Section 16
Continuing Review Of CORIHS-Approved Activities
(including Amendments and Unanticipated Problem / SAE Reporting)

A. Observation of Research by CORIHS
B. Oversight Compliance
C. Renewal Procedures
D. Amendments to Approved Studies
E. Unanticipated Problems and Serious Adverse Events
     Reporting Requirements
F. Amendment- or Unanticipated Problem- related changes to consent/permission/assent forms

A. Observation of Research by CORIHS

CORIHS has the authority to inspect records and to observe (or have a third party observe) the consent process and the research of any activity that it approves.

B. Oversight Compliance

The Office of Research Compliance has initiated a formal proactive program to oversee investigator compliance with IRB regulations. These are not 'for-cause' audits. When a protocol is chosen for review, the Principal Investigator of record will receive a questionnaire to complete regarding the protocol in question. Questions will be asked to assess procedural compliance with human subject regulations. The investigator may be contacted to provide copies of a random sampling of subject files for review. Depending on the responses provided, the review team (made up of IRB members, Research Compliance staff, and other administrators as appropriate) will decide what action must be taken, ranging from acceptance of current practice, to need for on-site inspection.

C. Renewal Procedures

See Section 6 regarding general information on CORIHS approval periods

IMPORTANT: It is the Principal Investigator's responsibility to maintain continued approval for his or her study.

The Office of Research Compliance sends reminder notices as follows:

1. Renewal Notices:


• Approximately 3 months prior to the end of the approval period, the investigator will be sent a memorandum outlining the materials that must be submitted in order to renew a project for the next approval period.
  
• After the initial notice to renew, the investigator will receive a final notice one month later.

CORIHS strongly urges that the investigator be aware of application deadlines and review time considerations (Section 4) to ensure continued coverage of project approval. The current CORIHS schedule of deadlines and meeting dates is available at: http://www.stonybrook.edu/research/humans/irbsched.html

• If continued approval has not been secured by the expiration date of the prior approval period, all research activities involving human subjects, human data or biological specimens pertaining to the study in question must be stopped immediately. The Office of Research Compliance must be contacted if and when the investigator wishes to reactivate the study.

2. Required renewal materials:


• Renewal application - requires full completion, followed by signatures of the principal investigator and chair of the department or departmental review committee.
• Publications: Attach a reprint of any publications/abstracts derived from your study since last approval.
• Consent/permission/assent forms:

Redacted Consent: If there has been accrual in the study, attach a copy of the form used to enroll a subject since the last approval date (remove subject's name and signature to preserve confidentiality but leave the date and name of person who obtained consent visible on the form). If your study has multiple consent forms, submit a redacted copy for each one used during the last approval period.

New Consent: If you plan on continuing accruing subjects over the next approval period, submit a 'clean' original consent/assent form(s) for review.

• Subject Recruitment Materials — If there will be continued recruitment of subjects, submit copies of all materials (advertisements, letters, flyers) to be used to recruit new subjects.
• Audit Reports — Attach a copy of any reports from audits/monitoring visits conducted by external organizations (e.g.,FDA, HHS, NCI, sponsors) since last CORIHS review.

3. Required Number of Copies of Materials:


• If the original project was assigned to the exempt category, two (2) copies of the materials referenced above must be submitted to the Coordinator for appropriate action.
• If the original project was assigned to the expedited category, three (3) copies of the materials referenced above must be submitted to the Coordinator for appropriate action.
• If the original project was assigned for review by the full committee, fifteen (15) copies of the materials referenced above must be submitted to the Coordinator for appropriate action.

As stated above, review time considerations are as outlined in Section 4.

CORIHS reserves the right to obtain outside verification from sponsors, collaborating investigators, etc. regarding protocol status at time of continuing review.

4. Four Renewal Limit on CORIHS-Approved Activities:

A study may only be renewed four (4) times. After such time, a complete, 5 year Continued Approval application must be submitted in order for the study to be continued (see below for exceptions). The new submission should incorporate all amendments, revised aims, and funding sources that have become applicable over the years during which the project has been active. A complete, current protocol must be submitted at this time, as well as all consent documents to be used.

The requirement for new submission (using the 5 Year Renewal Application) is waived if:

1. the human subject aspects of the study are now limited to data analysis, OR
2. enrollment has ended, subjects have completed all research-related intervention, AND the study is now limited to long-term follow-up of subjects, OR
3. there has been no enrollment and there have been no amendments to the study during the time it has been active with CORIHS.

If A, B or C applies, the activity must STILL be renewed. Open the following link and complete the standard renewal application: http://www.stonybrook.edu/research/forms/hsrenewal.doc
Attach all REQUIRED MATERIALS AS STATED IN THE APPLICATION DIRECTIONS.

D. Amendments to Approved Studies

CORIHS approval for studies is contingent upon many assurances by the investigator, including the fact that s/he will:

• conduct every aspect of the project as approved by CORIHS.
  
• promptly report any revisions or amendments to the research activity for review and approval by CORIHS prior to commencement of the revised protocol (The only exception to this policy is in situations where changes in protocol are required to eliminate apparent, immediate hazards to the subject).

All amendments to approved protocols must be submitted to CORIHS for review and approval prior to commencement of the revised study or use of a revised consent/permission/assent form. Three copies of all materials pertaining to the amendment should be submitted for review.

Major Amendments, i.e., those involving a substantive increase in risk to the subject, are brought to full committee with a primary reviewer assigned to present the issues in question and start committee deliberations.

Minor Amendments, i.e., those that do NOT involve a substantive increase in risk to the subject, are reviewed via the expedited review process, which is fully described in Section 2.B.

Any amendment submitted from a pharmaceutical company must be accompanied by a summary of all associated protocol revisions.

E. Unanticipated Problems and SAE Reporting

1. Introduction


As a CORIHS-approved investigator, you are responsible for prompt reporting to the IRB of  "any unanticipated problems involving risks to subjects or others…" ( 45CFR46.103 (b) (5) and 21CFR56.108 (b) (1) )

2. Why do you have to report unanticipated problems involving risks to subjects or others?

During the conduct of the activity, the committee depends on the investigator to promptly inform them of any unanticipated problems involving risks to subjects or others (UP), including serious adverse events (SAE), that occur in subjects enrolled in their studies.

CORIHS may determine that the study protocol and/or consent forms need to be updated, and/or currently enrolled subjects need to be informed of the new information to determine whether or not they wish to continue, or that the risk to subjects has changed such that the study must be stopped.

3. What are the 'Unanticipated Problems involving risks to subjects or others' (UP) that must be reported?

UPs are unexpected events that occur during the course of the research activity that can negatively impact the risks to research subjects or others. UPs can take many forms. Here are some examples:

• An investigator’s laptop or PDA with stored data, which can be linked back to a subject’s identity, is lost or stolen.
  This is a UP involving risk to subjects’ confidentiality.



• A subject calls an investigator complaining that he believes he was asked to be involved in a research procedure that wasn’t in the consent form, i.e., he may not have been consented properly for the study.
  This is a UP involving risk to subjects’ rights.



• A sponsor notifies all sites in a multi-site study that one site has discovered that the central lab that was used to process blood values for the entire study had made an error in some of that site’s specimens.
  This is a UP that may involve physical risks to subjects at all sites, including SBU (i.e., any site that used the lab for processing lab values).



• An investigator accidentally punctures himself with a needle while administering an experimental drug to a subject.
  This is a UP involving physical risk to others.



• An investigator realizes that s/he or her/his staff did not follow, or have not been following, IRB-approved protocol procedures.
  This is a UP that may involve many kinds of risks to subjects, depending on what procedures were/were not followed.

4. Unanticipated Serious Adverse Event (USAE): A UP that must be reported, where experimental drugs/biologics/devices are involved

A serious adverse event involving drugs, biologics or devices (21CFR312.32 and 812.3) is a death, a life threatening event, or an event that results in any of the following outcomes: inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, a congenital anomaly/birth defect. It is also defined as a significant medical event that requires medical or surgical intervention to prevent death, a life threatening event, or one of the other outcomes listed above (e.g., allergic bronchospasm, convulsions, development of drug dependency).

If the event is onsite and unanticipated, (i.e., not identified by nature or severity in the risks section of the most current IRB-approved consent form for the study) AND was not caused by expected disease progression, clinically-indicated treatment or activity unrelated to the research procedures, then the event is considered to be a USAE and must be reported to CORIHS.

5. Mechanism of Reporting to CORIHS

Only UPs and USAEs should be reported to CORIHS, as they occur, for review and action. Any other events that are reported (e.g., anticipated SAE’s) outside of the required reporting schedule will be filed in the appropriate IRB file, without review or action.

The SBU UP/USAE form should be used to submit the UP/USAE information to CORIHS. Other relevant reports (e.g., IND safety reports, Medwatch reports) should be included as well.

NOTE: The Principal Investigator must sign the SBU UP/USAE form unless s/he has submitted to the Office of Research Compliance a statement that a) names a designee to complete and sign on PI's behalf, and b) provides assurance that the PI retains full responsibility for the required reporting process, as outlined in this section.

The Reporting Form may be completed and submitted by a co-investigator listed on the relevant CORIHS-approved study only if the Principal Investigator or his/her designee is physically absent from the University during a period of time within which mandatory reporting of the adverse event is required.

Anticipated serious adverse events should be tallied and summarized at the time of continuing review on the continuing review form. Those that occurred in subjects enrolled through SBU should be presented individually, while off-site events can be presented in summary from the sponsor.

6. CORIHS Review of UP/USAE Forms



Unanticipated Problems will be reviewed by the Office of Research Compliance staff to confirm that the reported incident constitutes a UP (in consultation with the chair, as needed), and to make an initial determination regarding action. If it is determined that immediate action may be required, the UP will be forwarded to the chair for review. If chair concurs, PI will be notified regarding steps to be taken to ensure protection of rights/welfare of research subjects (or staff, as appropriate), pending review and action by the full committee. If immediate action is not required, the UP may, at the chair's discretion, be placed in the agenda for full review at the next CORIHS meeting. Pre-review may be conducted by 1 or more IRB members.

On-site Unanticipated Serious Adverse Events will be forwarded to the IRB Chair for review and determination of need for immediate action, pending review and action by the full committee, or acknowledgement to investigator.

Off-site Unanticipated Serious Adverse Events will be reviewed by the Office of Research Compliance (ORC). If the definition of USAE is met, confirmation will be made that sponsor and FDA have been notified (per UP/USAE form), and the form will be filed in the applicable CORIHS file. ORC reviewer may at his/her discretion, send the USAE to a CORIHS member or full committee for review. An acknowledgement letter regarding these submitted USAE's will not be sent to PI unless IRB determines that further action or clarification is required.

As a result of review, the risks section of the consent form may need to be revised to include the possibility and likelihood of the problem/event, or subjects who are currently enrolled in the study may need to be made aware of the problem/event (in which case an addendum to the consent form that they signed may need to be drafted). A revised consent form/consent addendum may be submitted at the time of reporting, if the PI believes such action is warranted, prior to CORIHS review.

CORIHS will forward to the Institutional Official for Human Subject Protections (I.O.) any unanticipated problems involving risks to subjects or others. OHRP and/or FDA will be notified by the I.O., where appropriate.

7. Reporting Requirements

A. Additional Investigator Reporting Requirements

• Investigators are responsible for complete compliance with FDA and sponsor adverse event reporting requirements, where applicable.
• Regardless of charts below, if the SBU investigator receives correspondence from the sponsor or the FDA mandating reporting to IRB for required revisions to consent documents and/or notification of UP/USAE to current subjects, correspondence must be submitted to CORIHS immediately for action.
• All Data Safety Monitoring Board (DSMB) reports or interim safety results generated locally or by sponsor must be submitted to CORIHS as soon as available.

B. Unanticipated Problems OR Unanticipated Serious Adverse Events occurring in Gene Therapy Protocols

ALL UP/USAE's occurring in subjects enrolled in gene therapy protocols must be reported to CORIHS within 3 working days of occurrence (if SBU subject) or receipt by SBU investigator (if non-SBU subject).

Gene Therapy Protocol	SBU Subject	Non-SBU Subject
UP	Report within 3 working days of occurrence	Report to CORIHS upon receipt of UP
USAE	Report to CORIHS within 3 working days of occurrence	Report to CORIHS upon receipt of USAE

C. Unanticipated Problems (not including USAE's)

Unanticipated problems (not including USAE’s) should be submitted to the Office of Research Compliance as soon after they have occurred as possible, but no later than 5 working days of occurrence (if SBU subject) or receipt by SBU Investigator (if non-SBU subject). Submission of a PI signed SBU Unanticipated Problems/SAE Form is required.

	SBU Subject	Non-SBU Subject
Unanticipated Problem	Report within 5 working days of occurrence	Report to CORIHS within 5 working days of receipt of UP

D. SAE's occurring in Subjects Enrolled through Stony Brook University, or enrolled through sites that have a direct relationship with SBU (via subcontract, etc.):

SBU SAE	Death/ Life Threatening/ Other Serious
Anticipated	Cumulative summary report required at time of Continuing Review
Unanticipated	Report to CORIHS within 5 working days of occurrence

E. SAE's occurring in Subjects Enrolled through NON-SBU sites, (multi-center and/or industry sponsored, etc.):

Non-SBU SAE	Death/ Life Threatening/ Other Serious
Anticipated	Cumulative summary report (by sponsor, if applicable) required at time of Continuing Review
Unanticipated	Report to CORIHS within 5 working days of receipt of USAE

F. Amendment- or Unanticipated Problem (or SAE)- related changes to consent/permission/assent forms

Changes to consent/permission/assent forms that are required as a result of an amended protocol, or subsequent to review of Unanticipated Problems or SAEs (i.e., addition to the risks section of the consent form), should be made to the most current CORIHS-approved version. The revised version would be used to consent new subjects for enrollment in the study. However, in order to inform subjects who are already enrolled in the study of the changes to the study, the following format should be used (if the study involves minors, an additional addendum directed to the parent, as well as a revised assent form, should be drafted as well):

Put on Departmental Letterhead

Project Title:
Investigators:

Addendum to Consent Form

You have already agreed to be a volunteer in the research study referenced above.

In the consent form you signed (attached), you were informed that you would be told of any new information that might affect your willingness to continue in this study.

This addendum serves to tell you that …(e.g., your participation will be extended another 3 weeks….OR…An additional 3 tsp. of blood will be taken at your 4th visit….OR….it has been determined that the experimental drug used in this study can cause…etc.).

(If applicable, explain why the change is being implemented and provide details regarding relevant changes to risks, benefits, alternative treatments, etc. that occur as a result of the revised protocol.)

You are reminded that:

• All other information from your original consent form (attached) remains unchanged.
• Your participation in this study continues to be voluntary. You do not have to be in this study if you don't want to be.
• You have the right to change your mind and leave the study at any time without giving any reason, and without penalty.
• Any new information that may make you change your mind about being in this study will be given to you.
• You will get a copy of this consent addendum to keep.
• You do not waive any of your legal rights by signing this consent form.

If you have any questions about the study, you may contact [Dr. P. Investigator], at telephone # (631-XXX-XXXX).
If you have any questions about your rights as a research subject, you may contact Ms. Judy Matuk, Committee on Research Involving Human Subjects, (631) 632-9036.

If you sign below, it means that you have read (or have had read to you) the information given in this consent form, and you would like to continue to be a volunteer in this study.
________________________________
Subject Name

Subject Signature     Date

Signature of Person Obtaining Consent     Date

Return to Human Subjects Research at SBU

Last Updated: 2007-09-20