Reporting to the IRB – What You Need to Know

The UC Davis IRB requires investigators to report certain events or circumstances that occur during the conduct of a study.  Some events must be reported to the IRB within ten (10) working days of the research staff having knowledge of the event.

In most instances, reports are submitted for one of three reasons:

  • To inform the IRB of possible new risk information; or
  • To inform the IRB of possible non-compliance with the protocol, regulations or IRB requirements; or
  • To report expected changes such as closure to accrual because target enrollment is met.

Reporting Requirements:

New Risk Information

Investigators must report information that indicates a new or increased risk, or a new safety issue within five (5) working days of receipt of the information.  New risk information may be included in:

  • Data safety monitoring reports
  • Revised investigator brochures
  • Interim analysis reports
  • Data safety monitoring reports
  • New package insert or device label
  • Sponsor letter to investigators
  • IND safety reports that describe an event as unexpected and probably related to the study.

In some instances the following events might indicate a new or increased risk:

  • Protocol violation that harmed a subject
  • Subject complaint or withdrawal
  • A change to the protocol done without IRB approval to eliminate an apparent immediate hazard to a subject
  • Any change that significantly increases the risks to participants.

Non-Compliance

Investigators must also report non-compliance that is the result of action or inaction by the investigator or research staff.  Reports of non-compliance must be submitted within ten (10) working days of notification of the non-compliance.

Non-compliance is failure to follow the regulations or the requirements or determinations of the IRB.  In the case of research funded or conducted by the Department of Defense (DOD), Non-Compliance includes failure of a person, group, or institution to act in accordance with Department of Defense (DOD) instruction 3216.02, its references, or applicable requirements.

Whenever any non-compliance is reported, the investigator must include a description of the actions that have been or will be taken to correct the non-compliance and the actions that will be taken to prevent future, similar non-compliance.  This plan is referred to as the Corrective and Preventive Action Plan (CAPA), and is very important.  The preventive action plan is based on the root cause for the event and regulatory authorities will be looking for this action plan during any inspection or audit. Please note that an adequate preventive action plan almost never consists solely of training.  Instead, a process revision, checklist, calendar or other tool should usually be used to prevent similar events in the future.

Investigators must ensure that the CAPA plan is followed and should also conduct a follow-up internal audit to assess whether the plan actually prevented mistakes.

Investigators must ensure the report includes sufficient information for the IRB to make the required determination.  For example, always indicate whether the non-compliance had any effect on the participant’s welfare or rights.  In other words, was the participant harmed in any way due to the non-compliance?  If so, what was the harm?

Non-compliance includes:

  • Failure to follow the requirements of the protocol (e.g. failure to conduct a protocol required procedure)
  • Failure to follow the regulations or the signed 1572 (e.g. failure to obtain consent, failure to account for the investigational product, failure to obtain IRB approval before making a change to or purposefully deviating from the protocol, conducting research after expiration of IRB approval of the protocol, etc.)
  • Failure to follow UC Davis Standard Operating Procedures, IRB requirements (e.g. failure to submit required reports within the expected time frame; failure to follow through with instruction on an IRB Letter, etc.)

IRB Review of Reports

The IRB is required to review the reports investigators submit and make determinations.  The following are descriptions of the determinations that could be made during the review.

  1. Unanticipated problems involving risks to participants or others (UPIRTSO):

UPIRTSOs include events such as deaths, life-threatening experiences, injuries, breaches of confidentiality that occur during or after the research study when the fact that the event occurred was:

  • Unexpected in terms of nature, severity, or frequency, given (a) the research procedures described in the protocol-related documents, and (b) the characteristics of the subject population being studied; AND
  • The event, incident, experience, or outcome may reasonably be regarded as caused by or probably caused by the procedures involved in the research; AND 
  • Harmful: The analysis of the event suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

In most instances, a single event is not a UPIRTSO because there are no data to show that the one event indicates that others may be at risk of harm.

In many instances the principal investigator of a clinical trial will indicate that the event is related, and the sponsor will indicate that the event is unrelated or only possibly related. Since the sponsor has the aggregate data from which to make an analysis, the sponsor is in the best position to determine relatedness.

A determination of UPIRTSO generally warrants consideration of substantive changes in the research protocol or informed consent process/document, or other corrective actions, in order to protect the safety, welfare, or rights of subjects or

When this determination is made, the IRB must also determine:

1. Whether the risks of the research are reasonable in relation to any expected benefit that might stem from the research;

2. Whether revisions to the protocol might mitigate the risk; and

3. Whether the informed consent document must be revised to include the new risk information (the consent document must describe all foreseeable risks of the research)

If the IRB determines the informed consent document must be revised, it will ask the investigator to halt enrollment of new participants until the revised consent form is approved. If an investigator has identified potential participants, s/he may submit an addendum to the previously approved consent form. The addendum can be used to provide the risk information to the newly enrolling participants and would need to be signed along with the main consent form.

  1. Non-Compliance, Serious Non-Compliance, Continuing Non-Compliance due to action or inaction of investigator or research team member

The IRB must review reports of non-compliance and determine whether the event is (1) serious non-compliance; (2) continuing non-compliance or (3) non-compliance that is not serious or continuing.  In some instances, reports of non-compliance could also result in a UPIRTSO determination.

Serious non-compliance is non-compliance that adversely affects the rights or welfare of subjects or the integrity of the research data.

Continuing non-compliance is a pattern of non-compliance that suggests the likelihood that, without intervention, instances of non-compliance will recur, or a repeated unwillingness to comply, or a persistent lack of knowledge of how to comply.

If the IRB determines that the event fits within the definition of serious or continuing non-compliance, the IRB must submit a report of the non-compliance to applicable regulatory authorities and institutional officials.

How to Submit a Report; Timeframes

  • Submit to IRB using IRB Form HRP 214 Reportable Information
  • Step by step instructions on how to submit an Reportable New Information report here
  • Time-frame:
    • Report information that could indicate a UPIRTSO (see description above) within five (5) working days of receipt of the information.
    • Report other information such as protocol deviations, notice of halt to accrual, etc. within ten (10) working days of receipt of the information.

Planned Protocol Deviations

In some instances, an investigator might want or need to purposefully deviate from the protocol requirements. This section describes the steps the investigator must take to initiate a planned deviation.

Example 1:

Participant XYZ enrolls in a study. After six months, the participant meets withdrawal criteria because she will undergo elective surgery and will need to take a corticosteroid after the procedure.  Corticosteroids are prohibited in this study. The investigator believes the participant is benefitting from the study drug and minimal exposure to the prohibited medication will not increase risk or affect study data. The investigator knows that continuing this patient in the study will be a planned protocol deviation. To comply with regulations, the investigator must obtain approval from the sponsor and the IRB.  To obtain IRB approval, the investigator must submit a Form HRP 213 Modification that describes the planned deviation and also provides justification. The IRB will review the report and determine whether the deviation can be approved.

Example 2:

Participant XYZ enrolls in a study. After two months the participant meets withdrawal criteria because she needs to take a prohibited medication for one week.  The investigator believes she is benefiting from the study drug and the minimal exposure to the prohibited medication will not increase risk or affect study data.  According the investigator brochure, the study drug cannot be abruptly discontinued and should be tapered slowly to reduce severe withdrawal symptoms. The investigator decides to continue the study drug to prevent the patient from experiencing withdrawal.  According to 21 CFR 312.66, an investigator can purposefully deviate from the protocol to prevent imminent hazard to the participant. Instead of obtaining prior approval from the sponsor and IRB, s/he must report the deviation. Regulations require a report to the IRB within five working days of the deviation.

If a planned deviation needs to happen quickly investigators should contact the IRB to discuss options when time permits.  For additional information  contact the IRB Education Team.

Frequently Asked Questions

  1. What is the difference between non-compliance and a deviation from the protocol, and does it need to be reported to the IRB?

Perhaps.  Non-compliance is described as a failure to follow the regulations or the requirements or determinations of the IRB, which is the result of action or inaction by the investigator or research staff.  A deviation is described as a failure to follow the protocol procedures, sponsor requirements, and in many cases, can be considered non-compliance as defined above.  In some cases, these deviations could be considered unanticipated problems involving risks to subjects or others, depending on the situation. 

Instances where a subject missed an appointment or didn’t take all of his/her study drug is usually considered  deviation but is not considered no-compliance because the  event is not the result of an action or inaction by the investigator or research staff.

In contrast, if the researcher team forgets to obtain a subject’s signature on a consent documented consent, as required by the protocol and/or IRB, or if a subject was enrolled who did not meet the inclusion criteria (see FAQ question 6 below), the IRB would determine the deviation to be non-compliance, and require the PI to provide a corrective and preventive action plan.  In some cases, depending on the severity and frequency of the situation, IRB staff will forward a report to the full committee for a determination as to whether the deviation meets the definition of serious or continuing non-compliance applies.

  1. What is the difference between an adverse events that is “possibly related” versus “probably related,” and does it matter when submitting to the IRB?

The IRB only requires adverse events believed to be “probably related” (along with unexpected and serious) to be submitted to the IRB.  If the event is determined to be more than 50% likely related to the study drug/study procedures, we consider this to be “probably related” and must be submitted to the IRB within five (5) working days.   

 Anything less than 50% likely related is considered “possibly related” or unknown.  Unless otherwise indicated by the sponsor, possibly related adverse events (including those that are unexpected and serious) do not need to be submitted to the IRB as an RNI (HRP-214).  However, should a follow up report come through that changes the relatedness from possibly to related or probably related, you must submit a copy of the adverse event report to the IRB within five (5) working days.

  1. Research Compliance and Integrity completed an audit of our study, and we just received their report. Do I need to submit this report to the IRB?

Perhaps.  The only time an audit report needs to be submitted to the IRB is when the report includes non-compliance due to the action or inaction of the investigator or research team member.  Some of the most common non-compliance issues found during these audits include incorrect enrollment numbers, missing signed consent forms or HIPAA Authorizations, and not following the study procedures.   If such non-compliance is described in the report, you must submit a copy of the report and include a corrective and preventive action plan to the IRB within ten (10) working days of receiving the report.

  1. I received a monitoring visit report (or a follow up). Do I need to submit this report to the IRB?

Perhaps. The only time a monitoring report or follow up report needs to be submitted to the IRB is when the report includes information that must be submitted such as non-compliance due to the action or inaction of the investigator or research team member.  If such non-compliance is described in the report, you must submit a copy of the report and include a corrective and preventive action plan to the IRB within ten (10) working business days of receiving the report.  If the follow up report includes a completed or updated corrective and preventive action plan, you must submit a copy of the report to the IRB within ten (10) working days of receiving the report.  It is recommended that you include a statement on the RNI form (HRP-214) indicating the report/submission is a follow up, and what new information is included.

  1. I received an IND Safety Report from the sponsor. The report states that I must submit a copy to the IRB according to IRB requirements.  Must I submit this report?

Perhaps. The IND safety reports that must be submitted to the IRB are reports that include information about an adverse event that is unexpected (the event wasn’t expected or the frequency or severity of the event was not expected), serious, and the event is related or probably related to the study (see FAQ question 2 above for the definition of probably related). 

  1. The investigator wants to enroll a patient who meets one of the exclusion criteria. The sponsor has approved the patient’s inclusion in the study. May the investigator include this individual and report the inclusion to the IRB as Non-Compliance?

No.  Investigators must not make any changes to the protocol (including planned protocol deviations) without first obtaining IRB approval unless the change is necessary to protect participants from an immediate hazard.   Instead, the investigator must submit a modification to the IRB and obtain approval of the modification for this one patient before the patient can be enrolled.  If enrollment is time-sensitive, the investigator may request an ad-hoc IRB Meeting so the proposed modification can be considered.