Type of ORIO

Brief Description, Examples and Additional Information

Reporting
(calendar days)

eR Section

Protocol Deviation / Violation

Protocol deviations include both purposeful and accidental variances in the procedures outlined for a study in its IRBMED approved protocol, or the IRBMED application(s), or by State or Federal regulations. Different terms are used in to refer to these variances including "Protocol Exceptions" and "Protocol Violations".

Regulations require IRBMED approval of all proposed changes in research activity PRIOR to implementation, including those that are sponsor approved. When changes are necessary to eliminate apparent immediate hazards to the subject, implement the change and report by a formal submission within 7 days after the action is taken. Amendments may not be implemented prior to obtaining the approval, including those changes perceived to reduce risk (other than those taken to eliminate apparent immediate hazards).

The IRBMED requests the following information regarding protocol deviations/violations:

• Description of the deviation
• Justification or reasons for the deviation
• Notice of whether a corresponding protocol amendment will be submitted to the IRBMED
• Justification for inclusion of the subject's data in the study despite the deviation, if the investigator plans to use the data
• Report the event or pattern and how it was/will be corrected or addressed and how it will be avoided in the future

The sub-categories and examples below illustrate common types of occurrences.

7 days

6

• Deliberate Procedural Deviations (or exceptions)

As an investigator, you may decide, for one subject (or more if they are seen on the same day as the discovery of the protocol error), to follow a procedure different from that set forth in your protocol. Reasons may include subject safety or a change in circumstances of the study. The sponsor may be involved in the decision to deviate.

Whenever you judge that a deviation or change from the approved research plan is necessary to eliminate apparent immediate hazards to the subject or others, you should implement the change. An amendment to the protocol and, if needed, to the informed consent document must then be submitted to IRBMED within 7 days (or as soon as possible if the revised protocol is coming from a sponsor). You must obtain IRBMED approval before implementing a deviation or change that does not serve to eliminate an immediate hazard. In some situations, it may be most appropriate for you to cease enrollment until the needed change is requested and approved. Contact the IRBMED office for further guidance.

Examples where a deliberate deviation IS permissible:

• An investigator realizes that a diagnostic blood test was not described in the protocol but is needed to regulate serum levels of the study drug.

Since this scenario involves a compromise to subject safety, the investigator may deviate from the protocol and then immediately report the deviation to the IRBMED.

• Newly published information indicates that one of the drugs used on a study has the same efficacy, with significantly fewer side effects, when administered at a lower dose than had been the previous standard of care (and the dose approved in the protocol).

If the higher dose poses significant hazards to subjects, the investigator may decrease it and then promptly report the change to IRBMED. The investigator should ensure that the decision is in keeping with all principles of good clinical and research practice.

If, on the other hand, the study will maintain a favorable risk/benefit ratio without a change in dosage, and the investigator decides not to change the protocol, s/he must submit an ORIO, notifying IRBMED of the new information, and a consent amendment, notifying subjects of the new information, and await IRBMED approval before proceeding.

Examples where a deliberate deviation IS NOT permissible:

• The protocol indicates that a nurse will conduct intake interviews and review the consent document with subjects. The nurse retires, so the study coordinator will carry out the procedure instead.

Since this scenario involves no compromise to subject safety, the investigator must submit an amendment and await IRBMED approval before proceeding.

• A sponsor believes that study data to date indicate that a potential participant could safely participate but doesn’t meet currently approved eligibility criteria.

Since this scenario involves no compromise to subject safety, the investigator must submit an amendment and await IRBMED approval before proceeding.

• Accidental Procedural Deviations

For one or more subjects, a member of the research team inadvertently follows a procedure different from that set forth in the approved protocol. Report the event or pattern, how it was/will be corrected or addressed, and how it will be avoided in the future.

Event: A subject is enrolled in the study but does not meet the eligibility criteria stated in the protocol and/or informed consent document.

What the report will include: The team member in question is relatively new to the position and was not familiar with the approved protocol. Therefore, they did not complete the case report forms appropriately. To assure this will not happen in the future; the team member will be trained on the completion of the case report forms and will be closely observed in the future to assure that all study procedures are completed appropriately and fully.

• Appointment / Visit Deviations

Report appointment deviations such as missed exams, tests, appointments or treatments, only when the subject is not withdrawn from the study (report withdrawn subjects in the Scheduled Continuation Review application).

Example:

• The clinic and lab are closed during the Holidays.  All appointments will be moved to before or after the holiday for completion.

• Dosage / Intervention Errors or Deviations

If a subject receives an incorrect dosage, medication, or intervention, due to misidentification or improper labeling, report the occurrence to the IRBMED. If the occurrence was not an adverse event (physical, social, or emotional harm or risk of harm), submit the occurrence as an ORIO. If it was an adverse event, submit it as an AE. Report the event or pattern, how it was/will be corrected or addressed, and how it will be avoided in the future.

Examples:

• Two subjects who should have received a substance abuse survey and interview instead received a sexual abuse survey and interview.
• The pharmacy provided the wrong medication. It was administered to three healthy control subjects on three different days without incident before the study nurse discovered the error.

• Breach of Confidentiality or Privacy

If confidential information about a subject is revealed in inappropriate settings, or to persons without a need to know, or by data exposure (computer security breach, documents left unsecured, lost laptop), report this event or pattern and how it was/will be corrected or addressed. NOTE: Immediately after identifying a breach, contact the UMHS Privacy Office, at 734-615-4759, or anonymously, at 866-482-1252.

If you must commit a breach of confidentiality in order to comply with legal or ethical obligations, and if your informed consent document does not already note such a possibility, inform the IRBMED.

Examples:

• Lost laptop, which is reported to have unencrypted data on it.
• A stack of completed case report forms is left in the cafeteria.
• Investigator suspects potential child abuse during the course of a study. The report to the UM’s Child Protection Team should be reported to the IRBMED if this type of disclosure or the need to disclose information under state or federal law was not noted in the informed consent document.

• Consenting / Assenting Process Deviations or Problems

Report to the IRB in the event of a deviation from the IRBMED-approved consenting process or any other consenting problem. Report the event or pattern, how it was/will be corrected or addressed, and how it will be avoided in the future.

Examples:

• A subject participated in some part of a study (e.g., an eligibility screening procedure) prior to giving consent and signing the informed consent document.
• The currently approved informed consent document for the study was not used in the consenting process.
• Subjects did not receive a copy of the informed consent document used in the consenting process.
• Subject signed the informed consent document but was not given the opportunity to discuss and ask questions about the study.
• Proper records of the informed consent documents were not maintained.

Subject Incarceration

Regulations and guidance from DHHS require that IRBs conduct special review not only on studies that intend to recruit prisoners, but also to re-review studies according to the Prisoner Research Regulations when a research subject becomes a prisoner, or when a study not originally reviewed for prisoner recruitment seeks to enroll a prisoner. When the PI and the subject wish to enroll or continue a prisoner's participation in the study the following steps must be taken:

• Page one of the co-chairs of the IRBMED through UMHS paging (See About IRBMED: Emergencies).
• Send an urgent email to the IRBMED office immediately (the same day as the study is notified of the incarceration or possibility of prisoner enrollment).
• Do not perform any study intervention or interaction (except those necessary to eliminate apparent immediate hazards to the subject) until contacted by an IRBMED co-chair or otherwise directed by the UMHS Legal Office. If an intervention/interaction was required to protect the subject, all of these steps must still be followed.
• Prepare and submit an ORIO Application in eResearch.

• Provide as much information as possible about the subject's incarceration including: Name of facility where subject is incarcerated, address of facility, phone number and name of contact person within the facility.
• Reasons why new subject should be enrolled or existing subject's participation in the study should continue
• For studies involving administration of drugs, devices, surgery or other type of intervention that would normally be conducted in a medical facility, explain where and under what circumstances the invention will now take place

Examples of situations requiring notice to IRBMED prior to any further study intervention or interaction:

• A research subject is arrested and held in jail awaiting trial. For the subject's health and safety, the PI believes administration of the study drug should continue during incarceration.
• During a 20 year study, the investigator discovers a subject is serving a prison term. The subject wants to continue participation (being interviewed by phone once a year) in the study during her prison stay.
• A Phase III Chemotherapy Trial offers the best or only option for cancer treatment of a prisoner in a state prison.
• A participant in a depression study is committed to hospital while on a study anti-depressant that should not be abruptly discontinued.

7 days

7

Accident or Incident Report involving:

Accidents or incidents that impact the research must be reported to the IRBMED. Report any events that intrude on the science of the study (procedures cannot be followed or data is lost).

7 days

8

• Data / Specimen / Computer (including Breach of Confidentiality or Privacy)

Report to the IRBMED any event that harms or destroys the study data or specimens to the degree that the information cannot be restored.

Examples:

• A computer virus has destroyed electronic data, or a fire has destroyed paper documents.
• A freezer containing tissue samples collected for the study fails before specimens have been analyzed.
• A sub-investigator leaves UM, takes the data, and refuses to return it.
• A researcher or staff member has falsified data.

• Facility

Report to the IRBMED any event that harms or destroys the study facility to the degree that the study is significantly interrupted or must be discontinued. (Not all data, specimen, or facility accidents are reportable ORIOs; the underlined words set the bar.) If subjects need to be re-contacted, or repeat procedures are necessary in order to restore the data, you must submit a protocol amendment, as well as an ORIO.

Examples:

• During the week necessary tests are to be performed, a fire or tornado damage closes the facility, and no alternate facility is available.

• Subjects

Report to the IRBMED any accident/incident that involves, but did not harm, a subject or others, only if the accident/incident is definitely, probably, or possibly related to the research intervention. (If the event causes physical or psychological harm to the subject or others, report the incident as an AE).

Example:

• Subject receives blood screening as part of study protocol prior to receiving a second dose of study medication.  The blood test shows abnormal lab values and a distinct change from previous values.  This should be reported to the IRB as an AE.

• Subject is involved in an auto accident on his/her way home from a research procedure involving several blood-draws and glucose infusions.

• If someone was hurt, report an adverse event.
• If no one was hurt, but the accident was related to the study, report as an ORIO.
• If a subject was in an accident unrelated to the study, and no one was hurt, do not report it.

Notification of Audit / Inspection / Inquiry

Notify the IRBMED as soon as possible following notification of an audit and/or prior to a site visit.

Example:

• FDA conducts an inspection as part of the approval process for a New Drug Application. Study teams must (1) notify the IRB as soon as they are informed of the upcoming visit (section 9); and (2) submit any documentation received upon completion of the visit (section 10).

ASAP
or
7 days for urgent safety or regulatory issues
or
SCR for routine reports

9

Investigator Responsibility on the Routine Reporting of Audits, Inspections, Reports and Correspondence to/from Oversight Bodies

Investigators and research staff are expected to cooperate with evaluations, inspections, and audits performed by authorized internal oversight authorities, including the IRB, the Office for Human Research Compliance Review (OHRCR), Cancer Center Clinical Trials Office and the Office of University Audits. Cooperation is also expected for external reviews (e.g., by Entities such as industry sponsors or Government Agencies such as the FDA, NCI or NIH Office of Research Integrity). Any internal or external investigation, inspection or other review and its outcome must be reported to the IRB responsible for the research in question. Researchers should consult with their administrators, the IRBs, MICHR, and as appropriate the Office of the Vice President for Research (OVPR) and/or General Counsel for assistance and representation.
Reports to or from oversight bodies, agencies or entities should be submitted to the IRBMED for review according to the table below for Adverse Events (AEs) or Other Reportable Information or Occurrences (ORIOs); OR as required in the IRBMED approved Study Specific Adverse Event Reporting Timetable which may allow for non-concurrent reporting.

Examples:

• FDA conducts an inspection as part of the approval process for a New Drug Application. Study teams need to notify the IRB as soon as they are informed of the upcoming visit and submit any documentation received upon completion of the visit
• FDA conducts a for-cause site visit and provides the investigator with a Form 483 that contains findings/observations.
• National Cancer Institute releases a summary report about the use of a study agent being used in UM studies as well as agents being used in cancer studies not being conducted at UM.
• A study sponsor conducts a routine or yearly audit.
• Sponsor determines that Adverse Events were not reported to the IRBMED at the correct time and sends a packet of information containing AEs from multiple sites.
• Study Teams must submit the results of an internal, not-for-cause audit, following the visit of the Office for Human Research Compliance Review.

7 days for urgent safety or regulatory issues
or
SCR for routine reports

10

Pertinent Publications / Public Announcements

The study team should report publication or announcements that could have an impact on the study. This includes scientific publication, media coverage, or any public heath announcement that:

• may impact subject willingness to participate in study (such as negative, coercive, or confusing media attention)
• may impact risk or benefit to subject
• necessitates change to study protocol or change to informed consent document
• necessitates information letter to subject
• presents any other significant impact on the study

Example:

• FDA has decided to take one of the drugs in your study off the market or added additional warnings to the label.

14 Days

11

Complaint

When subjects or others make complaints (to the principal investigator, the study team, or IRBMED), federal regulations require that investigators report those complaints to IRBMED at the time of the scheduled continuation review.

If the nature of a complaint suggests a life-threatening risk and/or a change in the risk/benefit assessment, you should report the complaint as soon as possible, along with any appropriate amendments to the protocol and/or informed consent document.

You should also report any complaint that highlights a systemic problem involving unanticipated risks to subjects or others.

Please notify IRBMED if, in addressing the complaint, the investigator or research team requires advice or assistance from the IRBMED office (734-763-4768), Health System Legal Office (734-764-2178), or Public Relations (734-764-2220).

To report a complaint prior to the time of scheduled continuing review, contact the IRBMED office and submit the report as an ORIO in eResearch.

Please note that complaints whose eResearch status is Held for Scheduled Continuation will not be reviewed until you submit a scheduled continuing review application. The system is not designed to route the complaint automatically to the IRBMED’s inbox. If you would like IRBMED to review the complaint prior to the next SCR, notify the regulatory team, either by email or by posted correspondence in eResearch.

SCR for routine
or
Contact IRBMED with potentially serious issue(s).

12

Subject Withdrawal

To track withdrawals as they occur.  This is optional--routine withdrawals may be reported in aggregate in the continuing review (renewal or termination) submission.

14 days
or
Time of the SCR

13

Report Submitted to IRB to Report a Lapse of Study

Study activity conducted during lapse of IRB approval.

Example:

• Investigators neglect to submit their SCR on time and continue to enroll subjects and/or continue study related activities on one or more subjects.

ASAP
or
Submitted with SCR

14