjects located in the United States). It also requires that EEA entities inform subjects of their privacy rights and remedies related to their personal data.  If the entity processes personal data collected from individuals in the EEA, the GDPR may apply even if that entity is not in the EEA. See the next FAQ for information about current stance of the United States (U.S.) on the GDPR’s applicability to U.S. government agencies. 

The GDPR is not a U.S. law. The U.S. Government is not subject to GDPR, e.g., it does not automatically apply, because the U.S. is not part of the EEA. Further, Institutes and Centers do not have the legal authority to agree to follow GDPR and bind NIH to its terms.

There is an absence of an official recognition by the EEA that U.S. laws ensure an adequate level of protection (an “adequacy decision”) under the EEA standards. NIH is unable to use standard, GDPR-approved data protection clauses as they conflict with U.S. law and policy of federal agencies.

Due to uncertainties in the scope and interpretation of the GDPR requirements, the Department of State is advising U.S. government agencies not to sign, or agree to, contractual language that implies that the U.S. government complies with or will comply with the GDPR.

Any NIH investigator who is asked to provide GDPR language to participants on behalf of the sponsor should contact Heather Bridge (heather.bridge@nih.gov), who will facilitate next steps with the Office of the General Counsel (OGC). For example, current practice within the NIH Intramural Research Program is to provide a separate GDPR information sheet for participants rather than insert GDPR language into research consents.  Information sheets must be reviewed and approved by OHSRP, working with OGC, and approved by the IRB before being provided to subjects. Further, NIH investigators should not promise to or answer questions about the EU GDPR on behalf of the Sponsor. Instead, NIH investigators should refer the subject to the Sponsor’s point of contact or webpage that explains the rights of “data subjects,” which will be included in the above-referenced information sheet. 

Personal data under GDPR is more broadly defined than under the Common Rule and is explained in the European Union’s webpage “What is personal data?”

There are additional requirements for processing “special categories” of personal data.  Special categories of personal data comprise the following (and include data often collected for research purposes):

• Racial or ethnic origin
• Data concerning health
• Data concerning a natural person’s sex life or sexual orientation
• Genetic data
• Biometric data used for the purpose of uniquely identifying an individual
• Political opinions, religious or philosophical beliefs, or trade union membership.

Processing¹ covers a wide range of operations performed on personal data, including by manual or automated means. It includes the collection, recording, organization, structuring, storage, adaptation or alteration, retrieval, consultation, use, disclosure by transmission, dissemination or otherwise making available, alignment or combination, restriction, erasure or destruction of personal data.

[1] Data “processing” as defined on the European Commission (EC) website, EU data protection rules

A controller alone or jointly determines the purposes and means of processing personal data (e.g. acts as a collaborator on a research project) while a processor processes personal data on behalf of the controller (e.g. a fee-for-service lab for a research projects). Both are regulated under the GDPR, but controllers have more responsibilities.

Examples of when the GDPR may apply to non-governmental entities (i.e., not to NIH) include the following if the organization/entity:

• Monitors the behavior of individuals in the EEA
  • Conducting research with participants located in the EEA could involve activities that fall into this category (e.g. a US-based sponsor serves as a lead site for a multi-site protocol with sites in the EEA)
• Offers goods or services to individuals in the EEA (irrespective of whether connected to payment) and could include examples related to research such as the following:
  • Clinical Trial Agreement between a US based sponsor and an EEA study site
  • US based sponsor provides investigational product (IP) to EEA study sites
• Is established in the EEA and acts as a data controller or processor

• European Commission (EC). EU data protection rules. (website)
• NIH OSP.  GDPR: Crossing the Data Sharing Bridge, One Regulation at a Time (2019)
• PRIM&R. EU General Data Protection Regulations: What US Research Institutions Need to Know (2018) [At the bottom, enter information and click “Launch”]
• SACHRP. Attachment B-European Union’s General Data Protection Regulations (2018)

“Prisoner” is defined in the federal regulations as any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing (45 CFR 46.303(c)).

This means that individuals are prisoners if they are in any kind of penal institution, such as a prison, jail, or juvenile offender facility, and their ability to leave the institution is restricted. Prisoners may be convicted felons or may be untried persons who are detained pending judicial action, for example, arraignment or trial.  However, as noted in the regulatory definition above, the term “prisoner” also goes beyond those being held in a traditional jail or prison and includes, for example, individuals with mental illness who are committed involuntarily to a psychiatric facility as an alternative to prosecution or incarceration.

The OHRP Prisoner Research FAQs provide the following helpful examples:

• Individuals who are detained in a residential facility for court-ordered substance abuse treatment as a form of sentencing or alternative to incarceration are prisoners; however, individuals who are receiving non-residential court-ordered substance abuse treatment and are residing in the community are not prisoners.
• Individuals with psychiatric illnesses who have been committed involuntarily to an institution as an alternative to a criminal prosecution or incarceration are prisoners; however, individuals who have been voluntarily admitted to an institution for treatment of a psychiatric illness, or who have been civilly committed to nonpenal institutions for treatment because their illness makes them a danger to themselves or others, are not prisoners.
• Parolees who are detained in a treatment center as a condition of parole are prisoners; however, persons living in the community and sentenced to community-supervised monitoring, including parolees, are not prisoners.
• Probationers and individuals wearing monitoring devices are generally not considered to be prisoners; however, situations of this kind frequently require an analysis of the particular circumstances of the planned subject population. Institutions may consult with OHRP when questions arise about research involving these populations.

Research conducted or supported by the Department of Health and Human Services (HHS) is subject to the relevant HHS regulations for protection of human research subjects.  This means that research conducted by NIH as an agency within HHS must comply with these federal regulations as well as the requirements of the subparts.  In addition to requirements at Subpart A,  Subpart C of these regulations specifically addresses the requirements when conducting human subjects research with prisoners.  Details of the regulatory requirements that relate to enrolling prisoners are addressed below.

Prior to the 1970s, there were many examples of abuse, exploitation, coercion, conflict of interest, lack of informed consent and other unethical practices that occurred during research conducted with prisoners.  (See Bonham and Moreno (2008) and Christopher, Gorey and Rich (2022) as listed in the References for discussion of such research.)  In 1976, the National Commission for the Protections of Biomedical and Behavioral Research released its review of the ethical issues surrounding inclusion of prisoners in research in its Report and Recommendations: Research Involving Prisoners.  In this report, the National Commission took the position that “prisoners are, as a consequence of being prisoners, more subject to coerced choice and more readily available for the imposition of burdens that others will not willingly bear,” and that they should “be protected against those forces that appear to compel their choices.”  Their view was that “the appropriate expression of respect [for persons] consists in protection from exploitation.” This belief formed the basis for the current regulations involving prisoner research as codified in Subpart C of the federal regulation for protection of research subjects.

1. Biomedical or behavioral research conducted or supported by Department of Health and Human Services (HHS) may involve prisoners as subjects only if:
   1. The institution responsible for the conduct of the research has certified to the Secretary of HHS (“the Secretary”) that the IRB  has approved the research under § 46.305 of this subpart (which describes the duties of the IRB in such research as described in the question below titled "What does the IRB need to do in order to approve a protocol that anticipates enrollment of prisoners?"); and
   2. In the judgment of the Secretary the proposed research involves solely the following:
      1. Study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
         1. This category could include study of conditions related to incarceration that pose no greater than minimal risk such as HIV/hepatitis status, mental illness or substance abuse and, for example, might also include socio-behavioral research or secondary research.
      2. Study of prisons as institutional structures or of prisoners as incarcerated persons,    provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
      3. Research on conditions particularly affecting prisoners as a class:
         1. Studies in this category may proceed only after the Secretary has consulted with appropriate experts including experts in penology [penology means the study of punishment of crime/treatment of the offender], medicine and ethics and published a notice in the Federal Register (FR) of the intent to approve such research.
         2. This category can include research that is greater than minimal risk and does not require that there be prospect of direct benefit.
         3. Examples provided in the regulations include vaccine trials and research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction and sexual assaults.
      4. Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject.
         1. In cases in which such studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups ( e.g., placebo control) which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology, medicine and ethics, and published notice, in the FR, of his intent to approve such research.
2. 2003 Epidemiologic Waiver allows HHS Epidemiology Research that does not fit into the existing categories (68 Fed. Reg. 36929 (Jun. 20, 2003).
   1. This applies to epidemiology research if the sole purpose of the research is:
      1. To describe the prevalence/incidence of a disease by identifying all cases, or
      2. To study potential risk factor associations for a disease.
   2. In this case, the IRB certifies to OHRP that it has applied the relevant regulatory conditions (45 CFR 46.305(a)(2)-(7)), and the IRB must determine and document that:
      1. There is no more than minimal risk and no more than inconvenience to the prisoner-subjects, and
      2. Prisoners are not a focus of the research.
   3. Examples of research allowed under this category could include disease monitoring systems, health registries and various other epidemiological studies.
3. Human subjects research that is exempt from IRB review only as follows:
   1. Exempt research involving prisoners is not allowed in research approved under the pre-2018 Common Rule.
   2. Under the (revised) 2018 Common Rule, research that otherwise meets the requirement as exempt may only be conducted with prisoners if it is aimed at involving a broader subject population that only incidentally includes prisoners. Examples of exempt research that only incidentally includes prisoners include:
      1. Exempt secondary research use of information or biospecimens from subjects who are prisoners if that analysis is not seeking to examine prisoners as a population and only incidentally includes prisoners in the broader study.
      2. An exempt study that recruits subjects from a local community center to participate in a comparison of HIV educational materials even if some of the subjects became prisoners after enrollment.
4. Prisoners cannot be involved in emergency research where the requirement for informed consent has been waived by the Secretary under the authority of 45 CFR 46.101(i).

The definition of minimal risk is different than the one used in Subparts A, B, and D.  The definition as it relates to prisoners (45 CFR 46.303(d)) is:

The probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons.

Note that this definition:

• Refers to “physical or psychological” harm as opposed to “harm” or “discomfort.”
• Uses the “healthy” person standard. At NIH, “healthy persons” is interpreted to mean healthy persons who are not incarcerated.

1. Investigators should be mindful of applicable state or local law, as well as Tribal law. Each state has a Department of Corrections (DOC) with specific regulations/rules, and links to specific state DOC sites can be found on the gov website that provides information about corrections departments by state
2. Determine that you are allowed to collect data from the incarcerated person in that institution/state.
   1. You will likely need to fill out paperwork in the jurisdiction and/or state where the study is taking place.
   2. If you only want to enroll one individual at a specific prison, it is possible they will allow you to do this with institutional permission.
   3. Once determined, provide this documentation of permission from the institution/ DOC when you submit the protocol to the IRB.
3. Protocol considerations: If you are only enrolling a few people who may be prisoners, and prisoners are not your targeted population, add a subsection in your protocol addressing this specific population of subjects. Broadly detail the ways in which data collection would or would not change based on the person being incarcerated. You should first reach out to the relevant penal institution(s) to gain an understanding of the institution/jurisdiction, and what that institution/jurisdiction will allow.
   1. You then need to decide if you will go into the facility to collect all This should be stated in your protocol along with how you will ensure privacy and the ability of the participant to communicate with the team if needed. For example, will you provide them prepaid and pre-addressed envelopes or provide them with money on their phone account in order to be able to call and report an adverse event?
   2. This is not about merely ensuring privacy. You may not be able to do certain activities with people who are incarcerated unless the institution permits it, or unless it is so noninvasive that it makes institutional permission unnecessary for contact (e.g., mail correspondence). However, even correspondence can be read by DOC officials, meaning that privacy of the incarcerated subject cannot be guaranteed.
   3. If any data collection must be done outside the facility, how do you propose to transport the incarcerated subject or what data will you simply not collect? It is unlikely that a DOC will use its resources to transport an inmate for non-essential travel (non-emergency or not mandated travel), and they will not allow a study team to transport a prisoner. Prisoners are usually transported in shackles and kept under guard even for medical procedures outside of the facility
4. Consent Considerations
   1. Consider how you will obtain consent and describe that process in the protocol. Even in the case where you simply want to ask questions as a scheduled visitor at the facility and will not collect samples (possibly helping get around larger institutional permissions), this will still be tricky and there are several ways to accomplish this. This interaction will not be like a typical informed consent process unless you have full institutional permission to interact with the incarcerated person in a research-specific way that would go well beyond what a typical visitor could do.
   2. Create a new consent form for incarcerated potential subjects which adds to each existing section, where appropriate, language that is appropriate for this population based on what you have in the protocol. Your consent form must also describe any special conditions related to follow-up and how follow-up will occur. This should also be described in the protocol. The following should be included in addition to generic consent language:
      1. “Your legal standing, including your sentence or any term of probation or parole will not be impacted by your decision to take part in this study or to refuse to volunteer for this study.” When enrolling prisoners, this language about parole is required in the consent form in order for the IRB to approve it.
      2. “No data collected will be shared with the Department of Corrections.”… etc.   

If the IRB makes the appropriate findings regarding the waiver or alteration of informed consent requirements as required in Subpart A (§ 46.116 (e)-(f)), research involving prisoners may be approved with a waiver or alteration of informed consent. Note the following caveats below:

1. However, if informed consent is waived or altered, Subpart C of 45 CFR 46 still requires that the prisoner-subjects be clearly informed in advance that participation in the research will have no effect on their parole if such notification is relevant. 
2. In cases of emergency research where the requirement for informed consent has been waived by the Secretary of HHS under the authority of 45 CFR 46.101(i), prisoners cannot be enrolled.

1. When the convened IRB reviews a protocol that includes a plan to enroll prisoners as subjects:
   1. At least one member of the board must include a prisoner, or a prisoner representative with appropriate background and experience that provides a close working knowledge, understanding and appreciation of prison conditions from the perspective of the prisoner.
   2. Except for the IRB member who is the prisoner/prisoner representative as required above, a majority of the Board cannot have any association with the prison(s) involved, apart from their membership on the Board.
2. In order to approve research that involves prisoners, the IRB must find that, in addition to the requirements of Subpart A, the following seven conditions are met and must document the justification for each finding:
   1. The IRB must find that research falls into one of the categories noted in the above question titled "What research with prisoners can I conduct under the applicable federal regulations?".
   2. Any possible advantages accrued to the prisoner through participation, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not so great that they impair prisoners’ ability to weigh risks of the research against the value of such advantages in the limited choice environment of the prison.
   3. Risks are same as those would be accepted by non-prisoner volunteers.
   4. Procedures for selection of subjects is fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners. Unless the PI provides the IRB with written justification for following some other procedures, control subjects must be randomly selected from the group of available prisoners who meet the characteristics needed for the protocol.
   5. The information is presented in language which is understandable to prisoners.
   6. Adequate assurance exists that parole boards will not take into consideration the prisoner’s participation in the research in making decisions regarding parole. The informed consent document must clearly state that participation in the research will not impact parole. If the IRB has waived informed consent, the prisoners must still be informed that participation in the research will not impact parole as is explained in the above question titled "Can the IRB waive or alter informed consent if the research involves prisoners?".
   7. For studies where post-study follow up care will be needed, there must be adequate provision for this follow up that takes into account the varying length of individual prisoners’ sentences and for informing the prisoners of this fact in the informed consent document.

The NIH IRB must send a Certification Form to OHRP for all protocols that it oversees that involve prisoners including studies that fall under the Epidemiologic Waiver.  The Certification Form will include the following:

1. The research proposal (i.e., IRB approved protocol, IRB application forms, and information requested by the IRB at Initial Review);
2. The risk category determined by the IRB along with the IRB ‘s justification for the category selected; and
3. If the research is approved under the Epidemiologic Waiver, the Certification Form will include the IRB’s determination and justification regarding:
   1. minimal risk/inconvenience, and
   2. prisoners are not the focus of the research.

Note that the research cannot be initiated until OHRP issues its approval.

1. If a subject becomes incarcerated and the IRB and OHRP have not previously approved prisoner participation on your research protocol, you must notify IRBO as soon as possible using the relevant event/reportable new information form in the NIH eIRB system.
2. All research interactions, interventions with, and obtaining identifiable private information about the now-incarcerated prisoner-subject, must be halted until IRB and OHRP approval is obtained.
3. If it is in the best interest of the subject to remain on study while incarcerated, you must promptly notify IRBO and obtain permission from the IRB Chair to continue activities needed to ensure the safety and welfare of the now prisoner-subject until IRB and OHRP approval is obtained.
   1. Submit an amendment in the NIH electronic IRB system for review by the convened IRB requesting permission for the prisoner-subject to remain on study and include any additional safeguards and changes to procedures (if any) needed for the now-prisoner-subject to remain on the research.
4. No research activities involving the prisoner-subject may take place prior to IRB approval and receipt of a letter of authorization from OHRP, except for those necessary for the welfare or safety of the prisoner-subject.
5. If the IRB disapproves continued participation of the prisoner-subject, the subject must be taken off study.
6. A subject may move into and out of “prisoner” status without requiring IRB review under Subpart C so long as no research interactions occur while the subject is considered a prisoner. You still must notify the IRB  as soon as possible using the relevant event/reportable new information form in the eIRB system. For example, if a subject on a natural history study becomes incarcerated on a minor drug charge resulting only in a short jail sentence, and no research activities occur during their incarceration, they may resume study participation when they are no longer considered a prisoner.  In such a case, review under the Subpart C regulations is not required.
7. If you are not sure whether Subpart C would apply in a given situation, please consult IRBO immediately.

68 Fed. Reg. 36929 (Jun. 20, 2003) - Waiver of the Applicability of Certain Provisions of DHHS Regulations for Protection of Human Research Subjects for Department of Health and Human Services Conducted or Supported Epidemiologic Research Involving Prisoners as Subjects

45 CFR 46, Subpart C:  Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects

Bonham VH, Moreno JD. Research with Captive Populations: Prisoners, Students and Soldiers. In The Oxford Textbook of Clinical Research Ethics, EJ Emmanuel, C Grady, RA Crouch, RK Lie, FG Miller, and D Wendler (Eds), (2008), Oxford University Press, NY, NY.

Christopher PP, Gorey JG, Rich, J. Subpart C Research: Additional Protections for Prisoners. In Institutional Review Board Management and Function, EA Bankert, BG Gordon, EA Hurley and SP Shriver (Eds), (2022), Jones and Bartlett Learning, Burlington, MA.

NIH HRPP Policy 401, Research Involving Prisoners

OHRP Prisoner Research FAQs

OHRP Guidance – Prisoner Involvement in Research (May 23, 2003)

When a protocol undergoes initial approval, the protocol’s consent document is reviewed to ensure that all known risks to research subjects are included and communicated in a way that can be easily understood.  These risks can vary depending on the type of research study that is being conducted.

Once a study starts enrollment, there may be new risks that are identified that were not anticipated.  These can be risks to the physical or mental safety of participants, risks to the rights or privacy of subjects, or even unanticipated issues with confidentially.  It is not unexpected for this to happen and these new risks need be communicated so that subjects can make an informed decision if they would like to continue to participate in the research.

There are several ways that new risks can be identified.  The most common way is from events that occur on a research protocol.  These could be physical or mental adverse events which were not included in the consent document or that occurred at a greater severity or frequency than previously known.  Another example would be a large data breach that affected all your research subjects.  This should sound familiar because these are examples of unanticipated problems that are reportable to the IRB.  If you are reporting a possible unanticipated problem to the IRB, you should be considering if there is a new risk that needs to be communicated to subjects.

New risks to your research participants may also be identified outside of your protocol.  The most common ways are through new research publications, drug safety-related labeling changes, and sponsor’s or manufacturer’s IND Safety reports.

• Recent publications related to your research might contain new information that identifies additional risks to your subjects or raises questions about the efficacy of your research.
• Drug safety-related labeling changes (SrLC) were formally known as MedWatch notifications. If your study involves FDA approved drugs, then new risks may be identified after the initial FDA approval through Phase 4 trials or through community adverse event reporting.  It is the responsibility of the investigator to keep informed of any major changes, such as a new boxed warning.  The FDA has a database where you can search for SrLCs.   You can also sign up to receive email notification.
• If your study involves a drug/device that is not FDA approved and under an IND/IDE, then you may receive Safety Reports from a sponsor/manufacturer.  These reports may contain new risks that apply to your research that need to be communicated to participants.  If the information in these reports rises to the level of needing to be reported to the IRB, then you should also consider if participants also need to be informed.  Please see the FAQ on IND Safety Reports for details on when these reports need to be sent to the IRB.

Informing research participants of new risks is part of the ongoing consent process that occurs from first contact and continues until the participant is taken off study.  Just like your initial consent document needs to contain IRB approved language, the language used to communicate new risks also must receive prior IRB approval.  There are several ways that new risks can be communicated to participants.  The mode of communication can vary based of the type of information being communicated and where the participants are in the research process.  Your plan for notification of subjects should be a part of your proposed actions at the time you notify the IRB of the new risks in the eIRB system.

• Revised Consent/Assent Documents: A modification to the protocol consent document is going to be the most common way to communicate new risk information. When the modification containing the revised consent language is approved by the IRB, the approval outcome letter will contain instruction on which subjects must go through the reconsent process.  The expectation is that those instructions are followed and reconsent is performed in a timely manner.  To not follow the instruction of the IRB constitutes noncompliance and is considered a reportable event.
• Information Letter: For certain new risks or events that occur, an IRB approved information letter may be sufficient for notification. This letter can be sent either physically and/or electronically.  The proposed letter needs to be submitted to the IRB for prior approval via a modification.  An information letter may also be an option used to communicate new risks quickly to participants that can be used if changing the consent document may take too long.  In this case, the IRB may require an information letter to be followed up by reconsent using a revised consent/assent document.
• Verbal Script: For certain new risks or events that occur, an IRB approved verbal script may be sufficient for notification. The script is usually used to inform subjects of the new information by phone.  The script needs to be submitted to the IRB for prior approval via a modification.  A verbal script may also be an option used to communicate new risks quickly to participants that can be used if changing the consent document may take too long.  In this case, the IRB may require verbal notification to be followed up by reconsent using a revised consent/assent document.

If there is a safety risk to participants that requires action to eliminate apparent immediate hazards, the investigator may inform the participants using language not approved by the IRB.  However, new information that puts research participants at this level of immediate risk would also most likely be reportable via a Reportable New Information (RNI) form.  You may be required to follow-up this initial discussion with IRB approved language using a method discussed in question 3.  If there are any questions that occur during an emergency situation, the investigator is encouraged to contact the IRB or OHSRP Leadership directly.

It is not sufficient to only inform the subjects of any new risks.  It is also the responsibility of the investigator to timely and adequately document the process.  If you have access to a medical record system where you document research activities, such as CRIS at the NIH Clinical Center, then any discussion regarding communication of risk should be documented in a note.  This is important since this is proof that the investigator has upheld their responsibilities for auditing purposes.  If no medical record is available, then the contacts should be documented in the research record.

• Emergency immediate notification: In your note, you should include what exact information was conveyed to the participant to ensure that they were adequately informed of the new risk.
• Revised Consent/Assent Documents: The consent/assent documents should be filled out appropriately. A note should be entered in the medical record that documents that the consent process was performed appropriately.
• Information Letter: Document in the medical/research record that the letter was sent. Confirmation of receipt may be required.
• Verbal Script: Documentation of the conversation needs to be recorded in the medical/research record. The note should include whether the subject is willing to continue participation in the research and that they have had a chance to ask and have any questions addressed.  If you attempt to contact a subject and are unable to reach them, that attempt should also be documented.

• A HUD is a legally marketed medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals in the United States per year.
• Requests for HUD designation are made to the FDA's Office of Orphan Products Development. Details of this process can be found at 21 CFR 814.102.
• Use of the HUD under the approved indication does not constitute research (a clinical investigation) unless safety and efficacy data are being collected. (See question #8 below that addresses when use of a HUD is considered a clinical investigation.)
• Within the NIH Intramural Research Program (IRP), approval by the convened IRB for use in the facility is required before a HUD can be used for clinical care (as part of medical practice), except for emergency situations. (See section below related to use of a HUD in emergency situations.)

• An HDE is a marketing application for a HUD that provides a channel for manufacturers to develop devices to benefit small patient populations.
• HDEs provide an exemption from the typical FDA requirements that are applied to most medical devices (for example those approved or cleared via the PMA or 510k path), when they are used in compliance with the FDA-approved indication(s).
• To approve an HDE, the FDA must find that the device:
  • Will not expose patients to an unreasonable or significant risk of illness or injury and that the probable benefit outweighs the risk
  • Would not be available to a person without an HDE and no comparable device (other than another HDE or IDE) is available
  • The disease or condition affects not more than 8000 persons in the US annually.

• Ensure that a HUD used under an HDE is administered only in institutions after an IRB has approved the use of the HUD for clinical care at that facility.
• Notify the FDA of any withdrawal of approval for the use of a HUD by the Reviewing IRB within 5 working days after being notified of the withdrawal of approval.

• NIH IRB approval of the use of the HUD in the facility (e.g., at the Clinical Center) must be obtained before it can be used at the NIH.
• Once approved at the NIH, a HUD can be used according to its approved labeling and indication(s) to treat or diagnose patients. It can also be used “off label” as a part of medical practice.  Note that if you are using it off label as part of medical practice, you cannot collect any research data about the safety or effectiveness of the device other than that data collected as part of the clinical care of that patient.
• Following the approval of the use of the HUD at the NIH, the IRB does not need to review or be notified of each individual use of the HUD for clinical care.
• Once the HUD is approved for use at the NIH, it may be used off-label for clinical care (not research) without additional IRB notification or approval.
• For initial review of a HUD, the IRB must perform their review at a convened meeting, but subsequent reviews may be conducted by expedited procedures.
• The IRB will evaluate the risks to patients posed by the device, ensure that the risks are minimized and evaluate whether the risks are reasonable in relation to the proposed use of the device when it conducts initial review of a HUD. The IRB will also assess whether the proposed use of the device is consistent with the product labeling and HDE approval order as well as review any information that will be provided to the patient about the device (for example, the patient information sheet).

• The NIH IRB does not require that an informed consent document be submitted for approval and use.
• The NIH IRB does require that the treating physician provide the patient with an information sheet describing the HUD. This should be submitted to the IRB for review.
• The information sheet should be clear that effectiveness has not been demonstrated, it is a HUD, and it is approved by the FDA to either treat or diagnose the specific disease or condition.
• The information sheet should make no reference to research.

• The NIH IRB does not require that an informed consent document be submitted for approval and use.
• The NIH IRB does require that the treating physician provide the patient with an information sheet describing the HUD. This should be submitted to the IRB for review.
• The information sheet should be clear that effectiveness has not been demonstrated, it is a HUD, and it is approved by the FDA to either treat or diagnose the specific disease or condition.
• The information sheet should make no reference to research.

When reviewing HUD submissions, IRB members should consider the following:

• Are risks minimized by using procedures that do not unnecessarily expose patients to risk, and are risks reasonable in relation to the device being used and its probable benefit?
• Are there adequate provisions to protect the privacy of the patients and the confidentiality of any data being collected?
• Is the device being used within the scope of the FDA HDE approval order?
• As no written consent is required at the NIH IRP, is the patient or LAR provided a patient information sheet or brochure for the device?

• The collection of safety and efficacy data about the HUD is considered a clinical investigation and is subject to FDA regulations relating to investigational devices (21 CFR 812), IRB review and informed consent (sections 21 CFR Part 56 and 21 CFR Part 50, respectively), as well as HHS regulations (45 CFR 46), as applicable.
• Clinical investigation of a HUD is research and must be reviewed and approved by an IRB.
• If safety and efficacy data are collected about a HUD, and it is being used within its HDE-approved indication, no IDE is required (21 CFR Part 812). Therefore, no SR or NSR determination needs to be made by the IRB.
• If the use of the HUD in the clinical investigation is not within its HDE-approved indication, the investigation is subject to the IDE rules at 21 CFR 812, and the IRB must make a determination as to whether the investigation is a non-significant risk (NSR) study requiring IRB submission only, or a significant risk (SR) study requiring submission to the FDA.
  • When a HUD is used in a clinical investigation, investigators are required to report events to the study sponsor as described in the protocol and 21 CFR 812. In addition to other required reporting, investigators must report any unanticipated adverse device effect (UADE) to the sponsor as soon as possible but no later than 10 working days after the investigator first learns of the effect. If the UADE is also an actual or suspected unanticipated problem, it must be reported to the IRB within seven calendar days of an investigator becoming aware consistent with event reporting requirements in Policy 801, Reporting Research Events.  A UADE is defined as “Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.”

• If a physician, in an emergency situation (i.e., patient has serious or immediately life-threatening condition necessitating use of the HUD), determines that IRB approval for the use of the HUD at the facility cannot be obtained in time to prevent serious harm or death to a patient, a HUD may be used without prior approval. In this situation:
• The HDE holder may ship the HUD, based on the physician’s certification of the emergent need.
• FDA regulations require that physician provide such notification to the Chair of the IRB in writing within 5 days of the emergency use of the device. Such written notification must include the identification of the patient involved, the date on which the device was used, and the reason for the use.

• If you are the HDE holder, you are subject to FDA’s post approval reporting requirements which are described at 21 CFR 814.126.
• HDE holders and users must follow the FDA device reporting requirements as specified in 21 CFR 803.

Contact the NIH Office of IRB Operations at irb@od.nih.gov or the Regulatory Support Section of the Clinical Center Office of Research and Compliance at REGSupportORSC@nih.gov for any questions or guidance you may require.

FDA Resources

• 21 CFR 814 Subpart H-Humanitarian Use Devices
• Guidance Document- Humanitarian Use Device (HUD) Designations (2013)
• Guidance Document-Humanitarian Use Device Exemption Program (2019)
• Humanitarian Use Device (HUD) Designation Program
• Education and Media Resources for HUD Program
• Chowdhury K. Humanitarian Use Device (HUD) Program Overview (slides)
• Headlee D. Humanitarian Device Exemption (HDE): Overview and Pre-approval Activities (slides)
• Headlee D. Humanitarian Device Exemption (HDE): Post-approval Activities (slides). Includes information about responsibilities of HDE holders and IRBs.

NIH Policy 501, Research Involving FDA Regulated Devices (Section E.5)

NIH Policy 801, Reporting Research Events

Craddock T. Humanitarian Use Devices. In Institutional Review Board Management and Function, EA Bankert, BG Gordon, EA Hurley, and SP Shriver (Eds), (2022), Jones and Bartlett Learning, Burlington, MA.