Frequently Asked Questions
UPIRSOs (AE, SAE, and non-AE reporting)
“UPIRSO” is an acronym for the term Unanticipated Problems Involving Risks to Subjects or Others. UPIRSOs are new (usually bad) information requiring corrective actions to protect subjects or others.
UPIRSOs may occur at your site (a local UPIRSO) or be reported to you via investigator letters and safety reports (an external UPIRSO).
Events (e.g., AEs, SAEs, non-AEs), incidents, or outcomes must meet all three of the following criteria to be considered a UPIRSO:
- Unexpected in nature, frequency, or severity (i.e., generally not expected in a subject’s underlying condition or not expected as a risk of the study; therefore, not included in the investigator’s brochure, protocol, or informed consent document), and
- Probably or definitely related to participation in the research, and
- Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, social, legal, or financial harm) than was previously known or recognized.
If an event only meets one or two UPIRSO criteria, it is NOT a UPIRSO and should NOT be submitted via a RE.
“Others” include those who may be affected by the research even though they are not participating in the research. Examples include, but are not limited to:
- New information shows that the study drug/device/intervention/procedure may cause harm to fetuses
- A family member ingests the subject’s investigational study drug
- A subject’s PHI has been lost, stolen, or disclosed to unauthorized recipients, which may affect or expose the subject’s spouse to harms or risks (physical, psychological, social, legal, or financial)
- A member of the study team is harmed during the conduct of the study
- The study device is found to give false results, which may affect or expose the subject’s spouse to harms or risks (physical, psychological, social, legal, or financial)
AEs and SAEs that occur at your site or are reported to you through safety reports and investigator letters are only promptly reported to the UTSW IRB (or UTSW HRPP for reliance studies) via RE if they are UPIRSOs (i.e., the event meets all 3 UPIRSO criteria).
The first step is to determine whether the event is expected due to the subject’s condition or predisposing risk factors (also referred to as prior medical history or pre-existing conditions) which may have caused or contributed to the event.
The majority of AEs/SAEs that occur in research are expected in light of:
- Known toxicities and side effects of the research interventions or procedures;
- Expected natural progression of subjects’ underlying diseases, disorders, and conditions; or
- Subjects’ predisposing risk factors.
Therefore, most (but not all) individual AEs (events that happen to only one subject) do not meet UPIRSO criteria No. 1 and are not required to be promptly reported to the UTSW IRB (or UTSW HRPP for reliance studies) via a RE.
If the event is not expected due to the subject’s underlying condition or predisposing risk factors, review the study’s ICF, IB, package insert, and/or instructions for use.
If the event is listed as a risk of the study and is occurring as expected in frequency and severity, the event is considered “expected.”
If the event/risk is not listed as a risk of the study or if the risk is listed but is more severe or occurring more frequently than specified, the event is considered “unexpected.”
Sponsors’ comments, assessments, or conclusions in the SUSAR or MedWatch may state something like:
- “Possible attribution to study drug cannot be completely excluded,” or
- “The Company agrees with the investigator that the event could be related to the study drug; however, the event is confounded by the subject’s medical history of X, Y, and Z.”
When the cause of an event is confounded by other factors, only possibly related to the research, or the research intervention may be a contributing factor or cannot be completely excluded, the event does not meet UPIRSO criteria No. 2 because it is not probably or definitely related to the research.
If there is not enough information to determine whether the event meets all three UPIRSO criteria, do not promptly report the event to the UTSW IRB (or UTSW HRPP for reliance studies) via a RE.
If/when additional information becomes available indicating the event meets all three UPIRSO criteria, promptly report the event to the UTSW IRB (or UTSW HRPP for reliance studies) via a RE. The five-day reporting “clock” starts when the PI becomes aware that the event meets all three UPIRSO criteria.
The event is probably not a UPIRSO. UPIRSOs necessitate changes or other corrective actions to protect the safety, welfare, or rights of subjects or others.
Corrective actions typically include modifying the study documents (e.g., IB, protocol, ICF), implementing new study processes or procedures, and/or notifying or re-educating subjects.
The UTSW HRPP/IRB does not accept or acknowledge AEs/SAEs that are not UPIRSO.
As stated in FDA’s Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs – Improving Human Subject Protection, the volume of AEs/SAEs reported to IRBs is inhibiting, rather than enhancing, the ability of IRBs to protect human subjects. Reporting only AEs/SAEs that are UPIRSOs eases the burden for investigators and IRBs and makes the information the IRB receives more informative and useful.
Refer the sponsor to the UTSW HRPP policy on UPIRSOs and report the event at the next CR or notice of study closure, whichever comes first.
Noncompliance is any failure to follow:
- Applicable federal regulations, state and local laws, or institutional policies governing human subjects protections, or
- The requirements or determinations of the IRB, including the requirements of the approved investigational plan (e.g., protocol, Smartform, ICD)
- Noncompliance can result from performing an act that violates these requirements or failing to act when required
The convened IRB determines whether noncompliance is serious and/or continuing.
See the HRPP Policy & Procedure Manual for the definitions and reporting requirements of noncompliance, serious noncompliance, and continuing noncompliance.
Per federal regulations and UTSW HRPP policy, only changes intended to eliminate an apparent immediate hazard to subjects or to protect the life or physical well-being of subjects in an emergency may be implemented without prior IRB approval.
Report emergency deviations to the reviewing IRB (and UTSW HRPP for reliance studies) within five working days of occurrence.
Unless a change was made to eliminate an apparent immediate hazard to subjects or to protect the life or physical well-being of subjects in an emergency, the change is considered noncompliance.
If the noncompliance appears to be serious or continuing noncompliance, promptly report it to the UTSW IRB (or UTSW HRPP for reliance studies) via a RE. If the noncompliance is neither serious nor continuing, report it at CR or notice of study closure, whichever comes first.
If there are no differences or the only differences between the two versions are administrative (change in contacts) or editorial (to correct typographical errors), do not report it to the UTSW IRB (or UTSW HRPP for reliance studies) via a RE. Report it at CR or notice of study closure, whichever comes first.
If the differences are more than administrative or editorial changes (for example, new risk information, new or additional study procedures or visits, or any other information that may affect a subject’s decision to stay in the study, etc.), submit a RE.
In the RE, you must specify the differences between the two ICF versions.
Very rarely will subject noncompliance be reported to the UTSW IRB (or UTSW HRPP for reliance studies) via a RE. Subject noncompliance is only reported via a RE if the noncompliance results in a UPIRSO. Otherwise, document subject noncompliance in the research record and report it at CR or notice of study closure, whichever comes first.
- Example: A subject overdoses on his/her study drug, but does not experience any AEs. Because the overdose is unexpected, definitely related to the research, and suggests an increased risk of harm to the subject, it meets all three UPIRSO criteria and must be promptly reported via a RE.
Missed or out-of-window study visits are not reported via a RE unless the subject experiences a UPIRSO as a result (this will be extremely rare). If this rare situation occurs on your study, submit the event as a UPIRSO via RE.
When subject noncompliance results in a UPIRSO, report the event as a “UPIRSO” in section 1.0 of the RE. In the RE, explain how the subject’s noncompliance resulted in the UPIRSO.
All research subjects have rights, which include, but are not limited to:
- The right to voluntarily decide whether to participate in research that is free of undue influence, coercion, or repercussions if they choose not to participate
- The right to be informed of the risks, benefits, and alternatives to study participation
- The right to protection from unreasonable risks and harms (physical, psychological, social, legal, and financial)
- The right to be informed of new findings which may affect their willingness to continue in the research
- The right to end study participation at any time without repercussions
- Principal Investigator
- Department Chair
- Institutional offices and officials, as applicable Study sponsors, if applicable
- Research officials at the performance site where the noncompliance occurred
- Federal and/or other regulatory oversight agencies, such as HHS/OHRP, FDA, DoD, etc., as applicable to the study
Root Cause Analyses & Corrective and Preventive Action (CAPA) Plans
The “root cause” is the underlying reason why an event occurred or did not occur.
Stating “the coordinator forgot” is not a root cause. The root cause is the reason why the coordinator forgot (e.g., was it a one-time mistake; is there a visit checklist and, if so, was it used; did the equipment malfunction; were the pharmacy orders incorrect; etc.)?
The root cause of the problem must be determined to be able to develop and implement an appropriate and adequate corrective and preventive action (CAPA) plan.
Corrective actions are those taken to act on or remedy a problem that has already occurred.
Preventive actions are those taken to eliminate the root cause of a problem so that it stops or minimizes the chances of it happening again.
Together, the combination is called a corrective and preventive action (CAPA) plan.
Yes. Successful completion of Human Subject Protection (HSP) and HIPAA Research is required for all research personnel listed on your eIRB study. If the protocol is a clinical trial, it is also necessary to complete Good Clinical Practice (GCP) training. Training is completed within CITI.
You will need to log in to your CITI account, update your email address to your institutional email (e.g., @utsouthwestern.edu) and “affiliate” with UT Southwestern in CITI. If the modules making up a course are the same at both institutions, any modules previously completed will not need to be repeated. In some cases, you may only need to take one or two additional modules to complete the course and meet the UTSW requirements
Human Subject Protection: Human Subject Protection (HSP) training must be renewed every 3 years.
Research HIPAA: Research HIPAA training is required one time.
Good Clinical Practice: Good Clinical Practice (GCP) training must be renewed every 3 years.
HSP and GCP training can take the user up to three hours, depending on the level of experience with human subject’s research. HIPAA Research can take up to 30 minutes.
Yes. You can save and come back to the website using your CITI username and password.
Note: If you ever forget your password or user name, you can go to “Forgot login information” at the home webpage to retrieve the information. Additionally, the HRPP Office may assist you with resetting your password.
Training requirements can currently be met by showing completion from a variety of sources. If you have already completed a training program, send a copy of the certificate of completion to the HRPP office who will determine if it meets the necessary course requirements. It may emailed to HRPP Office. HRPP@utsouthwestern.edu
The HRPP Office automatically receives notification of all training taken at CITI Program and the training will automatically populate in eIRB if “University of Texas Southwestern Medical Center” was selected as the Participating Institution and the institutional email address was used as the primary email address.
Absolutely. Once you complete the basic course(s), you may choose to take additional optional modules.
You may log in to your CITI account to print a Completion Certificate for your records.
- Submit amendments received from the lead research team in eIRB by selecting “Relying on a non-UT Southwestern IRB” as the type of modification (on the modification Smartform)
- Upload the following in eIRB:
- The clean ICF/Protocol/HIPAA as a revision to the current ICF/Protocol/HIPAA in eIRB
- Amendment approval letter from external IRB in eIRB
Regardless of the study status, always check the box that says “This study is a CIRB or a Humanitarian Use Device.”
Attach the renewal approval letter from IRB of record to the continuing review Smartform.
You must obtain approval from the IRB of record first, then you can submit it in a modification in eIRB for UT Southwestern HRPP to acknowledge it.
For NCI-CIRB studies, if the short form is listed in the documents approved as part of the Annual Institutional Worksheet, then you can submit it to UTSW HRPP without prior approval from NCI-CIRB.
NCI-CIRB Studies: you must submit a new study specific worksheet through IRB Manager, and then you may submit a modification in eIRB to change the PI. The new Study Specific Worksheet approval must be uploaded in of the eIRB study Smartform.
All other external IRBs: the external IRB must approve the PI change first, then you may submit the modification to eIRB to change the PI.
The Institutional Official (IO) is vested with the authority to make the decision whether or not to review for or rely on another IRB. At UT Southwestern, the IO is the Vice Provost and Dean of Research.
If the application is completed correctly and informed consent local context language is included, the acceptance letter will usually be issued in 7-10 business days.
Delays may occur if agreements have not been signed or if ancillary/safety committees have not issued final approval.
You must report the event to the Reviewing IRB (e.g., NCI CIRB or Commercial IRB) according to their reportable event policy and timelines and also to the UT Southwestern HRPP according to the HRPP Policy.