Memorandum

Department of
Veterans Affairs

Date:	December 6, 2006

From:	Chief Officer, Office of Research Oversight (ORO)(10R)

Subj:	Reporting Unanticipated Problems and Adverse Events to Institutional Review Boards

To:	Chief Research and Development Officer (CRADO)(12)

1.	This responds to a request from your office for ORO’s interpretation of regulatory requirements for reporting unanticipated problems and adverse events (AEs) in research to the responsible Institutional Review Board (IRB).

2.	Congruent with the Federal Policy (Common Rule) for the Protection of Human Subjects, VA regulations at 38 CFR 16.103(b)(5) require written procedures for promptly reporting “any unanticipated problems involving risks to subjects or others” (UPRs) to the IRB.  Food and Drug Administration (FDA) IRB regulations at 21 CFR 56.108(b)(1) contain the identical requirement. 

3.	The VA human subject protection regulations (38 CFR Part 16), FDA IRB regulations (21 CFR Part 56), and FDA investigational new drug regulations (21 CFR Part 312) contain no explicit requirements for promptly reporting AEs to the IRB.  However, FDA investigational device regulations at 21 CFR 812.150(a)(1) require that investigators report (serious) “unanticipated adverse device effects” to the IRB “no later than 10 working days after the investigator first learns of the effect.” 

4.	Thus, except for (serious) unanticipated adverse device effects, applicable regulations require that AEs be reported promptly to the IRB only when they constitute UPRs.

5.	UPRs and AEs constitute overlapping, but not identical, concepts (Attachment A).

a.	Any research-related problems involving risks that are not anticipated in terms of nature, severity, or frequency of occurrence (as documented in the protocol, consent document, or other materials approved by the IRB) must be reported promptly to the IRB. 

b.	Both risks to subjects and risks to other individuals (e.g., research personnel, subjects’ family members) are included in the concept of UPRs.  Risks may reflect any type of potential harm (e.g., physical, psychological, social, economic).

c.	Applicable regulations (e.g., FDA regulations at 21 CFR 312.32(a) and 21 CFR 812.3(s)) and policies (e.g., VHA Handbook 1200.5§3.a., Reporting AEs in Research to ORO) contain slightly different definitions of AEs.  To ensure compliance with all regulatory and policy requirements, ORO recommends adherence to the broad definition of AEs found in VHA Handbook 1058.1§5.a. where an AE is defined as “any untoward occurrence (physical, psychological, social, or economic) in a human subject participating in research” and where “the imminent threat of an AE” is included as a reportable event (VHA Handbook 1058.1§6.a.).

d.	UPRs include some (but not all) AEs, and AE’s include some (but not all) UPRs (see examples in Attachment A).  Only UPRs, and AEs that are also UPRs, must by regulation be reported promptly to the IRB. 

6.	VHA Handbook 1058.1§2.c. requires that IRBs responsible for VA research function under “Standard Operating Procedures (SOPs) that provide detailed instructions of how to report and manage AEs.” 

a.	Attachment B provides an algorithm of “yes/no” decisions that help identify situations that must be reported promptly to the IRB.

b.	At minimum, the VHA facility must ensure that its investigators consistently and reliably satisfy the reporting requirements for UPRs described in Item (2) above. 

c.	Operationally, SOPs should define types of reportable problems, including reportable AEs, so as to ensure that all UPRs are reported promptly to the IRB.

d.	Some VHA facilities require the IRB to be notified of any AEs that their investigators report to the Study Sponsor, even AEs that do not qualify as UPRs.  This is acceptable as long as the SOPs clearly describe which AEs must be reported to the IRB and when they must be reported.

e.	In any case, AEs that do not qualify as UPRs, and thus do not require prompt reporting to the IRB, should at least be summarized and reported to the IRB as part of the continuing review process.

7.	VHA facilities may use a variety of strategies (e.g., mandatory training, monitoring) to ensure full compliance with the requirements for reporting UPRs (including reportable AEs) to the IRB.

a.	A popular strategy employed by many facilities involves requiring a certain degree of “over-reporting” by investigators and the use of triage mechanisms to determine which of the items reported by investigators must actually be reviewed by the convened IRB.  

b.	This is accomplished operationally by requiring that certain of the “yes/no” determinations illustrated in Attachment B be made not by the investigator, but by one or more designated IRB-member reviewers not involved in the research. 

c.	In order for this approach to work effectively, the designated IRB-member reviewers who perform triage by making the required  “yes/no” determinations must have the clinical and/or professional expertise to evaluate the UPRs and AEs appropriately.

d.	The extent of “over-reporting” by investigators depends upon which “yes/no” determinations must be made by IRB reviewers rather than by the investigator.  Requiring determinations by IRB reviewers too early in the process may result in unproductive work for investigators and reviewers.  On the other hand, a certain degree of “over-reporting” by investigators may help the IRB understand and more effectively evaluate the risks associated with the study.

e.	Individual VHA facilities and their IRBs have the flexibility to determine which “yes/no” determinations in Attachment B may be made by their  investigators and which must be made by designated IRB-member reviewers.  

f.	ORO strongly recommends against allowing investigators to make all of the “yes/no” determinations in Attachment B, as this may result in un-reviewed problems that cause harm to future subjects.  

8.	In developing SOPs for reporting UPRs and AEs to the IRB, ORO recommends that each VHA facility carefully evaluate its research program to identify and operationalize the specific mechanisms that will be most effective for ensuring full compliance with regulatory requirements and optimal protections for human subjects within their particular program.  

9.	SOPs must also describe mechanisms to comply with the specific requirements for reporting to ORO in accordance with VHA Handbook 1058.1§6.a., which requires that AEs (and imminent threats of AEs) be reported to ORO when the AE results in:

a.	A substantive IRB action; or
b.	An unexpected death as determined by the IRB.

10.	In addition, SOPs must describe mechanisms to comply with other applicable reporting requirements (e.g., in accordance with 38 CFR 16.103(b)(5), reporting serious or continuing noncompliance or the suspension or termination of IRB approval; in accordance with VHA Handbook 1200.5§7.d.(5), Requirements for Protection of Human Subjects in Research, notifying medical center officials and other officials, to the extent required under VA and other federal regulations and policies, about AEs that cause harm or risk to subjects or groups; local requirements for notifying the pharmacy and/or the R&D Committee; local requirements when the IRB or record is operated by another VHA facility or by the academic affiliate).  

11.	Do not hesitate to contact me should you have additional questions or concerns.

J. Thomas Puglisi, PhD, CIP

Attachments

cc: 	Acting Under Secretary for Health (10)
	Acting Principal Deputy Under Secretary for Health (10A)
	Deputy Under Secretary for Health for Operations and Management (10N)

   (USED WITH PERMISSION)

Adverse Events (AE)s that constitute Unanticipated Problems Involving Risks to Subjects or Others  (UPRs) must be reported to the IRB in accordance with the Common Rule and VA human subject protection regulations at 38 CFR 16.103(b)(5).  For Example:

A = AEs that ARE NOT UPRs (No regulatory requirement to report promptly to the IRB):

•	A subject experiences soreness and redness at the investigational drug injection site that are consistent in nature, severity, and frequency of occurrence with anticipated side effects described in the IRB-approved protocol and consent document. 
•	A subject experiences anxiety and stress, in response to interview questions about a traumatic event, that are consistent in nature, severity, and frequency of occurrence with anticipated reactions described in the IRB-approved protocol and consent document.

B = AEs that ARE UPRs (MUST be reported promptly to the IRB):

•	A subject experiences soreness and redness at the investigational drug injection site that are more severe than anticipated side effects described in the protocol and consent document. 
•	More subjects than anticipated in the protocol and consent document experience anxiety and stress in response to interview questions about a traumatic event. 
•	Two hours after receiving an investigational drug, a subject experiences intense headache and vomiting that last about an hour and then resolve. Neither was described in the protocol or consent document as a possible side effect of the research.

C = UPRs that ARE NOT AEs (MUST be reported promptly to the IRB):

•	A subject mistakenly receives twice the dose of an investigational drug than was stipulated in the protocol, but suffers no side effects and no indication of harm. 
•	A subject receives one dose of active drug instead of placebo but suffers no side effects and no indication of harm.
•	A laptop containing identifiable private information is stolen from a research lab but is recovered from a campus dumpster several hours later.  Data files remain intact.
•	A research assistant suffers a severe burn due to malfunctioning research equipment. 
•	During an interview on children’s play, a parent-subject confesses a continuing problem with child abuse. The protocol, consent document, and other materials approved by the IRB did not address how such situations would be handled.
•	The investigator receives a DSMB report indicating that researchers should look out for a particular side effect that may be occurring more frequently than anticipated.
•	The sponsor suspends new enrollments in a trial due to suspected manufacturing problems.
•	New studies in the published literature suggest that the drug being used in an investigator’s research may be associated with a previously unknown risk of stroke. 

A problem 
occurs during a research project.

An Adverse Event (AE) 1 
occurs during a research project.

  

Is the problem or event RELATED or POSSIBLY RELATED to the research?

Does the problem or event involve RISKS4 to ANYONE ELSE (e.g., subjects’ family members, research personnel, others)? 

≈≈≈
Facilities have flexibility in setting IRB reporting requirements.   

Does the problem or event involve RISKS4 to SUBJECTS?

Was the problem or event ANTICIPATED as to NATURE, SEVERITY, and FREQUENCY as described in the protocol, consent document, or other materials approved by the IRB?

Is the AE “SERIOUS” as defined by FDA, 2
i.e., did the AE result in (or need medical or surgical intervention to prevent) death, a life-threatening experience, inpatient hospitalization,  prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or jeopardy to a subject rights, safety, or welfare? 

NO3

YES3

NO3

YES3

NO3

YES3

YES3

  NO3

  NO3

The problem or event MUST BE REPORTED PROMPTLY to the IRB.

YES3

 (ADAPTED WITH PERMISSION)
1 VHA Handbook 1058.1 defines an AE as “any untoward occurrence (physical, psychological, social, or economic) in a human subject” (§5.a.) and treats “the imminent threat of an AE” as reportable (§6.a.).
2  Based on 21 CFR 312.32(2) and 21 CFR 812.3(s).  VHA Handbook 1200.5§10.f. requires that Serious AEs and Unanticipated AEs be reported but does not specify the time interval for reporting.
3 Individual VHA facilities and their IRBs have the flexibility to determine which “yes/no” determinations may be made by investigators and which must be made by designated IRB-member reviewers.  Allowing investigators to make all of these determinations may result in un-reviewed problems that cause harm to future subjects.
4	Risks may reflect potential physical, psychological, social, or economic harm (VHA Handbook 1058.1§5.a.)